Compounds and compositions useful as inhibitors of IAPs

Abstract

The present disclosure provides compounds, pharmaceutically acceptable compositions thereof, and methods of using them. In certain embodiments, the present disclosure provides an inhibitor of IAP. In some embodiments, such compounds include those of the formulas described herein, or pharmaceutically acceptable salts thereof, wherein each variable is as defined and described herein. In some embodiments, the present disclosure provides 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.

Description

[Technical Field]

[0001] The present disclosure relates to compounds and methods useful for inhibiting inhibitor of apoptosis proteins (IAPs). The present disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the present disclosure, and methods of using the compositions to treat various diseases, disorders, and conditions described herein. [Background technology]

[0002] IAPs play a key role in regulating cancer cell survival and, therefore, have attracted considerable attention as potential targets for treating IAP-associated diseases, disorders, or conditions. Summary of the Invention [Means for solving the problem]

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

[0004] or a pharmaceutically acceptable salt thereof, wherein L1 is a first ligand; L2 is a second ligand; and the linker is [ka] (wherein R is a bivalent linker comprising

[0005] The compounds described herein, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of IAP-associated diseases, disorders, or conditions, including those described herein.

[0006] The compounds provided herein are also useful, for example, in the study of IAPs in biological and pathological phenomena, and in the comparative evaluation of new IAP inhibitors. [Brief explanation of the drawings]

[0007] [Figure 1] 1 shows the treatment of Barrett's Esophagus cells with compounds described herein, with the concentrations of compounds used and percent cell survival indicated.

[0008] [Figure 2] 1 shows the treatment of esophageal adenocarcinoma stem cells with compounds described herein, with the concentrations of compounds used and percent cell survival indicated.

[0009] [Figure 3A] Figure 1 shows the treatment of lung adenocarcinoma stem cells with compound I-1. Figure 2 shows the % survival of lung adenocarcinoma stem cells at high concentrations of compound I-1. Regardless of concentration, compound I-1 exhibits lethality comparable to other highly potent cytotoxic treatments. [Figure 3B] 1 shows the treatment of lung adenocarcinoma stem cells with compound I-1. 2 shows the % survival of lung adenocarcinoma stem cells at low concentrations of compound I-1. 3 Regardless of concentration, compound I-1 exhibits lethality comparable to other highly potent cytotoxic treatments.

[0010] [Figure 4A] Figure 1 shows the treatment of progressive Barrett's esophageal stem cells with compound I-1 in cells isolated from two different patients. Figure 2 shows the % survival of Barrett's esophageal stem cells from the first patient at high concentrations of compound I-1. [Figure 4B] 1 shows the treatment of progressive Barrett's esophagus stem cells with compound I-1 in cells isolated from two different patients. 2 shows the % survival of Barrett's esophagus cells from the first patient at low concentrations of compound I-1. [Figure 4C]Figure 1 shows treatment of progressive Barrett's esophagus stem cells with compound I-1 in cells isolated from two different patients. Figure 2 shows the % survival of Barrett's esophagus cells from a second patient at high concentrations of compound I-1. [Figure 4D] 1 shows the treatment of progressive Barrett's esophageal stem cells with compound I-1 in cells isolated from two different patients. 2 shows the % survival of Barrett's esophageal stem cells from a second patient at low concentrations of compound I-1.

[0011] [Figure 5A] Figure 1 shows the treatment of Barrett's high-grade dysplasia with compound I-1. Figure 2 shows the % survival of Barrett's high-grade dysplasia stem cells at high concentrations of compound I-1. [Figure 5B] Figure 1 shows the treatment of Barrett's high-grade dysplasia with compound I-1. Figure 2 shows the % survival of Barrett's high-grade dysplasia stem cells at low concentrations of compound I-1. [Figure 5C] Figure 1 shows the treatment of diffuse gastric cancer with compound I-1. Figure 2 shows the survival percentage of diffuse gastric cancer stem cells at high concentrations of compound I-1. [Figure 5D] Figure 1 shows the treatment of diffuse gastric cancer with compound I-1. Figure 2 shows the survival percentage of diffuse gastric cancer stem cells at low concentrations of compound I-1.

[0012] [Figure 6A] Figure 1 shows the treatment of Barrett's low-grade dysplasia with compound I-1. Figure 2 shows the % survival of Barrett's low-grade dysplasia stem cells at high concentrations of compound I-1. [Figure 6B] Figure 1 shows the treatment of Barrett's low-grade dysplasia with compound I-1. Figure 2 shows the % survival of Barrett's low-grade dysplasia stem cells at low concentrations of compound I-1. [Figure 6C] Figure 1 shows the treatment of esophageal adenocarcinoma with compound I-1. Figure 2 shows the % survival of esophageal adenocarcinoma stem cells at high concentrations of compound I-1. [Figure 6D] Figure 1 shows the treatment of esophageal adenocarcinoma with compound I-1. Figure 2 shows the % survival of esophageal adenocarcinoma cells at low concentrations of compound I-1.

[0013] [Figure 7A] Treatment of various diseases with compounds I-2 and I-5. Figure 1 shows the % survival of diffuse gastric adenocarcinoma with ascites cells with various concentrations of compounds I-2 and I-5. [Figure 7B] Figure 1 shows the treatment of various diseases with compounds I-2 and I-5. Figure 2 shows the % survival of progressive Barrett's cells with various concentrations of compounds I-2 and I-5. [Figure 7C] Treatment of various diseases with compounds I-2 and I-5 Figure 1 shows the % survival of high-grade serous ovarian cancer cells with various concentrations of compounds I-2 and I-5. [Figure 7D] Figure 1 shows the treatment of various diseases with compounds I-2 and I-5. Figure 2 shows the % survival of gastric cancer with various concentrations of compounds I-2 and I-5. [Figure 7E] Treatment of various diseases with compounds I-2 and I-5. Figure 1 shows the % survival of taxol-resistant ovarian cancer stem cells with various concentrations of compounds I-2 and I-5.

[0014] [Figure 8A] 1 shows the treatment of Barrett's low-grade dysplasia with compounds I-1, I-2, I-6, and I-3. 1 shows the % survival of Barrett's low-grade dysplasia stem cells at various concentrations of I-1, I-2, I-6, and I-3. [Figure 8B] 1 shows the treatment of Barrett's high-grade dysplasia with compounds I-1, I-2, I-6, and I-3. 1 shows the % survival of Barrett's high-grade dysplasia stem cells at various concentrations of I-1, I-2, I-6, and I-3.

[0015] [Figure 9] 1 shows the treatment of pancreatic cancer with compounds I-9; I-10; I-3; I-11. 1 shows the % survival of pancreatic cancer stem cells at various concentrations of I-9; I-10; I-3; I-11.

[0016] [Figure 10] The compounds described herein demonstrate limited toxicity to healthy hepatic stem cells.

[0017] [Figure 11] The compounds described herein demonstrate limited toxicity to healthy lung stem cells. DETAILED DESCRIPTION OF THE INVENTION

[0018] 1. General Description of Certain Embodiments of the Invention: In certain embodiments, the present disclosure provides inhibitors of IAP. In some embodiments, such compounds include those of the formula described herein, or pharmaceutically acceptable salts thereof, wherein each variable is as defined and described herein. In some embodiments, the present disclosure provides compounds of formula I: [ka]

[0019] or a pharmaceutically acceptable salt thereof, wherein L1 is a first ligand; L2 is a second ligand; and the linker is [ka] (wherein R is a bivalent linker comprising

[0020] 2. Compounds and Definitions: The compounds of the present disclosure include those generally described above and are further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise specified. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0021] The terms "aliphatic" or "aliphatic group," as used herein, mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocycle," "carbocyclic," "alicyclic," or "cycloalkyl"), and has one point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (i.e., "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0022] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl) means one or more of the following:

[0023] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0024] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" as used herein is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0025] As used herein, the term "lower alkyl" refers to a C 1-4 Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0026] The term "halogen" means F, Cl, Br, or I.

[0027] The term "aryl," as used herein, refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments, "aryl" refers to aromatic ring systems, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl.

[0028] As used herein, the term "heteroaryl" refers to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; groups having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and groups having 1 to 5 heteroatoms in addition to carbon atoms. As used herein, the term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples of heteroaryl rings on compounds of Formula I and its subformulas include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, 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" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include rings that are optionally substituted.

[0029] Additionally, when two groups cyclize to form an optionally substituted heteroaryl ring having at least one nitrogen atom, the nitrogen atom in the ring may be selected from N or NR, as defined below, where valence permits. † It will be understood that this may be the case.

[0030] As used herein, the terms "heterocycle," "heterocyclic," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 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).

[0031] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle," "heterocyclic," "heterocyclic ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclic ring is fused with one or more aryl, heteroaryl, or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl, where the radical or point of attachment is on the heterocycle. Heterocyclic groups can be monocyclic or bicyclic.

[0032] Additionally, when two groups cyclize to form an optionally substituted heterocyclic ring having at least one nitrogen atom, the nitrogen atom in the ring may be selected from N or NR, as defined below, where valence permits. † It will be understood that this may be the case.

[0033] As described herein, compounds may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, means that one or more hydrogens in the specified portion of the compound are replaced with a suitable substituent. "Substituted" applies to one or more hydrogens that are either explicit or implicit from the structure (e.g., [ka] At least [ka] refers to; [ka] At least [ka] [ka] [ka] or [ka] Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions.

[0034] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH) 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) 0-4 SR°; optionally substituted with R° -(CH2) 0-4 Ph; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 Ph; optionally substituted with R° -CH=CHPh; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -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)ON(R°)22; or -(C 1-4 linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted as defined below and independently represents hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent instances of R° taken together with the intervening atom(s) form a 3-12 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.

[0035] Suitable monovalent substituents on R° (or the ring formed by two independent instances of R° and their intervening atoms) are independently halogen, —(CH) 0-2 R λ ,-(Halo R λ ), -(CH2) 0-2 OH, -(CH2) 0-2 OR λ , -(CH2) 0-2 CH(OR λ )2;-O(HaloR λ ), -CN, -N3, -(CH2) 0-2 C(O)R λ , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR λ , -(CH2) 0-2 SR λ , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR λ , -(CH2) 0-2 NR λ 2, -NO2, -SiR λ 3. -OSiR λ 3. -C(O)SR λ 、 -(C 1-4 Linear or branched alkylene)C(O)OR λ , or -SSR λ and each R λis unsubstituted or, if preceded by "halo", substituted with only one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph-O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0036] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include: ═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, R * each independent of the group is hydrogen, C which may be substituted as defined below 1-6 aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbons of "optionally substituted" groups of compounds of Formula I and its subformulas include -O(CR * 2) 2-3O- (wherein each independent R * is selected from hydrogen, a C1-6 aliphatic which may be substituted as defined below, or an unsubstituted, 5-6 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] R * Suitable substituents on the aliphatic group include halogen, -R λ , (Halo R λ), OH, -OR λ , -O(HaloR λ ), -CN, -C(O)OH, -C(O)OR λ , -NH2, -NHR λ , -NR λ 2, or -NO2 (wherein each R λ is unsubstituted or, if preceded by "halo", substituted with only one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † are listed, and each R † are independently hydrogen, C which may be substituted as defined below 1-6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent ones of which, together with their intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] R †Suitable substituents on the aliphatic group are independently halogen, —R λ , (Halo R λ ), OH, -OR λ , -O(HaloR λ ), -CN, -C(O)OH, -C(O)OR λ , -NH2, -NHR λ , -NR λ 2, or -NO2 (wherein each R λ is unsubstituted or, if preceded by "halo", substituted with only one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonate. Examples of salts include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0041] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0042] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, e.g., R and S configurations of each asymmetric center, Z and E double bond isomers, Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomers are within the scope of the disclosure. Additionally, unless otherwise stated, the disclosure also includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the structure of the present invention comprise a carbon atom replaced by a C-enriched carbon atom are within the scope of the present disclosure. Such compounds are useful, 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 comprise one or more deuterium atoms.

[0043] Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that remain substantially unchanged when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0044] The recitation of a list of chemical groups within any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0045] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsies or extracts thereof obtained from animals (e.g., mammals); and blood, saliva, urine, stool, semen, tears, or other bodily fluids, or extracts thereof; or purified versions thereof. For example, the term "biological sample" refers to any solid or liquid sample obtained from, excreted, or secreted by any living organism, including unicellular microorganisms (such as bacteria and yeast) and multicellular organisms (e.g., plants and animals, e.g., vertebrates or mammals, particularly healthy or apparently healthy human subjects, or human patients suffering from a condition or disease to be diagnosed or investigated). Biological samples can be in any form, including solid material (e.g., tissues, cells, cell pellets, cell extracts, cell homogenates, or cell fractions), or biopsies, or biological fluids. Biological fluids may be obtained from any site (e.g., blood, saliva (or mouthwash containing oral 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 bodily secretion), transudate, exudate (e.g., fluid obtained from an abscess or any other site of infection or inflammation), or joint (e.g., a normal joint or a joint affected by a disease such as rheumatoid arthritis, osteoarthritis, gout, or septic arthritis). Biological samples can be obtained from any organ or tissue (including biopsy or autopsy specimens) or can include cells (either primary or cultured cells), or medium conditioned by any cell, tissue, or organ. Biological samples may also include sections of tissue, e.g., frozen sections taken for histological purposes. Biological samples also include mixtures of biological molecules, including proteins, lipids, carbohydrates, and nucleic acids, produced by partial or total fractionation of cell or tissue homogenates. The sample is preferably taken from a human subject, although the biological sample may be derived from any animal, plant, bacterial, viral, yeast, etc. As used herein, the term animal refers to human and non-human animals at any stage of development, including, for example, mammals, birds, reptiles, amphibians, fish, worms, and single cells. Cell cultures and live tissue samples are considered to be numerous 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, or pig). The animal may be a transgenic animal or a human clone. If desired, the biological sample may be subjected to preliminary processing, including preliminary isolation methods.

[0046] As used herein, "IAP-associated disease or disorder" or alternatively "IAP-mediated disease or disorder" means any disease or deleterious condition in which an IAP or a variant thereof is 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.

[0047] As used herein, the term "subject" refers to a mammal, and includes humans and animal subjects, such as domestic animals (e.g., horses, dogs, cats, etc.). As used herein, the terms "subject" and "patient" are used interchangeably. In some embodiments, "patient" or "subject" refers to an animal, preferably a mammal, and most preferably a human.

[0048] 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 in which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles 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, buffer substances such as phosphates or carbonates, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as glycine, sorbic acid, potassium sorbate, and protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat. The amount of the compounds described herein that can be combined with a carrier material to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration, and the like.

[0049] As used herein, the term "unit dosage form" refers to a physically discrete unit of the compound and / or composition thereof provided, appropriate for the subject to be treated. However, it will be understood that the total daily usage of the active agent (i.e., the compounds and compositions described herein) will be determined by the attending physician within the scope of sound medical judgment. The specific effective amount level for any particular subject (i.e., patient) or organism will depend on various factors, including the disorder being treated, the severity of the disorder, the activity of the specific active agent used, the specific composition used, the age, weight, general health, sex, and diet of the subject, the time of administration, route of administration, and excretion rate of the specific active agent used, the duration of treatment, and similar factors well known in the medical field.

[0050] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0051] As used herein, a "therapeutically effective amount" refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those skilled in the art, the effective amount of a substance can vary depending on factors such as the desired biological endpoint, the substance being delivered, the target cell or tissue, and the like. For example, an effective amount of a compound provided in a formulation for treating a disease, disorder, and / or condition is an amount that alleviates, ameliorates, relieves, inhibits, prevents, delays the onset of, reduces the severity of, and / or reduces the incidence of, one or more symptoms or characteristics of the disease, disorder, and / or condition. In some embodiments, a "therapeutically effective amount" is at least the minimum amount of a provided compound or a composition comprising a provided compound sufficient to treat one or more symptoms of an IAP-mediated disease or disorder.

[0052] As used herein, the terms "treatment," "treat," and "treating" mean to partially or completely alleviate, inhibit, delay the onset of, prevent, reduce, and / or alleviate a disorder or condition described herein, or one or more symptoms of the disorder or condition. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term "treating" includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment can be administered even in the absence of symptoms. For example, a susceptible individual may be treated prior to the onset of symptoms (e.g., in light of a history of symptoms and / or genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, e.g., to prevent or delay recurrence. Thus, in some embodiments, the term "treating" includes preventing the recurrence or recurrence of a disease or disorder.

[0053] 3. Description of Exemplary Embodiments In some embodiments, the present disclosure provides a compound of formula I: [ka]

[0054] or a pharmaceutically acceptable salt thereof, wherein L1 is a first ligand; L2 is a second ligand; and the linker is [ka] (wherein R is a bivalent linker comprising

[0055] Without wishing to be bound by any particular theory, it is believed that L1 and L2 must be positioned at a specific distance from each other to achieve optimal biological activity. In some embodiments, L1 and L2 must be positioned at a distance of about 0.5-2.5 nm, as measured from the atom on each of L1 and L2 to which the linker is attached. Furthermore, without wishing to be bound by any particular theory, it is believed that such positioning of L1 and L2 relative to each other cannot be achieved using a rigid linear linker. For example, ADAD5582 contains a diyne linker having the following structure: [ka] See Hennessy et al., J. Med. Chem. 2013, 56, 9897-9919. Hennessy et al. report that linkers should have minimal steric requirements to avoid interfering with important binding interactions with the target protein. Hennessy et al. further recommend fully saturated linkers (i.e., [ka] ) reported that a shorter, less hydrophobic linker did not result in any appreciable change in cellular potency compared to compounds such as AZD5582. Hennessy et al. further speculate that shorter, less hydrophobic linkers may reduce the cell permeability of the compound and therefore its potency in cell-based assays. In some embodiments, the present disclosure demonstrates that, despite the teachings of Hennessy, compounds comprising less rigid, more hydrophilic linkers as described herein (e.g., compounds having linkers comprising sucrumamide) have improved activity compared to compounds comprising rigid, hydrophobic linkers, e.g., ADAD5582. See, e.g., Figures 1 and 2. Furthermore, Figures 1 and 2 demonstrate that compounds of Formula I are more potent than compounds having flexible, hydrophobic linkers such as SM-164 and BV6.

[0056] It will be appreciated that in some embodiments, compounds containing fewer hydrophobic linkers will have a lower log P than compounds containing more hydrophobic linkers, e.g., the log P of AZD5582 is calculated to be 6.14, while the log P of compound I-1 is calculated to be 5.5.

[0057] Thus, the present disclosure encompasses the insight that compounds of Formula I are uniquely potent against cancer cell lines due to the flexibility and hydrophilicity of the scramamide linker described herein.

[0058] Generally, L1 is a first ligand, and L2 is a second ligand, as defined above. In some embodiments, L1 and L2 are the same. In some embodiments, L1 and L2 are different.

[0059] In some embodiments, a ligand (e.g., L1 or L2) refers to a moiety that binds to a protein, e.g., at the 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.

[0060] In some embodiments, L1 is [ka] or [ka] is or comprises a group selected from:

[0061] In some embodiments, L2 is [ka] or [ka] is or comprises a group selected from:

[0062] Generally, as defined above, a linker may be: [ka] In some embodiments, the linker is a bivalent linker comprising formula X: [ka] or a pharmaceutically acceptable salt thereof (wherein X 1 and X 2 each independently represents a covalent bond or an optionally substituted divalent, saturated or partially unsaturated, linear or branched C 1-12 a hydrocarbon chain in which 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 hydrogen or an optionally substituted C 1-6 aliphatic; each -Cy- is independently an optionally substituted bivalent ring selected from 3-8 membered carbocyclene, 5-6 membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; phenylene; or 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; # represents the point of attachment to L1; $ represents the point of attachment to L2).

[0063] As generally defined above, X 1 and X 2 each independently represents a covalent bond or an optionally substituted divalent saturated or partially unsaturated, straight or branched chain C 1-12 A hydrocarbon chain, wherein 1 to 4 carbon atoms are optionally and independently replaced with -O-, -N(R)-, -C(O)-, -S-, -SO-, -SO2-, or -Cy-. In some embodiments, X1 and X 2 each independently represents a covalent bond or an optionally substituted divalent saturated or partially unsaturated, straight or branched chain C 1-6 A hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced with -O-, -N(R)-, or -C(O)-. In some embodiments, X 1 and X 2 each independently represents a covalent bond or an optionally substituted divalent saturated or partially unsaturated, straight or branched chain C 1-8 A hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced with -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 is different.

[0064] In some embodiments, X 1 is a covalent bond. In some embodiments, X 1 is an optionally substituted divalent saturated or partially unsaturated, straight or branched chain C 1-6 A hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced with -O-, -N(R)-, or -C(O)-. In some embodiments, X 1 is an optionally substituted divalent saturated or partially unsaturated, straight or branched chain C 3-6 A hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced with -O- or -N(R)-. In some embodiments, X 1 is an optionally substituted divalent saturated or partially unsaturated linear C 3-6 A hydrocarbon chain in which one to two carbon atoms are optionally replaced with -O-.

[0065] In some embodiments, X 1is an optionally substituted divalent saturated or partially unsaturated linear C hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C3 hydrocarbon chain.

[0066] In some embodiments, X 1 is an optionally substituted divalent saturated or partially unsaturated linear C4 hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C4 hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C4 hydrocarbon chain.

[0067] In some embodiments, X 1 is an optionally substituted divalent saturated or partially unsaturated linear C5 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C5 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C5 hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X 1is an optionally substituted divalent saturated linear C5 hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C5 hydrocarbon chain.

[0068] In some embodiments, X 1 is an optionally substituted divalent saturated or partially unsaturated linear C6 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C6 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C6 hydrocarbon chain in which two carbon atoms are replaced with -O-.

[0069] In some embodiments, X 1 is an optionally substituted divalent saturated or partially unsaturated linear C7 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C7 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C7 hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C7 hydrocarbon chain in which two carbon atoms are replaced with -O-.

[0070] In some embodiments, X 1is an optionally substituted divalent saturated or partially unsaturated linear C hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C8 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 1 is an optionally substituted divalent saturated linear C8 hydrocarbon chain in which two carbon atoms are replaced by -O-.

[0071] In some embodiments, X 1 teeth: covalent bond, [ka] [ka] [ka] [ka] [ka] or [ka] where # represents the point of attachment to L1.

[0072] In some embodiments, X 1 teeth: covalent bond, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] where # represents the point of attachment to L1.

[0073] In some embodiments, X 1 teeth, [ka] where # represents the point of attachment to L1.

[0074] In some embodiments, X 1 teeth, [ka] [ka] or [ka] where # represents the point of attachment to L1.

[0075] In some embodiments, X 2 is a covalent bond. In some embodiments, X 2is an optionally substituted divalent saturated or partially unsaturated, straight or branched chain C 1-6 A hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced with -O-, -N(R)-, or -C(O)-. In some embodiments, X 2 is an optionally substituted divalent saturated or partially unsaturated, straight or branched chain C 3-6 A hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced with -O- or -N(R)-. In some embodiments, X 2 is an optionally substituted divalent saturated or partially unsaturated linear C 3-6 A hydrocarbon chain in which one to two carbon atoms are optionally replaced with -O-.

[0076] In some embodiments, X 2 is an optionally substituted divalent saturated or partially unsaturated linear C hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C3 hydrocarbon chain.

[0077] In some embodiments, X 2 is an optionally substituted divalent saturated or partially unsaturated linear C4 hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C4 hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X2 is an optionally substituted divalent saturated linear C4 hydrocarbon chain.

[0078] In some embodiments, X 2 is an optionally substituted divalent saturated or partially unsaturated linear C5 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C5 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C5 hydrocarbon chain, in which one carbon atom is optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C5 hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C5 hydrocarbon chain.

[0079] In some embodiments, X 2 is an optionally substituted divalent saturated or partially unsaturated linear C6 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C6 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C6 hydrocarbon chain in which two carbon atoms are replaced with -O-.

[0080] In some embodiments, X 2is an optionally substituted divalent saturated or partially unsaturated linear C7 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C7 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C7 hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C7 hydrocarbon chain in which two carbon atoms are replaced with -O-.

[0081] In some embodiments, X 2 is an optionally substituted divalent saturated or partially unsaturated linear C hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C8 hydrocarbon chain, in which 1 to 2 carbon atoms are optionally replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C hydrocarbon chain, in which one carbon atom is replaced with -O-. In some embodiments, X 2 is an optionally substituted divalent saturated linear C8 hydrocarbon chain in which two carbon atoms are replaced by -O-.

[0082] In some embodiments, X 2 teeth: covalent bond, [ka] [ka] [ka] [ka] [ka] or [ka] where $ represents the point of attachment to L2.

[0083] In some embodiments, X 2 teeth: covalent bond, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] where $ represents the point of attachment to L2.

[0084] In some embodiments, X 2 teeth, [ka] where # represents the point of attachment to L2.

[0085] In some embodiments, X 2 teeth, [ka] [ka] or [ka] where # represents the point of attachment to L2.

[0086] As generally defined above, each R is hydrogen or an optionally substituted C 1-6 In some embodiments, R is independently selected from an optionally substituted C 1-6 It is aliphatic.

[0087] As generally defined above, each -Cy- is an optionally substituted bivalent ring selected from 3- to 8-membered carbocyclene, 5- to 6-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; phenylene; or 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur. In some embodiments, -Cy- is 3- to 8-membered carbocyclene. In some embodiments, -Cy- is 5- to 6-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. In some embodiments, -Cy- is phenylene. In some embodiments, -Cy- is 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0088] In some embodiments, the present disclosure provides a compound of formula Ia, Ib, or Ic: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein the linker is as defined above and described herein.

[0089] It will be appreciated that in some embodiments, the linker serves to position L1 and L2 at a particular distance from each other (eg, about 0.5-2.5 nm).

[0090] In certain embodiments of Formula Ia, the linker is sufficient to position L1 and L2 at a distance of about 0.5 to 2.5 nm between the C1 carbon atoms of their respective indanyl groups (denoted below with *): [ka]

[0091] In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, 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 their respective indanyl groups. In some embodiments of Formula Ia, the linker is sufficient to position L1 and L2 at a distance of about 0.7-0.8 nm, about 1.4-1.5 nm, or about 2.0-2.2 nm between the C1 carbon atoms of their respective indanyl groups. In some embodiments of Formula Ia, the linker is sufficient to position L1 and L2 at a distance of about 0.7 nm, about 1.5 nm, or about 2.1 nm between the C1 carbon atoms of their respective indanyl groups.

[0092] In certain embodiments of Formula Ib, the linker is sufficient to position L1 and L2 with a distance of about 1.5-2.5 nm between their respective benzylic carbon atoms (denoted below with *): [ka]

[0093] In some embodiments of Formula Ib, the linker is sufficient to position L1 and L2 at a distance of about 1.9 to 2.2 nm between their respective benzyl carbon atoms. In some embodiments of Formula Ib, the linker is sufficient to position L1 and L2 at a distance of about 1.9 to 2.0 nm between their respective benzyl carbon atoms. In some embodiments of Formula Ib, the linker is sufficient to position L1 and L2 at a distance of about 2.0 to 2.2 nm between their respective benzyl carbon atoms. In some embodiments of Formula Ib, the linker is sufficient to position L1 and L2 at a distance of about 2.1 to 2.2 nm between their respective benzyl carbon atoms. In some embodiments of Formula Ib, the linker is sufficient to position L1 and L2 at a distance of about 1.9 nm or about 2.1 nm between their respective benzyl carbon atoms.

[0094] In certain embodiments of Formula Ic, 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 benzyl carbon atom of L2 (denoted below with an *): [ka]

[0095] In some embodiments of Formula Ic, 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 benzyl carbon atom of L2. In some embodiments of Formula Ic, 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 benzyl carbon atom of L2. In some embodiments of Formula Ic, 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 benzyl carbon atom of L2.

[0096] In some embodiments, the compound of formula I is: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof. [Table 2]

[0097] 4. Uses, Formulations and Administration: Pharmaceutically acceptable compositions According to another embodiment, the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound in the composition described herein is effective to measurably inhibit the activity of an IAP (e.g., BIRC1 / NAIP, BIRC2 / cIAP1, BIRC3 / cIAP2, BIRC4 / XIAP, BIRC5 / Survivin, BIRC6 / Apollon, BIRC7 / ML-IAP, and BIRC8 / ILP2) or a variant thereof in a biological sample or in a patient. In certain embodiments, the compositions described herein are formulated for administration to a patient in need of such a composition. In some embodiments, the compositions described herein are formulated for oral administration to a patient.

[0098] The compounds and compositions, according to the methods of the present invention, are administered using any amount and any route of administration effective to treat or lessen the severity of a disorder provided herein (i.e., an IAP-mediated disease or disorder). The exact amount required will vary from subject to subject, depending on the species, age, and general health of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.

[0099] The compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intravesically, or via an implanted reservoir, hi some embodiments, the compositions are administered orally, intraperitoneally, or intravenously.

[0100] The sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may 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. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and physiological saline solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0101] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0102] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0103] To prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound therefore depends on its dissolution rate, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0104] In some embodiments, the pharmaceutically acceptable compositions provided are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, the pharmaceutically acceptable compositions described herein are administered with food. The pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavorings, or coloring agents may be added.

[0105] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch, or tapioca starch, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0106] Solid compositions of a similar type can also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can also be of a composition that releases the active ingredient(s) alone or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0107] The active compound may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is customary, such dosage forms can also contain additional substances other than inert diluents, 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 forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0108] 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, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0109] Alternatively, the pharmaceutically acceptable compositions described herein can be administered in the form of suppositories for rectal administration. 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, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0110] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compositions described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active ingredient.

[0111] The pharmaceutically acceptable compositions described herein may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0112] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0113] For topical application, provided pharmaceutically acceptable compositions 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, provided pharmaceutically acceptable compositions 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 ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0114] For intraocular use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for intraocular use, the pharmaceutically acceptable compositions can be formulated in an ointment, such as petrolatum.

[0115] The pharmaceutically acceptable compositions described herein can also be administered by nasal aerosol or inhalation. Such compositions can be prepared according to techniques well known in the art of pharmaceutical formulation, and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants. In some embodiments, the pharmaceutically acceptable compositions described herein can be typically administered in the form of a dry powder (alone, as a mixture in a dry blend with, for example, lactose, or as mixed-component particles mixed with, for example, phospholipids such as phosphatidylcholine) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0116] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of a compound(s) of the present disclosure, for example, in ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending the release of the active agent, propellant(s) as a solvent, and an optional surfactant, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0117] 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 sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Intraocular formulations, ear drops, and eye drops are also considered within the scope of this disclosure. Furthermore, this disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing 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 either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0118] Uses of the Compounds and Pharmaceutically Acceptable Compositions IAP (inhibitor of apoptosis) proteins, a family of anti-apoptotic proteins, play an important role in preventing apoptosis by blocking apoptotic signaling pathways and promoting 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 inhibitors of XIAP and CIAP.

[0119] Exemplary IAP inhibitors and antagonists include birinapant (a bivalent Smac mimetic and potent antagonist of XIAP and cIAP1, with Kd of less than 45 nM and 1 nM, respectively), LCL161 inhibitor (an IAP inhibitor that inhibits XIAP and cIAP1, with IC 50are 35 nM and 0.4 nM), ADAD5582 (an IAP antagonist that binds to the BIR3 domain cIAP1, cIAP2, and XIAP), SM-164 (a cell-permeable Smac mimetic that binds to the XIAP protein containing both the BIR2 and BIR3 domains, and has an IC 50 with a vasopressin level of 1.39 nM, functioning as a highly potent antagonist of XIAP), zebinapant (or AT-406, a potent, orally bioavailable Smac mimetic and IAP antagonist that binds to the XIAP, cIAP1, and cIAP2 proteins), GDC-0152 (a potent IAP inhibitor that binds to the BIR3 domain of XIAP, cIAP1, and cIAP2 and the BIR domain of ML-IAP), ASTX660 (an orally bioavailable dual antagonist of cIAP and XIAP), CUD These include C-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 activity of IAP family proteins (XIAP, cIAP-1, cIAP-2, and ML-IAP)), MX69 (an inhibitor of MDM2 / XIAP), MV1, polygalacin D, UC-112, ADAD5582 dihydrochloride, HY-125378m trinapant (ASTX660), and SBP-0636457.

[0120] In certain embodiments, the IAP inhibitor is a selective XIAP inhibitor (IC for XIAP inhibition). 50 However, the IC for CIAP inhibition 50 at least 10-fold lower, more preferably at least 20, 50, or 100-fold lower than SM-164), for example SM-164.

[0121] In some embodiments, compounds disclosed herein bind to one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2). In some embodiments, compounds disclosed herein inhibit the activity of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2).

[0122] 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 their variants or mutants can be assayed in vitro, in vivo, or in cell lines.In vitro assays include assays that determine the inhibition of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2), or their variants or mutants.An alternative in vitro assay quantifies the inhibitor's ability to bind to one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2), or their variants or mutants. Detailed conditions for assaying 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 described in the Examples below.

[0123] The provided compounds are inhibitors of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2) or variants or mutants thereof, and are therefore useful for treating one or more disorders associated with 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 a method of treating an IAP-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0124] 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 a provided compound.

[0125] As used herein, "IAP-associated disease or disorder" or alternatively "IAP-mediated disease or disorder" means any disease or deleterious condition in which an IAP, or a variant thereof, is 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 lessening 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 variants or mutants thereof are known or suspected to play a role.

[0126] In some embodiments, the present disclosure provides a method of treating, reducing the severity of, delaying the onset of, or inhibiting the progression of a disease or condition associated with one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2) or variants or mutants thereof, or one or more symptoms of the disease or condition, comprising 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, reducing the severity of, delaying the onset of, or inhibiting the progression of a disease or condition associated with one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2) or variants or mutants thereof, or one or more symptoms of the disease or condition, for which inhibiting or antagonizing the activity of one or more IAPs (e.g., NAIP, cIAP1, cIAP2, XIAP, survivin, Apollon, ML-IAP, or ILP2) or variants or mutants thereof is beneficial, comprising administering to a patient in need thereof a compound described herein, or a pharmaceutically acceptable composition thereof.

[0127] Thus, in some aspects and embodiments, provided compounds are useful for treating disorders responsive to the induction of apoptotic cell death, e.g., disorders characterized by dysregulation of apoptosis, including hyperproliferative diseases.

[0128] In some embodiments, provided are methods of treating or lessening the severity of cancer, comprising administering to a patient in need thereof a compound described herein or a pharmaceutically acceptable composition thereof. In some embodiments, the cancer is selected from the group consisting of 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 and neck cancer, breast cancer, ovarian cancer, lung cancer, small cell lung cancer, Wilms' tumor, 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 carcinoma, endometrial cancer, adrenocortical carcinoma, malignant pancreatic cancer, and malignant pancreatic cancer. Insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.

[0129] In some embodiments, a method for treating or lessening the severity of a pulmonary disease, disorder, or condition is provided, comprising administering to a patient in need thereof a compound described herein or a pharmaceutically acceptable composition thereof. In some embodiments, the pulmonary disease comprises an inflammatory disease or condition. In some embodiments, the pulmonary disease, disorder, or condition is chronic obstructive pulmonary disease (COPD), cystic fibrosis, airway inflammation, allergy(s), asthma, dyspnea, acute respiratory distress syndrome, pulmonary hypertension, lung 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.

[0130] Exemplary Methods for Making Compounds of the Present Disclosure In some embodiments, the compounds of the present disclosure can be prepared by various methods well known to those skilled in the art of organic synthesis. As an example, the compounds of the present invention can be synthesized using the methods described below and / or the methods described in WO2007 / 130626A2 and WO2010 / 142994A1, together with synthetic methods known in the field of organic synthetic chemistry or variations thereof, as will be understood by those skilled in the art. The compounds of the present application can be synthesized by the following steps outlined in the general scheme below. The starting materials are commercially available or are prepared by known procedures reported in the literature.

[0131] In some embodiments, compounds of formula Ia can be obtained using the method of general Scheme A below. [ka]

[0132] It will be appreciated that in some embodiments, compounds of formula Ia may be obtained using reagents and reaction conditions well known in the art, for example, as described in WO2010 / 142994A1, as shown in general Scheme A. In some embodiments, R a is a suitable moiety (or protected analog) that upon treatment with INT-6A provides a compound of formula Ia. In some embodiments, R' is a suitable moiety (or protected analog) that upon treatment with INT-5A provides a compound of formula Ia.

[0133] In some embodiments, compounds of formula Ib can be obtained using the methods of general Scheme B below. [ka]

[0134] It will be appreciated that in some embodiments, compounds of formula Ib may be obtained using reagents and reaction conditions well known in the art, for example, as described in WO2007 / 130626A2, as shown in general Scheme B.

[0135] In some embodiments, compounds of formula Ic can be obtained using the method of general Scheme C below. [ka]

[0136] It will be appreciated that in some embodiments, compounds of formula Ic may be obtained using reagents and reaction conditions well known in the art, for example, as described in WO2007 / 130626A2 and WO2010 / 142994A1, as shown in general Scheme C. In some embodiments, R a is a suitable moiety (or protected analog) that upon treatment with INT-6C provides a compound of formula Ic. In some embodiments, R' is a suitable moiety (or protected analog) that upon treatment with INT-5A provides a compound of formula Ic. [Example]

[0137] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods refer to the synthesis of specific compounds of the present disclosure, it will be understood that the following general methods, and others known to those of skill in the art, are applicable to all compounds and subclasses and species of each of these compounds described herein.

[0138] Example 1: Treatment of pulmonary disease This example demonstrates the treatment of lung disease with the compounds described herein. Specifically, this example demonstrates the treatment of Barrett's esophagus (BE; a precursor lesion to esophageal adenocarcinoma (EAC)). Cells isolated from individuals diagnosed with or suffering from Barrett's esophagus are treated with the compounds shown. Barrett's esophagus cells are particularly sensitive to compounds I-1 and I-2 described herein (see Figure 1). Barrett's esophagus cells are significantly more sensitive to compounds I-1 and I-2 than the other compounds listed in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0139] Example 2: Treatment of Pulmonary Disease This example further demonstrates the effectiveness of the compounds described herein in treating lung disease. Specifically, esophageal adenocarcinoma stem cells isolated from multiple independent individuals were treated with the compounds described herein. Figure 2 shows a comparison of the compounds described herein (e.g., I-1 and I-2) with other compounds (e.g., the IAP inhibitors listed in Table 1). Notably, esophageal adenocarcinoma stem cells were significantly more sensitive to compounds I-1 and I-2 than the other compounds listed in Table 1. Esophageal adenocarcinoma stem cells from additional individuals were tested and treated with high (nM) or low (pM) concentrations of I-1 (Figures 6C and 6D), further demonstrating the sensitivity of lung disease to the compounds described herein.

[0140] Furthermore, various concentrations of the compounds described herein were tested on isolated progressive Barrett's esophagus stem cells. Progressive Barrett's esophagus stem cells isolated from one individual were treated with high (nM) or low (pM) concentrations of I-1 (Figures 4A and 4B, respectively). Similar treatment of progressive Barrett's esophagus stem cells from different individuals also demonstrates the sensitivity of lung disease to compounds described herein (e.g., I-1). See Figures 4C and 4D. Figure 7B further demonstrates this sensitivity. Progressive Barrett's esophagus stem cells isolated from additional individuals are significantly sensitive to compound I-2 described herein, but not to compound I-5.

[0141] Additionally, various concentrations of the compounds described herein were tested on isolated Barrett's dysplastic stem cells of various grades (i.e., high and low). Figures 5A and 5B show that high-grade Barrett's dysplastic stem cells are sensitive to I-1. Figures 6A and 6B show that low-grade Barrett's dysplastic stem cells are sensitive to I-1. Compounds I-1, I-2, I-6, and I-3 were tested at various concentrations on Barrett's low-grade dysplastic stem cells obtained from one individual (Figure 8A) and Barrett's high-grade dysplastic stem cells obtained from another individual (Figure 8B).

[0142] Example 3: Cancer Treatment In addition to the above cancers (e.g., esophageal adenocarcinoma), this example further demonstrates the sensitivity of various cancers to the compounds described herein. Specifically, lung adenocarcinoma stem cells from additional individuals were tested and treated with higher (nM) or lower (pM) concentrations of I-1 (Figures 3A and 3B). These results demonstrate the sensitivity of cancers to the compounds described herein.

[0143] Furthermore, stem cells isolated from individuals with diffuse gastric cancer were tested and treated with high or low concentrations of I-1 (Figures 5C and 5D). Stem cells isolated from two additional individuals with diffuse gastric cancer were tested and treated with compounds I-2 and I-5 (Figures 7A and 7D). Notably, gastric cancer stem cells were sensitive to I-2, but not to compound I-5, as described herein.

[0144] As further evidence of the breadth of disease susceptibility to the compounds described herein, pancreatic cancer stem cells were isolated and treated with compounds I-9, I-10, I-3, and I-11. Figure 7C shows the sensitivity of high-grade serous ovarian cancer stem cells to the compounds described herein. Additionally, Figure 7E shows the sensitivity of taxol-resistant ovarian cancer stem cells to the compounds described herein. Example 4: The compounds described herein are non-toxic

[0145] This example demonstrates that the compounds described herein are not toxic to healthy cells. Healthy liver cells were treated with various known compounds and compounds described in this disclosure (Figure 10). Additionally, healthy lung cells were treated with various known compounds and compounds described in this disclosure (Figure 11). The compounds of the present invention did not exhibit toxicity except at higher concentrations.

[0146] Example 5: Methods for testing the efficacy of compounds described herein This example describes the methods used to test the efficacy of the compounds described herein. The selective proliferation of cancer stem cells, their precursor lesions, and normal and chronically diseased epithelial tissues is described in the following references: Briefly, biopsy tissue is made into a single-cell suspension and plated onto a lawn of irradiated 3T3-J2 feeder cells in proprietary StemEcho medium. A library of colonies emerges within 7–10 days. Single-cell-derived clones are generated by single-cell FACS sorting in 384-well plates, and wells containing individual colonies are expanded, analyzed by molecular genetics, and propagated as individual clones.

[0147] Approximately 400,000 cells from individual clones associated with specific disease states (cancer, chronic inflammatory disease) are seeded onto 384-well plates pre-seeded with irradiated feeder cells, grown for 5 days, and then exposed to test compounds in a serial dilution format. After 2–5 days, the cells are fixed using paraformaldehyde, and human cells are labeled with a human-specific antibody followed by a fluorochrome-conjugated secondary antibody. Human cell numbers are quantified using high-throughput imaging technology (CellInsight CX7 LED, Thermo), and data are analyzed in Excel.

[0148] References: 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.

[0149] Yamamoto Y,Wang Suggests Paths to Initiation and Progression of a Precancerous Lesion. Nat Commun. 2016 Jan 19;7:10380.

[0150] 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.

[0151] 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.

[0152] 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).

[0153] 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.

[0154] 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.

[0155] While we have described a number of embodiments of this invention,it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore,it will be appreciated that the scope of this invention is to be defined by the appended claims rather than the specific embodiments that have been represented by way of examples.

Claims

1. Compounds of Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof (In the formula, L1 is the first ligand; L2 is a second ligand; The linker is 【Chemistry 2】 (wherein the bivalent linker comprises

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

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

4. Each of L1 and L2 is independently: 【Chemistry 3】 or 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

5. L1 is: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof.

6. L1 is: 【Chemistry 6】 or a pharmaceutically acceptable salt thereof.

7. L2 is: 【Chemistry 7】 or a pharmaceutically acceptable salt thereof.

8. L2 is: 【Chemistry 8】 or a pharmaceutically acceptable salt thereof.

9. The compound has formula Ia, Ib, or Ic: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 or a pharmaceutically acceptable salt thereof.

10. The linker has formula X: 【Chemistry 12】 or a pharmaceutically acceptable salt thereof. １ and X ２ each independently represents a covalent bond or an optionally substituted divalent saturated or partially unsaturated, straight or branched chain C １－１２ a hydrocarbon chain, wherein 1 to 4 carbon atoms are optionally and independently selected from -O-, -N(R)-, -C(O)-, -S-, -SO-, -SO ２ -, or -Cy-; As generally defined above, each R is hydrogen or an optionally substituted C １－６ independently selected from aliphatic; each -Cy- is an optionally substituted bivalent ring selected from a 3- to 8-membered carbocyclene, a 5- to 6-membered saturated or partially unsaturated heterocyclene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; phenylene; or a 5- to 6-membered heteroarylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur; # represents the point of attachment to L1; $ represents the point of attachment to L2).

11. X １ and X ２ The compound of claim 10, wherein

12. X １ and X ２ The compound of claim 10, wherein:

13. X １ and X ２ each independently represents a covalent bond or an optionally substituted divalent saturated or partially unsaturated, straight or branched chain C １－６ 11. The compound of claim 10, which is a hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally and independently replaced with -O-, -N(R)-, or -C(O)-.

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

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

16. X １ is an optionally substituted divalent saturated linear C ３ 16. The compound of any one of claims 10, 13, or 15, which is a hydrocarbon chain, wherein one carbon atom is replaced with -O-.

17. X １ is an optionally substituted divalent saturated linear C ４ 16. The compound of any one of claims 10, 13, or 15, which is a hydrocarbon chain.

18. X １ is an optionally substituted divalent saturated linear C ５ 16. The compound of any one of claims 10, 13, or 15, which is a hydrocarbon chain, wherein one carbon atom is replaced with -O-.

19. X １ is an optionally substituted divalent saturated linear C ５ 16. The compound of any one of claims 10, 13, or 15, which is a hydrocarbon chain.

20. X １ is an optionally substituted divalent saturated linear C ６ 16. The compound of any one of claims 10, 13, or 15, which is a hydrocarbon chain, wherein one carbon atom is replaced with -O-.

21. X １ is an optionally substituted divalent saturated linear C ６ 16. The compound of any one of claims 10, 13, or 15, which is a hydrocarbon chain, wherein two carbon atoms are replaced with -O-.

22. X １ が, shared combination, 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 or 【Chemical 21】 16. The compound of any one of claims 10, 13, or 15, (where # represents the point of attachment to L1).

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

24. X ２ is an optionally substituted divalent saturated or partially unsaturated linear C ３－６ 23. The compound of any one of claims 10 or 13-22, which is a hydrocarbon chain, wherein 1 to 2 carbon atoms are optionally replaced with -O-.

25. X ２ is an optionally substituted divalent saturated linear C ３ 25. The compound of any one of claims 10, 13-22, or 24, which is a hydrocarbon chain, wherein one carbon atom is replaced with -O-.

26. X ２ is an optionally substituted divalent saturated linear C ４ The compound of any one of claims 10, 13-22, or 24, which is a hydrocarbon chain.

27. X ２ is an optionally substituted divalent saturated linear C ５ 25. The compound of any one of claims 10, 13-22, or 24, which is a hydrocarbon chain, wherein one carbon atom is replaced with -O-.

28. X ２ is an optionally substituted divalent saturated linear C ５ The compound of any one of claims 10, 13-22, or 24, which is a hydrocarbon chain.

29. X ２ is an optionally substituted divalent saturated linear C ６ 25. The compound of any one of claims 10, 13-22, or 24, which is a hydrocarbon chain, wherein one carbon atom is replaced with -O-.

30. X ２ is an optionally substituted divalent saturated linear C ６ 25. The compound of any one of claims 10, 13-22, or 24, which is a hydrocarbon chain, wherein two carbon atoms are replaced with -O-.

31. X ２ が, shared combination, 【Chemical 22】 【Chemical 23】 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 【Chemical 27】 【Chemical Formula 28】 【Chemical 29】 or 【Chemistry 30】 25. The compound of any one of claims 10, 13-22, or 24, wherein $ represents the point of attachment to L2.

32. The compound is a compound of formula Ia: 【Chemical 31】 or a pharmaceutically acceptable salt thereof, wherein the linker is sufficient to position L1 and L2 at a distance of about 0.7 to 2.2 nm between the C1 carbon atoms of their respective indanyl groups (denoted below with *): 【Chemical 32】

33. 33. The compound of claim 32, wherein the linker is sufficient to position L1 and L2 at a distance of about 0.7-0.8 nm, about 1.4-1.5 nm, or about 2.0-2.2 nm between the C1 carbon atoms of their respective indanyl groups.

34. The compound is a compound of formula Ib: 【Chemical 33】 or a pharmaceutically acceptable salt thereof. The linker is sufficient to position L1 and L2 with a distance of about 1.9-2.2 nm between their respective benzylic carbon atoms (indicated below with *): 【Chemical 34】

35. The compound is a compound of formula Ic: 【Chemistry 35】 or a pharmaceutically acceptable salt thereof. 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 benzyl carbon atom of L2 (denoted below with *): 【Chemical 36】

36. The compound is: 【Hua 37-1】 【Hua 37-2】 【Hua 37-3】 【Hua 37-4】 or a pharmaceutically acceptable salt thereof.

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

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

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

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

41. 41. The method of 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. 40. The method of claim 39, wherein the one or more IAP-associated diseases or disorders are pulmonary diseases, disorders, or conditions.

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

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