Compounds and compositions useful as IAP inhibitors

Abstract

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

Description

Technical Field

[0001] The present disclosure relates to compounds and methods useful for inhibiting apoptosis protein inhibitors (IAPs). The present disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the present disclosure and methods of using such compositions to treat various diseases, disorders, and afflictions as described herein. Background Art

[0002] IAPs play an important role in controlling cancer cell survival. Thus, IAPs have drawn extensive attention as potential targets for treating IAP-related diseases, disorders, or afflictions. Summary of the Invention

[0003] In some embodiments, the present disclosure provides the recognition that there remains a need to find IAP inhibitors that can be used as therapeutic agents. It has now been found that the compounds of the present disclosure and their pharmaceutically acceptable salts and compositions are effective as IAP inhibitors. In some embodiments, the present disclosure provides compounds of Formula I:

[0004]

[0005] or a pharmaceutically acceptable salt thereof, wherein: L1 is a first ligand; L2 is a second ligand; and the linker is a bivalent linker comprising The bivalent linker.

[0006] The compounds described herein and their pharmaceutically acceptable compositions can be used to treat a variety of diseases, disorders, or afflictions related to IAP. Such diseases, disorders, or afflictions include those described herein.

[0007] The compounds provided herein can also be used to study the role of IAP in biological and pathological phenomena, such as, for example, and the comparative evaluation of new IAP inhibitors. Brief Description of the Drawings

[0008] Figure 1 Depicts the treatment of Barrett's esophagus cells with the compounds described herein. The concentration of the compound used and the percentage of cell survival are provided.

[0009] Figure 2 Depicts the treatment of esophageal adenocarcinoma stem cells with the compounds described herein. The concentration of the compound used and the percentage of cell survival are provided.

[0010] Figure 3 depicts the treatment of lung adenocarcinoma stem cells with Compound I-1. Figure 3A Depicts the survival % of lung adenocarcinoma stem cells at a higher concentration of Compound I-1. Figure 3BDepicts the survival % of lung adenocarcinoma stem cells at lower concentrations of Compound I-1. Regardless of the concentration, Compound I-1 exhibits a lethality comparable to that of another highly effective cytotoxic treatment.

[0011] Figure 4 depicts the treatment of advanced Barrett's esophagus stem cells isolated from two different patients with Compound I-1. Figure 4A Depicts the survival % of Barrett's esophagus stem cells from the first patient at higher concentrations of Compound I-1. Figure 4B Depicts the survival % of Barrett's esophagus stem cells from the first patient at lower concentrations of Compound I-1. Figure 4C Depicts the survival % of Barrett's esophagus stem cells from the second patient at higher concentrations of Compound I-1. Figure 4D Depicts the survival % of Barrett's esophagus stem cells from the second patient at lower concentrations of Compound I-1.

[0012] Figure 5 depicts the treatment of high-grade dysplastic Barrett's esophagus and diffuse gastric cancer with Compound I-1. Figure 5A Depicts the survival % of high-grade dysplastic Barrett's esophagus stem cells at higher concentrations of Compound I-1. Figure 5B Depicts the survival % of high-grade dysplastic Barrett's esophagus stem cells at lower concentrations of Compound I-1. Figure 5C Depicts the survival % of diffuse gastric cancer stem cells at higher concentrations of Compound I-1. Figure 5D Depicts the survival % of diffuse gastric cancer stem cells at lower concentrations of Compound I-1.

[0013] Figure 6 depicts the treatment of low-grade dysplastic Barrett's esophagus and esophageal adenocarcinoma with Compound I-1. Figure 6A Depicts the survival % of low-grade dysplastic Barrett's esophagus stem cells at higher concentrations of Compound I-1. Figure 6B Depicts the survival % of low-grade dysplastic Barrett's esophagus stem cells at lower concentrations of Compound I-1. Figure 6C Depicts the survival % of esophageal adenocarcinoma stem cells at higher concentrations of Compound I-1. Figure 6D Depicts the survival % of esophageal adenocarcinoma stem cells at lower concentrations of Compound I-1.

[0014] Figure 7 depicts the treatment of various diseases with Compounds I-2 and I-5. Figure 7A Depicts the survival % of diffuse gastric adenocarcinoma with ascites cells at different concentrations of Compounds I-2 and I-5. Figure 7B Depicts the survival % of advanced Barrett's cells at different concentrations of Compounds I-2 and I-5. Figure 7CDepicts the survival % of high-grade serous ovarian cancer cells at different concentrations of Compound I-2 and I-5. Figure 7D Depicts the survival % of gastric cancer at different concentrations of Compound I-2 and I-5. Figure 7E Depicts the survival % of paclitaxel-resistant ovarian cancer stem cells at different concentrations of Compound I-2 and I-5.

[0015] Figure 8 depicts the treatment of low-grade dysplastic Barrett's esophagus and high-grade dysplastic Barrett's esophagus with Compounds I-1, I-2, I-6, and I-3. Figure 8A Depicts the survival % of low-grade dysplastic Barrett's esophagus stem cells at different concentrations of I-1, I-2, I-6, and I-3. Figure 8B Depicts the survival % of high-grade dysplastic Barrett's esophagus stem cells at different concentrations of I-1, I-2, I-6, and I-3.

[0016] Figure 9 Depicts the treatment of pancreatic cancer with Compounds I-9, I-10, I-3, and I-11. Figure 9 Depicts the survival % of pancreatic cancer stem cells at different concentrations of I-9, I-10, I-3, and I-11.

[0017] Figure 10 Depicts the limited toxicity of the compounds described herein to healthy liver stem cells.

[0018] Figure 11 Depicts the limited toxicity of the compounds described herein to healthy lung stem cells. Detailed Description

[0019] 1. General description of certain embodiments of the present invention:

[0020] In certain embodiments, the present disclosure provides inhibitor IAP. In some embodiments, such compounds include compounds of the formula described herein or pharmaceutically acceptable salts thereof, wherein each variable is defined and described as herein. In some embodiments, the present disclosure provides a Compound I:

[0021]

[0022] or a pharmaceutically acceptable salt thereof, wherein: L1 is a first ligand; L2 is a second ligand; and the linker is a bivalent linker comprising

[0023] 2. Compounds and Definitions:

[0024] The compounds of the present disclosure include the compounds generally described above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. In addition, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5th Edition, Editors: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0025] As used herein, the term “aliphatic” or “aliphatic group” means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic and has a single point of attachment to the remainder of the molecule (also referred to herein as “carbocyclic”, “carbocyclic ring”, “alicyclic” or “cycloalkyl”). Unless otherwise indicated, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic and has a single point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched substituted or unsubstituted alkyl, alkenyl, and alkynyl groups and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0026] The term “heteroatom” means one or more oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of a basic nitrogen; or a replaceable nitrogen in a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0027] As used herein, the term "unsaturated" means that a moiety has one or more unsaturated units.

[0028] As used herein, the term "partially unsaturated" refers to a cyclic moiety that includes at least one double or triple bond. The term "partially unsaturated" as used herein is intended to cover rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0029] As used herein, the term "lower alkyl" means a straight or branched chain alkyl group having from C 1-4 to. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0030] The term "halogen" means F, Cl, Br, or I.

[0031] As used herein, the term "aryl" refers to monocyclic and bicyclic 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 including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, etc., which may be substituted with one or more substituents. Also included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as dihydroindenyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc.

[0032] As used herein, the term "heteroaryl" refers to a group having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; having 6, 10 or 14 π electrons shared in the ring arrangement; and having one to five heteroatoms in addition to carbon atoms. 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 basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furyl, 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 heterocyclic rings, wherein the linking group or point of attachment is on the heteroaromatic ring. Non-limiting examples of heteroaryl rings on the compounds of Formula I and its subgenera include indolyl, isoindolyl, benzothienyl, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which includes an optionally substituted ring.

[0033] In addition, it should be understood 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 long as the valence allows) N or as defined below.

[0034] As used herein, the terms "heterocycle", "heterocyclic group" and "heterocyclic" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety, the ring of which can be saturated or partially unsaturated and having one or more (preferably one to four) heteroatoms as defined above in addition to carbon atoms. When used in reference to the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl).

[0035] The heterocycle can be attached to its side group at any heteroatom or carbon atom that gives rise to a stable structure and any one of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxolanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl and quinuclidinyl. The terms "heterocycle", "heterocyclic group", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as dihydroindolyl, 3H–indolyl, chromanyl, phenanthridine, tetrahydroquinolinyl or tetrahydroisoquinolinyl, where the linking group or point of attachment is on the heterocyclic ring. The heterocyclic group can be monocyclic or bicyclic.

[0036] In addition, it should be understood 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 long as the valence allows) N or as defined below.

[0037] As described herein, a compound may contain an "optionally substituted" moiety. In general, whether or not preceded by the term "optionally", the term "substituted" means that one or more hydrogens of the specified moiety of the compound are replaced by a suitable substituent. "Substituted" applies to one or more hydrogens that are explicitly or implicitly present in the structure (e.g., at least means and means at least ). Unless otherwise specified, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the specified group, the substituents can be the same or different at each position.

[0038] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; –(CH2) 0–4 R°; –(CH2) 0–4 OR°; -O(CH2) 0-4 R o 、–O–(CH2) 0–4 C(O)OR°; –(CH2) 0–4 CH(OR°)2; –(CH2) 0– 4SR°; –(CH2) 0–4Ph, which may be substituted by R°; –(CH2) 0–4 O(CH2) 0–1 Ph, which may be substituted by R°; –CH=CHPh, which may be substituted by R°; –(CH2) 0–4 O(CH2) 0–1 -pyridyl, which may be substituted by R°; –NO2; –CN; –N3; -(CH2) 0–4 N(R°)2; –(CH2) 0–4 N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2) 0–4 N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2) 0–4 N(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) 0–4 C(O)R°; –C(S)R°; –(CH2) 0–4 C(O)OR°; –(CH2) 0–4 C(O)SR°; -(CH2) 0–4 C(O)OSiR°3; –(CH2) 0–4 OC(O)R°; –OC(O)(CH2) 0–4 SR°、SC(S)SR°; –(CH2) 0–4 SC(O)R°; –(CH2) 0–4 C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°、-(CH2) 0–4 OC(O)NR°2; -C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; -(CH2) 0–4 SSR°; -(CH2) 0–4 S(O)2R°; –(CH2) 0–4 S(O)2OR°; –(CH2) 0–4 OS(O)2R°; –S(O)2NR°2; -(CH2) 0–4 S(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; –(C 1–4 linear or branched alkylene)O–N(R°)2; or –(C 1–4a straight-chain or branched alkylene)C(O)O–N(R°)2, where each R° may be substituted as defined below and is independently hydrogen, C 1–6 aliphatic, –CH2Ph, –O(CH2) 0–1 Ph, -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, as defined above, two independently occurring R° together with the intervening atom form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0039] Suitable monovalent substituents on R° (or on the ring formed by two independently occurring R° together with the intervening atom) are independently halogen, –(CH2) 0–2 R ● 、 –(haloR ● ), –(CH2) 0–2 OH, –(CH2) 0–2 OR ● 、 –(CH2) 0–2 CH(OR ● )2; -O(haloR ● ), –CN, –N3, –(CH2) 0–2 C(O)R ● 、 –(CH2) 0–2 C(O)OH, –(CH2) 0–2 C(O)OR ● 、 –(CH2) 0–2 SR ● 、 –(CH2) 0–2 SH, –(CH2) 0–2 NH2, –(CH2) 0–2 NHR ● 、 –(CH2) 0–2 NR ● 2, –NO2, –SiR ● 3, –OSiR ● 3, -C(O)SR ● 、 –(C 1–4 straight-chain or branched alkylene)C(O)OR ● or –SSR ● where each R ● is unsubstituted or, in the case of being preceded by "halo", is substituted only by one or more halogens and is independently selected from C 1–4 aliphatic, –CH2Ph, –O(CH2) 0–1Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atoms of R° include ═O and ═S.

[0040] Suitable divalent substituents on the saturated carbon atoms 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)) 2–3 O– or –S(C(R * 2)) 2–3 S–, wherein each independently occurring R * is selected from hydrogen, C 1–6 aliphatic (which may be substituted as defined below) or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to the ortho-substitutable carbon of an “optionally substituted” group of a compound of formula I or a subgenus thereof include: –O(CR * 2) 2–3 O–, wherein each independently occurring R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below or an unsubstituted 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0041] R * Suitable substituents on the aliphatic group of 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, in the case of being preceded by “halo”, is substituted by one or more halogens only, and is independently C 1–4 aliphatic, –CH2Ph, –O(CH2) 0–1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0042] Suitable substituents on the replaceable nitrogen of an “optionally substituted” group include or where each is independently hydrogen, C 1–6 aliphatic which may be substituted as 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 above definition, two independently occurring together with the intervening atoms form an unsubstituted 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0043] Suitable substituents on the aliphatic group of ● are independently halogen, –R ● , -(haloR ● ), –OH, –OR ● , –O(haloR ● ), –CN, –C(O)OH, –C(O)OR ● , –NH2, –NHR ● 2 or NO2, where each R ● is unsubstituted or, in the case of being preceded by “halo”, is substituted only by one or more halogens and is independently C 1–4 aliphatic, –CH2Ph, –O(CH2) 0–1 Ph or a 3- to 6-membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0044] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc. 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. described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts include salts derived from suitable inorganic acids and organic acids with bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by the reaction of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc.

[0045] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1–4 -alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0046] Unless otherwise indicated, structures depicted herein are also intended to include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) of the structure; for example, the R and S configurations at each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the present disclosure are within the scope of the present disclosure. Unless otherwise indicated, all tautomeric forms are within the scope of the present disclosure. In addition, unless otherwise indicated, the present disclosure also includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention (including replacement of hydrogen by deuterium or tritium, or carbon by 13 C or 14 C-enriched carbon) are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present disclosure. In some embodiments, the compounds of the present disclosure contain one or more deuterium atoms.

[0047] Combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that permit the preparation, detection, and in certain embodiments, the recovery, purification, and use of the compound for one or more of the purposes disclosed herein.

[0048] The recitation of a list of chemical groups in the definition of any variable herein includes defining the variable as any single group or combination of the listed groups. The recitation of embodiments of a variable herein includes the embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0049] As used herein, the term "biological sample" includes, but is not limited to, a cell culture or an extract thereof; biopsy material obtained from an animal (e.g., a mammal) or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or an extract thereof; or a purified version thereof. For example, the term "biological sample" refers to any solid or liquid sample obtained from, excreted by, or secreted by any living organism, including single-celled microorganisms (such as bacteria and yeasts) and multi-cellular organisms (such as plants and animals, e.g., vertebrates and mammals), particularly healthy or apparently healthy human subjects or human subjects suffering from a disorder or disease to be diagnosed or studied. A biological sample can be in any form, including solid materials such as tissues, cells, cell pellets, cell extracts, cell homogenates, or cell fractions; or biopsies or biological fluids. Biological fluids can be obtained from any site (e.g., blood, saliva (or mouthwash containing buccal cells), tears, plasma, serum, urine, bile, semen, cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleural fluid, or cells therefrom, aqueous humor, or vitreous humor, or any body excretions), exudates, effusions (e.g., fluids obtained from an abscess or any other infected or inflamed site), or fluids obtained from joints (e.g., normal joints or joints affected by diseases such as rheumatoid arthritis, osteoarthritis, gout, or septic arthritis). A biological sample can be obtained from any organ or tissue (including biopsy or autopsy specimens), or can include cells (whether primary cells or cultured cells) or media conditioned by any cell, tissue, or organ. A biological sample can also include tissue sections, such as frozen sections collected for histological purposes. A biological sample also includes a mixture of biomolecules produced by partial or complete fractionation of a cell or tissue homogenate, including proteins, lipids, carbohydrates, and nucleic acids. Although the sample is preferably taken from a human subject, a biological sample can be from any animal, plant, bacterium, virus, yeast, etc. The term "animal" as used herein refers to humans at any stage of development and non-human animals, including, for example, mammals, birds, reptiles, amphibians, fish, worms, and single-celled organisms. Cell cultures and tissue samples are considered plural for animals. In certain exemplary embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, and / or pig). The animal can be a transgenic animal or a human clone. If desired, the biological sample can be subjected to preliminary processing, including preliminary separation techniques.

[0050] As used herein, "IAP-related disease or disorder" or alternatively "IAP-mediated disease or disorder" means any disease or other adverse medical condition in which IAP or its mutants are known or suspected to play a role. In some embodiments, the IAP is selected from BIRC1 / NAIP, BIRC2 / cIAP1, BIRC3 / cIAP2, BIRC4 / XIAP, BIRC5 / survivin, BIRC6 / Apollon, BIRC7 / ML-IAP, and BIRC8 / ILP2.

[0051] As used herein, the term "subject" means a mammal and includes human and animal subjects such as domestic animals (e.g., horses, dogs, cats, etc.). The terms "subject" and "patient" may be used interchangeably. In some embodiments, "patient" or "subject" means an animal, preferably a mammal, and most preferably a human.

[0052] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol, and lanolin. The amount of the carrier substance combined to produce a single dosage form composition will vary depending on the host being treated, the particular mode of administration, and the like.

[0053] As used herein, the expression "unit dosage form" refers to physically discrete units of the provided compound and / or its composition that are suitable for the subject to be treated. However, it should be understood that the attending physician will determine, within the scope of sound medical judgment, the total daily dosage of the active agent (i.e., the compounds and compositions described herein). For any particular subject (i.e., patient) or organism, the specific effective dose level will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific active agent employed; the specific composition employed; the age, weight, general health, gender, and diet of the subject; the time of administration, the route of administration, and the excretion rate of the specific active agent employed; the duration of treatment; and similar factors well known in the medical arts.

[0054] As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques.

[0055] As used herein, "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount sufficient to treat, diagnose, prevent, and / or delay the onset of a disease, disorder, and / or affliction when administered as part of a dosing regimen to a subject having or susceptible to the disease, disorder, and / or affliction. One of ordinary skill in the art will understand that 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, an effective amount of a compound provided in a formulation for treating a disease, disorder, and / or affliction is an amount that results in a reduction, improvement, alleviation, inhibition, prevention, delay in onset, reduction in severity, and / or reduction in incidence of one or more symptoms or characteristics of the disease, disorder, and / or affliction. In some embodiments, a "therapeutically effective amount" is at least the minimum amount of the provided compound or composition comprising the provided compound that is sufficient to treat one or more symptoms of an IAP-mediated disease or disorder.

[0056] As used herein, the terms "treatment / treat / treating" refer to partially or completely reducing, inhibiting, delaying the onset, preventing, improving, and / or alleviating a disorder or affliction or one or more of its symptoms as described herein. In some embodiments, treatment may be administered after one or more signs or symptoms have developed. In some embodiments, the term "treatment" includes preventing or arresting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual (e.g., based on a symptom history and / or based on genetic or other susceptibility factors) prior to the occurrence of symptoms. Treatment may also be continued after symptoms have subsided, e.g., to prevent or delay recurrence. Thus, in some embodiments, the term "treatment" includes preventing the recurrence or relapse of a disease or disorder.

[0057] 3. Description of Exemplary Embodiments:

[0058] In some embodiments, the present disclosure provides a compound of Formula I:

[0059]

[0060] or a pharmaceutically acceptable salt thereof, wherein: L1 is a first ligand; L2 is a second ligand; and the linker is a bivalent linker comprising of.

[0061] Not wishing to be bound by any particular theory, it is believed that L1 and L2 need to be positioned at a certain distance from each other to achieve optimal 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 atoms on each of L1 and L2 to which the linker is attached. Additionally, not 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 using a rigid linear linker. For example, AZD5582 contains a diyne linker having the following structure

[0062]

[0063] See Hennessy et al., J. Med. Chem. 2013, 56, 9897 - 9919. Hennessy et al. reported that the linker should have minimal steric requirements to prevent disruption of critical binding interactions with the target protein. Hennessy et al. also reported that a fully saturated linker (i.e., ) did not result in any significant change in cellular potency relative to compounds such as AZD5582. Hennessy et al. also speculated that shorter, less hydrophobic linkers would reduce the cellular permeability of the compound and thus result in lower potency in cell - based assays. In some embodiments, the present disclosure provides the insight that, despite the teachings of Hennessy, compounds containing less rigid, more hydrophilic linkers (e.g., the compounds described herein (e.g., compounds having a linker containing squaramide)) exhibit improved activity compared to compounds having rigid, hydrophobic linkers such as AZD5582. See, for example Figure 1 and Figure 2 . Additionally, Figure 1 and Figure 2 show that the compounds of Formula I are more potent than compounds having flexible hydrophobic linkers such as SM - 164 and BV6.

[0064] In some embodiments, it should be understood that compounds containing less hydrophobic linkers have a lower logP relative to compounds containing more hydrophobic linkers. For example, the logP of AZD5582 is calculated to be 6.14, while the logP of compound I - 1 is calculated to be 5.5.

[0065] Accordingly, the present disclosure encompasses the insight that due to the flexibility and hydrophilicity of the squaramide linker as described herein, the compounds of Formula I have unique efficacy against cancer cell lines.

[0066] As generally defined above, L1 is a first ligand; L2 is a second ligand. In some embodiments, L1 and L2 are the same. In some embodiments, L1 and L2 are different.

[0067] In some embodiments, a ligand (e.g., L1 or L2) refers to a moiety that binds to a protein, such as 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, the IAP is selected from NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, and ILP2.

[0068] In some embodiments, L1 is or comprises a group selected from

[0069]

[0070] In some embodiments, L2 is or comprises a group selected from

[0071]

[0072] As generally defined above, a linker is a bivalent linker comprising In some embodiments, the linker has formula X:

[0073]

[0074] or a pharmaceutically acceptable salt thereof, wherein:

[0075] X 1 and X 2 are each independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight-chain or branched-chain C 1-12 hydrocarbon chain, wherein 1-4 carbon atoms are optionally and independently substituted with -O-, -N(R)-, -C(O)-, -S-, -SO-, -SO2-, or -Cy-; each R is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group; each -Cy- is independently an optionally substituted bivalent ring selected from: a 3- to 8-membered carbocyclic group, a 5- to 6-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; a phenylene group; or a 5- to 6-membered heteroarylene group 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.

[0076] As generally defined above, X 1 and X 2 are each independently a covalent bond or an optionally substituted bivalent, saturated or partially unsaturated, straight-chain or branched-chain C 1-12 hydrocarbon chain, wherein 1-4 carbon atoms are optionally and independently replaced with -O-, -N(R)-, -C(O)-, -S-, -SO-, -SO2-, or -Cy-. In some embodiments, X 1 and X2 Each is independently a covalent bond or an optionally substituted divalent, saturated or partially unsaturated, straight-chain or branched-chain C 1-6 hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced by -O-, -N(R)- or -C(O)-. In some embodiments, X 1 and X 2 Each is independently a covalent bond or an optionally substituted divalent, saturated or partially unsaturated, straight-chain or branched-chain C 1-8 hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced by -O-, -N(R)- or -C(O)-. In some embodiments, X 1 and X 2 are the same. In some embodiments, X 1 and X 2 are different.

[0077] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain or branched-chain C 1-6 hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced by -O-, -N(R)- or -C(O)-. In some embodiments, X 1 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain or branched-chain C 3-6 hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced by -O- or -N(R)-. In some embodiments, X 1 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C 3-6 hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally replaced by -O-.

[0078] In some embodiments, X 1 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C3 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C3 hydrocarbon chain, wherein 1 carbon atom is optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C3 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C3 hydrocarbon chain.

[0079] In some embodiments, X 1is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C4 hydrocarbon chain, wherein one carbon atom is optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C4 hydrocarbon chain, wherein one carbon atom is optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C4 hydrocarbon chain.

[0080] In some embodiments, X 1 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C5 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain, wherein one carbon atom is optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain, wherein one carbon atom is replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain.

[0081] In some embodiments, X 1 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain, wherein one carbon atom is replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain, wherein two carbon atoms are replaced by -O-.

[0082] In some embodiments, X 1 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C7 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C7 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C7 hydrocarbon chain, wherein one carbon atom is replaced by -O-. In some embodiments, X 1is an optionally substituted divalent, saturated, straight-chain C7 hydrocarbon chain in which 2 carbon atoms are replaced by -O-.

[0083] In some embodiments, X 1 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C8 hydrocarbon chain in which 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C8 hydrocarbon chain in which 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C8 hydrocarbon chain in which 1 carbon atom is replaced by -O-. In some embodiments, X 1 is an optionally substituted divalent, saturated, straight-chain C8 hydrocarbon chain in which 2 carbon atoms are replaced by -O-.

[0084] In some embodiments, X 1 is:

[0085] a covalent bond,

[0086] where # represents the point of attachment to L1.

[0087] In some embodiments, X 1 is:

[0088] a covalent bond,

[0089] where # represents the point of attachment to L1.

[0090] In some embodiments, X 1 is where # represents the point of attachment to L1.

[0091] In some embodiments, X 1 is where # represents the point of attachment to L1.

[0092] In some embodiments, X 2 is a covalent bond. In some embodiments, X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain or branched C 1-6 hydrocarbon chain in which 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)- or -C(O)-. In some embodiments, X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain or branched C 3-6A hydrocarbon chain in which 1 to 2 carbon atoms are optionally and independently replaced by -O- or -N(R)-. In some embodiments, X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C 3-6 hydrocarbon chain in which 1 to 2 carbon atoms are optionally replaced by -O-.

[0093] In some embodiments, X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C3 hydrocarbon chain in which 1 carbon atom is optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C3 hydrocarbon chain in which 1 carbon atom is optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C3 hydrocarbon chain in which 1 carbon atom is replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C3 hydrocarbon chain.

[0094] In some embodiments, X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C4 hydrocarbon chain in which 1 carbon atom is optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C4 hydrocarbon chain in which 1 carbon atom is optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C4 hydrocarbon chain.

[0095] In some embodiments, X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C5 hydrocarbon chain in which 1 to 2 carbon atoms are optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain in which 1 to 2 carbon atoms are optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain in which 1 carbon atom is optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain in which 1 carbon atom is replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain.

[0096] In some embodiments, X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C6 hydrocarbon chain in which 1 to 2 carbon atoms are optionally replaced by -O-. In some embodiments, X2 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

[0097] In some embodiments, X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C7 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C7 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C7 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C7 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

[0098] In some embodiments, X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C8 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C8 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C8 hydrocarbon chain, wherein 1 carbon atom is replaced by -O-. In some embodiments, X 2 is an optionally substituted divalent, saturated, straight-chain C8 hydrocarbon chain, wherein 2 carbon atoms are replaced by -O-.

[0099] In some embodiments, X 2 is:

[0100] a covalent bond,

[0101] where $ represents the point of attachment to L2.

[0102] In some embodiments, X 2 is:

[0103] a covalent bond,

[0104]

[0105] Wherein $ represents the connection point to L2.

[0106] In some embodiments, X 2 is Wherein # represents the connection point to L2.

[0107] In some embodiments, X 2 is Wherein # represents the connection point to L2.

[0108] As generally defined above, each R is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C 1-6 aliphatic group.

[0109] As generally defined above, each -Cy- is an optionally substituted divalent ring independently selected from the following: a 3- to 8-membered carbocyclic group, a 5- to 6-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a phenylene group; or a 5- to 6-membered heteroaromatic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; In some embodiments, -Cy- is a 3- to 8-membered carbocyclic group. In some embodiments, -Cy- is a 5- to 6-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is a phenylene group. In some embodiments, -Cy- is a 5- to 6-membered heteroaromatic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0110] In some embodiments, the present disclosure provides compounds of formula I-a, I-b, or I-c:

[0111]

[0112]

[0113] or a pharmaceutically acceptable salt thereof, wherein the linker is incorporated as defined above and as described herein.

[0114] In some embodiments, it should be appreciated that the linker is used to position L1 and L2 relative to each other at a specific distance (e.g., between about 0.5 - 2.5 nm).

[0115] 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 corresponding indanyl group (indicated hereinafter by *):

[0116]

[0117] 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 corresponding indanyl group (indicated hereinafter by *). In some embodiments of Formula I-a, the linker is sufficient to position L1 and L2 at a distance of about 1.0 - 2.2 nm between the C1 carbon atoms of the corresponding indanyl group. 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 corresponding indanyl group. 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 corresponding indanyl group. 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 corresponding indanyl group. 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 corresponding indanyl group. 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 corresponding indanyl group. 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 corresponding indanyl group. 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 corresponding indanyl group. 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 corresponding indanyl group. 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 corresponding indanyl group. 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 corresponding indanyl group.

[0118] 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 corresponding benzylic carbon atoms (indicated hereinafter by *):

[0119]

[0120] In some embodiments of formula I-b, the linker is sufficient to position L1 and L2 at a distance of about 1.9 - 2.2 nm between the corresponding 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 corresponding 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 corresponding 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 corresponding 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 corresponding benzylic carbon atoms.

[0121] 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 hereinafter by *):

[0122]

[0123] 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.

[0124] In some embodiments, the compounds of formula I are selected from:

[0125]

[0126]

[0127]

[0128] or a pharmaceutically acceptable salt thereof.

[0129] Compound logP PSA I-1 5.49 276.20 I-2 5.46 257.74 I-3 7.80 257.74 I-4 5.42 239.28 I-5 4.55 297.68 I-6 3.61 319.16 I-7 5.14 300.70 I-8 5.92 300.70 I-9 6.24 257.74 I-10 7.02 257.74 I-11 8.58 257.74

[0130] 4. Use, formulation and administration:

[0131] Pharmaceutically acceptable compositions

[0132] According to another embodiment, the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or excipient. In certain embodiments, the amount of the compound in the composition described herein is such that it can effectively and measurably inhibit the activity of IAP (e.g., BIRC1 / NAIP, BIRC2 / cIAP1, BIRC3 / cIAP2, BIRC4 / XIAP, BIRC5 / survivin, BIRC6 / Apollon, BIRC7 / ML-IAP and BIRC8 / ILP2) or its mutants in a biological sample or a patient. In certain embodiments, the composition described herein is formulated for administration to a patient in need thereof. In some embodiments, the composition described herein is formulated for oral administration to a patient.

[0133] The compounds and compositions according to the methods of the present disclosure can be administered in any amount and by any route of administration effective to treat the conditions provided herein (i.e., IAP-mediated diseases or disorders) or to alleviate their severity. The precise amount required will vary between different subjects depending on the type of subject, age and general condition, severity of the infection, particular agent, its mode of administration, etc. The compounds described herein are preferably formulated as unit dosage forms for ease of dosing and consistency.

[0134] The pharmaceutical compositions of the present disclosure can be administered orally, parenterally, by inhalation aerosol, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intracisternally or via an implanted reservoir. In some embodiments, the composition can be administered orally, intraperitoneally or intravenously.

[0135] The sterile injectable form of the composition described herein can be an aqueous or oily suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be employed. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0136] For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, and natural pharmaceutically acceptable oils such as olive oil or castor oil (especially in their polyoxyethylated forms) can also be used in the preparation of injectables. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants such as carboxymethyl cellulose or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants such as Tween, Span and other emulsifiers or bioavailability enhancers commonly used in manufacturing pharmaceutically acceptable solid, liquid or other dosage forms can also be used to achieve the purpose of the formulation.

[0137] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0138] To prolong the action of the compounds of the present disclosure, it is often necessary to slow down the absorption of the compounds injected subcutaneously or intramuscularly. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. The absorption rate of the compound depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as poly(lactide-co-glycolide). The rate of release of the compound can be controlled according to the ratio of the compound to the polymer and the nature of the particular polymer used. 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 compatible with body tissues.

[0139] In some embodiments, the provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions described herein may be administered without food. In other embodiments, the pharmaceutically acceptable compositions described herein may be administered with food. The pharmaceutically acceptable compositions described herein may be administered orally 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, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are usually also added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is 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.

[0140] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium phosphate and / or with: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) adsorbents such as kaolin and bentonite, 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 contain buffering agents.

[0141] Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose (lactose or milk sugar) and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also have compositions that cause the active ingredient to be released only or preferentially in a delayed manner in a certain part of the intestine. Examples of embedding compositions that may be used include polymeric substances and waxes. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsule formulations using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0142] The active compound can also be in microencapsulated form together with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the art of pharmaceutical formulations. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. As is common practice, such dosage forms may also contain additional substances in addition to the inert diluent, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form can also contain buffering agents. They may optionally contain opacifying agents and may also be compositions such that they release the active ingredient only, or preferentially, at a certain site in the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0143] 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 compound, the liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizing and emulsifying agents such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan and mixtures thereof. In addition to the inert diluent, the oral compositions may also include adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0144] Alternatively, the pharmaceutically acceptable compositions described herein can be used for rectal administration in the form of suppositories. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0145] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and will thus melt in the rectal or vaginal cavity and release the active compound.

[0146] The pharmaceutically acceptable compositions described herein can also be administered topically, especially when the treatment target includes regions or organs that are easily accessible by topical administration, including diseases of the eye, skin, or lower intestine. For each of these regions or organs, suitable topical formulations are readily prepared.

[0147] Local administration to the lower intestine can be achieved with a rectal suppository formulation (see above) or with a suitable enema formulation. Topical transdermal patches can also be used.

[0148] For topical administration, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient 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.

[0149] For ophthalmic applications, the provided pharmaceutically acceptable composition can be formulated into a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, into a solution in isotonic, pH-adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutically acceptable composition can be formulated into an ointment such as petrolatum.

[0150] The pharmaceutically acceptable compositions described herein can also be administered by nasal aerosol or inhaler. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and can be prepared as solutions in physiological saline with benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. In some embodiments, the pharmaceutically acceptable compositions described herein can be administered by inhalation, typically in dry powder form (alone, as a mixture, e.g., a dry blend with lactose, or as blended component particles, e.g., mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, nebulizer, atomizer (preferably an atomizer that generates fine droplets using electrohydrodynamics), or sprayer, with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder can contain a bioadhesive, such as chitosan or cyclodextrin.

[0151] The pressurized container, pump, nebulizer, atomizer, or sprayer contains a solution or suspension of one or more compounds of the present disclosure, including, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, dissolving, or extending the release of the active substance, one or more propellants as solvents, and optionally a surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0152] Dosage forms for topical or transdermal administration of the compounds disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffering agents that may be required. Ophthalmic formulations, otic drops, and eye drops are also encompassed within the scope of the present disclosure. In addition, the present disclosure encompasses the use of transdermal patches, which have the added advantage of controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymeric matrix or gel.

[0153] Uses of the Compounds and Pharmaceutically Acceptable Compositions

[0154] IAP (inhibitor of apoptosis) proteins, which are anti-apoptotic protein families, play an important role in evading apoptosis as they can both block the apoptotic signal transduction pathway and 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 that act as dual XIAP and CIAP inhibitors.

[0155] Exemplary IAP inhibitors and antagonists include Birinapant (a bivalent Smac mimetic, which is a potent antagonist of XIAP and cIAP1 with Kds of 45 nM and less than 1 nM, respectively), LCL161 inhibitor (an IAP inhibitor that inhibits XIAP and cIAP1 with IC 50 values of 35 and 0.4 nM, respectively), AZD5582 (AZD5582 is an IAP antagonist that binds to the BIR3 domain of cIAP1, cIAP2, and XIAP), SM-164 (a cell-permeable Smac mimetic compound that binds to the XIAP protein containing BIR2 and BIR3 domains with IC 50with a value of 1.39 nM and can serve as a very potent antagonist of XIAP), BV6 (an antagonist of cIAP1 and XIAP), Xevinapant (or AT-406, a potent and orally bioavailable Smac mimetic and IAP antagonist that binds to XIAP, cIAP1, and cIAP2 proteins), GDC-0152 (a potent IAP inhibitor that binds to the BIR3 domain of XIAP, the BIR domains of cIAP1, cIAP2, and ML-IAP), ASTX660 (an orally bioavailable dual antagonist of cIAP and XIAP), CUDC-427 (a potent second-generation pan-selective IAP antagonist), Embelin (or embelic acid, a potent non-peptidic XIAP inhibitor). APG-1387 (a bivalent SMAC mimetic and IAP antagonist that blocks the activities of IAP 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.

[0156] In certain embodiments, the IAP inhibitor is a selective XIAP inhibitor (IC of XIAP inhibition 50 is no more than one-tenth, more preferably no more than one-twentieth, one-fiftieth, or one-hundredth of the IC of CIAP inhibition), such as SM-164. 50

[0157] In some embodiments, the compounds disclosed herein bind to one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2). In some embodiments, the compounds disclosed herein inhibit the activities of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2).

[0158] The activity of the compounds described herein as inhibitors of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP or ILP2) or variants or mutants thereof can be determined in vitro, in vivo or in cell lines. In vitro assays include determining an assay of inhibition of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP or ILP2) or variants or mutants thereof. Alternative in vitro assays quantify the ability 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. The detailed conditions for determining the compounds described herein as inhibitors 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 are set forth in the examples below.

[0159] 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 thus can be used to treat one or more disorders associated with the activity of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP or ILP2). Accordingly, in some aspects and embodiments, the present disclosure provides methods for treating IAP-mediated diseases, disorders or afflictions, comprising the step of administering to a patient in need thereof a compound of the present disclosure or a pharmaceutically acceptable composition thereof.

[0160] In some embodiments, the present disclosure provides methods 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 the provided compound.

[0161] As used herein, "IAP-related disease or disorder" or alternatively "IAP-mediated disease or disorder" means any disease or other adverse condition in which IAP or its mutants are known or suspected to play a role. In some embodiments, the IAP is selected from BIRC1 / NAIP, BIRC2 / cIAP1, BIRC3 / cIAP2, BIRC4 / XIAP, BIRC5 / survivin, BIRC6 / Apollon, BIRC7 / ML-IAP, and BIRC8 / ILP2. Accordingly, another embodiment of the present disclosure relates to treating or reducing the severity of one or more diseases in which one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2) or their variants or mutants are known or suspected to play a role.

[0162] In some embodiments, the present disclosure provides a method of treating a disease or disorder or one or more symptoms thereof, reducing its severity, delaying its onset, or inhibiting its progression, which is related to one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2) or their variants or mutants, comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure or a pharmaceutically acceptable composition thereof. In some embodiments, the present disclosure provides a method of treating a disease or disorder or one or more symptoms thereof, reducing its severity, delaying its onset, or inhibiting its progression, in which it is advantageous to inhibit or antagonize the activity of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2) or their variants or mutants, comprising the step of administering to a patient in need thereof a compound described herein or a pharmaceutically acceptable composition thereof.

[0163] In some aspects and embodiments, the compounds provided can thus be used to treat diseases responsive to the induction of apoptotic cell death, e.g., conditions characterized by dysregulated apoptosis, including hyperproliferative diseases.

[0164] In some embodiments, the present disclosure provides methods for treating cancer or reducing the severity of cancer, including administering to a patient in need thereof a compound, a pharmaceutically acceptable salt thereof, or a composition described herein. In some embodiments, the cancer is breast cancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain cancer, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck cancer, breast cancer, ovarian cancer, lung cancer, small cell lung cancer, nephroblastoma, cervical cancer, testicular cancer, bladder cancer, pancreatic cancer, gastric cancer, colon cancer, prostate cancer, genitourinary cancer, thyroid cancer, esophageal cancer, myeloma, multiple myeloma, adrenal cancer, renal cell cancer, endometrial cancer, adrenocortical cancer, malignant pancreatic insulinoma, malignant carcinoid, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocythemia, Hodgkin's disease, non-Hodgkin lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia, and retinoblastoma.

[0165] In some embodiments, the present disclosure provides methods for treating IAP-mediated diseases, disorders, or afflictions, including the step of administering to a patient in need thereof a compound of the present disclosure or a pharmaceutically acceptable composition thereof. In some embodiments, the pulmonary diseases include inflammatory diseases or afflictions. In some embodiments, the pulmonary disease, disorder, or affliction is chronic obstructive pulmonary disease (COPD), cystic fibrosis, airway inflammation, allergy, asthma, dyspnea, acute respiratory distress syndrome, pulmonary hypertension, pulmonary inflammation, bronchitis, airway obstruction, bronchoconstriction, microbial infection, viral infection (such as SARS), idiopathic pulmonary fibrosis, asthma, bronchopulmonary dysplasia (BPD), chronic bronchitis, or emphysema, or COVID-19.

[0166] Exemplary methods for making the compounds of the present disclosure

[0167] In some aspects, the compounds of the present disclosure can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the following methods and / or the methods described in WO 2007 / 130626A2 and WO2010 / 142994A1, as well as synthetic methods known in the field of synthetic organic chemistry, or variants thereof understood by those skilled in the art. The compounds of the present application can be synthesized by the following steps outlined in the following general scheme. The starting materials can be commercially available or made by methods known in the reported literature.

[0168] In some embodiments, the compound of formula I-a can be obtained by the method of General Scheme A below:

[0169] General Scheme A. Exemplary synthesis of the compound of formula I-a.

[0170]

[0171] In some embodiments, it should be understood that the compound of formula Ia can be obtained using reagents and reaction conditions well known in the art (e.g., as described in WO 2010 / 142994A1) as shown in General Scheme A. In some embodiments, R a is a suitable moiety (or a protected analogue) which, upon treatment with INT-6A, gives the compound of formula I-a. In some embodiments, R′ is a suitable moiety (or a protected analogue) which, upon treatment with INT-5A, gives the compound of formula I-a.

[0172] In some embodiments, the compound of formula I-b can be obtained by the method of General Scheme B below:

[0173] General Scheme B. Exemplary synthesis of the compound of formula I-b.

[0174]

[0175] In some embodiments, it should be understood that the compound of formula I-b can be obtained using reagents and reaction conditions well known in the art (e.g., as described in WO2007 / 130626A2) as shown in General Scheme B.

[0176] In some embodiments, the compound of formula I-c can be obtained by the method of General Scheme C below:

[0177] General Scheme C. Exemplary synthesis of the compound of formula I-c.

[0178]

[0179] In some embodiments, it should be understood that the compound of formula I-c can be obtained using reagents and reaction conditions well known in the art (e.g., as described in WO 2007 / 130626A2 and WO 2010 / 142994A1) as shown in General Scheme C. In some embodiments, R a is a suitable moiety (or a protected analogue) which, upon treatment with INT-6C, gives the compound of formula I-c. In some embodiments, R′ is a suitable moiety (or a protected analogue) which, upon treatment with INT-5A, gives the compound of formula I-c.

[0180] Example

[0181] As depicted in the following examples, in certain exemplary embodiments, the compounds are prepared according to the following general methods. It should be understood that although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to those of ordinary skill in the art can be applied to all compounds described herein and subclasses and species of each of these compounds.

[0182] Example 1: Treatment of Lung Diseases

[0183] This example demonstrates the treatment of lung diseases with the compounds described herein. Specifically, this example demonstrates the treatment of Barrett's esophagus (BE; a precursor lesion of esophageal adenocarcinoma (EAC)). Cells isolated from individuals diagnosed with or suffering from Barrett's esophagus were treated with the indicated compounds. Barrett's esophagus cells are particularly sensitive to Compounds I-1 and I-2 as described herein (see Figure 1 ). Compared with other compounds listed in Table 1, Barrett's esophagus cells are significantly more sensitive to Compounds I-1 and I-2.

[0184] Table 1.

[0185]

[0186]

[0187]

[0188]

[0189] Example 2: Treatment of Lung Diseases

[0190] This example further demonstrates the efficacy of the compounds described herein in the treatment of lung diseases. Specifically, esophageal adenocarcinoma stem cells isolated from multiple different individuals were treated with the compounds described herein. Figure 2 A comparison of the compounds described herein (e.g., I-1 and I-2) with other compounds (e.g., IAP inhibitors listed in Table 1) was demonstrated. Notably, esophageal adenocarcinoma stem cells are significantly more sensitive to Compounds I-1 and I-2 compared with other compounds listed in Table 1. Esophageal adenocarcinoma stem cells from another individual were tested and treated with a higher (nM) or lower (pM) concentration of I-1 ( Figure 6C and Figure 6D ), further demonstrating the sensitivity of lung diseases to the compounds described herein.

[0191] In addition, various concentrations of the compounds as described herein were tested on isolated late-stage Barrett's esophageal stem cells. Isolated late-stage Barrett's esophageal stem cells from one individual were treated with higher (nM) or lower (pM) concentrations of I-1 (respectively Figure 4A and 4B ). Similar treatments on late-stage Barrett's esophageal stem cells from different individuals also demonstrated the sensitivity of lung diseases to the compounds as described herein (e.g., I-1), see Figure 4C and Figure 4D . Figure 7B This sensitivity was further demonstrated. Late-stage Barrett's esophageal stem cells isolated from additional individuals were particularly sensitive to compound I-2 as described herein, but not sensitive to compound I-5.

[0192] In addition, different concentrations of the compounds as described herein were tested on isolated dysplastic Barrett's stem cells at different levels (i.e., high grade and low grade). Figure 5A and 5B demonstrated that high-grade dysplastic Barrett's esophageal stem cells were sensitive to I-1. Figure 6A and 6B demonstrated that low-grade dysplastic Barrett's esophageal stem cells were sensitive to I-1. Compound I-1, I-2, I-6, and I-3 were tested at different concentrations on low-grade dysplastic Barrett's esophageal stem cells from one individual ( Figure 8A ) and high-grade dysplastic Barrett's esophageal stem cells from another individual ( Figure 8B ).

[0193] Example 3: Treatment of Cancer

[0194] In addition to the above cancers (e.g., esophageal adenocarcinoma), this example further demonstrated the sensitivity of various cancers to the compounds as described herein. Specifically, lung adenocarcinoma stem cells from another individual were tested and treated with higher (nM) or lower (pM) concentrations of I-1 ( Figure 3A and Figure 3B ). These results demonstrated the sensitivity of cancer to the compounds as described herein.

[0195] In addition, stem cells isolated from an individual with diffuse gastric cancer were tested with higher or lower concentrations of I-1 ( Figure 5C and Figure 5D ). Stem cells isolated from two other individuals with diffuse gastric cancer were tested and treated with compounds I-2 and I-5 ( Figure 7A and 7D ). Notably, gastric cancer stem cells were sensitive to I-2 as described herein, but not sensitive to compound I-5.

[0196] To further demonstrate the spectrum of disease that is sensitive to compounds as described herein, pancreatic cancer stem cells were isolated and treated with compounds 1-9, 1-10, 1-3, and 1-11. Figure 7C The sensitivity of high-grade serous ovarian cancer stem cells to the compounds described herein was demonstrated. In addition, Figure 7E The sensitivity of Taxol-resistant ovarian cancer stem cells to the compounds described herein was demonstrated.

[0197] Example 4: The compounds described herein are non-toxic

[0198] This example demonstrates that the compounds described herein are non-toxic to healthy cells. Healthy liver cells were treated with various known compounds and compounds as described in the present disclosure ( Figure 10 Healthy lung cells were treated with various known compounds as well as the compounds described in the present disclosure ( Figure 11 ). Except at higher concentrations, the compounds of the present invention showed no toxicity.

[0199] Example 5: Methods for Testing the Efficacy of Compounds Described Herein

[0200] This example describes a method for testing the efficacy of compounds described herein. The following references describe the selective growth of stem cells of cancer, its precursor lesions, and normal and chronic disease epithelial tissues. In short, biopsy tissue was broken down into single cell suspensions and inoculated onto irradiated 3T3-J2 feeder cell lawns in a special StemEcho culture medium, and colony libraries were formed within 7-10 days. Single cell-derived clones were generated by single cell FACS sorting into 384-well plates, and wells with single colonies were amplified, analyzed by molecular genetics, and grown into discrete clones.

[0201] Approximately 400,000 cells from discrete clones associated with specific disease states (cancer, chronic inflammatory diseases) were seeded into 384-well plates previously seeded with irradiated feeder cells, allowed to grow for 5 days, and then exposed to test compounds in the form of serial dilutions. After 2-5 days, the cells were fixed with paraformaldehyde and human cells were labeled with human-specific antibodies and then labeled with secondary antibodies labeled with fluorescent dyes. The number of human cells was quantified by high-throughput imaging technology (CellInsight CX7LED, Thermo), and the data were analyzed by Excel.

[0202] References:

[0203] Wang X, Yamamoto Y, Wilson LH, Zhang T, Howitt B, Farrow MA, Kern F, Ning G, Yue Hong, Khor CC, Chevalier B, Bertrand D, Nagarajan N, Sylvester FA, Hyams JS, Devers T, Bronson R, Lacy DB, Ho KY, Crum CP, McKeon F and Xian W. (2015). Cloning and variation of ground state intestinal stem cells. Nature 522, 173 - 178.

[0204] Yamamoto Y, Wang X, Bertrand D, Kern F, Zhang T, Hu YY, Deluba M, Srivastava S, Ming T, Khor CC, Wilson L, Blaszyk H, Rolshud D, Liu JJ, Howitt B, Crum CP, Nagarajan N, Ho KY, McKeon F, and Xian W. 2016. Mutational Spectrum of Barrett’s Stem Cells Suggests Paths to Initiation and Progression of a Precancerous Lesion. Nat Commun. 2016 Jan 19; 7: 10380.

[0205] Qi Y, Mahalingam R, Flynn K, Rinaldi F, Liew AA, Neupane R, Vincent M, Crum CP, Ho KY, Hou JK, Hyams JS, Sylvester FA, McKeon F, and Xian W. (2019) An Efficient Method for Cloning Gastrointestinal Stem Cells from Patients via Endoscopic Biopsies. Gastroenterol. 156(1): 20 - 23.

[0206] Duleba M, Yamamoto Y, Neupane R, Rao W, Xie JZ, Qi Y, Liew AA, Niroula S, Zhang YT, Mahalingam R, Wang S, Goller K, Ajani JA, Vincent M, Ho KK, Hou JK, Hyams JS, Sylvester FA, Crum CP, McKeon F, and Xian W. (2019). Cloning of Ground State Intestinal Stem Cells from Endoscopic Biopsies. Nature Protocol. 15, 1612 - 1627.

[0207] W. Rao, S. Niroula, S. Wang, M. Vincent, F. McKeon, W. Xian, Protocol for Cloning Epithelial Stem Cell Variants from Human Lung. STAR Protoc 1(2020).

[0208] Rao W, Wang S, Duleba M, Niroula S, Goller K, Xie J, et al. Regenerative metaplastic clones in COPD lung drive inflammation and fibrosis. Cell 2020, 181, 848 - 864.e818.

[0209] Wang S, Rao W, Hoffman A, Lin J, Li J, Lin T, et al. Cloning a profibrotic stem cell variant in idiopathic pulmonary fibrosis. Sci Transl Med. 2023 15(693): eabp9528.

[0210] Although we have described many embodiments of the present invention, it will be apparent that our basic examples can be altered to provide other embodiments that utilize the compounds and methods of the present invention. Accordingly, it is to be understood that the scope of the present invention is defined by the appended claims and not by the specific embodiments presented by way of example.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: L1 is a first ligand; L2 is a second ligand; and The linker is a bivalent linker containing .

2. The compound according to claim 1, wherein each of L1 and L2 is independently a moiety that binds to one or more apoptosis protein inhibitors (IAPs).

3. The compound according to claim 2, wherein the IAP is selected from Cp-IAP, Op-IAP, XIAP, cIAP1, C-IAP2, NAIP, Livin, or survivin.

4. The compound according to any one of claims 1 - 3, wherein each of L1 and L2 independently comprises a group selected from: or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 - 4, wherein L1 is: or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 - 4, wherein L1 is: or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 - 6, wherein L2 is: or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1 - 6, wherein L2 is: or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1 - 3, wherein the compound has formula I-a, I-b, or I-c: or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1 - 9, wherein the linker has formula X: or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 each independently is a covalent bond or an optionally substituted divalent, saturated or partially unsaturated, straight-chain or branched C 1-12 hydrocarbon chain, wherein 1 to 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 C 1-6 aliphatic group; each -Cy- is independently an optionally substituted divalent ring selected from: a 3 - 8 membered carbocyclene; a 5 - 6 membered saturated or partially unsaturated heterocyclene having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a phenylene; or a 5 - 6 membered heteroarylene having 1 - 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; # represents the point of attachment to L1; and $ represents the point of attachment to L2.

11. The compound according to claim 10, wherein X 1 and X 2 are the same.

12. The compound according to claim 10, wherein X 1 and X 2 are different.

13. The compound according to claim 10, wherein X 1 and X 2 each independently is a covalent bond or an optionally substituted divalent, saturated or partially unsaturated, straight-chain or branched C 1-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally and independently replaced by -O-, -N(R)- or -C(O)-.

14. The compound according to claim 10 or 13, wherein X 1 is a covalent bond.

15. The compound according to claim 10 or 13, wherein X 1 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C 3-6 hydrocarbon chain, wherein 1-2 carbon atoms are optionally replaced by -O-.

16. The compound according to any one of claims 10, 13 or 15, wherein X 1 is an optionally substituted divalent, saturated, straight-chain C3 hydrocarbon chain in which one carbon atom is replaced by -O-.

17. A compound according to any one of claims 10, 13 or 15, wherein X 1 is an optionally substituted divalent, saturated, straight-chain C4 hydrocarbon chain.

18. A compound according to any one of claims 10, 13 or 15, wherein X 1 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain in which one carbon atom is replaced by -O-.

19. A compound according to any one of claims 10, 13 or 15, wherein X 1 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain.

20. A compound according to any one of claims 10, 13 or 15, wherein X 1 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain in which one carbon atom is replaced by -O-.

21. A compound according to any one of claims 10, 13 or 15, wherein X 1 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain in which 2 carbon atoms are replaced by -O-.

22. The compound according to any one of claims 10, 13 or 15, wherein X 1 is: Covalent bond where # represents the point of attachment to L1.

23. A compound according to any one of claims 10 or 13 - 22, wherein X 2 is a covalent bond.

24. A compound according to any one of claims 10 or 13 - 22, wherein X 2 is an optionally substituted divalent, saturated or partially unsaturated, straight-chain C 3-6 hydrocarbon chain, wherein 1 - 2 carbon atoms are optionally replaced by -O-.

25. A compound according to any one of claims 10, 13 - 22 or 24, wherein X 2 is an optionally substituted divalent, saturated, straight-chain C3 hydrocarbon chain in which one carbon atom is replaced by -O-.

26. A compound according to any one of claims 10, 13 - 22 or 24, wherein X 2 is an optionally substituted divalent, saturated, straight-chain C4 hydrocarbon chain.

27. A compound according to any one of claims 10, 13 - 22 or 24, wherein X 2 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain in which one carbon atom is replaced by -O-.

28. A compound according to any one of claims 10, 13 - 22 or 24, wherein X 2 is an optionally substituted divalent, saturated, straight-chain C5 hydrocarbon chain.

29. A compound according to any one of claims 10, 13 - 22 or 24, wherein X 2 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain in which one carbon atom is replaced by -O-.

30. A compound according to any one of claims 10, 13 - 22 or 24, wherein X 2 is an optionally substituted divalent, saturated, straight-chain C6 hydrocarbon chain in which 2 carbon atoms are replaced by -O-.

31. The compound according to any one of claims 10, 13 - 22 or 24, wherein X 2 is: Covalent bond, where $ represents the connection point to L2.

32. The compound according to any one of claims 1 - 31, wherein the compound has formula I-a or 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 corresponding indanyl groups indicated by * below:

33. The compound according to claim 32, 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 corresponding indanyl groups.

34. The compound according to any one of claims 1 - 31, wherein the compound has formula I-b: or 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 corresponding benzylic carbon atoms (indicated by * below):

35. The compound according to any one of claims 1 - 31, wherein the compound has formula I-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 hereinafter by *):

36. The compound according to claim 1, wherein the compound is selected from: Compound or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising the compound according to any one of claims 1 - 36 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle.

38. A method of inhibiting the activity of one or more IAPs or variants or mutants thereof in a biological sample or a patient, the method comprising the step of contacting the biological sample or administering to the patient a compound according to any one of claims 1 - 36 or a pharmaceutically acceptable salt thereof.

39. A method of treating a disease or disorder associated with one or more IAPs, the method comprising the step of administering to a patient in need thereof a compound according to any one of claims 1 - 40 or a pharmaceutically acceptable salt thereof.

40. The method according to claim 39, wherein the disease or disorder associated with one or more IAPs is cancer.

41. The method according to claim 40, wherein the cancer is acute myeloid leukemia, bladder cancer, breast cancer, colon cancer, diffuse large B - cell lymphoma, non - small cell lung cancer, ovarian cancer, pancreatic cancer or prostate cancer.

42. The method according to claim 39, wherein the disease or disorder associated with one or more IAPs is a pulmonary disease, disorder or affliction.

43. The method according to claim 42, wherein the pulmonary disease, disorder or affliction is chronic obstructive pulmonary disease (COPD), cystic fibrosis or COVID - 19.

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