Combinations of an IAP inhibtor, a tyrosine kinase inhibitor and an activator of the TNF a induced cell death pathway and their use in the treatment of proliferative diseases or disorders such as cancer or pulmonary diseases

Abstract

The present disclosure provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

Description

Attorney Docket No.: 2014215-0079 COMPOUNDS AND COMPOSITIONS USEFUL FOR TREATMENT OF PROLIFERATIVE DISEASE OR DISORDER BACKGROUND OF THE INVENTION

[0001] There is a continuing need to identify therapeutic modalities for treatment of disease (e.g., cancer and pulmonary diseases). Treatment of disease by combination therapy has demonstrated some effectiveness. However, there remains a substantial unmet medical need for treatments that are more effective for treating a variety of diseases. SUMMARY OF THE INVENTION

[0002] The present disclosure recognizes that treatment of diseases with a unique combination of inhibitors is particularly effective. Notably, 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.

[0003] In some embodiments, the present disclosure provides inhibitors of IAPs useful as therapeutic agents in combination with inhibitors of cellular kinases. It has now been found that compounds of the present disclosure, and pharmaceutically acceptable salts and compositions thereof, are effective as inhibitors of IAPs and effective in treatment of various diseases in combination with cellular kinases.

[0004] In some embodiments, the present disclosure provides a compound of formula I:Page 1 of 83 12623050v1Attorney 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 .

[0005] Compounds described herein, ancally 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. In some embodiments, 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. BRIEF DESCRIPTION OF THE DRAWING

[0006] Figures 1a-1l demonstrate the efficacy of the compounds described herein in double and triple compound combinations. Specifically, 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.

[0007] Figures 2a and 2b demonstrate the efficacy of the compounds described herein in double and triple compound combinations.

[0008] Figure 3 demonstrates the resistance of HPAF-II pancreatic adenocarcinoma cells to gemcitabine, 5-FU, and paclitaxel (PTX).

[0009] 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.

[0010] 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. Page 2 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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.

[0015] 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).

[0016] Figures 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 gemcitabine resistant clones undergo apoptosis in response to triple combo treatment.11D shows Western blot using antibodies against cleaved caspase 3 (c-Casp3), cIAP1, cIAP2, and alpha tubulin (^-tub) against lysates of gemcitabine-resistant clone treated 24hr with single, double and Page 3 of 83 12623050v1Attorney Docket No.: 2014215-0079 triple drug combination showing that the resistant cells undergo dramatic apoptosis in the presence of triple combo despite I-11 degraded CIAP1 and CIAP2 under all conditions when it is present.

[0017] 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. The apoptosis was abolished in the presence of RIPK1 inhibitor (GSK2982772) suggesting the death of the cells were mediated by RIPK1 activity.12B shows Western blot using antibodies against cleaved caspase 3 (c-Casp3) and alpha tubulin (^-tub) against triple negative breast cancer cells treated 24hr with single, double and triple combinations of ponatinib, I-1 and SM1-71. The cells underwent most significant apoptosis in the presence of triple combo.

[0018] 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. DEFENITIONS

[0019] About: As used herein, 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. In some embodiments, “about” refers to ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1% of a referenced value. Page 4 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0020] Administration: As used herein, the term “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.

[0021] Agent: As used herein, the term “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.).

[0022] Antagonist: As used herein, the term “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. In some embodiments, 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). In some embodiments, an “antagonist” may be referred to as an “inhibitor”.

[0023] Associated: 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. For example, a particular entity (e.g., polypeptide, genetic signature, metabolite, microbe, etc.) is considered to be associated with a particular disease, disorder, or condition, if its presence, level and / or form correlates with incidence of and / or susceptibility to the disease, disorder, or condition (e.g., across a relevant population). In some embodiments, 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. In some embodiments, 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. Page 5 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0024] Aliphatic: The term “aliphatic” or “aliphatic group”, as used herein, 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. Unless otherwise specified, 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. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) 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.

[0025] Biological Sample: As used herein the term “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. For example, the term “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. blood, saliva (or a mouth wash containing buccal cells), tears, plasma, serum, urine, bile, seminal fluid, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor, or any bodily secretion), a transudate, an exudate (e.g. Page 6 of 83 12623050v1Attorney Docket No.: 2014215-0079 fluid obtained from an abscess or any other site of infection or inflammation), or 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. Although the sample is preferably taken from a human subject, 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. Cell cultures and live tissue samples are considered to be pluralities of animals. In certain exemplary embodiments, 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. If desired, the biological sample may be subjected to preliminary processing, including preliminary separation techniques.

[0026] Combination therapy: As used herein, the term “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). In some embodiments, 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. In some embodiments, “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. For clarity, 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). Page 7 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0027] Comparable: As used herein, the term “comparable” refers to two or more agents, entities, situations, sets of conditions, etc., that may not be identical to one another but that are sufficiently similar to permit comparison there between so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed. In some embodiments, 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. For example, those of ordinary skill in the art will appreciate that 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.

[0028] Corresponding to: As used herein, 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. For example, in some embodiments, 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. For example, in some embodiments, a monomeric residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as “corresponding to” a residue in an appropriate reference polymer. For example, those of ordinary skill will appreciate that, for purposes of simplicity, 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 190thamino 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. For example, those skilled in the art will be aware of various sequence alignment strategies, including software programs such as, for example, BLAST, CS- Page 8 of 83 12623050v1Attorney 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.

[0029] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “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. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, 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). Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms.

[0030] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “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. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, 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. In some embodiments, a dosing regimen is correlated Page 9 of 83 12623050v1Attorney Docket No.: 2014215-0079 with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0031] Excipient: As used herein, the term “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.

[0032] 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. Alternatively or additionally, in some embodiments, 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.).

[0033] 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.

[0034] Parenteral: The phrases “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. Page 10 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0035] Patient or subject: As used herein, the term “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. In some embodiments, 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.

[0036] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, 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.). In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance.

[0037] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, 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.

[0038] Pharmaceutically acceptable carrier: As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically-acceptable material, composition or vehicle, such Page 11 of 83 12623050v1Attorney 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. Some examples of 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; Ringer’s solution; ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and / or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0039] Prevent or prevention: As used herein, the terms “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.

[0040] 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. In some embodiments, a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest. In some embodiments, a reference or control is a historical reference or control, optionally embodied in a tangible medium. Typically, as would be understood by those skilled in the art, a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment. Those skilled in the art will appreciate Page 12 of 83 12623050v1Attorney Docket No.: 2014215-0079 when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control.

[0041] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. In general, 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.

[0042] In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, 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.

[0043] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.

[0044] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0045] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroisomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an Page 13 of 83 12623050v1Attorney 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.

[0046] Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, 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.

[0047] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g.,2H or3H for H;11C,13C or14C for12C;13N or15N for14N;17O or18O for16O;36Cl for35 / 37Cl;18F for19F;131I for127I; etc). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0048] In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, 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.

[0049] In some embodiments, where 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. Those of ordinary skill in the art will appreciate that, in some embodiments, 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 (e.g., in a primary sample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a Page 14 of 83 12623050v1Attorney Docket No.: 2014215-0079 small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.

[0050] Therapeutic agent: As used herein, the phrase “therapeutic agent” in general refers to any agent that elicits a desired pharmacological effect when administered to an organism. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, the appropriate population may be a population of model organisms. In some embodiments, an appropriate population may be defined by various criteria, such as a certain age group, gender, genetic background, preexisting clinical conditions, etc. In some embodiments, 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. In some embodiments, 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. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans.

[0051] Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer 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. In some embodiments, 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.

[0052] Therapeutically effective amount: As used herein, the term “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 12623050v1Attorney Docket No.: 2014215-0079 regimen. In some embodiments, 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. As will be appreciated by those of ordinary skill in this art, 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. For example, 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. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.

[0053] It is understood by one skilled in the art that 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 (2H or D).

[0054] 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. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present application.

[0055] The term “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)).

[0056] The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation. Page 16 of 83 12623050v1Attorney 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.

[0059] The term “halogen” means F, Cl, Br, or I.

[0060] The term “aryl”, as used herein, 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. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments, “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.

[0061] The term “heteroaryl” as used herein, 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. The term “heteroatom” as used herein, 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. The terms “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 12623050v1Attorney 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. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[0062] Additionally, it will be appreciated that, when two groups cyclize to form an optionally substituted heteroaryl ring having at least one nitrogen atom, the nitrogen atom in the ring can be, as valency permits, N or N-R†, as defined infra.

[0063] 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. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro- 2H-pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N–substituted pyrrolidinyl).

[0064] 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. Examples of such 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. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, are 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. Page 18 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0065] Additionally, it will be appreciated that, when two groups cyclize to form an optionally substituted heterocyclic ring having at least one nitrogen atom, the nitrogen atom in the ring can be, as valency permits, N or N-R†, as defined infra.

[0066] As described herein, compounds may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety of compounds are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit ast fthe 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.

[0067] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O–(CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; –N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; –C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; –OC(O)(CH2)0–4SR^, SC(S)SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR^2; -C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; -(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; Page 19 of 83 12623050v1Attorney Docket No.: 2014215-0079 –(CH2)0–4OS(O)2R^; –S(O)2NR^2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; –C(NH)NR^2; –P(O)2R^; -P(O)R^2; -OP(O)R^2; –OP(O)(OR^)2; SiR^3; –(C1–4 straight or branched alkylene)O–N(R^)2; or –(C1–4 straight or branched alkylene)C(O)O– N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-to 6 membered heteroaryl ring), or a 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 a 3–12– membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0068] Suitable monovalent substituents on R^ (or the ring formed by taking two independent occurrences of R^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =O and =S.

[0069] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is smay 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 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)2–3O–, wherein each Page 20 of 83 12623050v1Attorney 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.

[0070] Suitable substituents on the aliphatic group of R*include halogen, –R^, -(haloR^), -OH, – OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5– to 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0071] 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 unsubstituted 3– to 12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0072] Suitable substituents on the aliphatic group of R†are independently halogen, –R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or -NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5– to 6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0073] Pharmaceutically Acceptable Salt As used herein, the term “pharmaceutically acceptable salt” refers to those salts 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 12623050v1Attorney 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. Other pharmaceutically acceptable 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, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0074] 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.

[0075] Unless otherwise stated, 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. Additionally, unless otherwise stated, the present disclosure also includes compounds that differ only in the presence of one or more Page 22 of 83 12623050v1Attorney Docket No.: 2014215-0079 isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-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. In some embodiments, compounds of this disclosure comprise one or more deuterium atoms.

[0076] Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, 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.

[0077] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0078] 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. 1. Inhibitors Of Inhibitors of Apoptosis (IAPs):

[0079] In certain embodiments, the present disclosure provides inhibitors of IAPs. In some embodiments, an IAP is selected from BIRC1 / NAIP, BIRC2 / cIAP1, BIRC3 / cIAP2, BIRC4 / XIAP, BIRC5 / Survivin, BIRC6 / Apollon, BIRC7 / ML-IAP and BIRC8 / ILP2.

[0080] 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 12623050v1Attorney Docket No.: 2014215-0079 promote survival. Eight members of this family have been described in humans (BIRC1 / NAIP, BIRC2 / cIAP1, BIRC3 / cIAP2, BIRC4 / XIAP, BIRC5 / Survivin, BIRC6 / Apollon, BIRC7 / ML-IAP and BIRC8 / ILP2). In certain embodiments, the agent is an IAP Inhibitor (i.e., an IAP Antagonist). Exemplary IAP Inhibitors include XIAP inhibitors, CIAP inhibitors, and agents acting as dual XIAP and CIAP inhibitors.

[0081] Exemplary 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 Smac mimetic and an antagonist of IAPs, and it binds to XIAP, cIAP1, and cIAP2 proteins), GDC-0152 (a potent IAPs inhibitor, and binds to the BIR3 domains of XIAP, cIAP1, cIAP2 and the BIR domain of ML-IAP), ASTX660 (an orally bioavailable dual antagonist of cIAPs and XIAPs), CUDC-427 (a potent second- generation pan-selective IAP antagonist), Embelin (or Embelic acid, a potent, nonpeptidic XIAP inhibitor). 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.

[0082] In some embodiments, compounds disclosed herein bind to one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2). In some embodiments, compounds disclosed herein inhibitor activity or one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2).

[0083] 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), or 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. Alternate in vitro assays quantitate the ability Page 24 of 83 12623050v1Attorney 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. Detailed conditions for assaying a compound described herein as an inhibitor of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP, or ILP2), or variants or mutants thereof, are well known in the art and set forth in the Examples below.

[0084] 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). Thus, in some aspects and embodiments, 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.

[0085] In some embodiments, 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.

[0086] In some embodiments, 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. In some embodiments, the present disclosure provides a compound of formula I:

[0087] or a pharmaceutically acceptable salt thereof, wherein: L1 is a first ligand; L2 is a second ligand; and linker is a bivalent linker comprisin .

[0088] In some embodiments, the present disclosure provides a compound of formula I:Page 25 of 83 12623050v1Attorney 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 .

[0090] Without wishing to be bound by any parit is believed that 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. For example, 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 relatAZD5582. Hennessy et al. further surmise that shorter, less hydrophobic linkers render compounds less cell-permeable and therefore less potent in cell- based assays. In some embodiments, 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. Page 26 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0092] In some embodiments, it will be appreciated that compounds comprising less hydrophobic linkers have lower logPs relative to compounds comprising more hydrophobic linkers. For example, the logP for AZD5582 is calculated to be 6.14, whereas the logP of compound I-1 is calculated to be 5.5.

[0093] Thus, the present disclosure encompasses the insight that compounds of formula I are uniquely potent against cancer cell lines due to the flexibility and hydrophilicity of squaramide linkers as described herein.

[0094] As generally defined above, L1 is a first ligand; and L2 is a second ligand. In some embodiments, L1 and L2 are the same. In some embodiments, L1 and L2 are different.

[0095] In some embodiments, a ligand (e.g., L1 or L2) refers to a moiety that binds to a protein, for example, at a ligand binding domain. In some embodiments, a ligand (e.g., L1 or L2) is a moiety that binds to an IAP. In some embodiments, an IAP is selected from NAIP, cIAP1, cIAP2, XIAP, Survivin, Apollon, ML-IAP and ILP2.

[0096] In some embodiments, L1 is or comprises a group selected from .

[0097] In someem o ments, s or comprses a group se ecte rom .Page 27 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0098] As generally defined above, linker is a bivalent linker comprisin In some embodiments, the linker is of formula X:or a pharmaceutically acceptable salt thereof, wherein: each of X1and X2is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-12hydrocarbon 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 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; # represents the point of attachment to L1; and $ represents the point of attachment to L2.

[0099] As generally defined above, each of X1and X2is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-12hydrocarbon chain, wherein 1-4 carbon atoms are optionally and independently replaced by -O-, -N(R)-, -C(O)-, -S-, -SO-, -SO2-, or -Cy-. In some embodiments, each of X1and X2is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-6hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)-, or -C(O)-. In some embodiments, each of X1and X2is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-8hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)-, or -C(O)-. In some embodiments, X1and X2are the same. In some embodiments, X1and X2are different. Page 28 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0100] In some embodiments, X1is a covalent bond. In some embodiments, X1is 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)-. In some embodiments, X1is 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)-. In some embodiments, X1is an optionally substituted bivalent, saturated or partially unsaturated, straight C3-6hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.

[0101] In some embodiments, X1is an optionally substituted bivalent, saturated or partially unsaturated, straight C3hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C3 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C3hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C3 hydrocarbon chain.

[0102] In some embodiments, X1is an optionally substituted bivalent, saturated or partially unsaturated, straight C4hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C4 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C4hydrocarbon chain.

[0103] In some embodiments, X1is an optionally substituted bivalent, saturated or partially unsaturated, straight C5hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C5hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain. Page 29 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0104] In some embodiments, X1is an optionally substituted bivalent, saturated or partially unsaturated, straight C6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C6hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X1is an optionally substitute bivalent, saturated, straight C6 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X1is an optionally substitute bivalent, saturated, straight C6hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

[0105] In some embodiments, X1is an optionally substituted bivalent, saturated or partially unsaturated, straight C7hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C7hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X1is an optionally substitute bivalent, saturated, straight C7 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X1is an optionally substitute bivalent, saturated, straight C7 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

[0106] In some embodiments, X1is an optionally substituted bivalent, saturated or partially unsaturated, straight C8hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X1is an optionally substituted bivalent, saturated, straight C8hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X1is an optionally substitute bivalent, saturated, straight C8hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X1is an optionally substitute bivalent, saturated, straight C8 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

[0107] In some embodiments, X1is: ,wherein # represents the point of attachment to L1. In some embodiments, X1is: Page 30 of 83 12623050v1Attorney Docket No.: 2014215-0079covalent bond, , , , ,

[0108] In some embodiments, X1is , wherein # represents the point of attachment to L1.

[0109] In some embodiments, X1is , , or, wherein # represents the point of attachment to L1.[ ] n some em odiments, X2is a covalent bond. In some embodiments, X2is an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-6hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)-, or - C(O)-. In some embodiments, X2is an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C3-6hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O- or -N(R)-. In some embodiments, X2is an optionally substituted bivalent, saturated or partially unsaturated, straight C3-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.

[0111] In some embodiments, X2is an optionally substituted bivalent, saturated or partially unsaturated, straight C3 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C3 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C3hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C3hydrocarbon chain. Page 31 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0112] In some embodiments, X2is an optionally substituted bivalent, saturated or partially unsaturated, straight C4 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C4hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C4 hydrocarbon chain.

[0113] In some embodiments, X2is an optionally substituted bivalent, saturated or partially unsaturated, straight C5hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C5hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C5hydrocarbon chain.

[0114] In some embodiments, X2is an optionally substituted bivalent, saturated or partially unsaturated, straight C6hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C6hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X2is an optionally substitute bivalent, saturated, straight C6hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X2is an optionally substitute bivalent, saturated, straight C6 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

[0115] In some embodiments, X2is an optionally substituted bivalent, saturated or partially unsaturated, straight C7hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C7 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X2is an optionally substitute bivalent, saturated, straight C7hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X2is an optionally substitute bivalent, saturated, straight C7 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-. Page 32 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0116] In some embodiments, X2is an optionally substituted bivalent, saturated or partially unsaturated, straight C8 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X2is an optionally substituted bivalent, saturated, straight C8hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X2is an optionally substitute bivalent, saturated, straight C8 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X2is an optionally substitute bivalent, saturated, straight C8hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

[0117] In some embodiments, X2is: covalent bond, , , , ,

[0118] In some embodiments, X2is:covalent bond ,wherein $ represents the point of attachment to L2.

[0119] In some embodiments, X2i , wherein # represents the point of attachment to L2.

[0120] In some embodiments or, wherein # represents the point of attachment to L2.Page 33 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0121] As generally defined above, 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 C1-6aliphatic.

[0122] As generally defined above, 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. In some embodiments, -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.

[0123] In some embodiments, the present disclosure provides a compound of formula I-a, I-b, or I-c:12623050v1Attorney Docket No.: 2014215-0079 I-bor a pharmaceutically acceptable salt thereof, wherein linker is as defined above and described herein.

[0124] In some embodiments, it will be appreciated that 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).

[0125] In certain embodiments of formula I-a, 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): .

[0126] In some embodiments of formula I-a, 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 12623050v1Attorney 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. In some embodiments of formula I-a, 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. In some embodiments of formula I-a, 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. 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 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.

[0127] In certain embodiments of formula I-b, 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 12623050v1Attorney Docket No.: 2014215-0079 .

[0128] In somL1 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. In some embodiments of formula I-b, 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.

[0129] In certain embodiments of formula I-c, 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 12623050v1Attorney 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. 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. 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.

[0131] In some embodiments, a compound of Formula I is selected from:Page 38 of 83 12623050v1Attorney Docket No.: 2014215-0079 O NHPage 39 of 83 12623050v1Attorney Docket No.: 2014215-007912623050v1Attorney Docket No.: 2014215-0079 oompoun 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. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. Exemplary Methods of Manufacturing Compounds of this Present Disclosure

[0133] In some aspects, compounds of the present disclosure may be made by a variety of ways well-known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using methods described below and / or as described in Page 41 of 83 12623050v1Attorney 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.

[0134] In some embodiments, 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., pp p - y obtained as shown in General Scheme A using reagents and reaction conditions well known in the art, e.g., as described in WO 2010 / 142994A1. In some embodiments, Rais a suitable moiety (or protected analog) where treatment with INT-6A affords a compound of formula I-a. In some embodiments, Rʹ is a suitable moiety (or protected analog) where treatment with INT-5A affords a compound of formula I-a.

[0136] In some embodiments, 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. Page 42 of 83 12623050v1Attorney Docket No.: 2014215-0079obtained as shown in General Scheme B using reagents and reaction conditions well known in the art, e.g., as described in WO 2007 / 130626A2.

[0138] In some embodiments, a compound of Formula I-c can be obtained using the method of General Scheme C below: General Scheme C. Exemplary Synthesis of Compounds of Formula I-c.Page 43 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0139] In some embodiments, it will be appreciated that compounds of formula I-c may be obtained as shown in General Scheme C using reagents and reaction conditions well known in the art, e.g., as described in WO 2007 / 130626A2 and WO 2010 / 142994A1. In some embodiments, Rais a suitable moiety (or protected analog) where treatment with INT-6C affords a compound of formula I-c. In some embodiments, Rʹ is a suitable moiety (or protected analog) where treatment with INT-5A affords a compound of formula I-c. 2. Inhibitors of Cellular Kinases

[0140] In some embodiments, 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. In some embodiments, a cellular kinase is a Serine / Threonine Protein Kinase (STPKs), a Tyrosine Kinase (TKs), or a Dual Specificity Protein Kinase (DSPKs). One of skill in the art will understand that TKs includes both receptor associated and non-receptor associated tyrosine kinases.

[0142] In some embodiments, the present disclosure provides treatments for a proliferative disease or disorder comprising tyrosine kinase inhibitors (TKIs). In some embodiments, 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). In some embodiments, a TKI inhibits the activity of one or more of epidermal growth factor receptor (EGFR), ALK (anaplastic lymphoma kinase), TRK Page 44 of 83 12623050v1Attorney 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).

[0143] In some embodiments, a treatment for a proliferative disease or disorder comprises a TKI. In some embodiments, a TKI is crizotinib, cabozantinib, ponatinib, nintedanib, lestaurtinib, altiratinib, foretinib, merestinib, osimertinib, almonertinib, furmonertinib (AST2818), lazertinib (YH25448) , BPI-7711, nazartinib (EGF816), brigatinib, poziotinib, ceritinib, lorlatinib, repotrectinib, lapatinib, neratinib, pyrotinib, tucatinib, donatinib, sorafenib, sunitinib, pazopanib, axitinib, apatinib, vandetanib, selpercatinib, pralsetinib, tepotinib, camaptinib, savolitinib, tepotinib, camaptinib, savolitinib, ibrutinib, acalabrutinib, or zanubrutinib. In some embodiments, a TKI is ponatinib.

[0144] In some embodiments, 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)). In some embodiments, an inhibitor of a kinase in the TNF^ induced cell death pathway inhibits the activity of MAPK, inhibitor of NF-κB kinase-α (IKKα), inhibitor of NF-κB kinase-^ (IKK^), TANK-binding kinase 1 (TBK1), TGFβ-activated kinase 1-binding protein 2 (TAB2); TGFβ-activated kinase 1-binding protein 3 (TAB3), TGFβ-activated kinase 1 (TAK1) . In some embodiments, a treatment for a proliferative disease or disorder comprises an inhibitor of a kinase in the TNF^ induced cell death pathway. In some embodiments, a treatment for a proliferative disease or disorder comprises an inhibitor of TAK1. In some embodiments 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). In some embodiments an inhibitor of TAK1 is 5Z-7-Oxozeaenol (CAS No. : 253863-19-3). Page 45 of 83 12623050v1Attorney Docket No.: 2014215-0079 3. Proliferative Diseases or Disorders

[0145] In some embodiments, the present disclosure provides methods and compositions useful for the treatment for various proliferative diseases or disorders. In some embodiments, a proliferative disease or disorder is one defined by excessive proliferation or infiltration of cells. In some embodiments, a proliferative disease or disorder is one defined by metaplasia or dysplasia. In some embodiments, 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.

[0146] In some embodiments, 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. In some embodiments, a disease associated stem cell is a stem cell that exhibits pro-inflammatory and / or pro-fibrotic features. In some embodiments, the present disclosure provides methods and compositions useful for eliminating or inhibiting the growth of disease associated stem cells. In some embodiments, a proliferative disease or disorder is any disease or disorder associated with aberrant growth of a disease associated stem cell derived from epithelial tissue.

[0147] In some embodiments, a proliferative disease or disorder contemplated by the present disclosure is a cancer. In some embodiments, a proliferative disease or disorder contemplated by the present disclosure is a pulmonary disease or disorder.

[0148] In some embodiments, the present disclosure provides compositions and method for treating, ameliorating, or lessening the severity of a cancer. In some embodiments, 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. In some embodiments a cancer is any aberrant or uncontrolled growth of an epithelial tissue. In some embodiments, 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 12623050v1Attorney 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 myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.

[0149] In some embodiments, the present disclosure provides compositions and methods for treating, ameliorating, or lessening the severity of a pulmonary disease, disorder, or condition. In some embodiments, 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. In some embodiments, a pulmonary disease comprises an inflammatory disease or condition. In some embodiments, a pulmonary disease is a disease associated with a stem cell that exhibits pro- inflammatory and / or pro-fibrotic features. In some embodiments, 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. 4. Uses, Formulation, and Administration: Page 47 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0150] In some embodiments, 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. In some embodiments, 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. In some embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient.

[0151] In some embodiments, 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). In some embodiments, the present disclosure provides, compositions, pharmaceutical compositions, preparations, or kits comprising a compound described herein (e.g., an inhibitor of IAP), a tyrosine kinase inhibitor, and / or an inhibitor of a kinase in the TNF^ induced cell death pathway. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 5Z-7-Oxozeaenol.

[0152] In some embodiments, 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. In some embodiments, components or agents of the present disclosure (e.g., an inhibitor of IAP, ponatinib and an inhibitor of a kinase in the TNF^ induced cell death pathway ) are not mixed together in the same composition. For example, the three agents are not part of the same solution or powder. Page 48 of 83 12623050v1Attorney Docket No.: 2014215-0079 In some embodiments, the agents or components are kept separate in different compositions and are delivered separately. In some embodiments, 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. In some embodiments, given synergistic interactions between inhibitors of IAP and cellular kinase inhibitors as described herein the amount of one or all agents is lower than the amount that is typically administered when the agent is administered alone. In certain embodiments, the amount of all three agents is lower.

[0153] In some embodiments, compositions, pharmaceutical compositions, preparations, or kits of the present disclosure may include other agents. In some embodiments, the other agents may be any other therapeutic agent that would be useful to administer to the subject. In certain embodiments, 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. In certain embodiments, the other therapeutic agent is another chemotherapeutic agent. In certain embodiments, 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. In some embodiments, the other therapeutic agent is an anti-inflammatory agent such as aspirin, ibuprofen, acetaminophen, etc., pain reliever, anti-nausea medication, or anti-pyretic. In certain embodiments, 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. In some embodiments, the other therapeutic agent is an electrolyte replacement or supplementation such as potassium, magnesium, and calcium, in particular, potassium and magnesium. In some embodiments, the other therapeutic agent is an anti-arrhythmic agent. In some embodiments, the other therapeutic agent is a platelet booster, for example, an agent that increases the production and / or release of platelets. In some embodiments, the other therapeutic agent is an agent to boost the production of blood cells such Page 49 of 83 12623050v1Attorney Docket No.: 2014215-0079 as erythropoietin. In certain embodiments, the other therapeutic agent is an agent to prevent hyperglycemia. In certain embodiments, the other therapeutic agent is an immune system stimulator.

[0154] It will also be appreciated that certain of the agents utilized in accordance with the present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable form thereof. According to the present invention, 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.

[0155] 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. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously.

[0157] 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium Page 50 of 83 12623050v1Attorney Docket No.: 2014215-0079 chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0158] For this purpose, 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. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0159] 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.

[0160] 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. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. 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). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Page 51 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0161] In some embodiments, provided pharmaceutically acceptable compositions 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. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0162] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, 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, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0163] 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. They may optionally contain Page 52 of 83 12623050v1Attorney 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. Examples of embedding compositions that can be used 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.

[0164] 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. In such solid dosage forms 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. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain 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. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0165] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0166] Alternatively, 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 12623050v1Attorney 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. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] For topical applications, 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. Alternatively, provided pharmaceutically acceptable 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.

[0171] For ophthalmic use, provided pharmaceutically acceptable 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 12623050v1Attorney Docket No.: 2014215-0079 benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0172] Pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation. Such 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. In some embodiments pharmaceutically acceptable 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. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0173] 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.

[0174] 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. Additionally, 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 12623050v1Attorney 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

[0176] 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.

[0177] 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. 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). This pattern was reflected in western blots of treated BE stem cells exposed to the IAP antagonists and ponatinib, which showed that only SM-164 and AZD-5582 induced a cleaved caspase 3 (c-Casp3) within the six-hour duration of exposure (Fig.1c), consistent with the degradation of cIAP1 and cIAP2.

[0178] Based on the properties of diverse IAP antagonists in combination with ponatinib towards BE stem cells, we employed synthetic chemistry to expand the repertoire of IAP antagonists available for these studies. We chose a squaramide linker strategy for generating Page 56 of 83 12623050v1Attorney Docket No.: 2014215-0079 bivalent IAP antagonists based on its planar structure and separation of the headgroups that contain the peptide memetic domains that interact with cIAP1, cIAP2, and XIAPs, and screened them in dose-response assays against BE stem cells in the presence and absence of ponatinib. While molecules asymmetric for the headgroups from SM164 and AZD-5582 about a squaramide-polyether linker proved ineffective, a series of symmetric molecules using the headgroup of AZD-5582 and a squaramide linker of varying lengths yielded several low nanomolar IAP antagonists that induced apoptosis in BE stem cells in a ponatinib-dependent manner (Extended data Fig.2a,2b). One of these, I-1, along with ponatinib, proved in co- cultures of normal esophageal (ESO) stem cells and stem cells of BE, low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinoma (EAC) to select for the domination of normal ESO stem cells (Fig.1d). Consistently, the treatment of normal ESO stem cells with the combination of I-1 and ponatinib resulted in the degradation of cIAP1 and cIAP2 but not the induction of cleaved Caspase 3 (Fig.1e). The benign effects of the I-1 / ponatinib combination on normal ESO stem cells was underscored by the effects of the combination on co- xenografts of LGD and normal ESO stem cells in mice. Seven treatments (5mg / kg;30mg / kg) over three weeks not only eliminated the LGD signal but resulted in an expanded population of normal ESO stem cells and the epithelia they form (Fig.1f,g).

[0179] While the mechanism by which IAP antagonists promote cell death of established lines of cancer cells via cIAP1 and cIAP2 degradation are well established, the synthetic lethality induced by IAP antagonists and the BCR-ABL inhibitor ponatinib was not obvious. Underscoring this question is that other BCR-Abl inhibitors, such as imatinib, nilotinib, dasatinib, and bosutinib, were not identified in our screens. Moreover, 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. Unlike the bulk of clinically deployed BCR-ABL inhibitors, detailed interaction and inhibition studies have shown that 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;). 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. Consistently, treatment of LGD Page 57 of 83 12623050v1Attorney Docket No.: 2014215-0079 stem cells with ponatinib alone results in the loss of S320 phosphorylation without the induction of apoptosis (Fig.1i), and the treatment of these cells with the novel IAP antagonist I-1 leads to a degradation of cIAP1 and cIAP2 without inducing cleaved Caspase 3 or either the inhibitory (Ser320) or activating (Ser166) phosphorylation of RIPK1. However, treatment with the combination of I-1 and ponatinib (Fig.1e) showed a loss of the inhibitory phosphorylation of RIPK1 at S320, the gain of activating phosphorylation of RIPK1 at S166, and the induction of apoptosis in a process blocked by a RIPK1 inhibitor but not a RIPK3 inhibitor.

[0180] To further probe the mechanism by which the IAP antagonist I-1 and ponatinib behave in a synthetic lethal manner, we examined triple combinations between I-1, ponatinib, and inhibitors of kinases previously included in the spectrum of ponatinib targets. While inhibitors to IKK, MK2, and p38MAPK did not augment the pro-apoptotic activity of the I- 1 / ponatinib combination, the TAK1 inhibitor 5Z-7-oxozeaenol showed a much stronger induction of cleaved Caspase 3 and cell death in LGD stem cells (Fig.1f). Thus, 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. That being said, the TAK1 inhibitor with I-1 in the absence of ponatinib does not achieve the enhanced apoptosis as the triple combination of I-1, ponatinib, and TAK1 inhibitor, suggesting that ponatinib is impacting targets in addition to TAK1 the regulation of cell death. Example 2: Treatment of Pancreatic Cancer

[0181] The present example demonstrates the efficacy of the triple combination described herein in the treatment of pancreatic cancer.

[0182] HPAF-II is a pancreatic adenocarcinoma cell line that is resistant to multiple oncology drugs (Figure 3). However, treatment of HPAF-II cells with the triple combination described herein, specifically 7352N, ponatinib, and 5Z-7 oxozeaenol (TAK1 inhibitor), results in a marked enhancement in caspase activation as indicated by cleaved caspase 3 (Figure 4a). Further, this efficacy is demonstrated by the cell death induced by the triple combination in shown Figure 4b.

[0183] To further demonstrate the efficacy of the triple combination described herein for the treatment of pancreatic cancer AsPC-1 cells, a cell line derived from nude mouse xenografts Page 58 of 83 12623050v1Attorney Docket No.: 2014215-0079 initiated with cells from the ascites of a 62-year-old, White, female patient with cancer of the pancreas (CRL-1682; ATCC) were treated as described in Figure 5. Notably the the triple combination described herein, specifically I-1 (7352N), ponatinib, and 5Z-7 oxozeaenol (TAK1 inhibitor), resulted in increased cleaved caspase 3. Example 3: Treatment of Various Cancers

[0184] The present example demonstrates treatment of various cancers with the combination of compositions described herein. Low Grade dysplasia (esophageal) (LGD)

[0185] 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. Notably treatment with I-1 and ponatinib did not result in caspase 3 activation to the same extent as the triple combination. Additionally, treatment with 7352N, ponatinib, 5Z-7 oxozeaenol (TAK1 inhibitor) and a RIPK1 inhibitor (GSK2982772 (Cas No.1622848-92-3) limited the caspase 3 activation confirming the caspase 3 activation is a result of signaling through the apoptosis pathway. Esophageal adenocarcinoma

[0186] Similar to LGD, treatment with the triple combination 7352N, ponatinib, and 5Z-7 oxozeaenol (TAK1 inhibitor), resulted in increased cleaved caspase 3. Also similar to LGD, treatment with I-1 and ponatinib did not result in caspase 3 activation to the same extent as the triple combination. Additionally, treatment with 7352N, ponatinib, 5Z-7 oxozeaenol (TAK1 inhibitor) and a RIPK1 inhibitor (GSK2982772 (Cas No.1622848-92-3) limited the caspase 3 ativation confirming the caspase 3 activation is a result of signaling through the apoptosis pathway. Figure 7. Triple Negative Breast Cancer (TNBC)

[0187] 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 12623050v1Attorney Docket No.: 2014215-0079 combination- I-1, ponatinib, and a TAK1 inhibitor (i.e.5Z-7 Oxozeaenol or SM1-71). Notably, the triple combination I-1, ponatinib, and a TAK1 inhibitor induced caspase 3 cleavage. Figure 8. Ovarian Cancer

[0188] 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. This concise synthesis provides an efficient route to a novel symmetric squaramide with potential biological applications. Scheme 1. Synthesis of 7532N: Page 60 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0190] . y . g p , TEA, CH2Cl2; (b) NaH, (1S, 2R)-cis-1-amino-2-indanol, THF, 47% over two steps; (c) H-L-Pro- OBzl.HCl, HATU, DIEA, DMF; (d) 4N HCl in dioxane; (e) Boc-N-Me-L-Ala-OH, HATU, DIEA, DMF; (f) H2, Pd / C, MeOH, quantitative yield over four steps; (g) HATU, DIEA, DMF, 85%; (h) H2, Pd / C, MeOH; (i) 3,4-Diethoxy-3-cyclobutene-1,2-dione; (j) 12% TFA in DCM, 86% over the last two steps. Experimental section:

[0191] General Procedures. All solvents and organic reagents were obtained from commercial sources and used without further purification unless otherwise stated. Semi- preparative reversed-phase high-performance liquid chromatography (RP-HPLC) was performed on a Varian semi-preparative system equipped with a Discovery C18569226-U RP-HPLC Page 61 of 83 12623050v1Attorney Docket No.: 2014215-0079 column (25 cm × 21.2 mm, 5 μm). The mobile phase consisted of a gradient of water (0.1% TFA) and acetonitrile, with a flow rate of 20 mL / min. Mass spectra and HPLC retention times were obtained using a Thermo LTQXL LC / MS system with a UV detector (monitoring at 215 and 254 nm) and an Agilent 300SB-C8 RP-HPLC column (4.6 × 100 mm, 3.5 μm). The mobile phase consisted of a gradient of A) water (0.1% TFA) and B) acetonitrile at a flow rate of 0.5 mL / min. Unless otherwise specified, all HPLC retention times are reported for an eluent gradient of 5% B for the first 3 min, followed by an increase from 5% to 98% B over 6 min, which was maintained for an additional 6 min.1H NMR spectra were recorded on a Bruker Avance 600 MHz spectrometer and are referenced according to the residual peak of the solvent based on literature values. Crude target compounds were purified by RP-HPLC using the Varian semi- preparative system described above. Synthesis of 2-(2-azidoethoxy)ethan-1-ol tosylate

[0192] To a solution of 2-(2-azidoethoxy)ethan-1-ol (1.8 g, 13.7 mmol) and triethylamine (2.25 mL, 16.1 mmol) in CH2Cl2 (10 mL) at 0 °C was added dropwise a solution of p- toluenesulfonyl chloride (2.15 g, 11.3 mmol) in CH2Cl2 (15 mL). The resulting suspension was stirred at room temperature overnight. Water (10 mL) was added and stirred for 20 min. The organic layer was separated, washed with 0.1 N KHSO4(2 x 10 mL) and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (0- 10% MeOH / CH2Cl2) to give the tosylate product (3.0 g). Synthesis of Compound 1

[0193] To a suspension of NaH (60% in mineral oil; 0.9 g, 22.5 mmol) in anhydrous THF (60 mL) at 0 °C was added slowly a solution of (1S,2R)-cis-1-amino-2-indanol (3.0 g, 20 mmol) in THF (100 mL). The mixture was warmed to room temperature over 30 min and then heated to reflux. A solution of the tosylate from above (3.0 g, 10.5 mmol) in THF (10 mL) was added dropwise. The reaction was refluxed for 6 h, cooled, carefully quenched with water (30 mL), and concentrated to remove THF. The aqueous residue was extracted with CH2Cl2(3 × 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-10% Page 62 of 83 12623050v1Attorney Docket No.: 2014215-0079 MeOH / CH2Cl2) to give compound 1 (1.4 g, 47% over 2 steps). LC-MS (ESI+) m / z: 263.22 [M + H]+; tR = 7.93 min. Synthesis of Compound 7532P1

[0194] N-Boc-L-Chg-OH (10.29 g, 40 mmol), HATU (16 g, 42 mmol), DIEA (15.2 mL, 92 mmol), and L-Pro-OBzl•HCl (10.2 g, 42 mmol) were combined in anhydrous DMF (200 mL) at 0 °C. The mixture was stirred at room temperature for 2 h and concentrated. The residue was partitioned between EtOAc (600 mL) and 0.25 N KHSO4(3 x 100 mL), saturated NaHCO3(3 x 100 mL), and brine (3 x 100 mL). The organic layer was dried over MgSO4, filtered, and concentrated to an oil. This was treated with 4 N HCl in dioxane (200 mL) at room temperature for 2 h. Concentration and co-evaporation with CH2Cl2(3 x 100 mL) provided H-L-Chg-L-Pro- OBzl•HCl (22.1 g) as an oil.

[0195] 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 H2balloon overnight. Filtration through Celite and concentration gave a residue that was triturated with hexane (200 mL). Decantation and drying provided 7532P1 (12.8 g, quantitative) as a white powder. LC-MS (ESI+) m / z: 901.63 [2M + Na]+, 462.69 [M + Na]+, 440.53 [M + H]+; tR= 10.78 min. Synthesis of Compound 2

[0196] Compound 7532P1 (527 mg, 1.2 mmol), HATU (480 mg, 1.2 mmol), DIEA (0.48 mL), and compound 1 (0.4 g, 1.5 mmol) were combined in anhydrous DMF (6 mL) at 0 °C. The mixture was stirred at room temperature for 2 h and concentrated. The residue was purified by preparative RP-HPLC (C18, 21.2 x 250 mm, 5 μm; 30-98% MeCN / 0.1% aq. TFA over 15 min, 20 mL / min, 215 nm). Lyophilization of the product fractions gave compound 2 (0.7 g, 85%) as a white powder. LC-MS (ESI+) m / z: 684.27 [M + H]+; tR= 10.37 min. Synthesis of Compound 7532N Page 63 of 83 12623050v1Attorney Docket No.: 2014215-0079

[0197] A solution of compound 2 (0.52 g, 0.76 mmol) in MeOH (20 mL) was hydrogenated over 10% Pd / C (60 mg) under a H2 balloon for 3 h. Filtration through Celite and concentration gave a residue that was redissolved in anhydrous THF (9 mL) and treated with diethyl squarate (12 μL, 0.082 mmol) under Ar overnight. Concentration and purification by preparative RP-HPLC (C18, 21.2 x 250 mm, 5 μm; 40-98% MeCN / 0.1% aq. TFA over 20 min, 20 mL / min, 215 nm) afforded the Boc-protected intermediate after lyophilization. This was treated with TFA (1.2 mL) in CH2Cl2(9 mL) at 0 °C and stirred at room temperature for 2 h. Concentration and purification by preparative RP-HPLC (C18, 21.2 x 250 mm, 5 μm; 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.1H NMR (600 MHz, D2O) δ 7.33 - 7.28 (m, 4H), 5.32 (d, J = 5.4 Hz, 1H), 4.48 - 4.34 (m, 3H), 4.03 - 3.90 (m, 2H), 3.75 - 3.65 (m, 8H), 3.10 - 2.99 (m, 2H), 2.70 (s, 3H), 2.30 - 2.25 (m, 1H), 2.15 - 1.95 (m, 3H), 1.83 - 1.64 (m, 6H), 1.51 (d, J = 7.2 Hz, 3H), 1.25 - 1.07 (m, 6H).13C NMR (151 MHz, DMSO-d6) δ 182.48, 171.39, 169.17, 168.48, 167.74, 158.17, 157.91 (TFA), 141.68, 140.23, 127.58, 126.37, 124.74, 124.32, 80.74, 70.17, 69.69, 68.68, 59.23, 56.04, 55.82, 55.42, 55.31, 47.34, 43.06, 36.38, 30.74, 29.10, 28.57, 28.24, 25.80, 25.68, 25.54, 24.63, 15.68. LC-MS (ESI+) m / z: 1194.06 [M + H]+, 598.08; tR= 8.63 min. 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). 1-day post seeding, indicated compounds were added by automation at the High Throughput Research and Screening Center of the Institute of Biosciences and Technology at the Texas A&M University (Houston, Texas). After treatment, plates were sealed with breathable membranes and maintained for 4 days in a 37°C, 7.5% CO2 incubator. Plates were then fixed, stained, and imaged. In brief, the treated 384-well plates were washed with phosphate buffered saline (Gibco, USA) and fixed with 4% paraformaldehyde at room temperature for 25 minutes. After fixation, Page 64 of 83 12623050v1Attorney Docket No.: 2014215-0079 plates were then stained with DAPI for 1hr at room temperature before imaging via a high- content automatic screening system (Thermo Scientific CellInsight CX7 LED, Thermo Fisher Scientific, Waltham, MA, USA).

[0200] Figure 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. Specifically, 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.

[0203] Treatment of gemcitabine resistant pancreatic cancer stem cells with a triple combination as described herein induced apoptosis as demonstrated by caspase 3 cleavage (Figure 11C). Additionally, a gemcitabine-resistant clone demonstrated significant apoptosis when treated with a triple combination described herein. Notably, treatment with 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). Taxol-Resistant Ovarian Cancer Cells

[0204] 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 12623050v1Attorney Docket No.: 2014215-0079 with a triple combination as described herein showed the most significant apoptosis as demonstrated by caspase 3 cleavage. The apoptosis was abolished in the presence of RIPK1 inhibitor (GSK2982772) suggesting the death of the cells were mediated by RIPK1 activity (Figure 12A). Triple Negative Breast Cancer Cells

[0205] 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). Crohn’s Pathogenic Stem Cells

[0206] Pathogenic stem cells cloned from Crohn’s patients treated with a triple combination (e.g., ponatinib, I-1, and SM-171) 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). Page 66 of 83 12623050v1

Claims

Attorney Docket No.: 2014215-0079 CLAIMS 1. A pharmaceutical composition comprising an IAP inhibitor and at least two cellular kinase inhibitors.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a single entity.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is a unit dosage form.

4. A combination comprising: an IAP inhibitor; a tyrosine kinase inhibitor; and an activator of the TNF^^ induced cell death pathway.

5. A method of treating a proliferative disorder comprising administering a tyrosine kinase inhibitor and an activator of the TNF^^ induced cell death pathway with an IAP inhibitor.

6. A method of treating a proliferative disorder comprising administering to a subject in need thereof an IAP inhibitor in combination with a tyrosine kinase inhibitor and an activator of the TNF^^ induced cell death pathway.

7. A method of treating a proliferative disorder comprising administering an IAP inhibitor to a subject in need thereof wherein the subject has received or is receiving a tyrosine kinase inhibitor and an activator of the TNF^^ induced cell death pathway.

8. A method of treating a proliferative disorder comprising administering a tyrosine kinase inhibitor and an activator of the TNF^^ induced cell death pathwayto a subject in need thereof wherein the subject has received or is receiving an IAP inhibitor. Page 67 of 83 12623050v1Attorney Docket No.: 2014215-0079 9. In a method of treating a disease with a tyrosine kinase inhibitor the improvement comprising administration of an IAP inhibitor and an activator of the TNF^^ induced cell death pathway.

10. The composition or method of any of the preceding claims wherein the proliferative disorder is a pulmonary disease or disorder.

11. The composition or method of any of the preceding claims wherein the proliferative disorder is a cancer.

12. The composition or method of any of the preceding claims wherein the activator of the TNF^^ induced cell death pathway, the tyrosine kinase inhibitor and the IAP inhibitor are delivered in the same composition.

13. The composition or method of any of the preceding claims wherein the activator of the TNF^^ induced cell death pathway, the tyrosine kinase inhibitor and the IAP inhibitor are not delivered in the same composition.

14. The composition or method of any of the preceding claims wherein the activator of the TNF^^ induced cell death pathway is a TAK1 inhibitor.

15. The composition or method of claim 14, wherein the TAK1 inhibitor is 5Z-7-Oxozeaenol, SM1-71, Takinib, LYTAK1, PF-04358168, PF-05381941, NG25, HS-276, hypothemycin, Epoxyquinol B, ABC-FP, or AZ-TAK1.

16. The composition or method of any of the preceding claims wherein the tyrosine kinase inhibitor is ponatinib.

17. The composition or method of any of the preceding claims wherein the IAP inhibitor is a compound of formula I:I Page 68 of 83 12623050v1Attorney 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 comprising .

18. The composition or method of 17, wherein each of L1 and L2 is independently a moiety that binds to one or more Inhibitor of Apoptosis Proteins (IAPs).

19. The composition or method of 18, wherein an IAP is selected from Cp-IAP, Op-IAP, XIAP, cIAP1, C-IAP2, NAIP, Livin, or Survivin.

20. The composition or method of any one of claims17-19, wherein each of L1 and L2 independently comprises a group selected from: ,or a pharmaceutically acceptable salt thereof.

21. The composition or method of any one of claims 17-20, wherein L1 is: Page 69 of 83 12623050v1Attorney Docket No.: 2014215-0079 , or a pharmaceutically acceptabe sa e eo .

22. The composition or method of any one of claims 17-20, wherein L1 is: ,or a pharmaceutically acceptable salt thereof.

23. The composition or method of any one of claims 17-22, wherein L2 is: ,or a pharmaceutically acceptable salt thereof. Page 70 of 83 12623050v1Attorney Docket No.: 2014215-0079 24. The composition or method of any one of claims 17-22, wherein L2 is: , or a pharmaceutically acceptablesa t t ereo .

25. The composition or method of any one of claims 17-19, wherein the compound is of formula I-a, I-b, or I-c:I-b Page 71 of 83 12623050v1Attorney Docket No.: 2014215-0079-c or a pharmaceutically acceptable salt thereof.

26. The composition or method of any one of claims 17-25, wherein the linker is of formula X:or a pharmaceutically acceptable salt thereof, wherein: each of X1and X2is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-12 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 C1-6aliphatic; 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 Page 72 of 83 12623050v1Attorney Docket No.: 2014215-0079 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; # represents the point of attachment to L1; and $ represents the point of attachment to L2.

27. The composition or method of claim 26, wherein X1and X2are the same.

28. The composition or method of claim 26, wherein X1and X2are different.

29. The composition or method of claim 26, wherein each of X1and X2is independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight or branched C1-6hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)-, or -C(O)-.

30. The composition or method of claim 26 or 29, wherein X1is a covalent bond.

31. The composition or method of claim 26 or 29, wherein X1an optionally substituted bivalent, saturated or partially unsaturated, straight C3-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.

32. The composition or method of any one of claims 26, 29, or 31, wherein X1is an optionally substituted bivalent, saturated, straight C3hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.

33. The composition or method of any one of claims 26, 29, or 31, wherein X1is an optionally substituted bivalent, saturated, straight C4hydrocarbon chain.

34. The composition or method of any one of claims 26, 29, or 31, wherein X1is an optionally substituted bivalent, saturated, straight C5hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. Page 73 of 83 12623050v1Attorney Docket No.: 2014215-0079 35. The composition or method of any one of claims 26, 29, or 31, wherein X1is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain.

36. The composition or method of any one of claims 26, 29, or 31, wherein X1is an optionally substitute bivalent, saturated, straight C6 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.

37. The composition or method of any one of claims 26, 29, or 31, wherein X1is an optionally substitute bivalent, saturated, straight C6hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

38. The composition or method of any one of claims 26, 29, or 31, wherein X1is:covalent bond ,orwherein # represents the point of attachment to L1.

39. The composition or method of any one of claims 26 or 29-38, wherein X2is a covalent bond.

40. The composition or method of any one of claims 26 or 29-38, wherein X2an optionally substituted bivalent, saturated or partially unsaturated, straight C3-6hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.

41. The composition or method of any one of claims 26, 29-38, or 40, wherein X2is an optionally substituted bivalent, saturated, straight C3 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. Page 74 of 83 12623050v1Attorney Docket No.: 2014215-0079 42. The composition or method of any one of claims 26, 29-38, or 40, wherein X2is an optionally substituted bivalent, saturated, straight C4 hydrocarbon chain.

43. The composition or method of any one of claims 26, 29-38, or 40, wherein X2is an optionally substituted bivalent, saturated, straight C5 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.

44. The composition or method of any one of claims 26, 29-38, or 40, wherein X2is an optionally substituted bivalent, saturated, straight C5hydrocarbon chain.

45. The composition or method of any one of claims 26, 29-38, or 40, wherein X2is an optionally substitute bivalent, saturated, straight C6hydrocarbon chain, wherein 1 carbon atom is replaced by -O-.

46. The composition or method of any one of claims 26, 29-38, or 40, wherein X2is an optionally substitute bivalent, saturated, straight C6 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

47. The composition or method of any one of claims 26, 29-38, or 40, wherein X2is: lt b d ,or, wherein $ represents the point of attachment to L2.

48. The composition or method of any one of claims 17-47, wherein the compound is of formula I-a Page 75 of 83 12623050v1Attorney Docket No.: 2014215-0079or a pharmaceutically acceptable salt thereof, wherein 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 indicated by * below: .

49. The composition or method of claim 48, wherein 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.

50. The composition or method of any one of claims 17-47, wherein the compound is of formula I-b: Page 76 of 83 12623050v1Attorney Docket No.: 2014215-0079or a pharmaceutically acceptable salt thereof, wherein the linker is sufficient to position L1 and L2 at a distance of about 1.9-2.2 nm between the respective benzylic carbon atoms (indicated by * below): .

51. The composition or method of any one of claims 17-47, wherein the compound is of formula I-c: Page 77 of 83 12623050v1Attorney Docket No.: 2014215-0079-c or a pharmaceutically acceptable salt thereof, wherein 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 (indicated by * below): .Page 78 of 83 12623050v1Attorney Docket No.: 2014215-0079 52. The composition or method of claim 17, wherein the compound is selected from:Page 79 of 83 12623050v1Attorney Docket No.: 2014215-0079 O NHPage 80 of 83 12623050v1Attorney Docket No.: 2014215-0079age o 12623050v1Attorney Docket No.: 2014215-0079 I-10 o53. The composition or method of claim 11, wherein the cancer is bladder cancer, breast cancer, colon cancer, liver cancer, lung cancer, ovarian cancer, esophageal cancer, cholangiocarcinoma, glioblastoma, medulloblastoma pancreatic cancer, or prostate cancer.

54. The composition or method of claim 10, wherein the pulmonary disease or disorder is chronic obstructive pulmonary disease (COPD), cystic fibrosis, iditopathic pulmonary fibrosis or COVID-19. Page 82 of 83 12623050v1

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