Survivin-targeted compounds

Abstract

Provided herein are compounds targeting survivin and pharmaceutically acceptable derivatives thereof. In one embodiment, the compounds facilitate the degradation of survivin by proteasome. Also provided herein are pharmaceutical compositions comprising the compounds and methods of using the compounds to treat a subject with cancer.

Description

Related inventions

[0001] This invention claims priority to U.S. Provisional Patent Application No. 63 / 583,827, filed September 19, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to chimeric compounds that target survivin. Furthermore, methods for treating diseases and conditions involving survivin expression or overexpression, including cancer, are also provided. Background Technology

[0003] Survivin is an apoptosis inhibitor protein (IAP) with a molecular weight of approximately 16.5 kDa. Its function is to inhibit the activation of caspase, thereby leading to a decrease in apoptosis levels. See Verdecia et al., *Nature Structural Biology*, 2000, Vol. 7(7), pp. 602-8; Chantalat et al., *Molecular Cell*, 2000, Vol. 6(1), pp. 183-189. Survivin is also known as BIRC5 (baculovirus apoptosis inhibitor repeat protein 5). All IAPs contain at least one BIR (baculovirus IAP repeat) domain. Survivin is unique among IAPs in that it contains only one BIR. Four subtypes of survivin are known: survivin, survivin-2B, survivin-Δ exon-3, and survivin-3B.

[0004] Survivin is expressed in most tumor cells, but rarely in normal, non-malignant adult cells. See Ambrosini et al., *Nature Medicine*, 1997, Vol. 3(8), pp. 917-921. Tamm et al. showed that survivin was expressed in all 60 different human tumor cell lines used in the National Cancer Institute's anticancer drug screening program, with the highest expression levels in breast and lung cancer cell lines and the lowest in renal cell carcinoma cell lines. See Tamm et al., *Cancer Research*, 1998, Vol. 58(23), pp. 5315–20. In gliomas, survivin expression is associated with malignant phenotype and poor prognosis. See Tong et al., *Journal of Oncology*, 2019, Vol. 18(1), pp. 359-367. Survivin can be considered an oncogene because its overexpression in most cancer cells leads to resistance to apoptosis and chemotherapy. Existing literature has shown that knocking out survivin in cancer cells disrupts microtubule formation and leads to polyploidization and apoptosis. See Castedo et al., *Oncogenes*, 2004, Vol. 23(16), pp. 2825-2837. Furthermore, literature has shown that the apoptosis-promoting factor p53 inhibits survivin expression at the transcriptional level. See Mirza et al., *Oncogenes*, 2002, Vol. 21(17), pp. 2613-2622.

[0005] PROTAC (Proteolytic Targeting Chimera) is a bifunctional compound containing one part targeting an E3 ubiquitin ligase and another part targeting a target protein (e.g., survivin). PROTAC binds to the target protein and pulls it close to an E3 ubiquitin ligase (e.g., cereblon), which then performs (multi)ubiquitination on the target protein, ultimately leading to its degradation by the proteasome.

[0006] In addition, PROTAC contains a portion that activates the ubiquitination N-degron pathway (i.e., the N-terminal regular pathway), thereby initiating proteasome degradation, and a portion that targets the target protein. See Pan et al., *Nature*, 2021, Vol. 600(7888), pp. 334-338; Kim et al., *International Journal of Molecular Sciences*, 2021, Vol. 22, p. 8323; Zhang et al., *Journal of Biochemistry*, 2023, Vol. 299(8), p. 104994. In short, the lifespan of a protein depends on the nature of its N-terminal residues. N-terminal residues that disrupt protein stability are called N-degrons, which are classified into type I and type II. Type I N-degrons contain positively charged amino acids, such as Arg, Lys, and His, while type II N-degrons contain hydrophobic residues, such as Phe, Trp, Tyr, Leu, and Ile. In such PROTACs, small molecules carrying an N-terminus ending with one of these amino acids (Arg, Lys, His, Leu, Ile, Phe, Tyr, or Trp) can serve as N-terminal degradation signal sequences (N-degrons).

[0007] There is an urgent need for compounds and compositions that can degrade and / or inhibit survivin activity, especially in the field of cancer treatment. Summary of the Invention

[0008] This invention relates to survivin-targeting chimeric compounds. In one embodiment, the compound is a PROTAC targeting survivin. In another embodiment, the compound used in the compositions and methods provided by this invention has the following structural formula:

[0009] ELX

[0010] Or a pharmaceutically acceptable derivative thereof, wherein E is a group targeting E3 ubiquitin ligase; L is a divalent chemical linker; and X is a moiety targeting survivin. For non-limiting examples of moieties targeting survivin, see Wendt et al., Bioorganic and Medicinal Chemistry Communications, 2007, Vol. 17, pp. 3122-3129; and Chettiar et al., Bioorganic and Medicinal Chemistry Communications, 2013, Vol. 23, pp. 5429-5433.

[0011] In another embodiment, the compound used in the compositions and methods provided by the present invention has Formula I:

[0012]

[0013] or its pharmaceutically acceptable derivatives, wherein variable R 1 -R 9 The definitions of L and E are as described elsewhere in this document.

[0014] In another embodiment, the compound used in the compositions and methods provided by the present invention has Formula II:

[0015]

[0016] or its pharmaceutically acceptable derivatives, wherein variable R 11 The definitions of n, Het, L, and E are as described elsewhere in this document.

[0017] In another embodiment, the compound used in the compositions and methods provided by the present invention has Formula III:

[0018]

[0019] or its pharmaceutically acceptable derivatives, wherein variable R 12 The definitions of m, Het, L, and E are as described elsewhere in this document.

[0020] In another embodiment, a method is provided for treating a disease or condition involving the expression or overexpression of survivin by applying a compound or composition provided by the present invention. In some embodiments, the disease or condition to be treated is cancer. In another embodiment, the cancer is glioblastoma. Attached Figure Description

[0021] Figure 1 The expression levels of survivin and β-tubulin in U87 cells were shown after a single treatment with compound 11, and DC expression was measured. 50 .

[0022] Figure 2 The expression levels of survivin and β-tubulin in GL261 cells were shown after a single treatment with compound 11.

[0023] Figure 3 The expression levels of survivin and β-tubulin in GL261 cells were shown 72 hours after a single treatment with compound 11 within a specified treatment time range.

[0024] Figure 4 The expression levels of survivin and β-tubulin in GL261 cells were shown after treatment with temozolomide (TMZ) in combination with compound 11.

[0025] Figure 5 The plasma concentration of compound 11 was shown after a single oral dose of 35.0 mg / kg in male SD rats.

[0026] Figure 6The mean plasma, brain, and CSF concentrations of compound 11 were shown after a single intravenous bolus injection of 2.00 mg / kg in male SD rats.

[0027] Figure 7A and 7B The results show the quantitative results of survivin protein levels as determined by Western Blot assay in U87 and GL261 glioblastoma cell lines 24 hours after treatment with a specified concentration of compound 11.

[0028] Figure 8A The results of Western blot analysis of GL261 glioblastoma cells treated with radiation and compound 11 (at concentrations of 0.01 µM, 0.1 µM, 0.5 µM, and 1.0 µM) are shown. Figure 8B The results show the colony formation analysis of GL261 glioblastoma cells after treatment with compound 11 (0.5 µM) and without compound 11, and after irradiation with specified doses (0 Gy, 2 Gy, 4 Gy, 6 Gy, 8 Gy).

[0029] Figure 9 The results of Western blot analysis of U87 glioblastoma cells treated with compound 11, with or without the addition of the proteasome inhibitor MG132 (Z-Leu-Leu-Leu-al), are shown.

[0030] Figure 10 The mean plasma concentration and mean brain tissue concentration of compound 11 over time after administration are shown. Detailed description

[0031] I. Definition

[0032] To facilitate understanding of the contents disclosed in this invention, some terms are defined as follows.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art. All patents, patent applications, published patent applications, and other publications are incorporated herein by reference in their entirety. If a term has multiple definitions, the definition in this section shall prevail unless otherwise stated.

[0034] The singular forms “a,” “an,” and “the” also apply to the plural, unless the context clearly specifies otherwise.

[0035] The term "subject" as used in this article refers to animals, such as mammals, including humans, such as patients.

[0036] As used herein, bioactivity refers to the in vivo activity of a compound, or the physiological response elicited after administration of a compound, composition, or other mixture to the body. Therefore, bioactivity encompasses both the therapeutic effects and pharmacokinetic properties of such compounds, formulations, and mixtures. Bioactivity can be observed in in vitro systems specifically designed to detect such activities.

[0037] As used herein, pharmaceutically acceptable derivatives of compounds include, but are not limited to, their salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, inclusion compounds, solvates, or hydrates. Such derivatives can be readily prepared by those skilled in the art using known derivatization methods. The synthesized compounds are suitable for administration to animals or humans without significant toxicity; they are either pharmacologically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as, but not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucosamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as, but not limited to, lithium, potassium and sodium; alkaline earth metal salts, such as, but not limited to, barium, calcium and magnesium; transition metal salts, such as, but not limited to, zinc; and inorganic salts, such as, but not limited to, sodium hydrogen phosphate and disodium phosphate; also including, but not limited to, salts of inorganic acids, such as, but not limited to, hydrochlorides and sulfates; and salts of organic acids, such as, but not limited to, acetates, lactates, malates, tartrates, citrates, ascorbic acid salts, succinates, butyrates, valerates, methanesulfonates and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters with acidic groups, including but not limited to carboxylic acids, phosphoric acids, phosphonic acids, sulfonic acids, sulfinic acids, and boric acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of the general formula C=C(OR), where R represents alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of the general formula C=C(OC(O)R), where R represents hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl. Pharmaceutically acceptable solvates and hydrates refer to complexes formed by a compound with one or more solvent or water molecules, or complexes formed with 1 to about 100, 1 to about 10, or 1 to about 2, 3, or 4 solvent or water molecules.

[0038] As used herein, treatment means any manner in which one or more symptoms of a disease or condition are improved or otherwise beneficially altered. Treatment also includes any pharmaceutical use of the compositions described herein, such as for the treatment of cancer.

[0039] As used herein, improvement of symptoms of a particular disease by application of a particular compound or pharmaceutical composition means any reduction of symptoms that can be attributed to or associated with the application of said compound or pharmaceutical composition, whether permanent or temporary, lasting or transient.

[0040] As used herein, unless otherwise stated, the term "management" includes preventing the recurrence of the disease or disorder in a subject who already has the disease or disorder, and / or prolonging the time a subject with the disease or disorder remains in remission. These terms include modulating the threshold, development, and / or duration of the disease or disorder, or altering how a subject responds to the disease or disorder.

[0041] As used in this article, DC 50 This refers to the amount, concentration, or dosage of a specific test compound used in an experiment to determine the degradation of a protein (such as survivin) by 50%.

[0042] When a part is represented by a conventional chemical formula and written from left to right, these representations also cover the chemically identical parts obtained by writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0043] Unless otherwise stated, the term "alkyl" (whether used alone or as part of other substituents) refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group, which may include divalent and polyvalent groups with the number of carbon atoms as indicated (i.e., C1-C1). 10 (Indicates 1 to 10 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and their homologues and isomers, as well as n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0044] Unless otherwise specified, the term "alkenyl" (whether used alone or as part of other substituents) refers to a straight-chain (i.e., unbranched) or branched hydrocarbon group having one or more carbon-carbon double bonds, which may include divalent and polyvalent groups, with the number of carbon atoms conforming to the specified range (i.e., C1-C2). 10 (Represents 1 to 10 carbon atoms). Examples of alkenyl groups include, but are not limited to, vinyl (i.e., vinyl), 2-propenyl, butenyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), and more advanced homologues and isomers.

[0045] Unless otherwise stated, the term "alkynyl" (whether used alone or as part of other substituents) refers to a straight-chain (i.e., unbranched) or branched hydrocarbon group having one or more carbon-carbon triple bonds, which may include divalent and polyvalent groups, with the number of carbon atoms as indicated (i.e., C1-C1). 10(Represents 1 to 10 carbon atoms). Examples of alkynyl groups include, but are not limited to, ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologues and isomers.

[0046] The term "alkylene" (whether used alone or as part of another substituent) refers to a divalent group derived from an alkyl group, such as, but not limited to, -CH2CH2CH2CH2-. Typically, alkyl (or alkylene) groups contain 1 to 24 carbon atoms, including groups containing 10 or fewer carbon atoms. "Lower alkyl" or "lower alkylene" refers to a shorter-chain alkyl or alkylene group, typically containing six or fewer carbon atoms.

[0047] The terms “alkoxy,” “alkylamino,” and “alkylthio” (or thioalkoxy) are used in their conventional sense to refer to an alkyl group that is attached to the rest of the molecule by an oxygen, amino, or sulfur atom, respectively.

[0048] Unless otherwise stated, the term "heteroalkyl" (whether used alone or in combination with other terms) refers to a straight-chain or branched hydrocarbon group composed of heteroatoms selected from O, N, P, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom may have alkyl substituents to satisfy valence requirements, and / or optionally be quaternized. The heteroatoms O, N, P, Si, and S may be located at any internal position within the heteroalkyl group. Examples include, but are not limited to, -CH2-CH2-O-CH3, CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. --A maximum of two heteroatoms can appear consecutively, for example, -CH2-NH-OCH3 and –CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" (whether used alone or as part of another substituent) refers to a divalent group derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-S-CH2CH2- and –CH2-S-CH2-CH2-NH-CH2-. --For alkylene and heteroalkylene linking groups, the direction in which the linking group formula is written does not imply the orientation of the linking group. For example, the formula –C(O)2R' represents both –C(O)2R' and –R'C(O)2.

[0049] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl" (whether used alone or in combination with other terms) refer to the cyclic form of "alkyl" and "heteroalkyl," respectively, including bicyclic, tricyclic, and bridged bicyclic groups. Furthermore, for heterocycloalkyl groups, the heteroatom may occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornenyl, bicyclo[2.2.2]octyl, etc. Examples of heterocyclic alkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, 2-piperazinyl, 1- or 2-azabicyclo[2.2.2]octyl, etc.

[0050] Unless otherwise stated, the term "halogen" (whether used alone or as part of other substituents) refers to a fluorine, chlorine, bromine, or iodine atom. Furthermore, terms such as "haloalkyl" mean both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0051] Unless otherwise stated, the term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent that may consist of a single ring or multiple rings (1 to 3 rings in one embodiment), which may be linked or covalently connected. The term "heteroaryl" refers to an aryl group containing 1 to 4 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms may be oxidized, and the nitrogen atom may optionally be quaternized. Heteroaryl groups may be attached to the rest of the molecule via carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrole, 2-pyrrole, 3-pyrrole, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinel, 2-benzimidazolyl, 5-indolyl, 1-isoquinolinyl, 5-isoquinolinyl, 2-quinoxolinyl, 5-quinoxolinyl, 3-quinolinyl, and 6-quinolinyl. Substituent groups for aryl and heteroaryl ring systems may be selected from the group of acceptable substituent groups described herein. The term "heteroaryl" refers to a heteroaryl group with a positive charge on one or more heteroatoms.

[0052] The term "oxo" as used in this article refers to an oxygen atom that forms a double bond with a carbon atom.

[0053] The terms above (e.g., "alkyl", "heteroalkyl", "aryl", and "heteroaryl") refer to both substituted and unsubstituted forms containing the indicated group. Non-limiting examples of the substituent portion of each group are provided below.

[0054] In one embodiment, the substituents of the alkyl, heteroalkyl, alkylene, alkenyl, heteroalkylene, heteroalkylene, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups are selected from deuterium, -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, SiR'R"R"', OC(O)R', -C(O)R', -CO2R', -CONR'R"', -OC(O)NR'R"', -NR"C(O)-R', NR'C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R'")=NR", NRC(NR'R")=NR', -S(O)R', S(O)2R', -S(O)2NR'R"', NRSO2R', -NRSO2NR'R"', -CN And –NO2, the amount of which ranges from zero to the number of hydrogen atoms in the group. -------- In one embodiment, the substituent moiety of cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl also includes substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl. In one embodiment, R', R", R'" and R"" are each independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or arylalkyl. When the compound described herein contains more than one R group. In cases where multiple R', R'', R''', and R'''' groups are present, each of these groups is chosen independently. When R' and R'' are attached to the same nitrogen atom, they can combine with that nitrogen atom to form a 4, 5, 6, or 7-membered ring. For example, the group NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. - Based on the above discussion of substituent groups, those skilled in the art should understand that the term "alkyl" is intended to include groups formed by attaching a group other than a carbon atom to a hydrogen atom, such as haloalkyl (e.g., -CF3 and –CH2CF3) and acyl (e.g., -C(O)CH3, C(O)CF3, -C(O)CH2OCH3, etc.).

[0055] In one embodiment, the substituents of the aryl and heteroaryl groups are selected from deuterium, halogens, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkenyl groups, and substituted and unsubstituted alkynyl groups, OR', -NR'R", -SR', -SiR'R"R"', OC(O)R', -C(O)R', CO2R', -CONR'R", OC(O)NR'R", -NR"C(O)R', NR'C(O)NR"R"', -NR"C(O)2R', NR-C(NR'R"R'")=NR"", NRC(NR'R")=NR'", -S( R', -S(O)2R', -S(O)2NR'R", NRSO2R', -CN and –NO2, -R', -N3, CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, ranging in number from zero to the total number of hydrogen atoms in the aromatic ring system; wherein, in one embodiment, R', R", R"' and R"" are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When the compound described herein contains more than one R group, for example, if multiple R', R'', R''' and R'''' groups are present, each of the above groups is selected independently.

[0056] Two substituent groups on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring conforming to the formula Q'-C(O)-(CRR'). q -Q''- ring, where Q' and Q" are each independently –NR-, -O-, -CRR'- or a single bond, and q is an integer between 0 and 3. - Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by substituents of the formula A(CH2)rB-, where A and B are each independently –CRR'-, -O-, -NR-, -S-, -S(O)-, S(O)2, -S(O)2NR'- or a single bond, and r is an integer between 1 and 4. ---- One single bond of the newly formed ring may be optionally replaced by a double bond. Alternatively, two substituent groups on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by substituents of the formula –(CRR')s-X'-(CR''R'''). d -Substitution, wherein s and d are each integers between 0 and 3, and X' is –O-, -NR'-, -S-, -S(O)-, -S(O)2-, or –S(O)2NR'-. In one embodiment, the substituents R, R', R" and R'" are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0057] As used herein, the term “heteroatom” or “cyclic heteroatom” includes oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0058] As used herein, a prodrug refers to a compound that, upon administration in vivo, undergoes metabolic or other chemical changes under physiological conditions through one or more steps or processes, or is otherwise converted into a biologically, pharmacologically, or therapeutically active form of the compound. Furthermore, prodrugs can be converted into biologically, pharmaceutically, or therapeutically active forms of the compound in an in vitro environment using chemical or biochemical methods. For example, a prodrug can be converted into the compound of this invention when placed in a transdermal patch reservoir together with suitable enzymes or chemical reagents.

[0059] Some of the compounds described herein can exist in both non-solventized and solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this disclosure. Some of the compounds provided by this invention can exist in various crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses described herein and should be considered within the scope of this disclosure.

[0060] Some of the compounds described herein contain asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, tautomers, geometric isomers, and monomeric isomers are all included within the scope of this disclosure. The compounds provided by this invention do not include compounds known in the art that are too unstable to be synthesized and / or isolated.

[0061] The compounds provided by this invention may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, these compounds can be radiolabeled with radioactive isotopes, such as tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds provided by this invention, whether or not they are radioactive, are included within the scope of this disclosure.

[0062] As used herein, a "linker group" is any divalent, trivalent, or multivalent chemical segment. The valence of a particular linker will be apparent to those skilled in the art from the context. In one embodiment, as used herein, a "linker group" is a divalent chemical segment.

[0063] As used in this article, "amino acid" refers to an organic compound that contains both amino and carboxylic acid functional groups.

[0064] II. Compounds used in the preparation of compositions and methods

[0065] In one embodiment, the present invention provides a compound for use in the compositions and methods provided by the present invention, having formula I:

[0066]

[0067] or pharmaceutically acceptable derivatives thereof, wherein:

[0068] L is a divalent chemical linker;

[0069] E is a group that targets E3 ubiquitin ligase; and

[0070] R 1 -R 9 Each of the following can be independently H, alkyl, haloalkyl, cycloalkyl, heteroalkyl, heterocycloyl, aryl, heteroaryl, aralkyl, heteroaryl, halogen, or OR 10 , where each R 10 Each can be independently H, alkyl, cycloalkyl, aryl, or aralkyl.

[0071] In another embodiment, R 1 -R 9 Each is independently H, alkyl, haloalkyl, halogen, or OR 10 , where each R 10 Each is independently an alkyl, cycloalkyl, or aralkyl group. In another embodiment, R 1 -R 9 Each is independently H, alkyl, haloalkyl, halogen, or OR 10 , where each R 10 Each is independently an alkyl, cycloalkyl, or aralkyl group. In another embodiment, R 1 -R 9 Each can be independently H, methyl, trifluoromethyl, halogen, or OR 10 , where each R 10 Each is independently an aralkyl group. In another embodiment, R 1 -R 9 Each can be independently H, chloro, methyl, trifluoromethyl, or OR 10 , where each R 10 It is an aralkyl group. In another embodiment, R 1 -R 9 Each is independently H, chloro, methyl, trifluoromethyl, or -O-benzyl. In another embodiment, R 1 -R 9 Both are H. In another embodiment, R 1 R 3 R 5 -R 7 and R 9 For H, R 2and R 4 It is -O-benzyl, R 8 It is chlorine. In another embodiment, R 1 -R 3 R 5 -R 7 and R 9 For H, R 4 It is -O-benzyl, R 8 It is chlorine.

[0072] In another embodiment, the present invention provides a compound for use in the compositions and methods provided by the present invention, having formula II:

[0073]

[0074] or pharmaceutically acceptable derivatives thereof, wherein:

[0075] L is a divalent chemical linker;

[0076] E is a group that targets E3 ubiquitin ligase;

[0077] R 11 It is an alkyl group;

[0078] n is an integer between 0 and 4; and

[0079] Het is a heteroaryl group that can be optionally substituted with an aryl group.

[0080] In another embodiment, R 11 It is a lower alkyl group. In another embodiment, R 11 It is methyl. In another embodiment, n is 0. In another embodiment, n is 1. In another embodiment, n is 0. In another embodiment, n is 3. In another embodiment, n is 4.

[0081] In another embodiment, Het is a furanyl group that may optionally be substituted with a phenyl group. In another embodiment, Het is a furanyl group that is substituted with a phenyl group, which may optionally be substituted with a carboxyl group (COOH). In another embodiment, Het is a furanyl group substituted with a 4-COOH-1-phenyl group. In another embodiment, Het is a 5-(4-COOH-1-phenyl)-2-furanyl group.

[0082] In another embodiment, the compound of formula II is:

[0083] .

[0084] In one embodiment, the present invention provides a compound for use in the compositions and methods provided by the present invention, having formula III:

[0085]

[0086] or pharmaceutically acceptable derivatives thereof, wherein:

[0087] L is a divalent chemical linker;

[0088] E is a group that targets E3 ubiquitin ligase;

[0089] R 12 It is an alkyl or cycloalkyl group;

[0090] m is an integer between 0 and 4; and

[0091] Het is a heteroaryl group that can be optionally substituted with an amino group.

[0092] In another embodiment, 12 It is an alkyl group. In another embodiment, R 12 It is methyl. In another embodiment, m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 3. In another embodiment, m is 4.

[0093] In another embodiment, Het is an amino-substituted heteroaryl group. In another embodiment, Het is an amino-substituted oxadiazolyl group. In another embodiment, Het is an amino-substituted 1-oxa-2,5-diazolyl group. In another embodiment, Het is 4-amino-1-oxa-2,5-diazol-3-yl.

[0094] In another embodiment, the compound of formula III is:

[0095] .

[0096] Connecting base L

[0097] Linking groups for bifunctional chimeric compounds (such as PROTAC and LYTAC) are well known in the art. See Troup et al., Exploring Targeted Antitumor Therapies, 2020, Vol. 1, pp. 273-312; WO 2019 / 060742; US2021 / 0220475. In one embodiment, the linking group L for the compounds provided by the present invention comprises a diol (including polyethylene glycol (PEG)), alkyl, acyl, amino, amide, alkynyl, triazole (e.g., linking two targeting groups via click chemistry), pyridazine (e.g., CLIPTAC), aryl (e.g., phenyl), piperazine, aziridine, and / or piperidine. The linking group L may be cleavable or non-cleavable. In one embodiment, the linking group L has photoswitching properties (e.g., a diazo linker).

[0098] In another embodiment, the linker L comprises piperazine, piperidine, aziridine, and / or alkyl groups. In another embodiment, L is piperidinyl-alkylene-piperazinyl. In another embodiment, L is piperidinyl-methylene-piperazinyl. In yet another embodiment, L is...

[0099] .

[0100] In another embodiment, L is piperidinyl-alkylene-azacyclobutyl. In another embodiment, L is piperidinyl-methylene-azacyclobutyl. In another embodiment, L is...

[0101] .

[0102] In another embodiment, L is an alkylamide linker. In another embodiment, L is C 4-10 -alkylene-C(O)-NH-. In another embodiment, L is

[0103] .

[0104] In another embodiment, L is a PEG linker. In yet another embodiment, L is (PEG). 2-6 -NH-. In another embodiment, L is

[0105] .

[0106] E3 ligase binder E

[0107] The E3 ligase binder E used for the compounds provided in this invention is well known in the art. See WO2022 / 066835, WO 2020 / 118098, WO 2021 / 041664, WO 2019 / 078522, WO 2021 / 188537, WO2021 / 105334, WO 2022 / 144416, WO 2021 / 143816, WO 2022 / 017365、WO 2022 / 146151、WO2022 / 148358、WO 2021 / 147889、WO 2021 / 143822、WO 2020 / 181232、WO 2019 / 043214、WO2020 / 263832、WO 2020 / 006233、WO 2015 / 200795, WO 2019 / 043217, WO 2019 / 204354; US Patent Publication Nos. US 2022 / 0062248, US 2019 / 0017998, 2020 / 0206201, 2020 / 0155690, 2021 / 0009559, 2018 / 0215731, 2021 / 0177825, 2019 / 0076541, 2021 / 0403454, 2021 / 0284624, 2021 / 0032245, 2020 / 0207764, 2022 / 0112211, 2019 / 0233433, 2020 / 0207733.

[0108] In one embodiment, E is a protein that binds cereblon, von Hippel-Lindau (VHL) proteins (e.g., VH032, VH285, VH298, VH101, VHL-e, and VHL-g), inhibitory apoptosis proteins (IAPs) (e.g., MV1, ME-BS, GDC-0152, LCL-161, AT-IAP, SNIPER(ER)-110, SNIPER(ER)-126), and mouse bimicrosome 2 homolog (MDM2) (e.g. Groups of ,Nutlin-3, RG7112 and idasanutlin), DCAFs (e.g., indisulam, E7820, KB02 and chloroquinoline sulfonamide (CQS)), RNF proteins (e.g., CCW16, nimbolide and EN219) or aryl hydrocarbon receptor (AhR) proteins (including FEM1B and KEAP1) (e.g., β-naphthylflavonoid (β-NF), EN106, CDDO-Me, KEAP1-L, PL). See Lee et al., Molecules, 2022, Vol. 27, p. 6515.

[0109] In another embodiment, E is a fragment bound to cereblon. In another embodiment, E comprises a fragment derived from an imide, amide, thioamide, or thioimide. In another embodiment, E comprises a phthalimide group or an analogue or derivative thereof. In another embodiment, E comprises a phthalimide-glutarimide group or an analogue or derivative thereof. In another embodiment, E comprises a thalidomide, lenalidomide, or pomalidomide group or an analogue or derivative thereof.

[0110] In another embodiment, E is a thalidomide derivative. In yet another embodiment, E has the following structure:

[0111]

[0112] Where R 13 It is H or alkyl; R 14 -R 16 Each can be independently H, halogen, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

[0113] In one embodiment, R 13 It is H.

[0114] In another embodiment, R 14 and R 15 It is H, R 16 It is H, halogen, alkyl, or cycloalkyl. In another embodiment, R 14 and R 15 It is H, R 16 It is a halogen. In another embodiment, R 14 and R 15 It is H, R 16 It's fluorine.

[0115] In another embodiment, E is the VHL ligand of the E3 ligase. See Diehl et al., Chemical Society Reviews, 2022, Vol. 51(19), pp. 8216-8257; Buckley et al., Journal of the American Chemical Society, 2012, Vol. 134(10), pp. 4465-4468; Bricelj et al., Frontiers in Chemistry, 2021, Vol. 9; Crew et al., Journal of Medicinal Chemistry, 2018, Vol. 61, pp. 583-598; Buckley et al., Angewandte Chemie International Edition, 2012, Vol. 51, pp. 11463-11467. Galdeano et al., *Journal of Medicinal Chemistry*, 2014, Vol. 57, pp. 8657-8663; Steinebach et al., *Chemical Science*, 2020, Vol. 11, pp. 3474-3486; Raina et al., *Proceedings of the National Academy of Sciences*, 2016, Vol. 113, pp. 7124-7129; Han et al., *Journal of Medicinal Chemistry*, 2019, Vol. 62, pp. 941-964; Hu et al., *Journal of Medicinal Chemistry*, 2019, Vol. 62, pp. 1420-1442.

[0116] In another embodiment, the E3 ligase VHL ligand is selected from:

[0117]

[0118] In another embodiment, the E3 ligase VHL ligand is A1 or B2.

[0119] In another embodiment, the compound used in the compositions and methods provided by the present invention is:

[0120] ,

[0121] ,

[0122] ,

[0123] or

[0124] .

[0125] In another embodiment, the E fragment targeting the E3 ubiquitin ligase is an N-terminal degradation signal sequence (N-degron). In another embodiment, E is a type I N-degron. In one embodiment, the type I N-degron is a positively charged amino acid. In another embodiment, the positively charged amino acid is Arg, Lys, or His. In another embodiment, E is a type II N-degron. In one embodiment, the type II N-degron is a hydrophobic amino acid. In another embodiment, the hydrophobic amino acid is Phe, Trp, Tyr, Leu, or Ile. In another embodiment, E is Arg, Lys, His, Phe, Trp, Tyr, Leu, or Ile. In one embodiment, E is an arginine residue.

[0126] In another embodiment, the compound used in the compositions and methods provided by the present invention is:

[0127] .

[0128] III. Synthesis of Compounds

[0129] The compounds provided by this invention can be synthesized using methods known in the art, with readily available starting materials. Please refer to the references cited herein regarding survivin-binding groups and E3 ligase-binding ligands.

[0130] IV. Pharmaceutical Compositions

[0131] The pharmaceutical compositions provided by this invention comprise a therapeutically effective amount of one or more compounds provided by this invention, as well as a pharmaceutically acceptable carrier, diluent, or excipient.

[0132] These compounds can be formulated into suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release formulations, or tinctures for oral administration; or sterile solutions or suspensions for ophthalmic or non-oral administration; and can also be formulated into transdermal patches and dry powder inhalers. Typically, these compounds are formulated into pharmaceutical preparations using techniques and processes well-known in the art (see Ansel, Introduction to Pharmaceutics (7th Edition, 1999)).

[0133] In these formulations, an effective concentration of one or more compounds or pharmaceutically acceptable salts is mixed with a suitable pharmaceutical carrier or excipient. In some embodiments, the concentration of the compounds in the composition is such that, after administration, an effective amount of the drug is delivered to treat, prevent, or improve the symptoms and / or progression of one or more diseases or conditions disclosed herein.

[0134] Typically, the compositions are formulated for single-dose administration. To formulate the compositions, the weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected carrier at an effective concentration to relieve or improve the treated symptoms. Pharmaceutical carriers suitable for administering the compounds provided by this invention include any such carriers known to those skilled in the art as being suitable for a particular route of administration.

[0135] Furthermore, these compounds can be used as the sole pharmaceutically active ingredient in a formulation or in combination with other active ingredients. Liposome suspensions, including tissue-targeting liposomes (such as tumor-targeting liposomes), may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods well known to those skilled in the art. For example, liposome formulations can be prepared with reference to existing techniques. Briefly, multilayer vesicles (MLVs) are formed by drying egg yolk phosphatidylcholine and cephalin-serine (7:3 molar ratio) inside a flask. A solution of the compounds provided in this invention in phosphate-buffered saline (PBS) free of divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, precipitated by centrifugation, and then resuspended in PBS.

[0136] The active ingredient is contained in a pharmaceutically acceptable carrier at a dose sufficient to exert a therapeutic effect without causing adverse side effects in the subject. The effective therapeutic concentrations of these compounds can be empirically determined by testing them in the in vitro and in vivo systems provided by this invention, and the dosage suitable for humans can be extrapolated accordingly. In some embodiments, the active ingredient is administered via a method of administration to achieve a therapeutically effective concentration of the drug. In some embodiments, companion diagnostics (see Olsen D and Jorgensen JT, Frontiers in Oncology, May 16, 2014, 4:105, doi:10.3389 / fonC.2014.00105) are employed to determine the therapeutic concentrations and safety profiles of the active compound in a specific subject or subject population.

[0137] The concentration of the active ingredient in a pharmaceutical composition depends on the absorption, tissue distribution, inactivation and excretion rate of the active ingredient, the physicochemical properties of the ingredient, the administration regimen, the dosage, and other factors known to those skilled in the art. For example, the administered dose may be sufficient to relieve the symptoms of one or more diseases or conditions disclosed in this invention.

[0138] In some embodiments, the therapeutically effective dose should achieve a serum concentration of the active ingredient of about 0.1 ng / mL to about 50-100 µg / mL. In one embodiment, the pharmaceutical composition provided by the present invention provides a dose of about 0.001 mg to about 2000 mg of the compound per kilogram of body weight per day. Pharmaceutical dosage units are prepared to provide about 1 mg to about 1000 mg in each dosage unit, and in some embodiments, about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients is provided.

[0139] The active ingredient can be administered in a single dose or divided into several small doses administered at regular intervals. It is understood that the exact dosage and treatment duration depend on the disease being treated and can be determined empirically using known testing protocols or extrapolated from in vivo or in vitro test data. It should be noted that concentrations and dosages may also vary depending on the severity of the condition to be alleviated. Furthermore, it should be understood that for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the administration; and the concentration ranges provided in this invention are merely examples and are not intended to limit the scope or implementation of the claimed compositions.

[0140] Therefore, one or more compounds provided by this invention, or pharmaceutically acceptable salts thereof, are mixed at an effective concentration or dose with a suitable pharmaceutical carrier or excipient for systemic, local, or topical administration, thereby preparing a pharmaceutical compound. The amount of the contained compound is sufficient to relieve one or more symptoms, or for treatment, delaying disease progression, or prevention. The concentration of the active ingredient in the composition will depend on the absorption, tissue distribution, inactivation, excretion rate of the active ingredient, dosing regimen, dosage, specific formulation, and other factors known to those skilled in the art.

[0141] The composition is intended for administration via appropriate routes of administration, including but not limited to oral, non-oral, subcutaneous, intravenous, intramuscular, intraperitoneal, subarachnoid, mucosal, intradermal, transdermal, buccal, rectal, topical, local, nasal, or inhalation administration. For oral administration, it may be formulated as capsules or tablets. The composition is in liquid, semi-liquid, or solid form and is formulated in a manner suitable for each route of administration.

[0142] Solutions or suspensions intended for non-oral, intradermal, subcutaneous, or local administration may contain any of the following components: sterile diluents such as water for injection, physiological saline, fixative oil, polyethylene glycol, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents; antimicrobial agents such as benzyl alcohol and methylparaben; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetate, citrate, and phosphate; and conditioning agents such as sodium chloride or glucose. Injectable formulations may be contained in ampoules, pen syringes, disposable syringes, or single- or multi-dose vials made of glass, plastic, or other suitable materials.

[0143] When the solubility of a compound is insufficient, compound dissolution methods may be employed. These methods are known to those skilled in the art and include, but are not limited to, the use of a co-solvent (such as dimethyl sulfoxide (DMSO)), the use of a surfactant (such as TWEEN®), or dissolution in an aqueous solution of sodium bicarbonate.

[0144] When this compound is mixed or added, the resulting mixture may be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on a variety of factors, including the intended route of administration and the solubility of the compound in the chosen carrier or solvent. The effective concentration is sufficient to relieve the symptoms of the disease, condition, or illness being treated and can be determined empirically.

[0145] The pharmaceutical compositions provided by this invention are intended for human and animal administration in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile injections or suspensions, oral solutions or suspensions, and oil-water emulsions containing appropriate amounts of the compound or its salts conforming to pharmaceutical standards. Pharmacologically active compounds and their salts can be formulated into single-dose or multi-dose dosage forms for administration. A single-dose dosage form refers to a physically discrete unit suitable for human and animal subjects and individually packaged in a manner conventional in the art. Each dose unit contains a predetermined amount of the therapeutically active ingredient sufficient to produce the desired therapeutic effect and is compounded with a desired pharmaceutical carrier, excipient, or diluent. Examples of single-dose dosage forms include ampoules, syringes, and individually packaged tablets or capsules. Single-dose dosage forms can be administered in fractional or multiple doses. Multi-dose dosage forms refer to multiple identical unit dosage forms packaged in a single container and administered in separate unit doses upon use. Examples of multi-dosage formulations include vials, bottled tablets or capsules, and pints or gallons of bottled formulations. Therefore, a multi-dosage formulation refers to a combination of multiple unit doses that are not individually separated on the packaging.

[0146] Sustained-release formulations can also be prepared. Examples of suitable sustained-release formulations include solid hydrophobic polymer semi-permeable matrices containing the compounds provided in this invention, in the form of molded articles, such as films or microcapsules. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (such as poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and L-glutamic acid ethyl ester, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPOT™, injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate copolymers and lactic acid-glycolic acid copolymers can sustain molecular release for over 100 days, some hydrogels release proteins for shorter periods. When encapsulated compounds remain in vivo for extended periods, exposure to moisture at 37°C may cause denaturation or aggregation, leading to loss of biological activity and potentially structural changes. Therefore, a reasonable stabilization strategy can be formulated based on the mechanism of action involved. For example, if the aggregation mechanism is found to be intermolecular S-S bonds formed through sulfur-disulfide bond exchange, stabilization can be achieved by modifying thiol residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix formulations.

[0147] In addition, dosage forms or formulations containing 0.005% to 100% of the active ingredient, with the remainder consisting of a non-toxic carrier, can be prepared. For oral administration, a pharmaceutically acceptable non-toxic composition can be prepared by adding any conventionally used excipient (such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or sodium saccharin). Such compositions include solutions, suspensions, tablets, capsules, powders, and sustained-release formulations, such as, but not limited to, implants and microcapsule delivery systems, and biodegradable biocompatible polymers such as collagen, ethylene-vinyl acetate copolymers, polyanhydride, polyglycolic acid, polyoxopropyl acetate, polylactic acid, etc. Methods for preparing these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001% to 100% of the active ingredient; in some embodiments, the active ingredient content is about 0.1% to 85%; while in other embodiments, the active ingredient content is about 75% to 95%.

[0148] Active compounds or pharmaceutically acceptable salts can be prepared by combining them with a carrier to prevent the compound from being rapidly excreted from the body, such as in sustained-release formulations or coatings.

[0149] The composition may include other active compounds to achieve the desired combination of properties. The compounds provided by this invention, or pharmaceutically acceptable salts thereof, may also be used in combination with another pharmacological preparation known in the art as effective in treating one or more of the aforementioned diseases or conditions (such as those related to oxidative stress) for therapeutic or preventative purposes. It should be understood that such combination therapies constitute another aspect of the compositions and treatment methods provided by this invention.

[0150] The lactose-free compositions provided by this invention may contain excipients well known in the art, such as those listed in the United States Pharmacopeia (USP) SP (XXI) / NF (XVI). Typically, lactose-free compositions contain pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredients, binders / fillers, and lubricants. Exemplary lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0151] This further includes anhydrous pharmaceutical compositions and dosage forms containing the compounds provided by this invention. For example, in the pharmaceutical field, adding water (e.g., 5%) is a widely accepted method for simulating long-term storage conditions to determine properties such as shelf life or stability over time of a formulation. See Jens T. Carstensen, *Pharmaceutical Stability: Principles and Practice*, 2nd ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In reality, water and heat can accelerate the decomposition of some compounds. Therefore, the effect of water on formulations can be critical, as moisture and / or humidity are commonly encountered during the production, handling, packaging, storage, transportation, and use of formulations.

[0152] The anhydrous pharmaceutical compositions and dosage forms provided by this invention can be prepared using anhydrous or low-moisture raw materials under low-moisture or low-humidity conditions. If significant exposure to moisture and / or humidity is anticipated during production, packaging, and / or storage, the pharmaceutical compositions and dosage forms containing lactose and at least one active ingredient comprising a primary or secondary amine should be anhydrous formulations.

[0153] The preparation and storage of anhydrous pharmaceutical compositions should maintain their anhydrous properties. Therefore, anhydrous compositions are packaged using materials known to prevent moisture absorption so that they can be placed in suitable formulation kits. Suitable packaging forms include, but are not limited to: sealed foil, plastic, single-dose containers (such as vials), blister packs, and strip packs.

[0154] A. Oral dosage form

[0155] Oral drug dosage forms are classified as solid, gel, or liquid. Solid dosage forms include tablets, capsules, granules, and bulk powders. Oral tablets include compressed tablets, chewable tablets, and tablets that may have enteric coating, sugar coating, or film coating. Capsules can be hard capsules or soft capsules, while granules and powders can be combined with other ingredients well known to those skilled in the art and provided in non-effervescent or effervescent forms.

[0156] In some embodiments, the formulation is a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, lozenges, and similar formulations may contain any of the following ingredients, or compounds with similar properties: binders; diluents; disintegrants; lubricants; slip agents; sweeteners; and flavoring agents.

[0157] Binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia gum, gelatin solution, sucrose, and starch paste. Lubricants include talc, starch, magnesium stearate or calcium stearate, lycopodium, and stearic acid. Diluents include lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate. Lubricants include, but are not limited to, colloidal silica. Disintegrants include croscarmellose sodium, carboxymethyl starch sodium, croscarmellose, alginate, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethyl cellulose. Colorants include any approved, certified water-soluble FD&C dyes and mixtures thereof; and water-insoluble FD&C dyes suspended on hydrated alumina. Sweeteners include artificial sweeteners such as sucrose, lactose, mannitol, and saccharin, as well as various spray-dried flavorings. Flavoring agents include natural flavorings extracted from fruits and other plants, as well as mixtures of synthetic compounds that produce a pleasant taste experience, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan oleate, diglyceride laurate, and polyvinyl lauryl ether. Emetic coating materials include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coating materials include hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate.

[0158] If oral administration is required, the compound can be formulated into a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated into an enteric-coated formulation to remain intact in the stomach and release the active compound in the intestines. The composition can also be used in combination with antacids or other similar ingredients.

[0159] When the dosage form is a capsule, in addition to the substances of the types mentioned above, it may also contain liquid carriers such as fatty oils. Furthermore, the dosage unit may also contain various other excipients that can alter its physical form, such as sugar coatings and other enteric coating substances. The compound can also be administered as a tincture, suspension, syrup, tablet, sprinkle, chewing gum, or similar preparation. Syrups, in addition to containing the active compound, may also contain sucrose as a sweetener, as well as certain preservatives, dyes, colorings, and flavorings.

[0160] The active ingredient can also be mixed with other active ingredients that do not affect the intended effect, or with substances that enhance the intended effect, such as antacids, H2 receptor antagonists, and diuretics. The active ingredient is the compound provided by this invention or a pharmaceutically acceptable salt thereof. Furthermore, higher concentrations of the active ingredient may be included, up to about 98% (by weight).

[0161] Pharmaceutically acceptable excipients contained in tablets include binders, lubricants, diluents, disintegrants, colorants, flavorings, and wetting agents. Enteric-coated tablets, due to their enteric coating, resist the action of gastric acid and dissolve or disintegrate in the neutral or alkaline environment of the intestine. Sugar-coated tablets are compressed tablets whose surface is coated with different numbers of pharmaceutically acceptable substances. Film-coated tablets are compressed tablets whose surface is coated with polymers or other suitable coating layers. Multi-compression tablets are tablets made using the aforementioned pharmaceutically acceptable substances through one or more compression processes. Colorants can also be used in the above dosage forms. Flavorings and sweeteners are used in compressed tablets, sugar-coated tablets, multi-compression tablets, and chewable tablets. Flavorings and sweeteners are particularly useful in the production of chewable tablets and lozenges.

[0162] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent particles, and effervescent formulations reconstituted from effervescent particles. Aqueous solutions include tinctures and syrups. Emulsions are classified as water-in-oil and oil-in-water. In some embodiments, suspensions are suspensions composed of microparticles or nanoparticles. In some embodiments, emulsions are emulsions composed of microparticles or nanoparticles.

[0163] Tinctures are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in tinctures include solvents. Syrups are concentrated aqueous solutions of sugars (such as sucrose) and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in another as tiny droplets. Pharmaceutically acceptable carriers used in emulsions include non-aqueous liquids, emulsifiers, and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances for non-effervescent granules (requiring formulation into an oral liquid) include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances for preparing effervescent granules that need to be dissolved in water to form an oral liquid include organic acids and carbon dioxide sources. Colorants and flavoring agents are used in all of the above dosage forms.

[0164] Solvents include glycerol, sorbitol, ethanol, and syrup. Preservatives include glycerol, methylparaben and propylparaben, sodium benzoate, and alcohol. Non-aqueous liquids used in the emulsion include mineral oil and cottonseed oil. Emulsifiers include gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspensors include sodium carboxymethyl cellulose, pectin, tragacanth, viggramm, and gum arabic. Diluents include lactose and sucrose. Sweeteners include sucrose, syrup, glycerol, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan oleate, dilaurate, and polyvinyl lauryl ether. Organic additives include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Colorants include any approved, certified water-soluble FD&C dyes and mixtures thereof. Flavorings include natural flavorings extracted from plants such as fruits, as well as mixtures of synthetic compounds that produce a pleasant taste experience.

[0165] For solid dosage forms, solutions such as propylene carbonate, vegetable oils, or triglycerides are encapsulated in gelatin capsules. Details of such solutions and their preparation and encapsulation methods can be found in U.S. Patents 4,328,245, 4,409,239, and 4,410,545. For liquid dosage forms, such as polyethylene glycol solutions, dilution with a sufficient amount of a pharmaceutically acceptable liquid carrier (such as water) can be added to facilitate dosing.

[0166] In addition, liquid or semi-solid formulations can be prepared by dissolving or dispersing the active compound or its salt in vegetable oils, diols, triglycerides, propylene glycol esters (such as propylene carbonate) and other such carriers, and then encapsulating these solutions or suspensions in hard or soft capsule shells. Other available formulations include (but are not limited to) formulations containing the following ingredients: the compounds provided in this patent, dialkylated monoalkylene glycols or polyalkylene glycols (including but not limited to 1,2-dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol), and one or more antioxidants such as di-tert-butyl-p-cresol (BHT), tert-butylhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0167] Other formulations include, but are not limited to, aqueous alcoholic solutions containing pharmaceutically acceptable acetals. The alcohols used in these formulations are any pharmaceutically acceptable, water-miscible solvents containing one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diacetal.

[0168] In all embodiments, the tablet and capsule formulations can be coated according to methods known to those skilled in the art to modulate or delay the dissolution of the active ingredient. For example, conventional enteric coatings such as phenyl salicylate, waxes, and cellulose acetate phthalate can be used.

[0169] B. Injectables, solutions and emulsions

[0170] This invention also relates to non-oral administration, typically referring to subcutaneous, intramuscular, or intravenous injection. Injectable formulations can be prepared in conventional dosage forms, including liquid solutions or suspensions, solid preparations suitable for dissolving in or suspending in a liquid prior to injection, and emulsions. In some embodiments, suspensions are suspensions composed of microparticles or nanoparticles. In some embodiments, emulsions are emulsions composed of microparticles or nanoparticles. Suitable excipients include water, physiological saline, glucose, glycerol, or ethanol. Furthermore, if desired, the pharmaceutical composition to be administered may also contain trace amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, stabilizers, solubilizers, and other similar substances, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrin. This invention also contemplates implanting sustained-release or continuous-release systems to maintain a constant dose. In short, the compounds provided in this invention are dispersed in a solid matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of acrylic acid and methacrylate, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate, with an outer layer of a polymer film, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acetate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, etc. This compound diffuses through the outer polymer membrane during the drug release rate regulation phase. The percentage of the active ingredient in such injectable formulations depends largely on its specific properties, the compound's activity, and the patient's needs. It is insoluble in bodily fluids and contains substances such as vinyl acetate, vinyl chloride, vinyl chloride copolymers of ethylene and propylene, ionic polymers of polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / ethyleneoxyethanol copolymers.

[0171] The composition can be administered via intravenous, subcutaneous, or intramuscular injection. Formulations for non-oral administration include: ready-to-use sterile injections, sterile dry soluble formulations (such as lyophilized powders, which must be mixed with a solvent before use), including subcutaneous tablets, ready-to-use sterile suspensions, sterile dry insoluble formulations (which must be mixed with a carrier before use), and sterile emulsions. The solution can be an aqueous solution or a non-aqueous solution.

[0172] If intravenous administration is used, suitable carriers include physiological saline or phosphate-buffered saline (PBS), as well as solutions containing thickeners and dissolving agents, such as glucose, polyethylene glycol, polypropylene glycol, and mixtures thereof.

[0173] Pharmaceutically acceptable carriers for non-oral formulations include aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifiers, chelating agents, and other pharmaceutically acceptable substances.

[0174] Aqueous carriers include sodium chloride injection, Ringer's solution, isotonic glucose injection, sterile water injection, and glucose Ringer's solution. Non-aqueous carriers for injection include plant-derived fixed oils, cottonseed oil, corn oil, sesame oil, and peanut oil. For injectable formulations packaged in multi-dose containers, if the ingredients contain phenols or phenolic compounds, mercury preparations, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride, and benzalkonium bromide, an antibacterial agent with an antibacterial or antifungal concentration must be added. Isotonic agents include sodium chloride and glucose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspensions and dispersants include sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifiers include polysorbate 80 (TWEEN® 80). Metal ion isolation or chelating agents include EDTA. Pharmaceutical carriers also include ethanol, polyethylene glycol, and propylene glycol for water-soluble formulations, and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0175] The concentration of the active pharmaceutical ingredient has been adjusted to ensure that each injection delivers an effective dose sufficient to produce the intended pharmacological effect. The exact dosage depends on the age, weight, and health condition of the subject or animal, a fact well-known in the field.

[0176] Single-dose injectable formulations are typically packaged in ampoules, vials, or syringes with needles. As is known and customary in the art, all formulations intended for non-oral administration must be kept sterile.

[0177] For example, intravenous or arterial infusion of a sterile aqueous solution containing the active ingredient is an effective route of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active ingredient, which can be injected as needed to produce the desired pharmacological effect.

[0178] Injectable formulations are suitable for both local and systemic administration. Typically, in a therapeutically effective dosage formulation, the concentration of the active compound is at least approximately 0.1% w / w and can reach up to approximately 90% w / w or higher; for example, the concentration of the active ingredient in the treated tissue should be greater than 1% w / w. The active ingredient can be administered as a single dose or divided into several smaller doses administered at intervals. It is understood that the exact dosage and treatment duration depend on the disease being treated and can be empirically determined using known testing protocols or extrapolated from in vivo or in vitro test data. It should be noted that concentration and dosage values ​​may also vary depending on the age of the treated individual. It should be further understood that for any given subject, the specific dosing regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration; and the concentration ranges provided in this invention are merely examples and are not intended to limit the scope or implementation of the claimed formulations.

[0179] The compound can be micronized or otherwise formulated as a suitable agent, or it can be derivatized to prepare a more soluble active product or prodrug. The morphology of the resulting mixture depends on a variety of factors, including the intended route of administration and the solubility of the compound in the chosen carrier or solvent. The effective concentration is sufficient to relieve the symptoms of the disease and can be determined empirically.

[0180] C. Lyophilized powder

[0181] This invention also relates to lyophilized powders, which, after reconstitution, can be administered in the form of solutions, emulsions, and other mixed formulations. They can also be formulated into solids or gels after reconstitution.

[0182] The sterile lyophilized powder is prepared by dissolving the compound provided by the present invention or a pharmaceutically acceptable salt thereof in a suitable solvent. The solvent may contain excipients to improve the stability of the powder or a reconstituted solution prepared from the powder, or other pharmacological components. Excipients that may be used include, but are not limited to, glucose, sorbitol, fructose, corn syrup, xylitol, glycerol, glucose, sucrose, or other suitable reagents. The solvent may also contain a buffer, such as citrate, sodium phosphate, or potassium phosphate, or other such buffers known to those skilled in the art, and in one embodiment, the pH is approximately neutral. The solution is then sterilely filtered and lyophilized under standard conditions well known to those skilled in the art to obtain the desired formulation. Typically, the resulting solution is dispensed into vials for lyophilization. Each vial will contain a single dose (including, but not limited to, 10-1000 mg or 100-500 mg) or multiple doses of the compound. The lyophilized powder can be stored under suitable conditions, such as between about 4°C and room temperature.

[0183] The lyophilized powder can be dissolved in water for injection to prepare a formulation for non-oral administration. For reconstitution, approximately 1-50 mg, 5-35 mg, or 9-30 mg of the lyophilized powder is added per milliliter of sterile water or other suitable solvent. The specific dosage depends on the compound selected. This value can be determined empirically.

[0184] D. Topical administration

[0185] The preparation method of the external mixture is the same as that described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, or similar preparation, and may be formulated as a cream, gel, ointment, lotion, solution, tincture, paste, suspension, ointment, foam, aerosol, rinse, spray, suppository, dressing, transdermal patch, or any other preparation suitable for local administration.

[0186] The compounds provided by this invention, or pharmaceutically acceptable salts thereof, can be formulated into aerosols for topical administration, such as by inhalation (see U.S. Patent Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids that can be used to treat inflammatory diseases, particularly asthma). These formulations for inhalation can be aerosols or nebulizer solutions, or ultrafine powders for nasal inhalation, and can be used alone or mixed with inert carriers such as lactose. In this case, the particle diameter of the formulation will be less than 50 micrometers or less than 10 micrometers.

[0187] The compounds provided by this invention can be formulated into topical or external preparations, for example, in the form of gels, creams, and lotions for external application to the skin and mucous membranes (such as the eyes), or for ocular, intraventricular, or intraspinal administration. Topical administration is suitable for transdermal administration, as well as ocular or mucous membrane administration, or for inhalation therapy. Administration can also be performed using nasal solutions containing only the active ingredient or in combination with other excipients that meet the required standards.

[0188] These solutions, especially those for ophthalmology, can be prepared as isotonic solutions of 0.01% to 10%, with a pH of approximately 5-7, and containing appropriate salts.

[0189] E. Mixtures suitable for other routes of administration

[0190] The present invention also considers other routes of administration, such as topical application, transdermal patches and rectal administration.

[0191] For example, pharmaceutical dosage forms for rectal administration include rectal suppositories, capsules, and tablets that produce systemic effects. Rectal suppositories, as referred to in this invention, are solid preparations for insertion into the rectum that melt or soften at body temperature, thereby releasing one or more components with pharmacological or therapeutic activity. Pharmaceutically acceptable substances used in rectal suppositories include a matrix or carrier, and substances used to increase the melting point. Matrixes include cocoa butter, glycerin gelatin, polyethylene glycol (polyoxyethylene glycol), and suitable mixtures of fatty acid monoglycerides, diglycerides, and triglycerides. A variety of different base combinations can be used. Agents for increasing the melting point of suppositories include cetylene and waxes. Rectal suppositories can be prepared by compression or molding. Examples of rectal suppositories weigh approximately 2 to 3 grams.

[0192] Tablets and capsules for rectal administration use the same pharmaceutically acceptable substances and are prepared using the same methods as oral formulations.

[0193] F. Sustained-release composition

[0194] The active ingredients provided by this invention can be administered via controlled-release methods or delivery devices well known to those skilled in the art. Examples include, but are not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and U.S. Patent Nos. 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,9 Those described in 22,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500, and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients in varying proportions using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeation systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, thereby providing a desired release profile. Suitable controlled-release formulations known to those skilled in the art, including those provided in this invention, can be readily selected for use with the active ingredients provided in this invention.

[0195] The common goal of all controlled-release pharmaceutical products is to improve the therapeutic effect of drugs, making them superior to non-controlled-release products. In one embodiment, the use of an optimized controlled-release formulation in medical treatment is characterized by curing or controlling the condition in the shortest time with the least amount of drug. In some embodiments, the advantages of controlled-release formulations include prolonged duration of drug action, reduced dosing frequency, and improved patient compliance. Furthermore, controlled-release formulations can be used to influence the onset time of drug action or other properties, such as drug blood concentration, thereby affecting the occurrence of side effects (such as adverse reactions).

[0196] Most controlled-release formulations are designed to initially release a certain amount of drug (active ingredient) to rapidly produce the desired therapeutic effect, and then gradually and continuously release additional amounts of drug to maintain this level of therapeutic or preventative effect over a longer period. To maintain a constant drug concentration in the body, the drug must be released from the dosage form at a rate sufficient to replace the amount metabolized and excreted. Controlled release of the active ingredient can be triggered by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0197] In some embodiments, the reagent may be administered via intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other delivery methods. In one embodiment, a pump may be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J.Med. 321:574 (1989)). In another embodiment, a polymeric material may be used. In yet another embodiment, the controlled-release system may be placed near the therapeutic target, requiring only a fraction of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, Vol. 2, pp. 115–138 (1984)).

[0198] In some embodiments, the controlled-release device is introduced into the subject, near a site of inappropriate immune activation or a tumor site. Other controlled-release systems are discussed in Langer's review (Science 249:1527-1533 (1990)). The active ingredient may be dispersed in a solid internal matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as acrylic acid and methacrylate hydrogels, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate, surrounded by an external coating. Polymer membranes, such as polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride and vinyl acetate, vinylidene chloride, copolymers of ethylene and propylene, ionomers such as polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / ethyleneoxyethanol copolymers, are insoluble in bodily fluids. The active ingredient then diffuses through the external polymer membrane in steps controlled by the release rate. The percentage of the active ingredient in such parenteral compositions is highly dependent on their specific properties and the needs of the subject.

[0199] G. Targeted formulations

[0200] The compounds provided by this invention, or their pharmaceutically acceptable salts, can also be formulated to target specific tissues, receptors, or other therapeutic areas within a subject, including liposome-based, resealed red blood cell, and antibody-based delivery systems. Many such targeting methods are well known to those skilled in the art. All such targeting methods are considered for use in the compositions provided by this invention. For non-limiting embodiments of the targeting method, please refer to, for example, U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0201] In one embodiment, the antibody-based delivery system is an antibody-drug conjugate (“ADC”), as described in Hamilton GS, Biologicals, Sep 2015, 43(5):318-32; Kim EG and Kim KM, Biomol. Ther. (Seoul), Nov 2015, 23(6):493-509; and Peters C and Brown S, Biosci. Rep., 12 June 2015, 35(4) pii: e00225, each of which is incorporated herein by reference.

[0202] In one embodiment, liposome suspensions, including tissue-targeting liposomes such as tumor-targeting liposomes, can also serve as druggable carriers. These can be prepared according to methods well known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Patent No. 4,522,811. Briefly, multilayer vesicles (MLVs) are formed by drying egg yolk phosphatidylcholine and cephalinositol serine (7:3 molar ratio) inside a flask. A solution of the compound provided by the present invention in phosphate-buffered saline (PBS) free of divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, precipitated by centrifugation, and then resuspended in PBS.

[0203] H. Products

[0204] The compound or its pharmaceutically acceptable salt may be packaged into an article comprising packaging material, the compound or its pharmaceutically acceptable salt provided by the present invention for treating, preventing or improving symptoms or progression of one or more diseases or disorders provided by the present invention, and a label indicating that the compound or its pharmaceutically acceptable salt is used for treating, preventing or improving symptoms or progression of one or more diseases or disorders provided by the present invention.

[0205] The articles of manufacture provided by this invention comprise packaging materials. Packaging materials for packaging pharmaceuticals are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, pens, bottles, and any packaging material suitable for the selected formulation and the intended mode of administration and treatment. A wide range of formulations of the compounds and compositions provided by this invention are contemplated herein.

[0206] In some embodiments, kits are also provided herein that, when used by medical practitioners, simplify the process of administering an appropriate amount of the active ingredient to a subject. In some embodiments, the kits provided by the present invention include a container and a dosage form of the compound provided by the present invention, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0207] In some embodiments, the kit includes a container containing a dosage form of a compound provided by the present invention, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, containing one or more other therapeutic agents provided by the present invention in a single container.

[0208] The kits provided by this invention may also include devices for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needle-free injectors, drop bags, patches, and inhalers. The kits provided by this invention may also include condoms for administering the active ingredient.

[0209] The kits provided by this invention may also include pharmaceutically acceptable carriers for administering one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reformulated for parenteral administration, the kit may include a sealed container containing a suitable carrier in which the active ingredient can be dissolved to form a particulate-free, sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable carriers include, but are not limited to: aqueous carriers, including but not limited to water for injection (USP), sodium chloride injection, Ringer's solution, glucose injection, glucose and sodium chloride injection, and lactated Ringer's solution; water-miscible carriers, including but not limited to ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous carriers, including but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0210] V. Administration

[0211] The compounds and pharmaceutical compositions provided by this invention can be administered in specific therapeutic or preventative amounts, at specific time intervals, in specific dosage forms, and in specific methods of administration as described below.

[0212] In some embodiments, the therapeutic or preventative effective amount of the compound is about 0.005 to about 1,000 mg per day, about 0.01 to about 500 mg per day, about 0.01 to about 250 mg per day, about 0.01 to about 100 mg per day, about 0.1 to about 100 mg per day, about 0.5 to about 100 mg per day, about 1 to about 100 mg per day, about 0.01 to about 50 mg per day, about 0.1 to about 50 mg per day, about 0.5 to about 50 mg per day, about 1 to about 50 mg per day, about 0.02 to about 25 mg per day, about 0.05 to about 10 mg per day, about 0.05 to about 5 mg per day, about 0.1 to about 5 mg per day, or about 0.5 to about 5 mg per day.

[0213] In some embodiments, the effective dose for treatment or prevention is approximately 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 45, 50, 60, 70, 80, 90, 100, or 150 mg per day.

[0214] In one embodiment, the recommended daily dose range of the compound or its derivatives provided by the present invention for the condition provided by the present invention is between about 0.5 mg and 50 mg per day, in one embodiment being a single dose once daily or divided into several doses throughout the day. In some embodiments, the dose range is between about 1 mg and 50 mg per day. In other embodiments, the dose range is between about 0.5 mg and 5 mg per day. Specific daily doses include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / day.

[0215] In one specific embodiment, a recommended starting dose may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, or 50 mg daily. In another specific embodiment, a recommended starting dose may be 0.5, 1, 2, 3, 4, or 5 mg daily. The dose may be gradually increased to 15, 20, 25, 30, 35, 40, 45, and 50 mg / day. In one specific embodiment, the compound may be administered at a dose of about 25 mg / day. In one specific embodiment, the compound may be administered at a dose of about 10 mg / day. In one specific embodiment, the compound may be administered at a dose of about 5 mg / day. In one specific embodiment, the compound may be administered at a dose of about 4 mg / day. In one specific embodiment, the compound may be administered at a dose of about 3 mg / day.

[0216] In some embodiments, the therapeutic or preventative effective dose is about 0.001 to about 100 mg / kg per day, about 0.01 to about 50 mg / kg per day, about 0.01 to about 25 mg / kg per day, about 0.01 to about 10 mg / kg per day, about 0.01 to about 9 mg / kg per day, about 0.01 to about 8 mg / kg per day, about 0.01 to about 7 mg / kg per day, about 0.01 to about 6 mg / kg per day, about 0.01 to about 5 mg / kg per day, about 0.01 to about 4 mg / kg per day, about 0.01 to about 3 mg / kg per day, about 0.01 to about 2 mg / kg per day, about 0.01 to about 1 mg / kg per day, or about 0.01 to about 0.05 mg / kg per day.

[0217] Dosage can also be expressed in units other than mg / kg / day. For example, the dose for parenteral administration can be expressed in mg / m² / day. Those skilled in the art will readily know how to convert the dose from mg / kg / day to mg / m² / day based on the subject's height or weight, or both (see www.fda.gov / cder / cancer / animalframe.htm). For example, for a 65 kg human, a dose of 1 mg / kg / day is approximately equal to 38 mg / m² / day.

[0218] In some embodiments, the amount of compound administered is sufficient to provide a steady-state plasma concentration of the compound, ranging from about 0.001 to about 500 micromoles, about 0.002 to about 200 micromoles, about 0.005 to about 100 micromoles, about 0.01 to about 50 micromoles, about 1 to about 50 micromoles, about 0.02 to about 25 micromoles, about 0.05 to about 20 micromoles, about 0.1 to about 20 micromoles, about 0.5 to about 20 micromoles, or about 1 to about 20 micromoles.

[0219] In other embodiments, the amount of compound administered is sufficient to provide a steady-state plasma concentration of the compound, ranging from about 5 to about 100 nanomoles, about 5 to about 50 nanomoles, about 10 to about 100 nanomoles, about 10 to about 50 nanomoles, or about 50 to about 100 nanomoles.

[0220] As used herein, the term "steady-state plasma concentration" refers to the concentration reached some time after administration of the compound or its derivatives provided by this invention. Once steady state is reached, the curve of the compound's plasma concentration over time will show small peaks and troughs.

[0221] In some embodiments, the amount of compound administered is sufficient to provide the maximum plasma concentration (peak concentration) of the compound, ranging from about 0.001 to about 50 μmol, about 0.002 to about 200 μmol, about 0.005 to about 100 μmol, about 0.01 to about 50 μmol, about 1 to about 50 μmol, about 0.02 to about 25 μmol, about 0.05 to about 20 μmol, about 0.1 to about 20 μmol, about 0.5 to about 20 μmol, or about 1 to about 20 μmol.

[0222] In some embodiments, the amount of compound administered is sufficient to provide the lowest plasma concentration (trough concentration) of the compound, ranging from about 0.001 to about 500 micromoles, about 0.002 to about 200 micromoles, about 0.005 to about 100 micromoles, about 0.01 to about 50 micromoles, about 1 to about 50 micromoles, about 0.01 to about 25 micromoles, about 0.01 to about 20 micromoles, about 0.02 to about 20 micromoles, about 0.02 to about 20 micromoles, or about 0.01 to about 20 micromoles.

[0223] In some embodiments, the amount of compound administered is sufficient to provide the area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 nanograms per milliliter, about 1,000 to about 50,000 nanograms per milliliter, about 5,000 to about 25,000 nanograms per milliliter, or about 5,000 to about 10,000 nanograms per milliliter.

[0224] The methods provided by this invention cover the treatment of patients, regardless of the age of the subject, although certain diseases or disorders are more common in certain age groups.

[0225] Depending on the disease to be treated and the condition of the subject, the compounds or derivatives thereof provided by this invention can be administered orally, via non-enteric routes (such as intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or inhalation, nasal, vaginal, rectal, sublingual, or local routes (such as transdermal or local). The compounds or derivatives thereof provided by this invention can be formulated alone or together into appropriate dosage units suitable for each route of administration and contain pharmaceutically acceptable excipients, carriers, adjuvants, and solvents.

[0226] In one embodiment, the compound or its derivative provided by the present invention is administered orally. In another embodiment, the compound or its derivative provided by the present invention is administered parenterally. In yet another embodiment, the compound or its derivative provided by the present invention is administered intravenously.

[0227] The compounds or derivatives thereof provided by this invention may be administered as a single dose, such as a single bolus injection or oral tablet or pill; or as a time-dependent dose, such as a continuous infusion over time or a fractionated bolus dose over time. If necessary, the compound may be repeatedly administered, for example, until the subject's condition is stable or remission, or until the subject's condition progresses or unacceptable toxicity occurs. For example, stable condition in solid tumors is generally defined as the measurable vertical diameter of the lesion not increasing by 25% or more from the last measurement. See the RECIST guidelines, Journal of the National Cancer Institute 92(3): 205-216 (2000). Stable condition or lack thereof is determined by methods known in the art, such as assessment of patient symptoms, physical examination, visualization of the imaged tumor using X-ray, CAT, PET, or MRI scans, and other commonly used assessment methods.

[0228] The compounds or derivatives thereof provided by this invention can be administered once daily (QD) or in multiple daily doses, such as twice daily (BID), three times daily (TID), and four times daily (QID). Furthermore, administration can be continuous (i.e., administered for several consecutive days or daily), intermittent, or cyclical (i.e., including periods of several days, weeks, or months of rest). As used herein, the term "daily" is intended to mean administering the therapeutic compound, such as the compounds or derivatives thereof provided by this invention, once or multiple times daily for a period of time. The term "continuous" is intended to mean administering the therapeutic compound, such as the compounds or derivatives thereof provided by this invention, daily without interruption for at least 10 days to 52 weeks. As used herein, the terms "intermittent" or "intermittently" are intended to mean periodically or irregularly stopping and restarting administration. For example, intermittent administration of the compounds or derivatives thereof provided by this invention may be one to six days per week, cyclical (e.g., daily administration for two to eight consecutive weeks, followed by a rest period of up to one week), or every other day. As used herein, the term "cyclical" is intended to mean daily or continuous administration of the therapeutic compound, such as the compounds or derivatives thereof provided by this invention, but with rest periods. In some of these embodiments, the drug is administered daily for one to six days, followed by a five- to seven-day withdrawal period.

[0229] In some embodiments, the dosing frequency ranges from approximately once daily to once monthly. In certain specific embodiments, the dosing frequency is once daily, twice daily, three times daily, four times daily, every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound or its derivative provided by the present invention is administered once daily. In another embodiment, the compound or its derivative provided by the present invention is administered twice daily. In yet another embodiment, the compound or its derivative provided by the present invention is administered three times daily. In still another embodiment, the compound or its derivative provided by the present invention is administered four times daily.

[0230] In some embodiments, the compound or its derivative provided by the present invention is administered once daily for a duration of 1 day to 6 months, 1 week to 3 months, 1 week to 4 weeks, 1 week to 3 weeks, or 1 week to 2 weeks. In some embodiments, the compound or its derivative provided by the present invention is administered once daily for 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, the compound or its derivative provided by the present invention is administered once daily for 4 days. In one embodiment, the compound or its derivative provided by the present invention is administered once daily for 5 days. In one embodiment, the compound or its derivative provided by the present invention is administered once daily for 6 days. In one embodiment, the compound or its derivative provided by the present invention is administered once daily for 1 week. In another embodiment, the compound or its derivative provided by the present invention is administered once daily for 2 weeks. In yet another embodiment, the compound or its derivative provided by the present invention is administered once daily for 3 weeks. In still another embodiment, the compound or its derivative provided by the present invention is administered once daily for 4 weeks.

[0231] VI. Treatment Methods

[0232] In another embodiment, a method is provided for treating a cancer subject by administering a compound or composition provided by the present invention. In one embodiment, the cancer is a survivin-expressing or overexpressing cancer. In another embodiment, the cancer is leukemia, lung cancer (including non-small cell lung cancer), colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, or breast cancer. In another embodiment, the cancer is glioma or glioblastoma.

[0233] In another embodiment, a method for inducing apoptosis by administering a compound or composition provided by the present invention is provided. In another embodiment, a method for degrading survivin by contacting survivin or a composition containing survivin with a compound or composition provided by the present invention is provided. In another embodiment, the survivin to be degraded is any one of survivin, suirvivin-2B, survivin-delta-ex-3, and survivin-3B.

[0234] In another embodiment, a method is provided for treating a cancer subject by administering a compound or composition provided by the present invention in combination with radiotherapy. In one embodiment, the cancer is a survivin-expressing or overexpressing cancer. In another embodiment, the cancer is leukemia, lung cancer (including non-small cell lung cancer), colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, or breast cancer. In another embodiment, the cancer is glioma or glioblastoma. In yet another embodiment, a method is provided for enhancing the efficacy of cancer radiotherapy by administering a compound or composition provided by the present invention to a subject receiving cancer radiotherapy.

[0235] VII. Combination therapy with a second active ingredient

[0236] The compounds or their derivatives provided by this invention may also be used in combination or in combination with other therapeutic agents for cancer treatment and / or prevention.

[0237] In one embodiment, this document provides a method for treating, preventing, or managing cancer, comprising administering to a subject a compound or a derivative thereof provided by the present invention, in combination with one or more second active ingredients. Those skilled in the art will understand that the choice of the second active ingredient depends on the type of cancer to be treated. Those skilled in the art can readily determine a suitable second active ingredient for a specific cancer.

[0238] As used herein, the term "combination" includes the use of multiple therapies (e.g., one or more preventative and / or therapeutic agents). However, the use of the term "combination" does not limit the order in which therapies (e.g., preventative and / or therapeutic agents) are administered to a subject with a disease or disorder. The first therapy (e.g., a prophylactic or therapeutic agent, such as the compounds provided in this invention, or derivatives thereof) may be administered to the subject before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to) the second therapy (e.g., a prophylactic or therapeutic agent), simultaneously with, or subsequently (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to) the second therapy (e.g., a prophylactic or therapeutic agent). Triple therapy is also considered herein.

[0239] The compounds or derivatives thereof provided by this invention may be administered to the subject simultaneously or sequentially via the same or different routes of administration. The suitability of a particular route of administration depends on the specific active ingredient itself (e.g., whether it can be administered orally without being broken down before entering the bloodstream) and the disease or disorder being treated.

[0240] The routes of administration for the compounds or derivatives thereof provided by this invention are independent of the routes of administration for the second therapy. In one embodiment, the compounds or derivatives thereof provided by this invention are administered orally. In another embodiment, the compounds or derivatives thereof provided by this invention are administered intravenously. Thus, according to these embodiments, the compounds or derivatives thereof provided by this invention are administered orally or intravenously, while the second therapy may be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, liposomes, by inhalation, vaginally, intraocularly, locally via catheter or stent, subcutaneously, intrafatally, intra-articularly, intrathecally, or in a sustained-release formulation. In one embodiment, the compounds or derivatives thereof provided by this invention are administered by the same route of administration as the second therapy, either orally or intravenously. In another embodiment, the compounds or derivatives thereof provided by this invention are administered by one route of administration, such as intravenously, while the second agent is administered by another route of administration, such as orally.

[0241] In one embodiment, the second active ingredient is administered intravenously or subcutaneously once or twice daily in a dose of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. The specific dosage of the second active ingredient depends on the specific pharmaceutical agent used, the type, severity, and stage of the disease being treated or managed, the dosage of the compound or its derivative provided by the present invention, and any optional additional active ingredients administered concurrently to the subject.

[0242] In the methods and compositions provided by this invention, one or more second active ingredients or agents may be used in combination with the compounds or derivatives thereof provided by this invention. The second active ingredient may be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule). In one embodiment, the second active ingredient is temozolomide (TMZ).

[0243] Examples of macromolecular active ingredients include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly therapeutic antibodies against cancer antigens. Typical macromolecular active ingredients are biomolecules, such as naturally occurring, synthetic, or recombinant proteins.

[0244] In one embodiment, the compound or its derivative provided by the present invention may be administered orally alone once daily in a dose range of about 0.1 to about 150 mg, about 1 to about 25 mg, or about 2 to about 10 mg, or in combination with a second active ingredient, before, during, or after conventional therapy.

[0245] VIII. Examples

[0246] The following examples are intended to illustrate some embodiments provided by the present invention, and are not intended to limit the scope of this disclosure.

[0247] Example 1

[0248] Preparation of compound 2

[0249]

[0250] At 10–25 °C, DIEA (40.9 g, 317 mmol, 55.2 mL, 5.00 equivalence) and SEM-Cl (31.7 g, 190 mmol, 33.6 mL, 3.00 equivalence) were added to a DMF (158 mL) solution of compound 1 (22.5 g, 63.4 mmol, 1.00 equivalence). The black mixture was then stirred at 10–25 °C for 2 hours. LC-MS showed complete consumption of compound 1 and detection of the target compound. The reaction mixture was quenched at 20–30 °C with 300 mL of aqueous NH4Cl solution and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with aqueous NaCl (100 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1), and TLC (plate 1: petroleum ether: ethyl acetate = 3:1, Rf(P1) = 0.2) yielded a black colloidal oil, which was confirmed by 1H NMR and LCMS. Then, 100 mL of MTBE was added to the oil and the mixture was concentrated under reduced pressure to give compound 2 (29.3 g, black colloidal oil).

[0251] 1H NMR (DMSO) δ 8.25 (dd, J = 7.76, 5.93 Hz, 1 H), 7.71 (d, J = 7.83 Hz, 1 H), 5.30 (dd, J = 13.08, 5.38 Hz, 1 H), 5.08 (s, 2 H), 3.43 - 3.61 (m, 2 H), 2.95 - 3.09 (m, 1H), 2.76 - 2.87 (m, 1 H), 2.51 - 2.60 (m, 1 H), 2.09 (m, 1 H), 0.84 (dtd, 2 H), -0.02 (s, 9H).

[0252] Example 2

[0253] Preparation of compound 3

[0254]

[0255] Compound 2 (5.00 g, 10.3 mmol, 1.00 equivalence), tert-butylpiperazine-1-carboxylate (2.30 g, 12.4 mmol, 1.20 equivalence), RuPhos (481 mg, 1.03 mmol, 0.10 equivalence), RuPhos-PdG2 (800 mg, 1.03 mmol, 0.10 equivalence), and cesium carbonate (6.71 g, 20.6 mmol, 2.00 equivalence) were dissolved in dioxane (50.0 mL) and stirred at 80–90 °C for 4 h under nitrogen protection. Liquid chromatography-mass spectrometry (LC-MS) showed complete consumption of compound 2 and detection of the target mass. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (70.0 mL × 3). The organic layers were combined, washed with brine (100 mL × 1), filtered, and concentrated under reduced pressure to give 22.0 g of residue. The residue was purified by preparative thin-layer chromatography (SiO2, plate 1: petroleum ether: ethyl acetate = 1 / 1, Rf(P1) = 0.3) to obtain a yellow oil, which was confirmed by 1H nuclear magnetic resonance (NMR) and LCMS. The oil was then concentrated under reduced pressure to give compound 3 (4.21 g, yellow solid).

[0256] ¹H NMR (dimethyl sulfoxide (DMSO)) δ 7.65 (doublet, J = 8.00 Hz, 1 hydroxyl group), 7.40 (triplet, J = 7.82 Hz, 1 hydroxyl group), 5.23 (doublet, J = 13.07, 5.44 Hz, 1 hydroxyl group), 5.07 (singlet, 2 hydroxyl groups), 3.44 - 3.59 (multiplet, 6 hydroxyl groups), 3.14 - 3.23 (multiplet, 4 hydroxyl groups), 2.96 - 3.08 (multiplet, 1 hydroxyl group), 2.74 - 2.84 (multiplet, 1 hydroxyl group), 2.54 - 2.62 (multiplet, 1 hydroxyl group), 2.02 - 2.11 (multiplet, 1 hydroxyl group), 1.43 (singlet, 9 hydroxyl groups), 0.84 (triplet, doublet, J = 13.07, 5.44 Hz, 1 hydroxyl group), δ 7.65 (doublet, J = 8.00 Hz, 1 hydroxyl group), 7.40 (triplet, J = 7.82 Hz, 1 hydroxyl group), 5.23 (doublet, J = 13.07, 5.44 Hz, 1 hydroxyl group), δ 7.65 (doublet, J = 8.00 Hz, 1 hydroxyl group), δ 7.40 (triplet, J = 7.82 ... 9.26, 6.94, 2.31 Hz (2 hydrogens), -0.02 (single peak, 9 hydrogens).

[0257] Example 3

[0258] Preparation of compound 4

[0259]

[0260] To a solution of compound 3 (4.10 g, 6.94 mmol, 1.00 equivalence) in acetonitrile (ACN, 41.0 mL), benzenesulfonic acid (5.49 g, 34.7 mmol, 5.00 equivalence) was added. The mixture was stirred at 50–60 °C for 2 h. LCMS showed complete consumption of compound 3 and detection of an intermediate. Triethylamine (TEA, 3.51 g, 34.7 mmol, 4.83 mL, 5.00 equivalence) and N,N'-dimethylethylenediamine (DMEDA, 795 mg, 9.02 mmol, 971 μL, 1.30 equivalence) were added at 0–10 °C, followed by stirring at 20–30 °C for 1 h. LCMS showed complete consumption of the intermediate and detection of a second intermediate. Then, TEA (4.21 g, 41.6 mmol, 5.80 mL, 6.00 equivalence) and di-tert-butyl dicarbonate (Boc₂O, 7.57 g, 34.7 mmol, 7.97 mL, 5.00 equivalence) were added at 20–30 °C, and the mixture was stirred at 20–30 °C for 4 hours. LC-MS showed complete consumption of the second intermediate and detection of the target compound. The reaction mixture was diluted with water (60.0 mL) and extracted with ethyl acetate (40.0 mL × 2). The organic layers were combined, washed with brine (30.0 mL × 1), dried over sodium sulfate (Na₂SO₄), filtered, and concentrated under reduced pressure to give a yellow oil. The oily substance was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to ethyl acetate / dichloromethane (DCM) = 1 / 1, plate 1: petroleum ether: ethyl acetate = 1 / 1, Rf(P1) = 0.2) to give compound 4 (1.94 g, yellow solid), which was confirmed by LCMS and 1H NMR.

[0261] ¹H NMR (DMSO) δ 11.11 (single, 1 hydroxyl group), 7.65 (doublet, J = 8.07 Hz, 1 hydroxyl group), 7.39 (triplet, J = 7.70 Hz, 1 hydroxyl group), 5.10 (doublet, J = 12.78, 5.32 Hz, 1 hydroxyl group), 3.50 (broad singlet, 4 hydroxyl groups), 3.20 (broad doublet, J = 4.77 Hz, 4 hydroxyl groups), 2.80 - 2.95 (multiplexes, 1 hydroxyl group), 2.51 - 2.69 (multiplexes, 2 hydroxyl groups), 1.99 - 2.08 (multiplexes, 1 hydroxyl group), 1.43 (singlet, 9 hydroxyl groups)

[0262] Example 4

[0263] Preparation of compound 5

[0264]

[0265] To a solution of compound 4 (1.70 g, 3.69 mmol, 1 equivalent) in acetonitrile (17.0 mL), benzenesulfonic acid (706 mg, 4.46 mmol, 1.21 equivalent) was added. The mixture was stirred at 50–60 °C for 1 h. LCMS showed complete consumption of compound 4 and the target mass was detected. Two such reactions were combined for post-processing. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to give compound 5 (1.90 g, yellow solid containing benzenesulfonic acid (PhSO3H)), confirmed by LCMS and 1H NMR.

[0266] ¹H NMR (DMSO) δ 11.12 (single, 1 hydroxyl), 8.76 (broad singlet, 2 hydroxyl), 7.69 (doublet, J = 8.07 Hz, 1 hydroxyl), 7.57 - 7.64 (multiplet, 2 hydroxyl), 7.48 (triplet, J = 7.76 Hz, 1 hydroxyl), 7.27 - 7.36 (multiplet, 3 hydroxyl), 5.11 (double doublet, J = 12.84, 5.38 Hz, 1 hydroxyl), 3.40 - 3.46 (multiplet, 4 hydroxyl), 3.30 (broad singlet, 4 hydroxyl), 2.81 - 2.97 (multiplet, 1 hydroxyl), 2.52 - 2.68 (multiplet, 2 hydroxyl), 1.99 - 2.08 (multiplet, 1 hydroxyl).

[0267] Example 5

[0268] Preparation of compound 8

[0269]

[0270] Compound 6 (13.0 g, 52.1 mmol, 1.00 equivalence), 3-benzyloxybenzaldehyde (compound 7, 16.6 g, 78.2 mmol, 1.50 equivalence), methyl cyanoacetate (7.75 g, 78.2 mmol, 6.90 mL, 1.50 equivalence), and ammonium acetate (20.1 g, 260 mmol, 5.00 equivalence) were dissolved in ethanol (EtOH, 195 mL) and stirred at 75–85 °C for 14 h. LC-MS showed complete consumption of compound 6 and detection of the target compound. The reaction mixture was added to 39.0 mL of water, filtered, the filter cake was washed with ethanol (39.0 mL), and concentrated under reduced pressure to give the residue. The residue was then purified by reversed-phase high-performance liquid chromatography (HPLC, neutral conditions, column: Kromasil Eternity XT 250 x 80 mm x 10 μm; mobile phase: (water (ammonium bicarbonate (NH4HCO3)) - acetonitrile (ACN)); gradient: B from 30% to 60% over 20 min). It was then concentrated under reduced pressure to give a yellow solid. The solid was dissolved in 1200 mL of dichloromethane / methanol (DCM / MeOH, 3 / 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 8 (11.1 g, yellow solid), confirmed by LCMS.

[0271] Example 6

[0272] Preparation of compound 9

[0273]

[0274] Compound 8 (4.00 g, 7.88 mmol, 1.00 equivalence), 4-(dimethoxymethyl)piperidine (1.88 g, 11.8 mmol, 1.50 equivalence), tris(dibenzylideneacetone)palladium (Pd2(dba)3, 721 mg, 0.787 mmol, 0.10 equivalence), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 981 mg, 1.58 mmol, 0.20 equivalence), and cesium carbonate (3.85 g, 11.8 mmol, 1.50 equivalence) were dissolved in N,N-dimethylformamide (DMF, 40.0 mL) and stirred at 115–125 °C for 2 hours under nitrogen protection. LCMS and thin-layer chromatography (TLC, plate 1: petroleum ether: ethyl acetate = 1 / 2, Rf(R1) = 0.2) showed compound 8 remaining and the target compound was detected. The reaction mixture was quenched at 20–30 °C with water (120 mL) and sodium chloride aqueous solution (20 mL), then filtered and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with sodium chloride aqueous solution (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (neutral conditions, column: Kromasil Eternity XT 250 x 80 mm x 10 μm; mobile phase: (water (NH₄HCO₃)-ACN); gradient: B from 25% to 55% over 20 min). The mixture was then concentrated under reduced pressure to remove acetonitrile and most of the water. 50 mL of sodium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 9 (1.38 g, brown solid), which was confirmed by LCMS.

[0275] Example 7

[0276] Preparation of compound 10

[0277]

[0278] Hydrochloric acid (HCl, 3 mol / L, 11.1 mL, 10.0 equivalent) was added to a tetrahydrofuran (THF, 11.0 mL) solution of compound 9 (1.95 g, 3.33 mmol, 1.00 equivalent), and the mixture was stirred at 30–40 °C for 2 h. LCMS showed that compound 9 remained and a main peak with the target mass was detected. Hydrochloric acid (3 mol / L, 2.00 mL, 1.80 equivalent) was added, and the mixture was stirred at 30–40 °C for 1 h. LCMS showed that compound 9 remained and a main peak with the target mass was detected. The pH was adjusted to 7–8 by adding a 15% aqueous solution of sodium hydroxide and sodium bicarbonate to the black reaction mixture at 10–20 °C, and then extracted with dichloromethane / methanol (3 / 1, 40.0 mL × 3). The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 10 (1.83 g, brown solid), which was confirmed by LCMS.

[0279] Example 8

[0280] Preparation of compound 11

[0281]

[0282] At 0–10 °C, a solution of compound 10 (344 mg, 637 μmol, 1.00 equivalence), compound 5b (364 mg, 702 μmol, 1.10 equivalence, containing PhSO3H), sodium acetate (NaOAc, 68.0 mg, 829 μmol, 1.30 equivalence), acetic acid (AcOH, 383 mg, 6.38 mmol, 365 μL, 10.0 equivalence) in dichloromethane (1.80 mL) and ethanol (1.80 mL) was added over 4 minutes in three batches, 2 minutes apart. The mixture was then stirred at 0–10 °C for 4 hours. LC-MS showed complete consumption of compound 10 and a main peak with the target mass was detected. At 20–30 °C, an aqueous sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 7–8, followed by extraction with dichloromethane (10.0 mL × 3). The organic layers were combined, washed with 8.00 mL of an aqueous sodium chloride solution, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a brown solid. Two batches of the brown solid were purified by preparative HPLC (neutral conditions, column: Kromasil Eternity XT 250 x 80 mm x 10 μm; mobile phase: (water (NH₄HCO₃)-ACN); gradient: B from 32% to 62% over 20 min). The purified compound was then concentrated under reduced pressure to give compound 11 (330 mg, orange solid), confirmed by LC-MS, HPLC, 1H NMR, and specific NMR.

[0283] Example 9

[0284] Preparation of compound 11

[0285]

[0286] At 0–10 °C, a solution of compound 10 (1.35 g, 2.50 mmol, 1.00 equivalence), compound 5 (1.43 g, 2.75 mmol, 1.10 equivalence, benzenesulfonic acid), sodium acetate (267 mg, 3.25 mmol, 1.30 equivalence), acetic acid (1.50 g, 25.0 mmol, 1.43 mL, 10.0 equivalence) in dichloromethane (7.00 mL) and ethanol (3.50 mL) was added in three portions (2 min apart) to a solution of pyridineborane (165 mg, 1.78 mmol, 178 μL, 0.71 equivalence) in dichloromethane (3.50 mL), continuously for 4 min. The mixture was then stirred at 0–10 °C for 4 h. Liquid chromatography-mass spectrometry (LC-MS) showed that compound 10 was completely consumed and a main peak with the target mass was detected. The reaction mixture was quenched by adding an aqueous sodium bicarbonate solution and adjusting the pH to 7-8 at 20-30°C, followed by extraction with dichloromethane / methanol (3 / 1, 40.0 mL × 3). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative high-performance liquid chromatography (prep-HPLC) (neutral conditions, column: Kromasil Eternity XT 250 x 80 mm x 10 µm; mobile phase: (water (ammonium bicarbonate)-acetonitrile); gradient: B from 32% to 62% over 20 min). The compound was then concentrated under reduced pressure to give compound 11 (916 mg, yellow solid), which was confirmed by LCMS, HPLC, and 1H NMR.

[0287] ¹H NMR (dimethyl sulfoxide) δ 11.11 (single peak, ¹H), 7.76 (broad single peak, ¹H), 7.64 (broad doublet, J=7.95 Hz, ¹H), 7.30–7.52 (multiplexes, 8H), 7.26 (broad doublet, J=7.21 Hz, ¹H), 7.19 (broad doublet, J=7.58 Hz, ¹H), 6.87 (broad singlet, ¹H), 6.63 (broad singlet, ¹H), 5.18 (single peak, 2H), 5.10 (broad doublet, J=7.95 Hz, 1H). =12.59, 5.26 Hz, 1H), 3.39 (broad doublet, J=9.05 Hz, 2H), 3.27 (broad singlet, 4H), 2.82-2.94 (multiplet, 1H), 2.65 (broad singlet, 8H), 2.37 (broad doublet, J=3.06 Hz, 2H), 1.97-2.11 (multiplet, 1H), 1.68-1.91 (multiplet, 3H), 1.23-1.39 (multiplet, 2H).

[0288] Example 10

[0289] Pharmacokinetic study of compound 11 in male SD rats after a single oral administration

[0290] Three male SD rats (7-10 weeks old) were orally administered compound 11 (dissolved in a 10% dimethyl sulfoxide / 10% ethanol / 80% water solution) at a dose of 35.0 mg / kg via gavage. The animals were fasted overnight before administration and continued to fast for 4 hours after administration. Plasma samples were collected via jugular vein at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. The concentration of compound 11 in each sample was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Results are as follows: Figure 5 As shown. 5.

[0291] Example 11

[0292] Brain penetration study of compound 11 in male SD rats after a single intravenous administration

[0293] Nine male SD rats (7-10 weeks old) were intravenously administered compound 11 (dissolved in 5% dimethyl sulfoxide, 5% polysorbate 80, and 90% water) at a dose of 2.0 mg / kg. The animals were fasted overnight before administration and continued to fast for 4 hours after administration. The animals were divided into three groups according to sampling time points: 2, 6, and 12 hours after administration. Plasma (via jugular vein), brain (collected after carbon dioxide euthanasia), and cerebrospinal fluid samples were collected from each animal at the designated time points. The concentration of compound 11 in each sample was determined by LC-MS / MS analysis. Results are as follows: Figure 6 As shown.

[0294] Example 12

[0295] like Figure 7A As shown, survivin protein levels in the U87 glioblastoma cell line were quantified by Western blotting after treatment with a specified concentration of compound 11 for 24 hours. Relative protein levels were calculated as the percentage of survivin protein levels in the compound 11-treated group compared to the control group U87 cells treated with dimethyl sulfoxide.

[0296] like Figure 7B As shown, survivin protein levels were quantified by Western blotting in the GL261 glioblastoma cell line after treatment with a specified concentration of compound 11 for 24 hours. Relative protein levels were calculated as the percentage of survivin protein levels in the compound 11-treated group compared to the control group GL261 cells treated with dimethyl sulfoxide.

[0297] Example 13

[0298] like Figure 8A As shown, GL261 glioblastoma cells were irradiated and treated with specified concentrations (0.01 μmol, 0.1 μmol, 0.5 μmol, and 1.0 μmol) of compound 11. GL261 cells irradiated with 2 Gy were analyzed (Western blotting). Compound 11 was added to both irradiated and unirradiated cells 1 hour after irradiation. Protein extracts were collected 48 hours after treatment with compound 11. The protein levels of poly(ADP-ribose) polymerase (PARP), cleaved PARP, phosphorylated ataxia-telangiectasia mutant protein at Ser1981 (phosphorylated ATM), phosphorylated checkpoint kinase 1 at Ser317 (phosphorylated CHK1), cleaved caspase 9, and cleaved caspase 3 were assessed by Western blotting. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control. These data indicate that: 1) treatment with compound 11 alone can induce a DNA damage response, manifested by increased phosphorylation levels of ATM and CHK1; 2) compound 11 enhances the efficacy of irradiation-induced DNA damage response; 3) compound 11 enhances the efficacy of irradiation-induced killing of cancer cells, manifested by increased levels of cleaved PARP protein; 4) compound 11 enhances the efficacy of irradiation-induced apoptosis in cancer cells, manifested by increased levels of cleaved caspase 3 and caspase 9 proteins.

[0299] like Figure 8BAs shown, colony formation experiments were conducted on GL261 glioblastoma cells treated with compound 11 (0.5 μmol) and those not treated with compound 11, in combination with specified doses of irradiation (0 Gy, 2 Gy, 4 Gy, 6 Gy, 8 Gy). 1000 GL261 cells were seeded into each well of a 6-well plate. After cell adhesion, the GL261 cells were irradiated, and compound 11 was added 1 hour after irradiation. Two weeks after treatment, the number of colonies in each well was counted. Viability was determined by calculating the ratio of the number of colonies in the treated group to the number of colonies in the untreated control group; calculations were performed separately for the compound 11-treated and untreated groups. The survival curves were fitted with a linear quadratic model. These data indicate that compound 11 enhanced the cytotoxic effect of irradiation.

[0300] Example 14

[0301] like Figure 9 As shown, U87 glioblastoma cells treated with compound 11 and those treated with or without the proteasome inhibitor MG132 were analyzed by Western blotting. U87 glioblastoma cells were treated with compound 11 alone (10 nmol, 100 nmol), MG132 alone (5 μmol), or a combination of compound 11 (10 nmol, 100 nmol) and MG132 (5 μmol). Survivin protein levels were assessed by Western blotting 24 hours after treatment. β-tubulin levels were used as an internal control. These data indicate that compound 11-induced survivin degradation is dependent on the ubiquitin-proteasome system.

[0302] Example 15

[0303] Compound 11 (dissolved in 10% dimethyl sulfoxide / 10% ethanol / 80% water, at a concentration of 20 mg / mL, a homogeneous, opaque suspension containing fine particles) was orally administered to fasted male C57BL / 6J mice. Figure 10 As shown, the concentrations of compound 11 were determined at specified time points (plasma (nm / mL): 0.25, 0.5, 1, 2, 3, 6, 8, and 12 hours; brain (nm / g): 0.5, 2, 6, and 12 hours). Analysis was performed by LC-MS / MS. The brain concentration at 12 hours was below the limit of quantitation (5 nm / g). The pharmacokinetic parameters of compound 11 are shown in the table below.

[0304]

[0305] These data indicate that compound 11 can penetrate the blood-brain barrier after oral administration in mice.

[0306] The scope of this disclosure is not limited to the embodiments disclosed in the examples, which are intended to be illustrative of a single aspect, and any equivalents are within the scope of this disclosure. In addition to the modifications shown and described herein, various modifications will arise from the foregoing description by those skilled in the art, and these modifications are intended to fall within the scope of the appended claims.

[0307] This article cites various references, such as patents, patent applications, and publications, all of which are incorporated herein by reference.

Claims

1. A compound of formula I: ELX Or a pharmaceutically acceptable derivative thereof, wherein E is a group targeting E3 ubiquitin ligase; L is a divalent chemical linker; L is a divalent chemical linker; and X is a group targeting survivin.

2. The compound of claim 1, having formula I: or pharmaceutically acceptable derivatives thereof, wherein: L is a divalent chemical linker; E is a group that targets E3 ubiquitin ligase; R 1 -R 9 Each of the following can be independently H, alkyl, haloalkyl, cycloalkyl, heteroalkyl, heterocycloyl, aryl, heteroaryl, aralkyl, heteroaryl, halogen, or OR 10 , where each R 10 Each can be independently H, alkyl, cycloalkyl, aryl, or aralkyl.

3. The compound of claim 2, wherein R 1 -R 9 Each is independently H, alkyl, haloalkyl, halogen, or OR 10 , where each R 10 Each can be independently alkyl, cycloalkyl, or aralkyl.

4. The compound of claim 2 or 3, wherein R 1 -R 9 Each is independently H, alkyl, haloalkyl, halogen, or OR 10 , where each R 10 Each can be independently alkyl, cycloalkyl, or aralkyl.

5. The compound according to any one of claims 2-4, wherein R 1 -R 9 Each can be independently H, methyl, trifluoromethyl, halogen, or OR 10 , where each R 10 Each is an aralkyl group independently.

6. The compound according to any one of claims 2-5, wherein R 1 -R 9 Each can be independently H, chloro, methyl, trifluoromethyl, or OR 10 , where each R 10 It is an aralkyl group.

7. The compound according to any one of claims 2-6, wherein R 1 -R 9 Each can be independently H, chloro, methyl, trifluoromethyl, or -O-benzyl.

8. The compound according to any one of claims 2-7, wherein R 1 -R 9 All are H.

9. The compound according to any one of claims 2-7, wherein R 1 R 3 R 5 -R 7 and R 9 For H, R 2 and R 4 It is -O-benzyl, R 8 It is chlorine.

10. The compound according to any one of claims 2-7, wherein R 1 -R 3 R 5 -R 7 and R 9 For H, R 4 It is -O-benzyl, R 8 It is chlorine.

11. The compound of claim 1, having formula II: or pharmaceutically acceptable derivatives thereof, wherein: L is a divalent chemical linker; E is a group that targets E3 ubiquitin ligase; R 11 It is an alkyl group; n is an integer between 0 and 4; and Het is a heteroaryl group that can be optionally substituted with an aryl group.

12. The compound of claim 11, wherein R 11 It is a lower alkyl group.

13. The compound of claim 11 or 12, wherein R 11 It is a methyl group.

14. The compound of any one of claims 11-13, wherein n is 0.

15. The compound of any one of claims 11-13, wherein n is 1.

16. The compound of any one of claims 11-13, wherein n is 2.

17. The compound of any one of claims 11-13, wherein n is 3.

18. The compound of any one of claims 11-13, wherein n is 4.

19. The compound of any one of claims 11-18, wherein Het is a furanyl group that may optionally be substituted with a phenyl group.

20. The compound of any one of claims 11-19, wherein Het is a phenyl-substituted furanyl group, which may optionally be substituted with a carboxyl group (COOH).

21. The compound of any one of claims 11-20, wherein Het is a furanyl group substituted with 4-COOH-1-phenyl.

22. The compound of any one of claims 11-21, wherein Het is 5-(4-COOH-1-phenyl)-2-furanyl.

23. The compound of claim 11: 。 24. The compound of claim 1, having formula III: or pharmaceutically acceptable derivatives thereof, wherein: L is a divalent chemical linker; E is a group that targets E3 ubiquitin ligase; R 12 It is an alkyl or cycloalkyl group; m is an integer between 0 and 4; and Het is a heteroaryl group that can be optionally substituted with an amino group.

25. The compound of claim 24, wherein R 12 It is an alkyl group.

26. The compound of claim 24 or 25, wherein R 12 It is a methyl group.

27. The compound of any one of claims 24-26, wherein m is 0.

28. The compound of any one of claims 24-26, wherein m is 1.

29. The compound of any one of claims 24-26, wherein m is 2.

30. The compound of any one of claims 24-26, wherein m is 3.

31. The compound of any one of claims 24-26, wherein m is 4.

32. The compound of any one of claims 24-31, wherein Het is an amino-substituted heteroaryl group.

33. The compound of any one of claims 24-32, wherein Het is an amino-substituted oxadiazolyl group.

34. The compound of any one of claims 24-33, wherein Het is an amino-substituted 1-oxa-2,5-diazolyl.

35. The compound of any one of claims 24-34, wherein Het is 4-amino-1-oxa-2,5-diazol-3-yl.

36. The compound of claim 24: 。 37. The compound of any one of claims 1-36, wherein L comprises polyethylene glycol (including polyethylene glycol (PEG)), alkyl, acyl, amino, amide, alkynyl, triazole (e.g., used when two target groups are linked by click chemistry), pyridazine (e.g., CLIPTACs), aryl (e.g., phenyl), piperazine, aziridine, and / or piperidine.

38. The compound of any one of claims 1-37, wherein L is cleavable.

39. The compound of any one of claims 1-37, wherein L is indestructible.

40. The compound of any one of claims 1-37, wherein L is photo-switchable (e.g., a diazoxide linker).

41. The compound of any one of claims 1-37, wherein L comprises piperazine, piperidine, aziridine and / or alkyl groups.

42. The compound of any one of claims 1-37 and 41, wherein L is piperidinyl-alkylene-piperazinyl.

43. The compound of any one of claims 1-37 and 41-42, wherein L is piperidinyl-methylene-piperazinyl.

44. The compound of any one of claims 1-37 and 41-43, wherein L is 。 45. The compound of any one of claims 1-37 and 41, wherein L is piperidinyl-alkylene-azacyclobutyl.

46. ​​The compound of any one of claims 1-37, 41 and 45, wherein L is piperidinyl-methylene-azacyclobutyl.

47. The compound of any one of claims 1-37, 41, and 45-46, wherein L is 。 48. The compound of any one of claims 1-37, wherein L is an alkylamide linker.

49. The compound of any one of claims 1-37 and 48, wherein L is C 4-10 -alkylene-C(O)-NH-.

50. The compound of any one of claims 1-37, 48 and 49, wherein L is 。 51. The compound of any one of claims 1-37, wherein L is a PEG linker.

52. The compound of any one of claims 1-37 and 51, wherein L is (PEG). 2-6 -NH-.

53. The compound according to any one of claims 1-37 and 51-52, wherein L is 。 54. The compound of any one of claims 1-53, wherein E is a protein that binds to cereblon, von Hippel-Lindau (VHL) proteins (e.g., VH032, VH285, VH298, VH101, VHL-e, and VHL-g), inhibitory apoptosis proteins (IAPs) (e.g., MV1, ME-BS, GDC-0152, LCL-161, AT-IAP, SNIPER(ER)-110, SNIPER(ER)-126), or mouse bimicrosome 2 homologs ( The groups of MDM2 (e.g., Nutlin-3, RG7112 and idasanutlin), DCAF (e.g., indisulam, E7820, KB02 and chloroquinoline sulfonamide (CQS)), RNF proteins (e.g., CCW16, nimbolide and EN219) or aryl hydrocarbon receptor (AhR) proteins (including FEM1B and KEAP1) (e.g., β-naphthylflavonoid (β-NF), EN106, CDDO-Me, KEAP1-L, PL).

55. The compound of any one of claims 1-54, wherein E is a fragment that binds cereblon.

56. The compound of any one of claims 1-55, wherein E comprises a fragment derived from an imide, amide, thioamide, or thioimide.

57. The compound of any one of claims 1-56, wherein E comprises a phthalimide group or an analogue or derivative thereof.

58. The compound of any one of claims 1-57, wherein E comprises a phthalimide-glutarimide group or an analogue or derivative thereof.

59. The compound of any one of claims 1-58, wherein E comprises a thalidomide, lenalidomide, or pomalidomide group or an analogue or derivative thereof.

60. The compound of any one of claims 1-59, wherein E is a thalidomide derivative.

61. The compound according to any one of claims 1-60, wherein E has the following structure: Where R 13 It is H or alkyl; R 14 -R 16 Each can be independently H, halogen, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl.

62. The compound of claim 61, wherein R 13 It's H.

63. The compound of claim 61 or 62, wherein R 14 and R 15 It is H, R 16 It is H, halogen, alkyl or cycloalkyl.

64. The compound according to any one of claims 61-63, wherein R 14 and R 15 It is H, R 16 It is halogen.

65. The compound of any one of claims 61-64, wherein R 14 and R 15 It is H, R 16 It's fluorine.

66. The compound of any one of claims 1-54, wherein E is an E3 ligase VHL ligand.

67. The compound of any one of claims 1-54 and 66, wherein E is a VHL ligand selected from the following E3 ligases: 。 68. The compound of any one of claims 1-54 and 66-67, wherein E is E3 ligand VHL ligand A1 or B2.

69. The compound of claim 1: or 。 70. The compound of any one of claims 1-54, wherein E is an N-terminal degradation signal sequence (N-degron).

71. The compound of any one of claims 1-54 and 70, wherein E is type I N-degron.

72. The compound of claim 71, wherein type I N-degron is a positively charged amino acid.

73. The compound of claim 72, wherein the positively charged amino acid is Arg, Lys, or His.

74. The compound of any one of claims 1-54 and 70-73, wherein E is arginine.

75. The compound of any one of claims 1-54 and 70, wherein E is type 2 N-degron.

76. The compound of claim 75, wherein type 2 N-degron is a hydrophobic amino acid.

77. The compound of claim 76, wherein the hydrophobic amino acid is Phe, Trp, Tyr, Leu, or Ile.

78. The compound of any one of claims 1-54, wherein E is Arg, Lys, His, Phe, Trp, Tyr, Leu, or Ile.

79. The compound of claim 1: 。 80. A pharmaceutical composition comprising the compound of any one of claims 1-79 and a pharmaceutically acceptable carrier.

81. A method of treating a cancer subject, comprising administering to the subject the compound of any one of claims 1-79 or the pharmaceutical composition of claim 80.

82. The method of claim 81, wherein the cancer is glioblastoma.

83. The method of claim 82, further comprising administering temozolomide to the subject.

84. The method of claim 81 or 82, wherein the subject is receiving radiation therapy.

85. A method for enhancing the efficacy of radiotherapy in a cancer subject, comprising administering to the subject the compound of any one of claims 1-79 or the pharmaceutical composition of claim 80.

Images