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WO2025217052A1 - Combinaisons d'un inhibtor iap, d'un inhibiteur de tyrosine kinase et d'un activateur de la voie de mort cellulaire induite par tnf et leur utilisation dans le traitement de maladies ou de troubles prolifératifs tels que le cancer ou des maladies pulmonaires - Google Patents

Combinaisons d'un inhibtor iap, d'un inhibiteur de tyrosine kinase et d'un activateur de la voie de mort cellulaire induite par tnf et leur utilisation dans le traitement de maladies ou de troubles prolifératifs tels que le cancer ou des maladies pulmonaires

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Publication number
WO2025217052A1
WO2025217052A1 PCT/US2025/023468 US2025023468W WO2025217052A1 WO 2025217052 A1 WO2025217052 A1 WO 2025217052A1 US 2025023468 W US2025023468 W US 2025023468W WO 2025217052 A1 WO2025217052 A1 WO 2025217052A1
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composition
saturated
straight
attorney docket
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PCT/US2025/023468
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English (en)
Inventor
Wa Xian
Frank Mckeon
Matthew Vincent
Richard E. RUSSELL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tract Pharmaceuticals Inc
University of Houston System
Original Assignee
Tract Pharmaceuticals Inc
University of Houston System
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Publication of WO2025217052A1 publication Critical patent/WO2025217052A1/fr
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure recognizes that a combination therapy comprising inhibitors of cellular kinases and inhibitors of Inhibitors of Apoptosis (IAPs) is uniquely effective in various diseases.
  • the present disclosure recognizes that a combination of a tyrosine kinase inhibitor (TKI), an activator of the TNF ⁇ induced cell death pathway (e.g., an inhibitor of a kinase in the RIPK1-dependent apoptosis (RDA) cascade), and an inhibitor of IAP is uniquely effective in various diseases.
  • TKI tyrosine kinase inhibitor
  • an activator of the TNF ⁇ induced cell death pathway e.g., an inhibitor of a kinase in the RIPK1-dependent apoptosis (RDA) cascade
  • an inhibitor of IAP is uniquely effective in various diseases.
  • the present disclosure provides inhibitors of IAPs useful as therapeutic agents in combination with inhibitors of cellular kinases.
  • the present disclosure provides a compound of formula I: Page 1 of 83 12623050v1 Attorney Docket No.: 2014215-0079 or a pharmaceutically acceptable salt thereof, wherein: L1 is a first ligand; L2 is a second ligand; and linker is a bivalent linker comprisin .
  • Compounds described herein, an cally acceptable compositions thereof are useful for treating a variety of diseases when provided in combination with inhibitors of cellular kinases to a subject suffering from a disease.
  • Compounds described herein, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases when provided in combination with inhibitors of tyrosine kinases and inhibitors of kinases in the TNF ⁇ induced cell death pathway.
  • the present disclosure provides a combination useful for treating a variety of diseases wherein the combination comprises an IAP inhibitor described herein, ponatinib, and an inhibitor of TAK1.
  • Figures 1a-1l demonstrate the efficacy of the compounds described herein in double and triple compound combinations.
  • Figures 1a-1l demonstrate the efficacy of a combination of compounds described herein in combination with ponatinib or in combination with ponatinib and an inhibitor of TAK1.
  • Figures 2a and 2b demonstrate the efficacy of the compounds described herein in double and triple compound combinations.
  • Figure 3 demonstrates the resistance of HPAF-II pancreatic adenocarcinoma cells to gemcitabine, 5-FU, and paclitaxel (PTX).
  • Figures 4a and 4b demonstrates the efficacy of the compounds described herein in combination with ponatinib and a TAK1 inhibitor in the activation of apoptosis in HPAF-II pancreatic adenocarcinoma cells.
  • Figure 5 demonstrates the efficacy of the compounds described herein in combination with ponatinib and a TAK1 inhibitor in the activation of apoptosis in AsPC1 pancreatic adenocarcinoma cells.
  • Figure 6 demonstrates the efficacy of the compounds described herein in combination with ponatinib and a TAK1 inhibitor in the activation of apoptosis in low grade dysplasia esophageal cells.
  • Figure 7 demonstrates the efficacy of the compounds described herein in combination with ponatinib and a TAK1 inhibitor in the activation of apoptosis in esophageal adenocarcinoma cells.
  • Figure 8 demonstrates the efficacy of the compounds described herein in combination with ponatinib and a TAK1 inhibitor in the activation of apoptosis in triple negative breast cancer cells.
  • Figure 9 demonstrates the efficacy of the compounds described herein in combination with ponatinib and a TAK1 inhibitor in the activation of apoptosis in ovarian cancer cells.
  • Figure 10 shows dose-response assay of viability of pathogenic stem cells in Crohn's disease (inflammatory gastric metaplasia) in response to either 7532N (I-1) or 7532N-G (I-11) with either ponatinib (“121”; 300nM) alone or with ponatinib (300nM) and SM1-71 (20nM).
  • FIGS 11A-11D shows sensitivity of gemcitabine resistant pancreatic cancer stem cells to a triple combination as described herein.
  • 11A shows representative images of three cancer stem cell clones derived from pancreatic cancer stained with human nuclei antibody (red) in the presence and absence of 10uM gemcitabine showing two clones are sensitive to gemcitabine treatment and the other one clone is resistant.
  • 11B shows a Western blot using antibodies against cleaved caspase 3 (c-Casp3) and alpha tubulin ( ⁇ -tub) against lysates of various pancreatic cancer stem cell clones treated 72hr with gemcitabine (10uM) showing the coexistence of sensitive and resistant clones in one pancreatic cancer patient.
  • 11C shows a Western blot using antibodies against cleaved caspase 3 (c-Casp3) and alpha tubulin ( ⁇ -tub) against lysates of resistant clones treated 24hr with triple combo (100nM each) showing that the
  • Figures 12A and 12B show sensitivity of ovarian and breast cancers to a triple combination as described herein.
  • 12A shows Western blot using antibodies against cleaved caspase 3 (c-Casp3) and alpha tubulin ( ⁇ -tub) against paclitaxel resistant high-grade ovarian cancer cells treated 24hr with single, double and triple combinations of ponatinib, I-1 and SM1- 71. The cells underwent apoptosis in the presence of triple combo.
  • Figures 13A and 13B shows sensitivity of pathogenic stem cells from Crohn’s patients to a triple combination described herein.
  • 13A shows a significant reduction of E- Cadherin positive epithelial stem cells in pathogenic stem cells treated with triple combo in comparison to the normal intestinal stem cells treated with triple combo.
  • 13B shows Western blot using antibodies against cleaved caspase 3 (c-Casp3) and alpha tubulin ( ⁇ -tub) against normal intestinal stem cells and pathogenic stem cells of Crohn’s treated 24hr with triple combinations of ponatinib, I-1 and SM1-71.
  • the pathogenic Crohn’s stem cells underwent apoptosis in the presence of triple combo indicated by the strong expression of cleaved caspase 3.
  • the term “about” refers to a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a range of values that within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.
  • “about” refers to ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1% of a referenced value.
  • Page 4 of 83 12623050v1 Attorney Docket No.: 2014215-0079 [0020]
  • Administration typically refers to the administration of a composition to a subject or system, for example to achieve delivery of an agent that is, or is included in or otherwise delivered by, the composition.
  • agent refers to an entity (e.g., for example, a lipid, metal, nucleic acid, polypeptide, polysaccharide, small molecule, etc., or complex, combination, mixture or system [e.g., cell, tissue, organism] thereof), or phenomenon (e.g., heat, electric current or field, magnetic force or field, etc.).
  • Antagonist may refer to an agent, or condition whose presence, level, degree, type, or form is associated with a decreased level or activity of a target.
  • An antagonist may include an agent of any chemical class including, for example, small molecules, polypeptides, nucleic acids, carbohydrates, lipids, metals, and/or any other entity that shows the relevant inhibitory activity.
  • an antagonist may be a “direct antagonist” in that it binds directly to its target; in some embodiments, an antagonist may be an “indirect antagonist” in that it exerts its influence by means other than binding directly to its target; e.g., by interacting with a regulator of the target, so that the level or activity of the target is altered).
  • an “antagonist” may be referred to as an “inhibitor”.
  • Two events or entities are “associated” with one another, as that term is used herein, if the presence, level, degree, type and/or form of one is correlated with that of the other.
  • a particular entity e.g., polypeptide, genetic signature, metabolite, microbe, etc.
  • two or more entities are physically “associated” with one another if they interact, directly or indirectly, so that they are and/or remain in physical proximity with one another.
  • two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.
  • Aliphatic means a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle”, “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • Biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from an animal (e.g., mammal) or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof; or purified versions thereof.
  • biological sample refers to any solid or fluid sample obtained from, excreted by or secreted by any living organism, including single-celled micro-organisms (such as bacteria and yeasts) and multicellular organisms (such as plants and animals, for instance a vertebrate or a mammal, and in particular a healthy or apparently healthy human subject or a human patient affected by a condition or disease to be diagnosed or investigated).
  • the biological sample can be in any form, including a solid material such as a tissue, cells, a cell pellet, a cell extract, cell homogenates, or cell fractions; or a biopsy, or a biological fluid.
  • the biological fluid may be obtained from any site (e.g.
  • a transudate e.g. Page 6 of 83 12623050v1 Attorney Docket No.: 2014215-0079 fluid obtained from an abscess or any other site of infection or inflammation
  • fluid obtained from a joint e.g. a normal joint or a joint affected by disease such as rheumatoid arthritis, osteoarthritis, gout or septic arthritis.
  • the biological sample can be obtained from any organ or tissue (including a biopsy or autopsy specimen) or may comprise cells (whether primary cells or cultured cells) or medium conditioned by any cell, tissue or organ.
  • Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.
  • Biological samples also include mixtures of biological molecules including proteins, lipids, carbohydrates and nucleic acids generated by partial or complete fractionation of cell or tissue homogenates.
  • biological samples may be from any animal, plant, bacteria, virus, yeast, etc.
  • the term animal, as used herein, refers to humans as well as non-human animals, at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms and single cells.
  • the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig).
  • An animal may be a transgenic animal or a human clone.
  • the biological sample may be subjected to preliminary processing, including preliminary separation techniques.
  • Combination therapy refers to those situations in which a subject is concomitantly exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents).
  • the two or more regimens may be administered concomitantly; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens.
  • “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to a subject receiving the other agent(s) or modality(ies) in the combination.
  • combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).
  • comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features.
  • Those of ordinary skill in the art will understand, in context, what degree of identity is required in any given circumstance for two or more such agents, entities, situations, sets of conditions, etc. to be considered comparable.
  • sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.
  • the phrase “corresponding to” refers to a relationship between two entities, events, or phenomena that share sufficient features to be reasonably comparable such that “corresponding” attributes are apparent.
  • the term may be used in reference to a compound or composition, to designate the position and/or identity of a structural element in the compound or composition through comparison with an appropriate reference compound or composition.
  • a monomeric residue in a polymer e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide
  • a residue in an appropriate reference polymer may be identified as “corresponding to” a residue in an appropriate reference polymer.
  • residues in a polypeptide are often designated using a canonical numbering system based on a reference related polypeptide, so that an amino acid “corresponding to” a residue at position 190, for example, need not actually be the 190 th amino acid in a particular amino acid chain but rather corresponds to the residue found at 190 in the reference polypeptide; those of ordinary skill in the art readily appreciate how to identify "corresponding" amino acids.
  • sequence alignment strategies including software programs such as, for example, BLAST, CS- Page 8 of 83 12623050v1 Attorney Docket No.: 2014215-0079 BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH/GLSEARCH, Genoogle, HMMER, HHpred/HHsearch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, SSEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE that can be utilized, for example, to identify “corresponding” residues in polypeptides and/or nucleic acids in accordance with the present disclosure.
  • software programs such as, for example, BLAST, CS- Page 8 of 83 12623050v1 Attorney Docket No.: 2014215-0079 BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH/GLSEARCH, Geno
  • Dosage form or unit dosage form may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject.
  • an active agent e.g., a therapeutic or diagnostic agent
  • each such unit contains a predetermined quantity of active agent.
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).
  • Dosing regimen or therapeutic regimen may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which is separated in time from other doses.
  • a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount.
  • a dosing regimen is correlated Page 9 of 83 12623050v1 Attorney Docket No.: 2014215-0079 with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).
  • Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect.
  • Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Improved, increased or reduced As used herein, the terms “improved,” “increased,” or “reduced,” or grammatically comparable comparative terms thereof, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with an agent of interest may be “improved” relative to that obtained with a comparable reference agent.
  • an assessed value achieved in a subject or system of interest may be “improved” relative to that obtained in the same subject or system under different conditions (e.g., prior to or after an event such as administration of an agent of interest), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc.).
  • Oral The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.
  • parenteral administration and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • Patient or subject refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and/or humans.
  • a patient is a human.
  • a patient or a subject is suffering from or susceptible to one or more disorders or conditions.
  • a patient or subject displays one or more symptoms of a disorder or condition.
  • a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and/or to treat a disease, disorder, or condition.
  • pharmaceutical composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • the active agent is present in unit dose amounts appropriate for administration in a therapeutic regimen to a relevant subject (e.g., in amounts that have been demonstrated to show a statistically significant probability of achieving a predetermined therapeutic effect when administered), or in a different, comparable subject (e.g., in a comparable subject or system that differs from the subject or system of interest in presence of one or more indicators of a particular disease, disorder or condition of interest, or in prior exposure to a condition or agent, etc.).
  • comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and/or magnitude sufficient to achieve statistical relevance).
  • compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and/or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • composition or vehicle means a pharmaceutically-acceptable material, composition or vehicle, such Page 11 of 83 12623050v1 Attorney Docket No.: 2014215-0079 as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • Prevent or prevention when used in connection with the occurrence of a disease, disorder, and/or condition, refer to reducing the risk of developing the disease, disorder and/or condition and/or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
  • Reference As used herein, the term “reference” describes a standard or control relative to which a comparison is performed. For example, in some embodiments, an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value.
  • a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest.
  • a reference or control is a historical reference or control, optionally embodied in a tangible medium.
  • a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment.
  • Page 12 of 83 12623050v1 Attorney Docket No.: 2014215-0079 when sufficient similarities are present to justify reliance on and/or comparison to a particular possible reference or control.
  • a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g/mol, less than about 1500 g/mol, less than about 1000 g/mol, less than about 800 g/mol, or less than about 500 g/mol. In some embodiments, a small molecule is not a polymer.
  • a small molecule does not include a polymeric moiety.
  • a small molecule is not and/or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide).
  • a small molecule is not and/or does not comprise a polynucleotide (e.g., is not an oligonucleotide).
  • a small molecule is not and/or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid.
  • a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent).
  • a small molecule is biologically active.
  • a small molecule is detectable (e.g., comprises at least one detectable moiety).
  • a small molecule is a therapeutic agent.
  • such a small molecule may be utilized in accordance with the present disclosure in the form of an Page 13 of 83 12623050v1 Attorney Docket No.: 2014215-0079 individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.
  • Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms.
  • such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.
  • certain small molecule compounds have structures that permit isotopic substitution (e.g., 2 H or 3 H for H; 11 C, 13 C or 14 C for 12 C; 13 N or 15 N for 14 N; 17 O or 18 O for 16 O; 36 Cl for 35/37 Cl; 18 F for 19 F; 131 I for 127 I; etc).
  • such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.
  • reference to a particular small molecule compound may relate to a specific form of that compound.
  • a particular small molecule compound may be provided and/or utilized in a salt form (e.g., in an acid-addition or base-addition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.
  • a small molecule compound is one that exists or is found in nature, that compound may be provided and/or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature.
  • a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest is distinct from the compound as it exists in the reference preparation or source.
  • Therapeutic agent in general refers to any agent that elicits a desired pharmacological effect when administered to an organism.
  • an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population.
  • the appropriate population may be a population of model organisms.
  • an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc.
  • a therapeutic agent is a substance that can be used to alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans.
  • a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.
  • Treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • therapeutically effective amount refers to an amount of a substance (e.g., a therapeutic agent, composition, and/or formulation) that elicits a desired biological response when administered as part of a therapeutic Page 15 of 83 12623050v1 Attorney Docket No.: 2014215-0079 regimen.
  • a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.
  • the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc.
  • the effective amount of compound in a formulation to treat a disease, disorder, and/or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and/or reduces incidence of one or more symptoms or features of the disease, disorder and/or condition.
  • a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.
  • compounds referred to herein may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( 2 H or D).
  • the compounds of the disclosure, or their pharmaceutically acceptable salts may contain chiral centers, which, unless specified otherwise, may be either of the (R) or (S) configuration, or which may comprise a mixture thereof. Accordingly, the present application includes stereoisomers of the compounds described herein, where applicable, either individually or admixed in any proportions. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • the term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation. Page 16 of 83 12623050v1 Attorney Docket No.: 2014215-0079 [0057] As used herein, the term “partially unsaturated”, as used herein, refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated”, as used herein, is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [0058] The term “lower alkyl”, as used herein, refers to a C1-4 straight or branched alkyl group.
  • Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • halogen means F, Cl, Br, or I.
  • aryl refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl” is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl refers to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples of heteroaryl rings on compounds of Formula I and subgenera thereof include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, Page 17 of 83 12623050v1 Attorney Docket No.: 2014215-0079 benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one.
  • a heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.
  • the nitrogen atom in the ring can be, as valency permits, N or N-R ⁇ , as defined infra.
  • heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro- 2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl where the radical or point of attachment is on the heterocyclyl ring.
  • a heterocyclyl group may be mono- or bicyclic.
  • “Substituted” applies to one or more hydrogens that are either explicit or implicit ast f 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.
  • Suitable monovalent substituents on R ⁇ are independently halogen, —(CH 2 ) 0– 2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 ; -O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, –(CH2)0–2NH2, –(CH2)0–2NHR ⁇ ,
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group of a compound of Formula I, and subgenera thereof, include: –O(CR * 2 ) 2–3 O–, wherein each Page 20 of 83 12623050v1 Attorney Docket No.: 2014215-0079 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 C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5– to 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)CH2C(O)R ⁇ , –S(O)2R ⁇ , -S(O) NR ⁇ –C(S)NR ⁇ –C(NH)NR ⁇ or –N(R ⁇ )S(O) R ⁇ ; wherein each R ⁇ is independent s defined below, unsubstituted –OPh, or an unsubstituted 5– to 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 of R ⁇ , taken together with their intervening atom(s) form an
  • 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– to 6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • compositions which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., Page 21 of 83 12623050v1 Attorney Docket No.: 2014215-0079 describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1– 19, incorporated herein by reference.
  • Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyl-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms are within the scope of the disclosure.
  • the present disclosure also includes compounds that differ only in the presence of one or more Page 22 of 83 12623050v1 Attorney Docket No.: 2014215-0079 isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
  • compounds of this disclosure comprise one or more deuterium atoms.
  • Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • the present disclosure recognizes the efficacy of a combination of inhibitors of IAP and inhibitors of cellular kinases in the treatment of various proliferative diseases and disorders.
  • the present disclosure provides inhibitors of IAPs.
  • the present disclosure recognizes that combination of inhibitors of IAPs described herein with tyrosine kinase inhibitors and inhibitors of kinases in the TNF ⁇ induced cell death pathway is particularly effective in treatment of various proliferative diseases and disorders.
  • IAPs Inhibitors Of Inhibitors of Apoptosis
  • an IAP is selected from BIRC1/NAIP, BIRC2/cIAP1, BIRC3/cIAP2, BIRC4/XIAP, BIRC5/Survivin, BIRC6/Apollon, BIRC7/ML-IAP and BIRC8/ILP2.
  • IAP Inhibitor of apoptosis proteins, a family of anti-apoptotic proteins, have an important role in evasion of apoptosis, as they can both block apoptosis-signaling pathways and Page 23 of 83 12623050v1 Attorney Docket No.: 2014215-0079 promote survival.
  • the agent is an IAP Inhibitor (i.e., an IAP Antagonist).
  • IAP Inhibitors include XIAP inhibitors, CIAP inhibitors, and agents acting as dual XIAP and CIAP inhibitors.
  • IAP inhibitors and antagonists include Birinapant (a bivalent Smac mimetic, which is a potent antagonist for XIAP and cIAP1 with Kds of 45 nM and less than 1 nM, respectively), LCL161 Inhibitor (an IAP inhibitor which inhibits XIAP and cIAP1 with IC50’s of 35 and 0.4 nM), AZD5582 (AZD5582 an IAP antagonist which binds to the BIR3 domains cIAP1, cIAP2, and XIAP), SM-164 (a cell-permeable Smac mimetic compound that binds to XIAP protein containing both the BIR2 and BIR3 domains with an IC50 value of 1.39 nM and functions as an extremely potent antagonist of XIAP), BV6 (an antagonist of cIAP1 and XIAP), Xevinapant (or AT-406, is a potent and orally bioavailable S
  • APG-1387 (a bivalent SMAC mimetic and an IAP antagonist, blocks the activity of IAPs family proteins (XIAP, cIAP-1, cIAP-2, and ML-IAP), MX69 (an inhibitor of MDM2/XIAP), MV1, Polygalacin D, UC-112, AZD5582 dihydrochloride, HY-125378m Tolinapant (ASTX660) and SBP-0636457.
  • compounds disclosed herein bind to one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2).
  • compounds disclosed herein inhibitor activity or one or more IAPs e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2.
  • IAPs e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2
  • the activity of a compound described herein as an inhibitor of one or more IAPs e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2
  • variants or mutants thereof can be assayed in vitro, in vivo, or in a cell line.
  • In vitro assays include assays that determine inhibition of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2), or variants or mutants thereof.
  • IAPs e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2
  • Alternate in vitro assays quantitate the ability Page 24 of 83 12623050v1 Attorney Docket No.: 2014215-0079 of the inhibitor to bind to one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2), or variants or mutants thereof.
  • IAPs e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2
  • IAPs e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2
  • variants or mutants thereof are well known in the art and set forth in the Examples below.
  • the provided compounds are inhibitors of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2), or variants or mutants thereof, and are therefore useful for treating one or more disorders associated with activity of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2).
  • the present disclosure provides a method for treating an IAP-mediated disease, disorder, or condition comprising the step of administering to a patient in need thereof a compound of the present disclosure, or pharmaceutically acceptable composition thereof.
  • the present disclosure provides a method of inhibiting one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2), or variants or mutants thereof, comprising contacting a cell with a provided compound.
  • IAPs e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2
  • inhibitors of IAPs include those of the formulae described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.
  • the present disclosure provides a compound of formula I: [0087] or a pharmaceutically acceptable salt th ereof, wherein: L1 is a first ligand; L2 is a second ligand; and linker is a bivalent linker comprisin .
  • the present disclosure provides a compound of formula I: Page 25 of 83 12623050v1 Attorney Docket No.: 2014215-0079 I [0089] or a pharmaceutically acceptable salt thereof, wherein: L1 is a first ligand; L2 is a second ligand; and linker is a bivalent linker comprisin .
  • L1 and L2 need to be positioned at a certain distance relative to each other to achieve optimum biological activity. In some embodiments, L1 and L2 need to be positioned at a distance of about 0.5-2.5 nm as measured from the atom on each of L1 and L2 to which the linker is attached. Further, without wishing to be bound by any particular theory, it is believed that such positioning of L1 and L2 relative to each other cannot be achieved with rigid linear linkers.
  • AZD5582 comprises a diyne linker having the structure . [0091] See Hennessy et al., J. Med. Chem.2013, 56, 9897-9919.
  • Hennessy et al. report that the linker should have minimal steric requirements to prevent disruption of critical binding interactions with the target protein. Hennessy et al. further report that a fully saturated linker (i.e., ) did not result in any appreciable change in the cellular potency relat AZD5582. Hennessy et al. further surmise that shorter, less hydrophobic linkers render compounds less cell-permeable and therefore less potent in cell- based assays.
  • the present disclosure provides the insight that, despite the teachings of Hennessy, compounds comprising less rigid, more hydrophilic linkers, such as those described herein (e.g., compounds having a linker comprising squaramide) demonstrate improved activity as compared to compounds with rigid, hydrophobic linkers such as AZD5582. See, for example, Figures 1 and 2. Additionally, Figures 1 and 2 demonstrate that compounds of formula I are more potent than compounds having flexible, hydrophobic linkers such as SM-164 and BV6.
  • L1 and L2 are different.
  • a ligand refers to a moiety that binds to a protein, for example, at a ligand binding domain.
  • a ligand e.g., L1 or L2 is a moiety that binds to an IAP.
  • an IAP is selected from NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP and ILP2.
  • L1 is or comprises a group selected from .
  • linker is a bivalent linker comprisin
  • the linker is of formula X: or a pharmaceutically acceptable salt thereof, wherein: each of X 1 and X 2 is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-12 hydrocarbon chain, wherein 1-4 carbon atoms are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -S-, -SO-, -SO2-, or -Cy-; each R is independently selected from hydrogen or an optionally substituted C1-6 aliphatic; each -Cy- is independently an optionally substituted bivalent ring selected from a 3- to 8-membered carbocycl
  • each of X 1 and X 2 is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-12 hydrocarbon chain, wherein 1-4 carbon atoms are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -S-, -SO-, -SO2-, or -Cy-.
  • each of X 1 and X 2 is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)-, or -C(O)-.
  • each of X 1 and X 2 is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-8 hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)-, or -C(O)-.
  • X 1 and X 2 are the same.
  • X 1 and X 2 are different. Page 28 of 83 12623050v1 Attorney Docket No.: 2014215-0079 [0100]
  • X 1 is a covalent bond.
  • X 1 is an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)-, or - C(O)-.
  • X 1 is an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C3-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O- or -N(R)-.
  • X 1 is an optionally substituted bivalent, saturated or partially unsaturated, straight C 3-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated or partially unsaturated, straight C 3 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated, straight C3 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated, straight C 3 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated, straight C3 hydrocarbon chain. [0102] In some embodiments, X 1 is an optionally substituted bivalent, saturated or partially unsaturated, straight C 4 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted bivalent, saturated, straight C4 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted bivalent, saturated, straight C 4 hydrocarbon chain.
  • X 1 is an optionally substituted bivalent, saturated or partially unsaturated, straight C 5 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted bivalent, saturated, straight C 5 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain. Page 29 of 83 12623050v1 Attorney Docket No.: 2014215-0079 [0104]
  • X 1 is an optionally substituted bivalent, saturated or partially unsaturated, straight C6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated, straight C 6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 1 is an optionally substitute bivalent, saturated, straight C6 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.
  • X 1 is an optionally substitute bivalent, saturated, straight C 6 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated or partially unsaturated, straight C 7 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated, straight C 7 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 1 is an optionally substitute bivalent, saturated, straight C7 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.
  • X 1 is an optionally substitute bivalent, saturated, straight C7 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated or partially unsaturated, straight C 8 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 1 is an optionally substituted bivalent, saturated, straight C 8 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 1 is an optionally substitute bivalent, saturated, straight C 8 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.
  • X 1 is an optionally substitute bivalent, saturated, straight C8 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-. [0107] In some embodiments, X 1 is: , wherein # represents the point of attachment to L1. In some embodiments, X 1 is: Page 30 of 83 12623050v1 Attorney Docket No.: 2014215-0079 covalent bond, , , , , [0108] In some embodiments, X 1 is , wherein # represents the point of attachment to L1. [0109] In some embodiments, X 1 is , , or , wherein # represents the point of attachment to L1.
  • X 2 is a covalent bond.
  • X 2 is an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 1-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)-, or - C(O)-.
  • X 2 is an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C 3-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O- or -N(R)-.
  • X 2 is an optionally substituted bivalent, saturated or partially unsaturated, straight C3-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated or partially unsaturated, straight C3 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated, straight C3 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated, straight C 3 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated, straight C 3 hydrocarbon chain.
  • X 2 is an optionally substituted bivalent, saturated or partially unsaturated, straight C4 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated, straight C 4 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated, straight C4 hydrocarbon chain.
  • X 2 is an optionally substituted bivalent, saturated or partially unsaturated, straight C 5 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted bivalent, saturated, straight C 5 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated, straight C 5 hydrocarbon chain.
  • X 2 is an optionally substituted bivalent, saturated or partially unsaturated, straight C 6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated, straight C 6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 2 is an optionally substitute bivalent, saturated, straight C 6 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.
  • X 2 is an optionally substitute bivalent, saturated, straight C6 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated or partially unsaturated, straight C 7 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated, straight C7 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 2 is an optionally substitute bivalent, saturated, straight C 7 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.
  • X 2 is an optionally substitute bivalent, saturated, straight C7 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated or partially unsaturated, straight C8 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 2 is an optionally substituted bivalent, saturated, straight C 8 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.
  • X 2 is an optionally substitute bivalent, saturated, straight C8 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X 2 is an optionally substitute bivalent, saturated, straight C 8 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-. [0117] In some embodiments, X 2 is: covalent bond, , , , , [0118] In some embodiments, X 2 is: covalent bond , wherein $ represents the point of attachment to L2. [0119] In some embodiments, X 2 i , wherein # represents the point of attachment to L2. [0120] In some embodiments or , wherein # represents the point of attachment to L2.
  • each R is independently selected from hydrogen or an optionally substituted C1-6 aliphatic. In some embodiments R is hydrogen. In some embodiments, R is optionally substituted C 1-6 aliphatic.
  • each -Cy- is independently an optionally substituted bivalent ring selected from a 3- to 8-membered carbocyclene, a 5- to 6-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; phenylene; or a 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur.
  • -Cy- is a 3- to 8-membered carbocyclene. In some embodiments, -Cy- is a 5- to 6-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur. In some embodiments, -Cy- is phenylene. In some embodiments, -Cy- is a 5- to 6- membered heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur.
  • the present disclosure provides a compound of formula I-a, I-b, or I-c: 12623050v1 Attorney Docket No.: 2014215-0079 I-b or a pharmaceutically acceptable salt thereof, wherein linker is as defined above and described herein.
  • the linker serves to position L1 and L2 at a particular distance relative to each other (e.g., between about 0.5-2.5 nm).
  • the linker is sufficient to position L1 and L2 at a distance of about 0.5-2.5 nm between the C1 carbon atoms of the respective indanyl groups (indicated by * below): .
  • the linker is sufficient to position L1 and L2 at a distance of about 0.7-2.2 nm between the C1 carbon atoms of the respective indanyl groups. In some embodiments of formula I-a, the linker is sufficient to position L1 and L2 at a distance of Page 35 of 83 12623050v1 Attorney Docket No.: 2014215-0079 about 1.0-2.2 nm between the C1 carbon atoms of the respective indanyl groups. In some embodiments of formula I-a, the linker is sufficient to position L1 and L2 at a distance of about 1.4-2.2 nm between the C1 carbon atoms of the respective indanyl groups.
  • the linker is sufficient to position L1 and L2 at a distance of about 1.8-2.2 nm between the C1 carbon atoms of the respective indanyl groups. In some embodiments of formula I-a, the linker is sufficient to position L1 and L2 at a distance of about 2.0-2.2 nm between the C1 carbon atoms of the respective indanyl groups. In some embodiments of formula I-a, the linker is sufficient to position L1 and L2 at a distance of about 1.2-1.8 nm between the C1 carbon atoms of the respective indanyl groups.
  • the linker is sufficient to position L1 and L2 at a distance of about 1.3-1.5 nm between the C1 carbon atoms of the respective indanyl groups. In some embodiments of formula I-a, the linker is sufficient to position L1 and L2 at a distance of about 0.7-1.5 nm between the C1 carbon atoms of the respective indanyl groups. In some embodiments of formula I-a, the linker is sufficient to position L1 and L2 at a distance of about 0.7-1.0 nm between the C1 carbon atoms of the respective indanyl groups.
  • the linker is sufficient to position L1 and L2 at a distance of about 0.7-0.8 nm between the C1 carbon atoms of the respective indanyl groups. In some embodiments of formula I-a, the linker is sufficient to position L1 and L2 at a distance of about 0.7-0.8, 1.4-1.5, or 2.0-2.2 nm between the C1 carbon atoms of the respective indanyl groups. In some embodiments of formula I-a, the linker is sufficient to position L1 and L2 at a distance of about 0.7, 1.5, or 2.1 nm between the C1 carbon atoms of the respective indanyl groups.
  • the linker is sufficient to position L1 and L2 at a distance of about 1.5-2.5 nm between the respective benzylic carbon atoms (indicated by * below): Page 36 of 83 12623050v1 Attorney Docket No.: 2014215-0079 . [0128] In som L1 and L2 at a distance of about 1.9-2.2 nm between the respective benzylic carbon atoms. In some embodiments of formula I-b, the linker is sufficient to position L1 and L2 at a distance of about 1.9-2.0 nm between the respective benzylic carbon atoms.
  • the linker is sufficient to position L1 and L2 at a distance of about 2.0-2.2 nm between the respective benzylic carbon atoms. In some embodiments of formula I-b, the linker is sufficient to position L1 and L2 at a distance of about 2.1-2.2 nm between the respective benzylic carbon atoms. In some embodiments of formula I-b, the linker is sufficient to position L1 and L2 at a distance of about 1.9 or 2.1 nm between the respective benzylic carbon atoms.
  • the linker is sufficient to position L1 and L2 at a distance of about 1.5-2.5 nm between the indanyl carbon atom of L1 and the benzylic carbon atom of L2 (indicated by * below): . age o 12623050v1 Attorney Docket No.: 2014215-0079 [0130] In some embodiments of formula I-c, the linker is sufficient to position L1 and L2 at a distance of about 1.7-2.3 nm between the indanyl carbon atom of L1 and the benzylic carbon atom of L2.
  • the linker is sufficient to position L1 and L2 at a distance of about 1.9-2.1 nm between the indanyl carbon atom of L1 and the benzylic carbon atom of L2. In some embodiments of formula I-c, the linker is sufficient to position L1 and L2 at a distance of about 1.9-2.1 nm between the indanyl carbon atom of L1 and the benzylic carbon atom of L2.
  • a compound of Formula I is selected from: Page 38 of 83 12623050v1 Attorney Docket No.: 2014215-0079 O NH Page 39 of 83 12623050v1 Attorney Docket No.: 2014215-0079 12623050v1 Attorney Docket No.: 2014215-0079 o ompoun og I-1 5.49 276.20 [0132]
  • Compounds of the present disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.
  • compounds of the present invention can be synthesized using methods described below and/or as described in Page 41 of 83 12623050v1 Attorney Docket No.: 2014215-0079 WO 2007/130626A2 and WO 2010/142994A1, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art.
  • Compounds of the present application can be synthesized by the following steps outlined in the General Schemes below. Starting materials are either commercially available or made by known procedures in the reported literature.
  • a compound of Formula I-a can be obtained using the method of General Scheme A below: General Scheme A. Exemplary Synthesis of Compounds of Formula I-a.
  • R a is a suitable moiety (or protected analog) where treatment with INT-6A affords a compound of formula I-a.
  • R ⁇ is a suitable moiety (or protected analog) where treatment with INT-5A affords a compound of formula I-a.
  • a compound of Formula I-b can be obtained using the method of General Scheme B below: General Scheme B. Exemplary Synthesis of Compounds of Formula I-b.
  • the present disclosure recognizes the importance of inclusion of inhibitors of kinases in treatment of various diseases. In some embodiments the present disclosure recognizes the efficacy of combining inhibitors of kinases with additional compounds in treatment of proliferative disease or disorder. In some embodiments the present disclosure recognizes the particular efficacy of combining inhibitors of kinases with IAP inhibitors as described herein. [0141] In some embodiments an inhibitor of a kinase targets a cellular kinase. One of skill in the art will understand various categories of cellular kinases based on a target of phosphorylation.
  • a cellular kinase is a Serine/Threonine Protein Kinase (STPKs), a Tyrosine Kinase (TKs), or a Dual Specificity Protein Kinase (DSPKs).
  • STPKs Serine/Threonine Protein Kinase
  • TKs Tyrosine Kinase
  • DSPKs Dual Specificity Protein Kinase
  • STPKs Serine/Threonine Protein Kinase
  • TKs Tyrosine Kinase
  • DSPKs Dual Specificity Protein Kinase
  • the present disclosure provides treatments for a proliferative disease or disorder comprising tyrosine kinase inhibitors (TKIs).
  • a substrate or target of a TKI is one or more of epidermal growth factor receptor (EGFR), ALK (anaplastic lymphoma kinase), TRK (tropomyosin receptor kinase), HER2 (human epidermal growth factor receptor), VEGFR (vascular endothelial growth factor receptor), RET, (Rearranged During Transfection ), MET/HGFR (mesenchymal–epithelial transition factor/hepatocyte growth factor receptor), MEK (MAPK/ERK Kinase), FGFR (fibroblast growth factor receptor 1), KIT, PGDFR (platelet-derived growth factor receptor), JAK (Janus kinase), BCR-ABL, SRC, FAK (focal adhesion kinase).
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • TRK tropomyosin receptor kinase
  • HER2 human epidermal growth factor receptor
  • a TKI inhibits the activity of one or more of epidermal growth factor receptor (EGFR), ALK (anaplastic lymphoma kinase), TRK Page 44 of 83 12623050v1 Attorney Docket No.: 2014215-0079 (tropomyosin receptor kinase), HER2 (human epidermal growth factor receptor), VEGFR (vascular endothelial growth factor receptor), RET, (Rearranged During Transfection ), MET/HGFR (hepatocyte growth factor receptor), MEK (MAPK/ERK Kinase), FGFR (fibroblast growth factor receptor 1), KIT, PGDFR (platelet-derived growth factor receptor), JAK (Janus kinase), TRK (tropomyosin receptor kinase) BCR-ABL, SRC, FAK (focal adhesion kinase).
  • EGFR epidermal growth factor receptor
  • ALK anaplastic lymphoma kinase
  • a treatment for a proliferative disease or disorder comprises a TKI.
  • a TKI is crizotinib, cabozantinib, ponatinib, nintedanib, lestaurtinib, altiratinib, foretinib, merestinib, osimertinib, almonertinib, furmonertinib (AST2818), lazertinib (YH25448) , BPI-7711, josartinib (EGF816), brigatinib, poziotinib, ceritinib, lorlatinib, repotrectinib, lapatinib, neratinib, pyrotinib, tucatinib, donatinib, sorafenib, sunitinib, pazopanib, axitini
  • a TKI is ponatinib.
  • the present disclosure provides treatments for a proliferative disease or disorder comprising inhibitors of kinases in the TNF ⁇ induced cell death pathway (e.g., as described in, for example, Loo and Bertrand Nature Reviews Immunology volume 23, pages289–303 (2023)).
  • an inhibitor of a kinase in the TNF ⁇ induced cell death pathway inhibits the activity of MAPK, inhibitor of NF- ⁇ B kinase- ⁇ (IKK ⁇ ), inhibitor of NF- ⁇ B kinase- ⁇ (IKK ⁇ ), TANK-binding kinase 1 (TBK1), TGF ⁇ -activated kinase 1-binding protein 2 (TAB2); TGF ⁇ -activated kinase 1-binding protein 3 (TAB3), TGF ⁇ -activated kinase 1 (TAK1) .
  • a treatment for a proliferative disease or disorder comprises an inhibitor of a kinase in the TNF ⁇ induced cell death pathway.
  • a treatment for a proliferative disease or disorder comprises an inhibitor of TAK1.
  • an inhibitor of TAK1 is 5Z-7-Oxozeaenol (CAS No. : 253863-19-3), SM1-71, Takinib (EDHS-206, CAS No. : 1111556-37-6), LYTAK1, PF-04358168, PF- 05381941, NG25, HS-276, hypothemycin, Epoxyquinol B, ABC-FP, and AZ-TAK1 (see, Scarneo et al. ACS Chem Biol.2022 Mar 18; 17(3): 536–544 and Totzke et al., Open Biol.1002 September 2020).
  • an inhibitor of TAK1 is 5Z-7-Oxozeaenol (CAS No. : 253863-19-3). Page 45 of 83 12623050v1 Attorney Docket No.: 2014215-0079 3.
  • Proliferative Diseases or Disorders [0145]
  • the present disclosure provides methods and compositions useful for the treatment for various proliferative diseases or disorders.
  • a proliferative disease or disorder is one defined by excessive proliferation or infiltration of cells.
  • a proliferative disease or disorder is one defined by metaplasia or dysplasia.
  • the present disclosure provides methods and compositions useful for the treatment of proliferative diseases or disorders responsive to induction of apoptotic cell death, e.g., disorders characterized by dysregulation of apoptosis.
  • a proliferative disease or disorder contemplated by the present disclosure is any disease or disorder associated with, caused by, or resulting from disease associated stem cells.
  • a disease associated stem cell is a stem cell that exhibits pro-inflammatory and/or pro-fibrotic features.
  • the present disclosure provides methods and compositions useful for eliminating or inhibiting the growth of disease associated stem cells.
  • a proliferative disease or disorder is any disease or disorder associated with aberrant growth of a disease associated stem cell derived from epithelial tissue.
  • a proliferative disease or disorder contemplated by the present disclosure is a cancer.
  • a proliferative disease or disorder contemplated by the present disclosure is a pulmonary disease or disorder.
  • the present disclosure provides compositions and method for treating, ameliorating, or lessening the severity of a cancer.
  • a method for treating, ameliorating, or lessening the severity of a cancer comprises administering to a subject in need thereof, a compound or combination as described herein, or a pharmaceutical salt or composition thereof.
  • a cancer is any aberrant or uncontrolled growth of an epithelial tissue.
  • a cancer is breast cancer, prostate cancer, lung cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head— neck cancer, glioma, glioblastoma, medulloblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung Page 46 of 83 12623050v1 Attorney Docket No.: 2014215-0079 carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, gastrointestinal cancer, rectal cancer, cholangiocarcinoma (bile duct cancer) thyroid carcinoma, esophageal carcinoma, myeloma, multiple myelo
  • the present disclosure provides compositions and methods for treating, ameliorating, or lessening the severity of a pulmonary disease, disorder, or condition.
  • a method for treating, ameliorating, or lessening the severity of a pulmonary disease, disorder, or condition comprises administering to a subject in need thereof, a compound or combination as described herein, or a pharmaceutical salt or composition thereof.
  • a pulmonary disease comprises an inflammatory disease or condition.
  • a pulmonary disease is a disease associated with a stem cell that exhibits pro- inflammatory and/or pro-fibrotic features.
  • a pulmonary disease, disorder, or condition is chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), cystic fibrosis, airway inflammation, allergy(ies), asthma, impeded respiration, Acute respiratory distress syndrome, pulmonary hypertension, lung inflammation, bronchitis, airway obstruction, bronchoconstriction, microbial infection, viral infection (such as SARS), idiopathic pulmonary fibrosis, bronchopulmonary dysplasia (BPD), chronic bronchitis or emphysema, interstitial lung diseases, COVID interstitial lung disease, or COVID-19.
  • COPD chronic obstructive pulmonary disease
  • ARDS acute respiratory distress syndrome
  • cystic fibrosis airway inflammation
  • allergy(ies) asthma
  • Acute respiratory distress syndrome pulmonary hypertension
  • lung inflammation bronchitis
  • airway obstruction e.g., bronchoconstriction
  • the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions described herein is such that it is effective to measurably inhibit activity of an IAP (e.g., BIRC1/NAIP, BIRC2/cIAP1, BIRC3/cIAP2, BIRC4/XIAP, BIRC5/Survivin, BIRC6/Apollon, BIRC7/ML-IAP and BIRC8/ILP2), or a mutant thereof, in a biological sample or in a patient or subject.
  • a composition described herein is formulated for administration to a patient in need of such composition.
  • a composition described herein is formulated for oral administration to a patient.
  • the present disclosure provides, compositions, pharmaceutical compositions, preparations, or kits comprising a compound described herein (e.g., an inhibitor of IAP) and/or one or more cellular kinase inhibitor(s).
  • a compound described herein e.g., an inhibitor of IAP
  • a tyrosine kinase inhibitor e.g., a tyrosine kinase inhibitor
  • an inhibitor of a kinase in the TNF ⁇ induced cell death pathway e.g., an inhibitor of IAP
  • the present disclosure provides, compositions, pharmaceutical compositions, preparations, or kits comprising a compound described herein (e.g., an inhibitor of IAP),ponatinib, and/or an inhibitor of a kinase in the TNF ⁇ induced cell death pathway.
  • a compound described herein e.g., an inhibitor of IAP
  • ponatinib e.g., an inhibitor of a kinase in the TNF ⁇ induced cell death pathway.
  • the present disclosure provides, compositions, pharmaceutical compositions, preparations, or kits comprising an inhibitor of IAP selected from I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, or I-11, ponatinib, and an inhibitor of TAK1.
  • compositions, pharmaceutical compositions, preparations, or kits comprising an inhibitor of IAP selected from I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, or I-11, ponatinib, and 5Z-7-Oxozeaenol.
  • compositions, pharmaceutical compositions, preparations, or kits of the present disclosure comprise therapeutically effective amounts of a compound described herein (e.g., an inhibitor of IAP) one or more cellular kinase inhibitor(s), e.g., ponatinib and an inhibitor of a kinase in the TNF ⁇ induced cell death pathway.
  • components or agents of the present disclosure are not mixed together in the same composition.
  • the three agents are not part of the same solution or powder.
  • Page 48 of 83 12623050v1 Attorney Docket No.: 2014215-0079 In some embodiments, the agents or components are kept separate in different compositions and are delivered separately.
  • a kit may contain a pharmaceutical composition of a compound described herein (e.g., an inhibitor of IAP), a pharmaceutical composition of a cellular kinase inhibitor, and a pharmaceutical composition of an inhibitor of a kinase in the TNF ⁇ induced cell death pathway.
  • a pharmaceutical composition of a compound described herein e.g., an inhibitor of IAP
  • a pharmaceutical composition of a cellular kinase inhibitor e.g., an inhibitor of IAP
  • a pharmaceutical composition of an inhibitor of a cellular kinase inhibitor e.g., an inhibitor of IAP
  • the amount of one or all agents is lower than the amount that is typically administered when the agent is administered alone.
  • the amount of all three agents is lower.
  • compositions, pharmaceutical compositions, preparations, or kits of the present disclosure may include other agents.
  • the other agents may be any other therapeutic agent that would be useful to administer to the subject.
  • the invention provides for the administration of a compound described herein (e.g., an inhibitor of IAP), a cellular kinase inhibitor, and an inhibitor of a kinase in the TNF ⁇ induced cell death pathway in combination with one or more other therapeutic agents, e.g., another cytotoxic agent, steroidal agent, analgesic, etc.
  • the other therapeutic agent is another chemotherapeutic agent.
  • the other therapeutic agent is a steroidal agent (e.g., prednisone, dexamethasone, prednisolone).
  • the other therapeutic agent may include an agent for alleviating or reducing any side effects of a compound described herein (e.g., an inhibitor of IAP), a cellular kinase inhibitor, and/or an inhibitor of a kinase in the TNF ⁇ induced cell death pathway.
  • the other therapeutic agent is an anti-inflammatory agent such as aspirin, ibuprofen, acetaminophen, etc., pain reliever, anti-nausea medication, or anti-pyretic.
  • the other therapeutic agent is an agent to treat gastrointestinal disturbances such as nausea, vomiting, stomach upset, and diarrhea. These additional agents may include anti-emetics, anti-diarrheals, fluid replacement, electrolyte replacement, etc.
  • the other therapeutic agent is an electrolyte replacement or supplementation such as potassium, magnesium, and calcium, in particular, potassium and magnesium.
  • the other therapeutic agent is an anti-arrhythmic agent.
  • the other therapeutic agent is a platelet booster, for example, an agent that increases the production and/or release of platelets.
  • the other therapeutic agent is an agent to boost the production of blood cells such Page 49 of 83 12623050v1 Attorney Docket No.: 2014215-0079 as erythropoietin.
  • the other therapeutic agent is an agent to prevent hyperglycemia.
  • the other therapeutic agent is an immune system stimulator.
  • a pharmaceutically acceptable form includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, protected forms, stereoisomers, isomers, reduced forms, oxidized forms, tautomers, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, an agent as otherwise described herein, or a metabolite or residue thereof, e.g., a prodrug.
  • Compounds and compositions, according to the present disclosure are administered using any amount and any route of administration effective for treating or lessening the severity of a proliferative disease or disorder provided herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent or combination of agents, its mode of administration, and the like. Compounds and/or combinations described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. [0156] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally or via an implanted reservoir.
  • compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium Page 50 of 83 12623050v1 Attorney Docket No.: 2014215-0079 chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di- glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • 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 medium prior to use.
  • In order to prolong the effect of a compound of the present disclosure it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection.
  • Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • compositions described herein are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food. Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compounds may optionally contain Page 52 of 83 12623050v1 Attorney Docket No.: 2014215-0079 opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by Page 53 of 83 12623050v1 Attorney Docket No.: 2014215-0079 mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa butter, beeswax and polyethylene glycols.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as Page 54 of 83 12623050v1 Attorney Docket No.: 2014215-0079 benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • Pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions described herein can be administered by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • a suitable propellant such as 1,1,1,2- tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the disclosure comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • Dosage forms for topical or transdermal administration of a compound disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be Page 55 of 83 12623050v1 Attorney Docket No.: 2014215-0079 controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • EXEMPLIFICATION [0175] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
  • Example 1 Induction of Apoptosis By Triple Combination
  • the present example demonstrates the efficacy of a triple combination described herein in the treatment of cancer. Specifically, the present example demonstrates the ability of the triple combination recited herein activates caspase and triggers apoptosis.
  • Tremendous efforts in the development of IAP antagonists have yielded a broad array of monovalent (e.g. Xevinapant, CUDC427, LCL161) and bivalent (e.g. Birinapant, SM- 164, APG-1387, AZD-5582, BV6) molecules (Fig.1a), though to date none has achieved clinical approval.
  • bivalent IAP antagonists To learn more about the relative efficacy of these IAP antagonists in a synthetic lethal combination with ponatinib, we compared their effects in dose-response assays in vitro against Barrett's esophagus (BE) stem cells. Consistent with the improved impact of bivalent IAP antagonists relative to monovalent species, the bivalent IAP antagonists, particularly SM-16433 and AZD-558235, other bivalent IAP antagonists, as well as the indicated monovalent IAP antagonists, proved less effective (Fig.1b).
  • I-1 esophageal stem cells and stem cells of BE
  • LGD low-grade dysplasia
  • HFD high-grade dysplasia
  • EAC esophageal adenocarcinoma
  • BCR-Abl inhibitors such as imatinib, nilotinib, dasatinib, and bosutinib, were not identified in our screens.
  • ponatinib has been shown to be an inhibitor of both RIPK1 and RIPK3, "executioner" kinases proximal to distinct cell death processes including apoptosis and necroptosis.
  • ponatinib impacts a number of kinases and other proteins in pathways governing the onset of apoptosis and necroptosis, including TAK1, TAB2, TAB3, p38MAPK, MAPKAPK2 (MK2), IKK ⁇ /IKK ⁇ , MLKL, as well as RIPK1 and RIPK3 (Fig.1h;).
  • TAK1, TAB2, TAB3, p38MAPK MAPKAPK2 (MK2), IKK ⁇ /IKK ⁇ , MLKL, as well as RIPK1 and RIPK3 (Fig.1h;).
  • Many of the kinases that ponatinib impacts have been implicated in the suppression of RIPK1 via the promotion of phosphorylation of S320 to offset the activating autophosphorylation of RIPK1 at S166.
  • TAK1 inhibition by ponatinib which has been well described, appears to be important to the mechanism by which ponatinib cooperates with IAP antagonists to trigger apoptosis in LGD stem cells.
  • Example 2 Treatment of Pancreatic Cancer
  • HPAF-II is a pancreatic adenocarcinoma cell line that is resistant to multiple oncology drugs ( Figure 3).
  • Example 3 Treatment of Various Cancers
  • LGD Low Grade dysplasia
  • Figure 6 demonstrates that the triple combination as described herein triggers apoptosis.
  • Treatment of low grade dysplasia stem cells isolated from a patient with I-1( 7352N), ponatinib, and 5Z-7 oxozeaenol (TAK1 inhibitor) resulted in increased cleaved caspase 3.
  • TAK1 inhibitor 5Z-7 oxozeaenol
  • TNBC cells HCC1143 were treated with a two compound combination (I-1 and ponatinib or I-1 and TAK1 inhibitor SM1-71 (Cas No.2088179-99-9)), a three compound Page 59 of 83 12623050v1 Attorney Docket No.: 2014215-0079 combination- I-1, ponatinib, and a TAK1 inhibitor (i.e.5Z-7 Oxozeaenol or SM1-71).
  • the triple combination I-1, ponatinib, and a TAK1 inhibitor induced caspase 3 cleavage.
  • Figure 8 8
  • Figure 9 demonstrates that treatment with the triple combination I-1, ponatinib, and a TAK1 inhibitor induced caspase 3 cleavage in ovarian cancer cells.
  • Example 4 Exemplary Synthesis Schemes Synthesis of 7532N (I-1) [0189] A novel synthesis of the symmetric squaramide 7532N is described. The intermediate, (1S, 2R)-cis-1-(2-(2-azidoethoxy)ethoxy)-2-indanol (Compound 1), was prepared by O-alkylation of (1S, 2R)-cis-1-amino-2-indanol with the tosylate of 2-(2-azidoethoxy)ethan- 1-ol.
  • the tripeptide intermediate 7532P1 was synthesized via a four-step sequence involving the coupling of N-Boc-L-Chg-OH with H-L-Pro-OBzl using HATU and DIEA, followed by Boc deprotection, coupling with N-Boc-N-Me-L-Ala-OH, and catalytic hydrogenation to remove the benzyl ester.
  • Intermediates 1 and 7532P1 were coupled, and the resulting azide (Compound 2) was reduced to the primary amine, which was subsequently conjugated with diethyl squarate to afford the symmetric squaramide. Finally, removal of the Boc protective groups using 12% TFA in DCM yielded the target compound 7532N.
  • N-Boc-N-Me-L-Ala-OH (7.74 g, 38 mmol) was coupled to the H-L-Chg-L-Pro- OBzl•HCl (15.3 g, 40 mmol) using HATU (15.2 g, 40 mmol) and DIEA (14.5 mL, 87.6 mmol) in DMF (200 mL) as described above. Purification by silica gel chromatography (25:1 CH2Cl2/MeOH) gave the protected tripeptide (16.6 g). This was hydrogenated over 10% Pd/C (2.0 g) in MeOH (200 mL) under a H 2 balloon overnight.
  • TFA over 20 min, 20 mL/min, 215 nm afforded the Boc-protected intermediate after lyophilization.
  • Concentration and purification by preparative RP-HPLC (C18, 21.2 x 250 mm, 5 ⁇ m; 10-98% MeCN/0.1% aq.
  • TFA over 20 min, 20 mL/min, 215 nm gave 7532N (100 mg, 86% over 2 steps) as a white powder after lyophilization.
  • Example 5 Efficacy of Compositions Described Herein on Inflammatory Diseases [0198] The present example further demonstrates treatment of diseases associated with inflammation and/or fibrosis. Specifically, the present example demonstrates lethality of compositions described herein to pathogenic stem cells isolated from Crohn’s disease patients. [0199] Approximately 2,000 pathogenic inflammatory gastric metaplasia stem cells from Crohn's terminal ileum were seeded on multiple 384-well plates (Griener Bio-One, USA).
  • FIG. 10 shows treatment of pathogenic gastric stem cells with compositions described herein resulted in lethality at a low dose with dose response curves.
  • Example 6 Treatment of Various Diseases with Compositions Described Herein [0201] The present example further demonstrates the efficacy of a triple combination described herein in the treatment of various diseases.
  • the present example further demonstrates the ability of the triple combination recited herein activates caspase and triggers apoptosis in disease cells.
  • Gemcitabine Resistant Pancreatic Cancer Stem Cells [0202] Cancer stem cell clones derived from pancreatic cancer of a single subject were treated with a combination as described herein. Notably, analysis of the isolated clones demonstrated coexistence of clones sensitive and resistant to gemcitabine. Nuclei staining and blotting for cleaved caspase 3 of pancreatic stem cell clones ( Figure 11A and 11B, respectively) showed coexistence of sensitive and resistant clones in one pancreatic cancer patient.
  • IAP inhibitor I- 11 resulted in degradation of cIAP1 and cIAP 2 whenever present but the combination of I-11 with a tyrosine kinase inhibitor (e.g., ponatinib) and a TAK1 inhibitor (e.g, TAK1) resulted in the most significant apotosis of gemcitabine resistant prostate cancer cells as demonstrated by caspase 3 cleavage ( Figure 11D).
  • a tyrosine kinase inhibitor e.g., ponatinib
  • TAK1 inhibitor e.g, TAK1 inhibitor
  • Paclitaxel resistant high-grade ovarian cancer cells were treated for 24hr with single (e.g., ponatinib or I-1), double (e.g., ponatinib and I-1) and triple (e.g., ponatinib, I-1, and SM-171) combinations of compounds.
  • Paclitaxel resistant high-grade ovarian cancer cells treated Page 65 of 83 12623050v1 Attorney Docket No.: 2014215-0079 with a triple combination as described herein showed the most significant apoptosis as demonstrated by caspase 3 cleavage.
  • Triple negative breast cancer cells were treated for 24hr with single (e.g., ponatinib or I-1), double (e.g., ponatinib and I-1) and triple (e.g., ponatinib, I-1, and SM-171) combinations of compounds.
  • Triple negative breast cancer cells treated with a triple combination as described herein showed the most significant apoptosis as demonstrated by caspase 3 cleavage ( Figure 12B).
  • Pathogenic stem cells cloned from Crohn’s patients treated with a triple combination demonstrated significant reduction in e-cadherin positive epithelial stem cells relative to normal intestinal stem cells treated with the same triple combination ( Figure 13A).
  • Western blot using antibodies against cleaved caspase 3 (c-Casp3) and alpha tubulin ( ⁇ -tub) against normal intestinal stem cells and pathogenic stem cells of Crohn’s treated 24hr with triple combinations of ponatinib, I-1, and SM1-71.
  • the pathogenic Crohn’s stem cells underwent apoptosis in the presence of triple combo indicated by the strong expression of cleaved caspase 3 (Figure 13B).

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Abstract

La présente invention concerne des composés, des compositions pharmaceutiquement acceptables de ceux-ci, et des procédés d'utilisation de ceux-ci.
PCT/US2025/023468 2024-04-08 2025-04-07 Combinaisons d'un inhibtor iap, d'un inhibiteur de tyrosine kinase et d'un activateur de la voie de mort cellulaire induite par tnf et leur utilisation dans le traitement de maladies ou de troubles prolifératifs tels que le cancer ou des maladies pulmonaires Pending WO2025217052A1 (fr)

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