Parp1 degrader and use thereof

Abstract

Disclosed are a compound represented by general formula I, or a hydrate, solvate, isotopically substituted form, isomer, prodrug or pharmaceutically acceptable salt thereof. L and E are as defined in the present disclosure.

Description

PARP1 Degrading Agent and Its Uses

[0001] Citation of relevant applications

[0002] This disclosure claims the benefit of Chinese Patent Application No. 202510123763.3, entitled "PARP1 Degrading Agent and Its Use", filed on January 24, 2025 with the State Intellectual Property Office of the People's Republic of China, the entire contents of which are incorporated herein by reference.

[0003] field

[0004] This disclosure generally relates to the biomedical field, and more specifically, to PARP1 degrading agents and their uses.

[0005] background

[0006] Poly(ADP-ribose) polymerases (PARPs) play important roles in many cellular processes, including replication, recombination, chromatin remodeling, and DNA damage repair. PARP1 and PARP2 are the most widely studied members of the PARP family and play key roles in DNA damage repair.

[0007] PARP1 is activated upon DNA damage, catalyzing the binding of its poly(ADP-ribose) (PAR) chain to target proteins. This PARylation modification attracts other DNA repair factors to the damage site. After repair is complete, PARP's own PARylation leads to its dissociation from DNA, allowing other DNA repair proteins to continue their repair work. Therefore, PARP binding to the damaged site, its catalytic activity, and dissociation from DNA are key steps in cancer cells' response to DNA damage induced by chemotherapy and radiotherapy.

[0008] Inhibiting PARP family enzymes has become a strategy to selectively kill cancer cells by blocking complementary DNA repair pathways. Studies have shown that tumor cells with BRCA1 or BRCA2 detrimental mutations are sensitive to PARP family inhibitors because they rely on the homologous recombination repair (HRR) pathway, which is defective to PARP enzymes. Although PARP inhibitors are primarily used for BRCA-mutated cancers, they are also being clinically tested in non-BRCA-mutated tumors with homologous recombination deficiency (HRD).

[0009] Although PARP inhibitors are used clinically, their toxicity and resistance limit their application. PROTAC molecules have the property of degrading proteins, which can overcome the limitations of PARP inhibitors. Studies have shown that PARP1 degraders can affect PARP1 function, providing a new avenue for disease mechanism research.

[0010] Overview

[0011] On the one hand, this disclosure relates to compounds represented by general formula I, their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts.

[0012] in,

[0013] L is selected from any substituted anhydride group or any substituted heterohydride group; and

[0014] E is selected from

[0015] On the other hand, this disclosure relates to pharmaceutical compositions comprising the compounds described herein, or their hydrates, solvates, isotopes, isomers, prodrugs, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

[0016] Furthermore, this disclosure relates to methods for preparing compounds of general formula I, their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts.

[0017] in,

[0018] L is selected from any substituted anhydride group or any substituted heterohydride group; and

[0019] E is selected from

[0020] The method includes:

[0021] Will and The compound shown reacts to give the compound represented by general formula I.

[0022] In another aspect, this disclosure relates to a method for degrading PARP1, which includes contacting PARP1 with the compounds described in this disclosure, or their hydrates, solvates, isotopes, isomers, prodrugs, pharmaceutically acceptable salts, or pharmaceutical compositions described in this disclosure.

[0023] On the other hand, this disclosure relates to a method for preventing or treating cancer, comprising administering to an individual in need of the method a preventive or therapeutically effective amount of the compound of this disclosure, or its hydrate, solvate, isotope, isomer, prodrug, pharmaceutically acceptable salt, or pharmaceutical composition of this disclosure.

[0024] Brief description of the attached figures

[0025] Figure 1 illustrates the effect of the disclosed compounds on protein expression in MDA-MB-436 / MX-1 cells, as determined using Western blotting.

[0026] Figure 2 shows the inhibitory activity of the compounds disclosed herein against MDA-MB-436 cells.

[0027] Detailed Explanation

[0028] The following description includes certain specific details to provide a comprehensive understanding of the various disclosed embodiments. However, those skilled in the art will recognize that the embodiments can be implemented without employing one or more of these specific details, but using other methods, components, materials, etc.

[0029] Unless otherwise required in this disclosure, throughout the specification and the claims, the words “comprising” and “including” shall be interpreted in an open-ended, inclusive sense, meaning “including but not limited to”.

[0030] Throughout this specification, the terms "an embodiment," "another embodiment," "an embodiment," or "certain embodiments" refer to including, in at least one embodiment, a specific reference element, structure, or feature related to that embodiment. Therefore, the phrases "an embodiment," "an embodiment," or "another embodiment" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. Furthermore, specific elements, structures, or features may be combined in one or more embodiments in any suitable manner.

[0031] It should be understood that the singular article “a” (corresponding to the English words “a”, “an” and “the”) used in this disclosure and the appended claims includes plural objects unless otherwise expressly stated in the text.

[0032] definition

[0033] Therefore, unless otherwise stated, the following terms used in the specification and appended claims shall have the following meanings:

[0034] The abbreviations preceding certain chemical groups in this disclosure indicate the total number of carbon atoms present in the indicated chemical group. For example, C1-C4 alkyl describes alkyl groups having a total of 1 to 4 carbon atoms as defined below, while C3-C... 10 Cycloalkyl groups are described below as having a total of 3 to 10 carbon atoms. The total number of carbons in the abbreviated symbols does not include carbons that may be present in substituents of the group.

[0035] In this disclosure, the term "hydrocarbon" refers to an aliphatic hydrocarbon group. The hydrocarbon moiety can be a "saturated hydrocarbon" group, meaning it does not contain any alkene or alkyne moiety. The hydrocarbon moiety can also be an "unsaturated hydrocarbon" moiety, meaning it contains at least one alkene or alkyne moiety. An "alkene" moiety refers to a straight-chain or branched hydrocarbon chain group consisting of two to eighteen carbon atoms and at least one carbon-carbon double bond, connected to the remainder of the molecule by single bonds, such as vinyl, propenyl, butenyl, pentenyl, pent-1,4-dienyl, etc., and an "alkene" moiety refers to a straight-chain or branched hydrocarbon chain group consisting of two to eighteen carbon atoms and at least one carbon-carbon triple bond, connected to the remainder of the molecule by single bonds. The hydrocarbon moiety, whether saturated or unsaturated, can be branched or straight-chain.

[0036] The hydrocarbon group may have 1 to 18 carbon atoms (whenever it appears in this disclosure, a numerical range such as “1 to 18” refers to every integer in the given range; such “1 to 18” means that the hydrocarbon group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. up to and including 18 carbon atoms, although this definition also covers the occurrence of the term “hydrocarbon” where no numerical range is specified).

[0037] The hydrocarbon group can be substituted in any way, that is, substituted or unsubstituted. When substituted, the substituent is selected individually and independently from one or more of the following groups: cycloalkyl, aromatic, heteroaromatic, heterocycloalkyl, hydroxyl, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinylamide, N-sulfinylamide, C-carboxyl, O-carboxyl, isocyanato, cyanothio, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are hydrocarbon groups as defined in this disclosure) or amino groups including mono- and di-substituted amino groups, and their protected derivatives. Typically, hydrocarbon groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, dodecyl, vinyl, propenyl, butenyl, ethynyl, propynyl, and butynyl. Whenever a substituent is described as "arbitrarily substituted," the substituent can be replaced by one of the substituents listed above.

[0038] In some implementations, “C1-C” 18 "Hydrocarbon group" refers to a hydrocarbon group as defined above, containing one to eighteen carbon atoms. C1-C 18 Hydrocarbon groups can be arbitrarily replaced as defined for hydrocarbon groups.

[0039] In some implementations, "C1-C6 hydrocarbon group" refers to a hydrocarbon group as defined above that contains one to six carbon atoms. The C1-C6 hydrocarbon group can be arbitrarily substituted as defined for hydrocarbon groups.

[0040] In some implementations, “C1-C” 12 "Hydrocarbon group" refers to a hydrocarbon group containing one to twelve carbon atoms as defined above. C1-C 12 Hydrocarbon groups can be arbitrarily replaced as defined for hydrocarbon groups.

[0041] In some implementations, “C5-C” 18 "Hydrocarbon group" refers to a hydrocarbon group as defined above, containing five to eighteen carbon atoms. (C5-C) 18 Hydrocarbon groups can be arbitrarily replaced as defined for hydrocarbon groups.

[0042] In some implementations, “C5-C” 16 "Hydrocarbon group" refers to a hydrocarbon group as defined above, containing five to sixteen carbon atoms. (C5-C) 16 Hydrocarbon groups can be arbitrarily replaced as defined for hydrocarbon groups.

[0043] In some implementations, “C5-C” 12 "Hydrocarbon group" refers to a hydrocarbon group containing five to twelve carbon atoms as defined above. (C5-C) 12 Hydrocarbon groups can be arbitrarily replaced as defined for hydrocarbon groups.

[0044] In some implementations, “C6-C” 16 "Hydrocarbon group" refers to a hydrocarbon group as defined above, containing six to sixteen carbon atoms. (C6-C) 16 Hydrocarbon groups can be arbitrarily replaced as defined for hydrocarbon groups.

[0045] In some implementations, “C7-C” 16 "Hydrocarbon group" refers to a hydrocarbon group as defined above, containing seven to sixteen carbon atoms. (C7-C) 16 Hydrocarbon groups can be arbitrarily replaced as defined for hydrocarbon groups.

[0046] In some implementations, “C8-C” 16 "Hydrocarbon group" refers to a hydrocarbon group as defined above, containing eight to sixteen carbon atoms. (C8-C) 16 Hydrocarbon groups can be arbitrarily replaced as defined for hydrocarbon groups.

[0047] In some embodiments, the hydrocarbon group of this disclosure is an alkyl group.

[0048] In this disclosure, the term "heteroalkyl group" refers to a hydrocarbon group containing one or more heteroatoms, wherein the heteroatoms may be selected from oxygen, sulfur and nitrogen atoms, and wherein the hydrocarbon group is as defined above.

[0049] The heteroalkyl group can be substituted in any way, i.e., substituted or unsubstituted. When substituted, the substituent is selected individually and independently from one or more of the following groups: cycloalkyl, aromatic, heteroaromatic, heterocycloalkyl, hydroxyl, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinylamide, N-sulfinylamide, C-carboxyl, O-carboxyl, isocyanato, cyanothio, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl groups as defined in this disclosure) or amino groups including mono- and di-substituted amino groups, and their protected derivatives. Whenever a substituent is described as being "arbitrarily substituted", the substituent can be replaced by one of the substituents mentioned above.

[0050] In some embodiments, the heteroalkyl group of this disclosure is a heteroalkyl group.

[0051] In this disclosure, the term "hydroalkyl group" itself, or as part of another substituent, means a divalent group derived from a hydrocarbon (including branched hydrocarbon groups). Exemplary hydroalkyl groups that can be used in this disclosure include, but are not limited to, -CH2CH2CH2CH2- and -CH(CH2)CH2CH2-.

[0052] The alkylene group may have 1 to 18 carbon atoms (whenever it appears in this disclosure, a numerical range such as “1 to 18” refers to every integer in the given range; such “1 to 18” means that the alkylene group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. up to and including 18 carbon atoms, although this definition also covers the occurrence of the term “alkylene” where no numerical range is specified).

[0053] The alkylene group can be substituted in any way, i.e., substituted or unsubstituted. When substituted, the substituent is selected individually and independently from one or more of the following groups: cycloalkyl, aromatic, heteroaromatic, heterocycloalkyl, hydroxyl, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinamide, N-sulfinamide, C-carboxyl, O-carboxyl, isocyanato, cyanothio, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl groups as defined in this disclosure), or amino groups including mono- and di-substituted amino groups, and their protected derivatives. Typically, alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentylene, hexylene, dodecylene, vinylene, propenylene, butyrenylene, propynylene, and butynylene. Whenever a substituent is described as being "arbitrarily substituted," the substituent can be replaced by one of the substituents listed above.

[0054] In some implementations, “C1-C” 18 "Hydroalkylene group" refers to the hydrocarbonene group defined above, containing one to eighteen carbon atoms. C1-C 18 The alkylene group can be arbitrarily substituted as defined for the alkylene group.

[0055] In some embodiments, "C1-C6 alkylene group" refers to an alkylene group as defined above, containing one to six carbon atoms. The C1-C6 alkylene group can be arbitrarily substituted as defined for alkylene groups.

[0056] In some implementations, “C1-C” 12 "Hydroalkylene group" refers to the hydroalkylene group defined above, containing one to twelve carbon atoms. C1-C 12 The alkylene group can be arbitrarily substituted as defined for the alkylene group.

[0057] In some implementations, “C5-C” 18 "Hydroalkylene group" refers to the hydrocarbonene group defined above, containing five to eighteen carbon atoms. (C5-C) 18 The alkylene group can be arbitrarily substituted as defined for the alkylene group.

[0058] In some implementations, “C5-C” 16 "Hydroalkylene group" refers to the hydrocarbonene group defined above, containing five to sixteen carbon atoms. (C5-C) 16The alkylene group can be arbitrarily substituted as defined for the alkylene group.

[0059] In some implementations, “C5-C” 12 "Hydroalkylene group" refers to the hydroalkylene group defined above, containing five to twelve carbon atoms. (C5-C) 12 The alkylene group can be arbitrarily substituted as defined for the alkylene group.

[0060] In some implementations, “C6-C” 16 "Hydroalkylene group" refers to the hydroalkylene group defined above, containing six to sixteen carbon atoms. (C6-C) 16 The alkylene group can be arbitrarily substituted as defined for the alkylene group.

[0061] In some implementations, “C7-C” 16 "Hydroalkylene group" refers to the hydrocarbonene group defined above, containing seven to sixteen carbon atoms. (C7-C) 16 The alkylene group can be arbitrarily substituted as defined for the alkylene group.

[0062] In some implementations, “C8-C” 16 "Hydroalkylene group" refers to the hydroalkylene group defined above, containing eight to sixteen carbon atoms. (C8-C) 16 The alkylene group can be arbitrarily substituted as defined for the alkylene group.

[0063] In some embodiments, the hydrocarbon group disclosed herein is an alkylene group.

[0064] In this disclosure, the term "heteroalkylene group" refers to an alkylene group containing one or more heteroatoms, wherein the heteroatoms may be selected from oxygen, sulfur and nitrogen atoms, and wherein the alkylene group is as defined above.

[0065] The heteroalkylene group can be substituted in any way, i.e., substituted or unsubstituted. When substituted, the substituent is selected individually and independently from one or more of the following groups: cycloalkyl, aromatic, heteroaromatic, heterocycloalkyl, hydroxyl, alkyloxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide, N-amide, S-sulfinylamide, N-sulfinylamide, C-carboxyl, O-carboxyl, isocyanato, cyanothio, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR'R" (R' and R" are alkyl groups as defined in this disclosure), or amino groups including mono- and di-substituted amino groups, and their protected derivatives. Whenever a substituent is described as being "arbitrarily substituted", the substituent can be replaced by one of the substituents mentioned above.

[0066] In some embodiments, the heteroalkylene group of this disclosure is a heteroalkylene group.

[0067] In this disclosure, the terms "hydrate, solvate, isotope, isomer, prodrug, or pharmaceutically acceptable salt" refer to the compound represented by formula I of this disclosure, which is a hydrate, solvate, isotope, isomer, prodrug, or pharmaceutically acceptable salt.

[0068] As used in this disclosure, the term "physiologically acceptable" refers to a carrier, diluent, or excipient that does not eliminate the biological activity and properties of the compound.

[0069] As used in this disclosure, the term "carrier" refers to a substance that enables the inclusion of a compound into a cell or tissue.

[0070] As used in this disclosure, the term "excipient" refers to an inert substance added to a pharmaceutical composition to provide (not limited to) bulk, consistency, stability, binding capacity, lubricity, and disintegration capacity of the composition.

[0071] As used in this disclosure, the term "diluent" refers to an ingredient in a pharmaceutical composition that does not have pharmaceutical activity but may be pharmaceutically necessary or desired.

[0072] In this disclosure, the term "mammal" refers to animals including, for example, dogs, cats, cattle, sheep, horses, and humans. In some embodiments, mammals include humans.

[0073] In this disclosure, the term "patient" refers to animals (e.g., humans), companion animals (e.g., dogs, cats, or horses), and livestock (e.g., cattle, pigs, and sheep). In some embodiments, the patient is a mammal that includes both males and females. In some embodiments, the patient is a human.

[0074] In this disclosure, the term "drug-acceptable" means a carrier, delivery unit, diluent, excipient, and / or salt that must be compatible with other components of the formulation and not be harmful to the recipient.

[0075] In this disclosure, the terms “arbitrary” or “optionally” mean that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition.

[0076] In this disclosure, the term "drug-acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or animals and has no adverse effects on the composition of the pharmaceutical composition.

[0077] In this disclosure, the term "carrier" is defined as a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is commonly used as a carrier because it readily introduces certain organic compounds into the cells or tissues of an organism.

[0078] In this disclosure, the term "drug-acceptable salt" includes "acceptable acid adduct salt" and "acceptable base adduct salt".

[0079] In this disclosure, the term "acceptable acid adduct salt" refers to those salts that retain the biological validity and properties of a free base, said acid adduct salt being biologically or otherwise suitable and formed using inorganic or organic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and such organic acids as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, phenylcarboxylic acid, 4-acetamidophenylcarboxylic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylaminosulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, etc. Ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, viscous acid, gentian acid, glucoheponic acid, gluconic acid, glucuronic acid, glutamic acid, glutamate, 2-oxoglutamate, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lacturonic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, viscous acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, undecenoic acid, etc.

[0080] In this disclosure, the term "acceptable base addition salt" refers to those salts that retain the biological validity and properties of a free acid, said base addition salt being suitable for biological or other purposes. These salts are prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. In some embodiments, the inorganic salt is an ammonium, sodium, potassium, calcium, or magnesium salt. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, heparin, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, aminobutanetriol, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. In some embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0081] In this disclosure, the term "solvent or solvent mixture" means any and all solvents. In some embodiments, the solvent or solvent mixture is an organic solvent and water, including but not limited to methanol, ethanol, 2-propanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, ethyl acetate, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, N,N-dimethylformamide, cyclohexane, cyclopentane, n-hexane, n-heptane, n-pentane, toluene, o-xylene, p-xylene, dimethyl sulfoxide (DMSO), pyridine, acetic acid, anisole, butyl acetate, isopropylbenzene, ethyl formate, formic acid, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1-propanol, 1-pentanol, propyl acetate, ethylene glycol, and 1-methyl-2-pyrrolidone, as well as mixtures of any and all two or more of these solvents. In some embodiments, the solvent or solvent mixture is a single solvent and a binary mixture. In some embodiments, the solvent or solvent mixture is a single solvent of water and an organic solvent, and a binary mixture of water and an organic solvent.

[0082] In this disclosure, the term "pharmaceutical composition" refers to an formulation formed by the compound described in this disclosure with a medium generally accepted in the art for delivering a bioactive compound to a mammal such as a human. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0083] In this disclosure, the term "therapeuticly effective amount" refers to the amount of a compound or combination of compounds that improves, reduces, or eliminates a particular disease or condition and its symptoms, or avoids or delays the onset of a particular disease or condition or its symptoms. The amount of the compound constituting a "therapeuticly effective amount" described in this disclosure will vary depending on the compound, the disease state and its severity, and the age, weight, etc., of the mammal to be treated; however, those skilled in the art can determine the amount of the compound described in this disclosure conventionally based on their own knowledge and this disclosure.

[0084] As used in this disclosure, "to treat" or "to treat" encompasses the treatment of a related disease or condition in mammals, such as humans, suffering from a related disease or ailment, and includes:

[0085] (i) To prevent the occurrence of disease or disease state in mammals, especially when the mammal is susceptible to the disease state but has not yet been diagnosed with the disease state;

[0086] (ii) Suppress the disease or disease state, that is, prevent it from occurring; or

[0087] (iii) Alleviate the disease or disease state, even if the disease or disease state subsides or does not progress.

[0088] As used in this disclosure, the terms “disease” and “disease state” may be used interchangeably or may be different, because a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology), and thus is not recognized as a disease, but rather as an undesirable disease state or symptom in which a clinician has identified a more or less specific set of symptoms.

[0089] In this disclosure, the term "physiologically acceptable" refers to a carrier or diluent that does not eliminate the biological activity and properties of the compound.

[0090] The compounds described in this disclosure, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomers, which may be defined according to absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- of amino acids. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using chiral columns. When the compounds described in this disclosure contain an alkene double bond or other geometrically asymmetric centers, unless otherwise stated, it means that the compounds include E and Z geometric isomers. Similarly, it also means that all tautomers are included.

[0091] In this disclosure, "stereoisomer" refers to a compound composed of identical atoms bonded by the same bonds, but having different three-dimensional structures that are not interchangeable. This disclosure covers various stereoisomers and mixtures thereof.

[0092] In this disclosure, "cis-trans isomers" refers to molecules with the same molecular formula that, due to factors such as the presence of double bonds or rings, restrict the free rotation of bonds, resulting in spatial configurations with different relative distances between adjacent atoms or groups of atoms.

[0093] In this disclosure, "tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomers of any of the said compounds.

[0094] As used in this disclosure, the term "prodrug" is used to refer to a compound that can be converted into the bioactive compound of the present invention under physiological conditions or by solvent decomposition. Therefore, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of the compounds of the present disclosure. A prodrug may be inactive when administered to an individual in need, but is converted into the active compound of the present invention in vivo. Prodrugs are typically rapidly converted into the parent compound of the present disclosure in vivo, for example, by hydrolysis in the blood. Prodrug compounds often offer advantages in solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24, (Elsevier, Amsterdam)). The discussion of prodrugs is provided in Higuchi, T., et al, “Pro-drugs as Novel Delivery Systems”, ACSSymposium Series, Vol. 14, and Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are cited in this article.

[0095] As used herein, the term "prodrug" is also intended to include any covalently bound carrier that releases the active compound of this disclosure in vivo when such prodrugs are administered to a mammalian subject. Prodrugs of the compounds of this disclosure can be prepared by modifying functional groups present on the compounds of this disclosure in such a manner that, in conventional operation or in vivo, these modified substances are cleaved into the parent compound of this disclosure. Prodrugs include compounds of this disclosure wherein a hydroxyl, amino, or thiol group is attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups, or amide derivatives of amine functional groups, etc., of the compounds of this disclosure.

[0096] As used in this disclosure, the term "isotope" refers to different nuclides of the same element that have the same number of protons but different numbers of neutrons.

[0097] As used in this disclosure, the term "abundance" refers to the percentage of atoms of a given isotope in its native element.

[0098] As used in this disclosure, the term "natural abundance" or "natural abundance" refers to the percentage of atoms of each isotope in a naturally occurring element. For example, the natural abundance of hydrogen isotopes: 1 H = 99.985%, 2 H = 0.015%. Natural abundance of oxygen isotopes: 16 O = 99.76%, 17 O = 0.04%, 18 O = 0.20%.

[0099] As used in this disclosure, the term "isotope enrichment index" refers to the ratio of the abundance of an isotope to its natural abundance. For example, a deuterium atom with an isotope enrichment index of 6000 refers to a deuterium atom with an abundance of 90%.

[0100] As used in this disclosure, the term "hydrogen" ("H") refers to hydrogen produced by the generation of hydrogen from sources with naturally occurring isotopic abundances. 1 H (99.985%) and 2 Hydrogen is composed of H (0.015%).

[0101] As used in this disclosure, the term "deuterium" ("D" and "d") refers to an isotope of hydrogen (H), the deuterium atom having one proton and one neutron in its nucleus, and its natural isotopic abundance is 0.015%. "d" x-y "This refers to substitution with x to y deuterium atoms. For example, methoxy-d3 refers to CD3O-."

[0102] In this disclosure, the term "PARP (Poly(ADP-ribose) polymerase)" refers to poly(ADP-ribose) polymerase. Detailed Implementation

[0103] On the one hand, this disclosure relates to compounds represented by general formula I, their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts.

[0104] in,

[0105] L is selected from either a substituted hydrocarbon group or a substituted heterohydrocarbon group; and

[0106] E is selected from

[0107] In some embodiments, the hydrocarbon group is C5-C. 16 Hydroxyl group.

[0108] In some embodiments, the heteroalkylene group is C5-C. 16 Heterohydrocarbon group.

[0109] In some implementations, the heteroatom is selected from oxygen, sulfur, and nitrogen atoms.

[0110] In some implementations, the number of heteroatoms is 1 to 6.

[0111] In some implementations, L is selected from

[0112] Where n is an integer selected from 1 to 6, and m is an integer selected from 3 to 11.

[0113] In some implementations, E is

[0114] In some implementations, E is

[0115] In some implementations, E is

[0116] In some embodiments, the compounds disclosed herein are selected from...

[0117] In some embodiments, the compounds disclosed herein exhibit high selectivity for PARP1 but no activity for PARP2.

[0118] Pharmaceutical Composition

[0119] On the other hand, this disclosure relates to pharmaceutical compositions comprising the compounds described herein, or their hydrates, solvates, isotopes, isomers, prodrugs, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, diluents, or excipients.

[0120] In some embodiments, the pharmaceutical compositions that can be used in this disclosure can be prepared as tablets, capsules, powders, syrups, liquids, suspensions, lyophilized powders for injection, or injections.

[0121] In some embodiments, the pharmaceutical compositions of this disclosure include physiologically acceptable surfactants, carriers, diluents, excipients, lubricants, suspensions, film-forming substances, coating aids, or combinations thereof, as well as compounds of this disclosure, or their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and, for example, at Remington's Pharmaceutical Sciences, 18 th The entire contents of Ed. Mack Publishing Co., Easton, PA (1990) are described here and are incorporated herein by reference.

[0122] Preservatives, stabilizers, dyes, sweeteners, flavorings, and fragrances can be provided in pharmaceutical compositions. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid can be added as preservatives. Additionally, antioxidants and suspensions can be used.

[0123] In different implementation schemes, alcohols, esters, sulfated aliphatic alcohols, etc., can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminate methyl silicate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogen phosphate, calcium hydroxymethyl cellulose, etc., can be used as excipients; magnesium stearate, talc, hardened oil, etc., can be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, soybean oil, etc., can be used as suspensions or lubricants; cellulose acetate, as a derivative of sugars such as cellulose or sugar, or methyl acetate-isobutylene ester copolymer, as a derivative of polyethylene, can be used as suspensions; and plasticizers such as phthalates can be used as suspensions.

[0124] Suitable routes of administration may include, for example, oral, rectal, transmembrane, local, or enteral administration; parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary, intrathecal, direct intracardiac, intraperitoneal, intranasal, or intraocular injection. Compounds can also be administered at a predetermined rate and / or timed, pulsatile manner in sustained-release or controlled-release dosage forms, including depot injections, osmotic pumps, pellets, and transdermal (including electromigration) patches.

[0125] The pharmaceutical compositions disclosed herein can be produced by known methods, such as conventional methods of mixing, dissolving, granulating, manufacturing tablets, grinding, emulsifying, encapsulating, retaining or compressing tablets.

[0126] Therefore, according to this disclosure, the pharmaceutical compositions used can be formulated using conventional methods with one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the treatment of the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the chosen route of administration. Any known techniques, carriers, and excipients can be used as suitably understood and appreciated in the art.

[0127] Injectable formulations can be prepared in the following conventional forms: as solutions or suspensions, solid dosage forms suitable for preparation as solutions or suspensions prior to injection, or as emulsions. Suitable excipients include, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, monosodium glutamate, cysteine ​​hydrochloride, etc. Additionally, if desired, the injectable pharmaceutical composition may contain small amounts of non-toxic excipients, such as wetting agents, pH buffers, etc. Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If desired, absorption-enhancing agents (e.g., liposomes) may be used.

[0128] For transmembrane administration, a permeabilizing agent suitable for permeability barriers may be used in the formulation.

[0129] Parenteral drug formulations, for example, administered by bolus or continuous infusion, include aqueous solutions of active compounds in water-soluble form. Alternatively, suspensions of the active compounds can be prepared as suitable oily injectable suspensions. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil, or other organic oils such as soybean oil, grapefruit oil, or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that enhance the solubility of the compound to prepare high-concentration formulations. The injectable formulation and additional preservatives may be present in a single dosage form, such as in ampoules or multi-dose containers. The composition may be in an oily or aqueous carrier in a dosage form such as a suspension, solution, or emulsion, and the composition may contain agents such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable carrier such as sterile pyrogen-free water before use.

[0130] For oral administration, the active compound can be readily formulated by combining it with a pharmaceutically acceptable carrier known in the art. Such a carrier allows the compounds of the invention to be formulated as tablets, pills, lozenges, capsules, liquids, gels, syrups, ointments, suspensions, etc., for oral ingestion by a method in which the active compound is mixed with a solid excipient, the resulting mixture is ground in any manner, and the granulated mixture is processed, if necessary, with the addition of a suitable excipient to obtain a tablet or lozenge core. Suitable excipients are particularly fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginate or alginate such as sodium alginate may be added if necessary. The lozenge core is then appropriately coated. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound dosages, dyes or pigments may be added to the tablet or lozenge coating. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, shellac solution, and suitable organic solvents or solvent mixtures. To identify or characterize different combinations of active compound dosages, dyes or pigments may be added to the tablet or lozenge coating.

[0131] Oral pharmaceutical formulations include push-in capsules made of gelatin, and soft, sealed capsules made of gelatin and plasticizers such as glycerin or sorbitol. Push-in capsules may contain the active ingredient mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All oral formulations should be administered at a dose suitable for this administration.

[0132] For oral administration, the composition can be formulated into tablets or lozenges using conventional methods.

[0133] For inhalation administration, the compounds used in this disclosure are conveniently delivered in the form of a spray from a pressurized pack or nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve to deliver the metering amount. Capsules and cartridges, such as gelatin, used in inhalers or blowpipes can be formulated as powder mixtures containing the compound and a suitable powder matrix such as lactose or starch.

[0134] This disclosure also discloses a variety of pharmaceutical compositions known in the pharmaceutical industry for use in intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compound in a water-soluble form, such as eye drops, or in gellan gum or hydrogel form; ophthalmic ointments; ophthalmic suspensions, such as microparticles, small polymer particles suspended in a liquid carrier medium, lipid-soluble formulations, and microspheres; and ophthalmic inserts. For stability and comfort, these suitable pharmaceutical formulations are most often and preferably formulated as sterile, isotonic, and buffered pharmaceutical formulations. Pharmaceutical compositions for intranasal delivery may also include drops and sprays, typically formulated to mimic nasal secretions in many ways to ensure maintenance of normal ciliary function. As is known to those skilled in the art, suitable formulations are most often and preferably isotonic, mildly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and suitable pharmaceutical stabilizers. Drug formulations for intraocular delivery include suspensions and ointments for topical application within the ear. Common solvents used in these ocular formulations include glycerin and water.

[0135] The compounds can also be formulated into rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

[0136] In addition to the aforementioned formulations, the compounds can also be formulated as reservoir-type formulations. Such long-acting formulations can be administered via implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Thus, the compounds can be formulated, for example, using suitable polymers or hydrophobic materials (e.g., emulsions acceptable in oils) or ion exchange resins, or formulated as slightly soluble derivatives such as slightly soluble salts.

[0137] For hydrophobic compounds, a suitable drug carrier can be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD cosolvent system, which consists of 3% w / v benzyl alcohol, 8% w / v nonpolar surfactant polysorbate 80™, and 65% w / v polyethylene glycol 300, with the volume made up by anhydrous ethanol. Of course, the proportions of the cosolvent system can be significantly altered without compromising its solubility and toxicity characteristics. Furthermore, the cosolvent components can be modified: for example, other low-toxicity nonpolar surfactants can be used instead of polysorbate 80™; the fragment size of polyethylene glycol can be altered; other biocompatible polymers such as polyvinylpyrrolidone can replace polyethylene glycol; and other sugars or polysaccharides can replace glucose.

[0138] Alternatively, other delivery systems for hydrophobic drug compounds can be used. Known examples of delivery media or carriers for hydrophobic drugs are liposomes and emulsions. While often at the cost of higher toxicity, certain organic solvents, such as dimethyl sulfoxide, can also be used. Additionally, sustained-release systems can be used to deliver compounds, such as semi-permeable matrices containing solid hydrophobic polymers of therapeutic drugs. Many sustained-release materials are known and established by those skilled in the art. Depending on their chemical properties, sustained-release capsules can release the compound over weeks to 100 days.

[0139] Reagents for intracellular drug delivery are administered using techniques known to those skilled in the art. For example, such reagents can be encapsulated in liposomes. During liposome formation, all molecules present in the aqueous solution are incorporated into the aqueous interior. The contents of the liposomes are not only unaffected by the external microenvironment, but are also efficiently delivered to the cytoplasm due to the fusion of the liposomes with the cell membrane. The liposomes can be coated with tissue-specific antibodies. The liposomes will be targeted to the desired organ and selectively absorbed by the desired organ. Alternatively, small hydrophobic organic molecules can be administered directly intracellularly.

[0140] Preparation method

[0141] Furthermore, this disclosure relates to methods for preparing compounds of general formula I, their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts.

[0142] in,

[0143] L is selected from either a substituted hydrocarbon group or a substituted heterohydrocarbon group; and

[0144] E is selected from

[0145] The method includes:

[0146] Will and The compound shown reacts to give the compound represented by general formula I.

[0147] In some implementations, The compound shown was deprotected under acidic conditions to give The compound shown.

[0148] In some embodiments, exemplary examples of acids that can be used in this disclosure include, but are not limited to, trifluoroacetic acid, hydrochloric acid, sulfuric acid, hydrofluoric acid, formic acid, and p-toluenesulfonic acid.

[0149] In some implementations, The compound shown was deprotected under acidic dioxane conditions to give The compound shown.

[0150] In some implementations, The compound shown reacts with the compound shown in H2N-L-NHBoc to give The compound shown, wherein

[0151] E is selected from

[0152] as well as

[0153] X is selected from H or O.

[0154] In some implementations, The compound shown reacts with the compound shown in BocHN-L-CO2H to obtain the desired result. The compound shown, wherein

[0155] E is selected from

[0156] Treatment methods and uses

[0157] In another aspect, this disclosure relates to a method for degrading PARP1, which includes contacting PARP1 with the compounds described in this disclosure, or their hydrates, solvates, isotopes, isomers, prodrugs, pharmaceutically acceptable salts, or pharmaceutical compositions described in this disclosure.

[0158] In some implementations, the contact is performed outside the body.

[0159] In some implementations, the contact takes place inside the body.

[0160] On the other hand, this disclosure relates to a method for preventing or treating cancer, comprising administering to an individual in need of the method a preventive or therapeutically effective amount of the compound of this disclosure, or its hydrate, solvate, isotope, isomer, prodrug, pharmaceutically acceptable salt, or pharmaceutical composition of this disclosure.

[0161] In some embodiments, the cancers that can be used in this disclosure are PARP1-mediated.

[0162] In some implementations, exemplary examples of cancers that can be used in this disclosure include, but are not limited to, breast cancer, pancreatic cancer, prostate cancer, peritoneal cancer, fallopian tube cancer, ovarian cancer, and cervical cancer.

[0163] In some implementations, exemplary examples of individuals that can be used for the purposes of this disclosure include, but are not limited to, mammals.

[0164] In some implementations, the individuals that can be used in this disclosure are humans.

[0165] Furthermore, this disclosure relates to compounds of general formula I used for the degradation of PARP1, including their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts.

[0166] in,

[0167] L is selected from either a substituted hydrocarbon group or a substituted heterohydrocarbon group; and

[0168] E is selected from

[0169] In some implementations, the degradation of PARP1 occurs in vitro.

[0170] In some implementations, the degradation of PARP1 occurs in vivo.

[0171] Furthermore, this disclosure relates to compounds of general formula I for the prevention or treatment of cancer in individuals, including their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts.

[0172] in,

[0173] L is selected from either a substituted hydrocarbon group or a substituted heterohydrocarbon group; and

[0174] E is selected from

[0175] In some embodiments, the cancers that can be used in this disclosure are PARP1-mediated.

[0176] In some implementations, exemplary examples of cancers that can be used in this disclosure include, but are not limited to, breast cancer, pancreatic cancer, prostate cancer, peritoneal cancer, fallopian tube cancer, ovarian cancer, and cervical cancer.

[0177] In some implementations, exemplary examples of individuals that can be used for the purposes of this disclosure include, but are not limited to, mammals.

[0178] In some implementations, the individuals that can be used in this disclosure are humans.

[0179] On the other hand, this disclosure relates to the use of compounds of general formula I, their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts, in the preparation of medicaments for the degradation of PARP1.

[0180] in,

[0181] L is selected from either a substituted hydrocarbon group or a substituted heterohydrocarbon group; and

[0182] E is selected from

[0183] In some implementations, the degradation of PARP1 occurs in vitro.

[0184] In some implementations, the degradation of PARP1 occurs in vivo.

[0185] Furthermore, this disclosure relates to the use of compounds of general formula I, their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts, in the preparation of medicaments for the prevention or treatment of cancer in an individual.

[0186] in,

[0187] L is selected from either a substituted hydrocarbon group or a substituted heterohydrocarbon group; and

[0188] E is selected from

[0189] In some embodiments, the cancers that can be used in this disclosure are PARP1-mediated.

[0190] In some implementations, exemplary examples of cancers that can be used in this disclosure include, but are not limited to, breast cancer, pancreatic cancer, prostate cancer, peritoneal cancer, fallopian tube cancer, ovarian cancer, and cervical cancer.

[0191] In some implementations, exemplary examples of individuals that can be used for the purposes of this disclosure include, but are not limited to, mammals.

[0192] In some implementations, the individuals that can be used in this disclosure are humans.

[0193] Administration method

[0194] The compound of this disclosure or its hydrate, solvate, isotope, isomer, prodrug, pharmaceutically acceptable salt, or pharmaceutical composition comprising at least one compound of this disclosure or its hydrate, solvate, isotope, isomer, prodrug, or pharmaceutically acceptable salt may be administered to a patient by any suitable systemic and / or local delivery method of the compound of this disclosure or its hydrate, solvate, isotope, isomer, prodrug, or pharmaceutically acceptable salt. Non-limiting examples of administration methods include (a) oral administration, including administration in capsule, tablet, granule, spray, syrup or other such forms; (b) non-oral administration, such as rectal, vaginal, urethral, ​​intraocular, intranasal or intraauricular administration, including administration in aqueous suspension, oily preparations or in drops, spray, suppositories, ointments, creams or ointments; (c) administration by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intracapsular injection, intraspinal injection, intrasternal injection, etc., including delivery by infusion pump; (d) localized administration, such as direct injection into the renal or cardiac region, for example by reservoir implantation; and (e) topically administration; as would be considered appropriate by those skilled in the art, is contact between the compounds described in this disclosure and living tissue.

[0195] The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining the method of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage form, appropriate pharmaceutical excipients, and other matters relating to the delivery of the compound, its stereoisomers, or pharmaceutically acceptable salts thereof to the recipient.

[0196] Suitable pharmaceutical compositions for administration include compositions containing an effective amount of the active ingredient to achieve their intended effect. The required therapeutically effective dose of the pharmaceutical composition described in this disclosure depends on the route of administration, the type of animal being treated (including humans), and the physical characteristics of the specific animal under consideration. The dose can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent drug treatment, and other factors recognized by those skilled in the art. More specifically, a therapeutically effective dose refers to the amount of compound that effectively prevents, alleviates, or improves disease symptoms, or prolongs the lifespan of the treated individual. The actual ability of those skilled in the art can well determine a therapeutically effective dose, particularly in accordance with the detailed disclosure provided herein.

[0197] As will be apparent to those skilled in the art, the dosage and specific route of administration for in vivo administration will vary depending on age, weight, the species of mammal being treated, the specific compound used, and the specific purpose of those compounds. Those skilled in the art can determine the effective dose level—that is, the dose level necessary to determine the desired effect—using conventional pharmacological methods. Typically, human clinical application of the product is initiated at a lower dose level, increasing the dose level until the desired effect is achieved. Alternatively, established pharmacological methods can be used to establish the effective dose and route of administration of the compositions identified by this method using acceptable in vitro studies.

[0198] In non-human animal studies, the application of a potential product begins at a higher dose level and is gradually reduced until the desired effect is no longer achieved or adverse side effects disappear. The dose range can be broad, depending on the expected effect and therapeutic indication. Typically, the dose can range from about 10 μg / kg body weight to 1000 mg / kg body weight, and in some embodiments from about 100 μg / kg body weight to 300 mg / kg body weight. Alternatively, as those skilled in the art will understand, the dose can be based on and calculated according to the patient's body surface area.

[0199] Physicians can select the exact formulation, route of administration, and dosage of the pharmaceutical compositions described in this disclosure based on the patient's condition. Typically, the dosage range of the composition administered to a patient can be from about 0.05 mg / kg to 3000 mg / kg of patient body weight. Depending on the patient's needs, the dosage may be given once or twice or more over a day or several days. Where the human dosage of the compound has been established under at least certain conditions, this disclosure will use those same dosages, or dosage ranges from about 0.1% to 500% of the established human dosage, and in some embodiments, dosage ranges from 25% to 250% of the established human dosage. In cases where no human dosage has been established, such as with newly discovered pharmaceutical compounds, an appropriate human dosage can be inferred from the median effective dose or median infectious dose, or other suitable values ​​from in vitro or in vivo studies, as quantified in toxicity studies and efficacy studies in animals.

[0200] It should be noted that, due to toxicity and organ dysfunction, the attending physician will know and when to terminate, interrupt, or adjust medication. Conversely, if the clinical response is inadequate (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level. The dosage administered in the treatment of the condition of interest will vary depending on the severity of the disease state and the route of administration. For example, the severity of the disease state can be assessed in part using standard prognostic methods. Furthermore, the dosage and possible dosing frequency will also vary based on the individual patient's age, weight, and response. Protocols equivalent to those discussed above can be used in veterinary medicine.

[0201] While an exact dosage can be determined based on drug-by-drug analysis, in most cases, some generalizations about the dosage can be made. Daily dosing regimens for adult patients are, for example, oral doses of 0.1 mg to 2000 mg of each active ingredient, or in some embodiments, 1 mg to 2000 mg of each active ingredient, such as 5 mg to 1500 mg of each active ingredient. In other embodiments, the intravenous, subcutaneous, or intramuscular dose of each active ingredient used is 0.01 mg to 1000 mg, or in some embodiments, 0.1 mg to 1000 mg, such as 1 mg to 800 mg. In the case of administering acceptable saline solutions, the dosage can be calculated based on free base. In some embodiments, the composition is administered 1 to 4 times daily. Alternatively, the compositions described in this disclosure can be administered by continuous intravenous infusion, or in some embodiments, at doses of up to 2000 mg of each active ingredient daily. As those skilled in the art will understand, in certain situations, it is necessary to administer the compounds described in this disclosure in amounts exceeding or far exceeding the above-described dosage range for the effective and rapid treatment of a rapidly progressing disease or infection. In some embodiments, the compounds are administered during continuous treatment, for example, for one or several weeks, or for several months or years.

[0202] Dosage and dosing intervals can be individually adjusted to provide plasma levels sufficient to maintain the modulated effect or minimum effective concentration (MEC) of the active moiety. The MEC varies for each compound, but it can be assessed from in vitro data. The required dose to achieve the MEC depends on individual characteristics and route of administration. However, plasma concentrations can be determined using HPLC (high-performance liquid chromatography) or bioassays.

[0203] The MEC value can also be used to determine the dosing interval. The composition should be administered using a treatment regimen that maintains plasma levels above the MEC for 10-90% of the time, 30-90% of the time in some embodiments, and 50-90% of the time in some embodiments.

[0204] In cases of local administration or selective absorption, the effective local concentration of a drug is independent of its plasma concentration.

[0205] Of course, the amount of the administered composition depends on the individual being treated, the individual's weight, the severity of their pain, the route of administration, and the prescribing physician's judgment.

[0206] The efficacy and toxicity of the compounds described in this disclosure can be evaluated using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing certain chemical motifs can be established by determining the toxicity of cell lines in vitro, such as mammalian cell lines and, in some embodiments, human cell lines. The results of such studies can generally predict toxicity in animals such as mammals, or more specifically, toxicity in humans. Alternatively, the toxicity of a particular compound in animal models such as mice, rats, rabbits, or monkeys can be determined using known methods. The efficacy of a particular compound can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for almost every type of disease state, including but not limited to cancer, cardiovascular disease, and various immune disorders. Similarly, acceptable animal models can be used to determine the efficacy of chemical agents for treating these disease states. When selecting a model to determine efficacy, a person skilled in the art can choose an appropriate model, dosage, route of administration, and treatment regimen under the guidance of prior art. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0207] If desired, the composition may be placed in a packaging or dispensing device, which may contain one or more unit dosage forms containing the active ingredient. The packaging may include, for example, metal or plastic foil, such as blister packs. The packaging or dispensing device may include instructions for use. The packaging or dispensing device may also include precautions related to the container, prescribed by a government agency regulating the production, use, or sale of the drug, reflecting that the drug form has been approved by that agency for human or animal administration. Such precautions may, for example, be labels approved for prescription drugs by the National Food and Drug Administration or the U.S. Food and Drug Administration, or approved product instructions. Compositions containing the compounds of this disclosure, their stereoisomers, or pharmaceutically acceptable salts thereof may also be prepared in suitable containers, formulated in compatible drug carriers, and labeled for the treatment of specified disease states.

[0208] The present disclosure will be explained in detail below through the following embodiments in order to better understand the various aspects of the disclosure and its advantages. However, it should be understood that the following embodiments are non-limiting and are only used to illustrate certain implementations of the present disclosure.

[0209] Example

[0210] While any person skilled in the art can prepare the compounds of this disclosure using the general techniques disclosed above, more detailed synthetic techniques for the compounds of this disclosure are provided elsewhere in this specification for convenience. Furthermore, all reagents and reaction conditions used in the synthesis are known to those skilled in the art and are available from common commercial sources. For example, various reagents used in the examples, including deuterated reagents, are available from Sigma-Aldrich Company Ltd.

[0211] Reagents and Consumables

[0212] instrument

[0213] Preparation Examples

[0214] Example 1

[0215] N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide

[0216] Step 1

[0217] [2-(2-aminoethoxy)ethyl]carbamate tert-butyl ester (407 mg, 1.99 mmol) and 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione (500 mg, 1.81 mmol) were dissolved in 5 mL of DMF, and DIPEA (600 μL, 3.62 mmol) was added. The mixture was heated to 90 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was extracted with EA and water. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA = 1:1-1:2 elution) to give a yellow-green solid compound IM1 (300 mg, yield: 36%). LCMS m / z (ES + [M+H] + =461.

[0218] Step 2

[0219] IM1 (300 mg, 0.65 mmol) was dissolved in 10 mL of methanol, and 5 mL of 1,4-dioxane solution in 4N HCl was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction system was concentrated, the solid was washed with petroleum ether, and filtered to give a yellow-green solid compound IM2 (250 mg, yield: 96%). LCMS m / z (ES) + [M+H] + =361. The compound can be used directly in the next reaction without further purification.

[0220] Step 3

[0221] IM2 (95 mg, 0.24 mmol) and IM3 (100 mg, 0.24 mmol, prepared according to the method in WO 2021260092 A1) were dissolved in 5 mL of DMF. HATU (137 mg, 0.36 mmol) and DIPEA (120 μL, 0.72 mmol) were added, and the reaction was stirred at room temperature for 2 h. After the reaction was complete, the reaction mixture was extracted with EA and water. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 30:1-10:1 elution) to give the title compound as a yellow solid (54 mg, yield: 30%).

[0222] LCMS m / z(ES + [M+H] + =758

[0223] 1 H NMR(500MHz, CDCl3)δ9.49(s,1H),8.33(s,1H),7.95(m,1H),7.79(m,1H),7.57(m,1H),7.47(m,1H),7.37-7.27(m,2H),7.06(m,1H) ,6.93(m,1H),6.50(m,1H),4.91(m,1H),3.81-3.62(m,9H),3.48(m,2H),3.28-3.11(m,6H),2.70(m,4H),2.60(s,3H),2.12(m,1H).

[0224] The compounds in Examples 2 to 6 were synthesized according to the method in Example 1.

[0225] Example 2

[0226] N-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide

[0227] The title compound was obtained as a yellow solid.

[0228] LCMS(ES + [M+H] + =802

[0229] 1 H NMR (500MHz, CDCl3) δ10.22(s,1H),8.98(s,1H),8.11-7.75(m,2H),7.57(m,1H),7.44(m,1H),7.32(m,1H),7.24(m,1H),7.06(m,1H),6 .88(m,1H),6.49(m,1H),4.91(m,1H),3.75(m,4H),3.66(m,8H),3.46(m,2H),3.18(m,4H),2.94-2.63(m,7H),2.60(s,3H),2.12(m,1H).

[0230] Example 3

[0231] N-(2-(2-(2-((2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide

[0232] The title compound was obtained as a yellow solid.

[0233] LCMS m / z(ES + [M+H] + =846

[0234] 1H NMR(500MHz, CDCl3)δ9.75(s,1H),8.91(s,1H),7.96(m,1H),7.87(m,1H),7.57(m,1H),7.47(m,1H),7.37-7.27(m,2H),7.09(m,1H),6.90( m,1H),6.46(m,1H),4.92(m,1H),3.79-3.60(m,16H),3.46(m,2H),3.18(m,6H),2.77(m,1H),2.67(m,4H),2.60(s,3H),2.16-2.08(m,1H).

[0235] Example 4

[0236] N-(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide

[0237] The title compound was obtained as a yellow solid.

[0238] LCMS m / z(ES + [M+H] + =890

[0239] 1 H NMR(500MHz,CDCl3)δ9.52(s,1H),8.87(s,1H),7.97(m,1H),7.81(m,1H),7.59(m,1H),7.52(m,1H),7.34(m,2H),7.10(m,1H),6.91(m,1H ),6.49(m,1H),4.95-4.89(m,1H),3.82-3.54(m,20H),3.53-3.42(m,3H),3.22(m,4H),2.90-2.66(m,6H),2.60(s,3H),2.16-2.09(m,1H).

[0240] Example 5

[0241] N-(17-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15-pentaheptadecyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide

[0242] The title compound was obtained as a yellow solid.

[0243] LCMS m / z(ES + [M+H] + =934

[0244] 1 H NMR(500MHz, CDCl3)δ9.53(s,1H),8.88(s,1H),8.03-7.93(m,1H),7.87(m,1H),7.57(m,1H),7.49(m,1H),7.37-7.26(m,2H),7.10(m,1H),6. 91(m,1H),6.49(m,1H),4.95-4.88(m,1H),3.85-3.54(m,25H),3.47(m ,2H),3.23(m,4H),2.92-2.65(m,6H),2.60(s,3H),2.18-2.07(m,1H).

[0245] Example 6

[0246] N-(20-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12,15,18-hexaoxanecoalkyl)-6-fluoro-5-(4-((5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)pyridineamide

[0247] The title compound was obtained as a yellow solid.

[0248] LCMS m / z(ES + [M+H] + =978

[0249] 1H NMR(500MHz, CDCl3)δ9.52(s,1H),8.87(s,1H),7.97(m,1H),7.81(m,1H),7.59(m ,1H),7.52(m,1H),7.34(m,2H),7.10(m,1H),6.91(m,1H),6.49(m,1H),4.95-4.89 (m,1H),4.50-4.37(m,1H),4.13(m,1H),4.06-3.99(m,1H),3.82-3.54(m,25H),3 .53-3.42(m,3H),3.22(m,4H),2.90-2.66(m,6H),2.60(s,3H),2.16-2.09(m,1H).

[0250] Example 7

[0251] 6-Fluoro-5-(4-(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-(2-(2-(2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-yl)-3,3-dimethyl-1-oxobut-2-yl)amino)-2-oxoethoxy)ethoxy)ethyl)pyridineamide

[0252] Step 1

[0253] Compound 1 (97 mg, 70% purity, 1 eq, synthetic reference WO 2023 / 143249A1), compound 2 (39 mg, 1 eq), and DIEA (97 mg, 5 eq) were dissolved in DMF (2 mL). HATU (68 mg, 1.2 eq) was added with stirring at room temperature. After the addition was complete, the reaction was maintained at room temperature for 1 hour. The reaction was detected as complete by LCMS. The reaction solution was added to water, extracted with ethyl acetate (10 mL × 3), the organic phase was dried and concentrated, and purified by TLC (DCM:MeOH = 15:1) to give compound 3 (55 mg, yield 52%) as a yellow solid. MS (M+H = 690.37).

[0254] Step 2

[0255] Compound 3 (55 mg, 1 eq) was dissolved in DCM (1 mL). Dioxane hydrochloride solution (0.5 mL, 4 M) was added to the reaction solution with stirring at room temperature. After the addition was complete, the reaction was maintained at room temperature for 1 hour. The reaction was detected as complete by LCMS. The reaction solution was evaporated to dryness to give compound 4 (40 mg, 93% yield) as a yellow solid. MS (M+H = 590.35).

[0256] Step 3

[0257] Compound 4 (15 mg, 1 eq), compound 5 (10 mg, 1 eq, synthetic reference WO 20212 / 60092 A1), and DIEA (16 mg, 5 eq) were dissolved in DMF (0.5 mL), and HATU (11 mg, 1.2 eq) was added with stirring at room temperature. After the addition was complete, the reaction was maintained at room temperature for 1 hour. The reaction was detected as complete by LCMS. The reaction solution was added with water, extracted with ethyl acetate (5 mL × 3), the organic phase was dried and concentrated, and purified by TLC (DCM:MeOH = 10:1) to give the title compound as a white solid (21.3 mg, yield 83%).

[0258] MS(M+H=987.45)

[0259] 1 H NMR (500MHz, DMSO-d6) δ12.45(s,1H),8.98(s,1H),8.41(d,J=7.8Hz,1H),8.37(t,J=6.0Hz,1H),7.85(dd,J=8.1,1.4Hz,1H),7 .59-7.49(m,2H),7.44-7.33(m,5H),7.29(d,J=15.4Hz,1H),5.14(d,J=3.5Hz,1H),4.89(p,J=7.1Hz,1H),4.54(d,J=9.6Hz,1H ),4.45(t,J=8.2Hz,1H),4.31-4.26(m,1H),3.98-3.94(m,2H),3.69(s,2H),3.63-3.52(m,8H),3.48-3.43(m,2H),3.21-3.13( m,4H),2.62-2.55(m,4H),2.45(s,3H),2.42(s,3H),2.07-2.01(m,1H),1.81-1.75(m,1H),1.35(d,J=7.0Hz,3H),0.92(s,9H).

[0260] The compounds in Examples 8 to 12 were synthesized according to the method in Example 7.

[0261] Example 8

[0262] 6-Fluoro-5-(4-(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((S)-13-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazo-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbamoyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecanyl)pyridineamide

[0263] The title compound was given as a white solid (16 mg, yield 48%).

[0264] MS(M+H=1031.56)

[0265] 1 H NMR (500MHz, DMSO-d6) δ12.47(s,1H),8.98(s,1H),8.44(d,J=7.7Hz,1H),8.33(t,J=5.9Hz,1H),7.85(dd,J=8.0,1.5Hz,1H),7.56(d d,J=10.6,8.1Hz,1H),7.52(d,J=8.3Hz,1H),7.44-7.34(m,5H),7.29(t,J=7.6Hz,1H),5.14(d,J=3.6Hz,1H),4.90(q,J=6.9Hz,1H), 4.54(d,J=9.6Hz,1H),4.44(t,J=8.2Hz,1H),4.28(s,1H),3.95(s,2H),3.69(s,2H),3.60-3.50(m,12H),3.42(q,J=5.9Hz,2H),3.19 -3.13(m,4H),2.62-2.55(m,4H),2.45(s,3H),2.42(s,3H),2.09-2.02(m,1H),1.79-1.73(m,1H),1.36(d,J=7.1Hz,3H),0.92(s,9H).

[0266] Example 9

[0267] 6-Fluoro-5-(4-(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((S)-16-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbamoyl)-17,17-dimethyl-14-oxo-3,6,9,12-tetraoxa-15-azaoctadecyl)pyridineamide

[0268] The title compound was given as a white solid (18.4 mg, 45% yield).

[0269] MS(M+H=1075.54)

[0270] 1 H NMR (500MHz, DMSO-d6) δ12.47(s,1H),8.98(s,1H),8.45(d,J=7.7Hz,1H),8.33(t,J=6.0Hz,1H),7.85(dd,J=8.1,1.5Hz,1H),7.56(dd,J=10 .6,8.1Hz,1H),7.52(d,J=8.3Hz,1H),7.43(dd,J=8.0,5.6Hz,2H),7.39-7.34(m,3H),7.32-7.25(m,1H),5.14(d,J=3.6Hz,1H),4.93-4.87( m,1H),4.54(d,J=9.6Hz,1H),4.44(t,J=8.3Hz,1H),4.31-4.26(m,1H),3.95(s,2H),3.69(s,2H),3.60-3.51(m,16H),3.41(q,J=5.9Hz,2H) ,3.20-3.13(m,4H),2.62-2.55(m,4H),2.45(s,3H),2.42(s,3H),2.0 9-2.01(m,1H),1.79-1.73(m,1H),1.37(d,J=6.9Hz,3H),0.93(s,9H).

[0271] Example 10

[0272] 6-Fluoro-5-(4-(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((S)-19-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbamoyl)-20,20-dimethyl-17-oxo-3,6,9,12,15-pentaoxa-18-azabenzoyl)pyridineamide

[0273] The title compound was given as a white solid (18 mg, yield 17%).

[0274] MS(M+H=1119.43)

[0275] 1H NMR (500MHz, DMSO-d6) δ9.90(s,1H),8.62(s,1H),8.13(t,J=5.7Hz,1H),7.86(d,J=8.8Hz,1H),7.74(d ,J=9.9Hz,1H),7.60-7.54(m,2H),7.42(d,J=8.4Hz,1H),7.35(dd,J=8.8,4.9Hz,1H),7.31-7.22(m,4H) ,5.10-5.00(m,1H),4.48(d,J=9.9Hz,1H),4.41-4.30(m,2H),4.13-4.04(m,2H),3.79-3.57(m,22H),3. 44-3.26(m,7H),2.91-2.81(m,4H),2.49(s,3H),2.22-2.09(m,5H),1.49(d,J=5.9Hz,3H),0.95(s,9H).

[0276] Example 11

[0277] 6-Fluoro-5-(4-(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((S)-22-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbamoyl)-23,23-dimethyl-20-oxo-3,6,9,12,15,18-hexaoxa-21-azacyclobutyl)pyridineamide

[0278] The title compound was given as a white solid (38.8 mg, 45% yield).

[0279] MS(M+H=1163.59)

[0280] 1H NMR (500MHz, DMSO-d6) δ12.47(s,1H),8.98(s,1H),8.45(d,J=7.7Hz,1H),8.33(t,J=6.0Hz,1H),7.85(dd,J=8.0,1.4Hz,1H),7.5 9-7.49(m,2H),7.45-7.41(m,2H),7.40-7.35(m,3H),7.29(t,J=7.7Hz,1H),5.13(d,J=3.6Hz,1H),4.90(p,J=6.9Hz,1H),4.54(d ,J=9.6Hz,1H),4.44(t,J=8.2Hz,1H),4.28(s,1H),3.96(s,2H),3.69(s,2H),3.61-3.49(m,24H),3.41(q,J=6.0Hz,2H),3.20-3. 12(m,4H),2.61-2.56(m,4H),2.45(s,3H),2.42(s,3H),2.08-2.01(m,1H),1.79-1.73(m,1H),1.37(d,J=7.0Hz,3H),0.93(s,9H).

[0281] Example 12

[0282] 6-Fluoro-5-(4-(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N-((S)-25-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)carbamoyl)pyrrolidine-1-carbamoyl)-26,26-dimethyl-23-oxo-3,6,9,12,15,18,21-hepta-24-azaheptaalkyl)pyridineamide

[0283] The title compound was given as a white solid (22.7 mg, yield 27%).

[0284] MS(M+H=1207.62)

[0285] 1H NMR (500MHz, DMSO-d6) δ12.47(s,1H),8.98(s,1H),8.45(d,J=7.7Hz,1H),8.33(t,J=6.0Hz,1H),7.85(dd,J=8.1,1.4Hz,1H),7.5 9-7.50(m,2H),7.45-7.42(m,2H),7.40-7.35(m,3H),7.29(t,J=7.6Hz,1H),5.14(d,J=3.6Hz,1H),4.90(p,J=6.9Hz,1H),4.54(d ,J=9.6Hz,1H),4.44(t,J=8.2Hz,1H),4.28(s,1H),3.96(s,2H),3.69(s,2H),3.61-3.48(m,28H),3.41(q,J=6.0Hz,2H),3.21-3. 13(m,4H),2.62-2.56(m,4H),2.45(s,3H),2.42(s,3H),2.08-2.02(m,1H),1.79-1.73(m,1H),1.37(d,J=7.0Hz,3H),0.93(s,9H).

[0286] Biological Examples

[0287] Biological Example 1

[0288] Effects of the disclosed compounds on MDA-MB-436 / MX-1PAR protein

[0289] 1. Cell treatment

[0290] 1) Take MDA-MB-436 / MX-1 cells in the logarithmic growth phase and seed them into a 24-well plate at a ratio of 3×105 cells / well.

[0291] 2) After culturing in the incubator for 24 hours, add GW03-496 and negative control (1640 medium) at final concentrations of 0.001 μM, 0.01 μM, 0.1 μM, 1 μM and 10 μM, and incubate in the incubator for 24 hours.

[0292] 3) After aspirating the cell supernatant, wash with PBS 1 to 2 times.

[0293] 4) Wash the cells with 2× protein loading buffer to completely lyse them, and heat in a 100°C metal bath for 20 min.

[0294] 2. Western blot

[0295] 1) Add 10 μL of sample to each well and perform electrophoresis (120V, 60min).

[0296] 2) Using eBlot TM L1 rapid wet transfer technology transfers proteins onto PVDF membranes.

[0297] 3) Block with milk-PBST solution for 30 min at room temperature.

[0298] 4) Dilute PARP1 (1:1000), PARP2 (1:1000) and H3 (1:1000) with primary antibody dilution buffer, incubate overnight at 4°C, and then wash 5 times with PBST for 5 min each time.

[0299] 5) Dilute the secondary antibody with skim milk at a ratio of 1:5000, incubate at room temperature for 1 hour, and then wash with PBST 5 times for 5 minutes each time.

[0300] 6) Remove excess washing solution from the membrane, add developer to the membrane, and use the Tanon imaging system for color development and imaging.

[0301] The results are shown in Table 1.

[0302] Table 1

[0303] As shown in Figure 1, the PARP1 protein level in MDA-MB-436 / MX-1 cells was significantly reduced after treatment with the compounds disclosed herein. This indicates that the compounds disclosed herein have high inhibitory activity and high selectivity against PARP1 (but no activity against PARP2).

[0304] Biological Example 2

[0305] Effect of the disclosed compounds on the survival rate of MDA-MB-436 cells

[0306] 1) Take MDA-MB-436 cells in the logarithmic growth phase and seed them into 96-well plates at a ratio of 200 cells / well.

[0307] 2) After 24 hours, add the compounds of Example 3 and the negative control (1640 medium) at final concentrations of 0 μM, 1 nM, 10 nM, 100 nM, 1 μM and 10 μM, and incubate in an incubator for 7 days.

[0308] 3) After 7 days, remove the cell culture medium, add MTT solution (diluted with PBS) at a concentration of 5 mg / mL, and incubate for 4 hours.

[0309] 4) At this point, there are blue crystals at the bottom of the well plate. Carefully remove the supernatant and add 100 μL LDMSO to each well to dissolve the crystals.

[0310] 5) OD detected using an ELISA reader 490 The numerical value is used to calculate cell viability.

[0311] Table 2

[0312] In this disclosure, relational terms such as first and second are used merely to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations.

[0313] As will be understood from the foregoing, although specific embodiments of this disclosure have been described for illustrative purposes, various modifications or alterations can be made by those skilled in the art without departing from the spirit and scope of this disclosure. All such modifications or alterations should fall within the scope of the appended claims.

Claims

1. A compound represented by general formula I, including its hydrate, solvate, isotope, isomer, prodrug, or pharmaceutically acceptable salt. in, L is selected from any substituted hydrocarbon group or any substituted heterohydrocarbon group; and E is selected from 2. The compound of claim 1, wherein the alkylene group is C5-C. 16 Hydroxyl group.

3. The compound of claim 1 or 2, wherein the heteroalkylene group is C5-C. 16 Heterohydrocarbon group.

4. The compound according to any one of claims 1 to 3, wherein the heteroatom is selected from oxygen, sulfur and nitrogen atoms.

5. The compound according to any one of claims 1 to 4, wherein the number of heteroatoms is 1 to 6.

6. The compound according to any one of claims 1 to 5, wherein L is selected from... Where n is an integer selected from 1 to 6, and m is an integer selected from 3 to 11.

7. The compound according to any one of claims 1 to 6, wherein E is...

8. The compound according to any one of claims 1 to 6, wherein E is 9. The compound according to any one of claims 1 to 6, wherein E is...

10. The compound according to any one of claims 1 to 9, wherein the compound is selected from...

11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10, or its hydrate, solvate, isotope, isomer, prodrug, pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is prepared as a tablet, capsule, powder, syrup, liquid, suspension, lyophilized powder for injection or injection.

13. A method for preparing compounds of general formula I, including their hydrates, solvates, isotopes, isomers, prodrugs, or pharmaceutically acceptable salts. in, L is selected from either a substituted hydrocarbon group or a human-substituted heterohydrocarbon group; and E is selected from The method includes: Will and The compound shown reacts to give the compound represented by general formula I.

14. The method of claim 13, wherein Will The compound shown was deprotected under acidic conditions to give The compound shown.

15. The method of claim 14, wherein Will The compound shown reacts with the compound shown in H2N-L-NHBoc to give The compound shown, wherein E is selected from as well as X is selected from H or O.

16. The method of claim 14, wherein Will The compound shown reacts with the compound shown in BocHN-L-CO2H to obtain the desired result. The compound shown, wherein E is selected from 17. A method for degrading PARP1, comprising contacting PARP1 with any one of the compounds of claims 1 to 10, or their hydrates, solvates, isotopes, isomers, prodrugs, pharmaceutically acceptable salts, or with the pharmaceutical composition of claim 11 or 12.

18. The method of claim 17, wherein the contact is performed in vitro.

19. A method for preventing or treating cancer, comprising administering to an individual in need of the method a preventive or therapeutically effective amount of the compound of any one of claims 1 to 10, or a hydrate, solvate, isotope, isomer, prodrug, pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 11 or 12.

20. The method of claim 19, wherein the cancer is PARP1-mediated.

21. The method of claim 19 or 20, wherein the cancer is selected from breast cancer, pancreatic cancer, prostate cancer, peritoneal cancer, fallopian tube cancer, ovarian cancer, and cervical cancer.

22. The method according to any one of claims 19 to 21, wherein the individual is a mammal, preferably a human.

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