PARP inhibitors having piperazine structure, their preparation method and their medical use

Abstract

The present invention discloses PARP inhibitors containing piperazine structure, their preparation method and their medical use.In particular, the present invention relates to novel compounds of general formula (1), (2), (3), (4) and (5) and / or their pharmaceutically acceptable salts, compositions containing compounds of general formula (1), (2), (3), (4) and (5) and / or their pharmaceutically acceptable salts, their preparation method and their use as PARP inhibitors in the preparation of antitumor drugs. [Formula 1] TIFF2024514703000068.tif130168

Description

[Technical field]

[0001] This application claims priority to Chinese Application No. 202110439238.4, filed on April 22, 2021, which is incorporated by reference in its entirety herein.

[0002] The present invention relates to the field of pharmaceutical chemistry, in particular to novel compounds having inhibitory activity against poly(ADP-ribose) polymerase (PARP), their preparation process and the use of such compounds in the preparation of antitumor drugs. [Background technology]

[0003] Poly(ADP-ribose) polymerase (PARP) is expressed in most eukaryotic cells and catalyzes the formation of ADP-ribose units or their polymers (PAR) on specific amino acid residues of itself or other proteins using nicotinamide adenine dinucleotide (NAD+) as a substrate, modifying the PAR of the protein and further controlling the degradation and function of the protein. The PARP family consists of seven isozymes including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), tankyrases such as PARP-5 (TANK-1, TANK-2, and TANK-3), PARP-7, and PARP-10 [de la Lastra CA.et al.,Curr Pharm Des.,13(9),933-962,2007]. Although the enzymes in the PARP family are diverse, PARP-1 is responsible for more than 90% of ADP-ribosylation (PAR) in cells. PARPs play important roles in events such as regulating chromosome structure, gene transcription, DNA replication and recombination, and DNA repair, among others. Among them, PARP-1 promotes ADP-ribosylation and polymerization, initiates DNA repair, and controls the recruitment and levels of DNA repair proteins during DNA repair.

[0004] When the DNA of tumor cells is damaged by chemotherapy drugs or ionizing radiation, PARP-1 is rapidly activated, NAD+ is incorporated as a substrate, and a large amount of PAR is synthesized at the DNA damage site to modify histones. DNA repair proteins are then recruited to initiate DNA repair. PARP-1 is mainly involved in the repair of single-stranded DNA breaks (SSBs). When PARP-1 is inhibited by PARP inhibitors, SSBs cannot be repaired, and during S-phase DNA replication, SSBs are converted to double-stranded DNA breaks (DSBs), thereby inhibiting the function of PARP-1 and causing the accumulation of DSBs in cells. Repair of DSBs by living organisms is mainly achieved by two methods, homologous recombination (HR) and non-homologous DNA end joining (NHEJ), of which repair by homologous recombination is the major method of S-phase DSB repair and has high repair reliability. BRCAl and BRCA2 play important roles in repair by homologous recombination. Deficiency of BRCA1 and BRAC2 limits DSB repair. Research has shown that BRCA1 / 2 mutations are found in ovarian, breast, and prostate cancers, and cancer cells with BRCA1 and BRCA2 deficiencies are particularly sensitive to PARP inhibitors. This is thought to be due to the fact that PARP inhibitors inhibit PARP-1, induce DSBs, and BRCA1 / 2 deficiency inhibits repair and induces cell death. Therefore, PARP inhibitors have a good effect on the clinical treatment of BRCA1 / 2-deficient tumors. PARP inhibitors can be used alone or in combination with chemotherapy and radiotherapy drugs, thereby achieving higher efficacy at lower doses. Olaparib is the first PARP inhibitor approved for marketing. With the expansion of indications for PARP inhibitors, PARP inhibitors have been widely used not only in the cancer field, but also in stroke, myocardial ischemia, inflammation, diabetes, etc. Summary of the Invention [Problem to be solved by the invention]

[0005] Although efforts to develop PARP inhibitors for the treatment of cancer and other diseases have been ongoing, such inhibitors lack specificity for PAPR family proteins, have significant toxicity and side effects, and are prone to drug resistance. Therefore, the development of specific and highly active PARP-1 inhibitors would be of significant clinical value. [Means for solving the problem]

[0006] (overview) The present invention provides a compound of general formula (1), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] (In general formula (1), R 1 is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R 2 is H or (C1-C3) alkyl, R 3 is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl; n is 1 or 2, R 4 and R 5 represents two substituents on the cycloalkyl ring, each independently being H or F; X 1 and X 2 are each independently CH or N.

[0007] In another particular embodiment of the present invention, the compound of general formula (1) has the following structure: [ka] has one of the following:

[0008] The present invention provides a compound of general formula (2), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] (In general formula (2), R 1 is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R 2 is H or (C1-C3) alkyl, X 3 and X 4 One of the groups is CH and the other is N, and X 5 is CR 6 or N and R 6 is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl, or X 3 and X 4 are both CH and X 5 is N, R 7 is H, (C1-C4) alkyl, or (C3-C4) cycloalkyl substituted with 0-2 F.

[0009] In another particular embodiment of the present invention, the compound of general formula (2) has the following structure: [ka] has one of the following:

[0010] The present invention provides a compound of general formula (3), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] (In general formula (3), R 1 is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R 3 is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl; R7 is H, (C1-C4) alkyl, or (C3-C4) cycloalkyl substituted with 0-2 F.

[0011] In another particular embodiment of the present invention, the compound of general formula (3) has the following structure: [ka] has one of the following:

[0012] The present invention provides a compound of general formula (4), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] (In general formula (4), R 1 is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R 2 is H or (C1-C3) alkyl, R 3 is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl; R 7 is H, (C1-C4)alkyl, or (C3-C4)cycloalkyl substituted with 0-2 F; X 1 and X 2 are each independently CH or N, but X 1 and X 2 are not both N at the same time.)

[0013] In another particular embodiment of the present invention, the compound of general formula (4) has the following structure: [ka] has one of the following:

[0014] The present invention provides a compound of general formula (5), or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof. [ka] (In general formula (5), R 1 is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R 3 is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl; R 7 is H, (C1-C4)alkyl, or (C3-C4)cycloalkyl substituted with 0-2 F; X 6 is NR 8 , O or CR 9 R 10 and R 8 is H or (C1-C3) alkyl, R 9 and R 10 are each independently H, (C1-C3) alkyl, (C1-C3) fluoroalkyl, or (C3-C4) cycloalkyl.

[0015] In another particular embodiment of the present invention, the compound of general formula (5) has the following structure: [ka] has one of the following:

[0016] Another object of the present invention is to provide a pharmaceutical composition containing a pharma- ceutical carrier, diluent and / or excipient and, as an active ingredient, a compound of the present invention represented by any one of the general formulas (1) to (5) or an isomer, crystalline form, pharma- ceutical acceptable salt, hydrate or solvate thereof.

[0017] Yet another object of the present invention is to provide a use of the compound of the present invention represented by the general formulas (1) to (5), or an isomer, a crystalline form, a pharma- ceutically acceptable salt, a hydrate or a solvate thereof, or the pharmaceutical composition, in the preparation of a medicament for treating, regulating or preventing a disease associated with PARP.

[0018] Yet another object of the present invention is to provide a method for treating, regulating or preventing a related disease mediated by PARP, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention represented by general formulas (1) to (5), or an isomer, crystal form, pharma- ceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition described above.

[0019] It is to be understood that both the foregoing general description and the following detailed description of the invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] (Synthesis of Compounds)

[0021] The preparation methods of the compounds of the general formula of the present invention are specifically described below, but these specific methods do not limit the present invention in any way.

[0022] The compounds of the above formulas can be synthesized using standard synthetic techniques in combination with the methods described herein, or well-known techniques. Furthermore, the solvents, temperatures and other reaction conditions described herein may vary. Starting materials for the synthesis of the compounds can be obtained synthetically or commercially. The compounds described herein and other related compounds with different substituents are described in March, ADVANCED ORGANIC CHEMISTRY, 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY, 4 thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3 rd Ed., (Wiley 1999). General methods for preparing compounds may be modified by using appropriate reagents and conditions to introduce various groups into the molecular formulas provided herein.

[0023] In one embodiment, the compounds described herein are prepared according to methods well known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the following description. In addition, the compounds of the present invention can be conveniently prepared by any combination of various synthetic methods described herein or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains. In one embodiment, the present invention further provides a method for preparing a compound of general formula (1), which is prepared according to the following general reaction schemes 1 to 5.

[0024] General reaction scheme 1 [ka]

[0025] Embodiments of compounds of general formula (1) may be prepared according to General Reaction Scheme 1, wherein R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 and n is as defined above. As shown in General Reaction Scheme 1, compound 1-1 is reacted with thionyl chloride to produce compound 1-2, and compound 1-2 and compound 1-3 are subjected to a substitution reaction to produce target compound 1-4.

[0026] General reaction scheme 2 [ka]

[0027] Embodiments of compounds of general formula (2) can be prepared according to General Reaction Scheme 2, where R 1 , R 2 , R 7 , X 3 , X 4 and X 5 is as defined above. As shown in General Reaction Scheme 2, compound 2-1 is reacted with thionyl chloride to produce compound 2-2, and compound 2-2 and compound 2-3 are subjected to a substitution reaction to produce the target compound 2-4.

[0028] General reaction scheme 3 [ka]

[0029] Embodiments of compounds of general formula (3) may be prepared according to General Reaction Scheme 3, wherein R 1 , R 3 and R 7 is as defined above. As shown in General Reaction Scheme 3, compound 3-1 is reacted with phosphorus oxychloride to produce compound 3-2, compound 3-2 is reacted with sodium methoxide to produce compound 3-3, compound 3-3 is reacted with methyllithium at low temperature to produce compound 3-4, compound 3-4 is subjected to the action of hydrochloric acid to produce compound 3-5, compound 3-5 is reduced with a reducing agent to produce compound 3-6, compound 3-6 is reacted with thionyl chloride to produce compound 3-7, and compound 3-7 and compound 3-8 are subjected to a substitution reaction to produce the target compound 3-9.

[0030] General reaction scheme 4 [ka]

[0031] Embodiments of compounds of general formula (4) can be prepared according to General Reaction Scheme 4, wherein R 1 , R 2 , R 3 , R 7 , X 1 and X 2 As shown in General Reaction Scheme 4, compound 4-1 is reacted with thionyl chloride to produce compound 4-2, and compound 4-2 and compound 4-3 are subjected to a substitution reaction to produce the target compound 4-4.

[0032] General Reaction Scheme 5 [ka]

[0033] Embodiments of compounds of general formula (5) may be prepared according to General Reaction Scheme 5, wherein R 1 , R 3 , R 7 and X 6 is as defined above. As shown in General Reaction Scheme 5, compound 5-1 is subjected to a carbonylation reaction in the presence of a reducing agent (e.g., triethylsilane) to obtain compound 5-2, compound 5-2 is reduced with a reducing agent to produce compound 5-3, compound 5-3 is reacted with thionyl chloride to produce compound 5-4, and compound 5-4 and compound 5-5 are subjected to a substitution reaction to produce the target compound 5-6.

[0034] Further forms of the compound

[0035] As used herein, "pharmaceutical acceptable" refers to a relatively non-toxic substance, such as a carrier or diluent, that does not cause a loss of biological activity or properties of a compound, e.g., when administered to an individual, the substance does not cause undesirable biological effects or deleterious interactions with any of its components.

[0036] The term "pharmaceutical acceptable salt" refers to an existing form of a compound that does not cause significant irritation to the receiving organism or eliminate the biological activity and properties of the compound.In certain embodiments, the pharmaceutical acceptable salt is obtained by reacting the compound of the general formula with an acid, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.

[0037] It is to be understood that pharma- ceutically acceptable salts include solvent addition forms or crystal forms, particularly solvates or polymorphs. Solvates include stoichiometric or non-stoichiometric amounts of solvent and are preferentially formed during crystallization in pharma- ceutical acceptable solvents such as water and ethanol. When the solvent is water, hydrates are formed, and when the solvent is ethanol, alcoholates are formed. Solvates of compounds of the general formula are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of the general formula are conveniently prepared by recrystallization in a water / organic solvent mixture, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, compounds described herein can exist in either unsolvated or solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0038] In other particular embodiments, the compound of the general formula is prepared in different forms, including but not limited to amorphous, crushed, and nanoparticle forms. Furthermore, the compound of the general formula may be a polymorph, including crystalline forms. A polymorph includes different lattice arrangements of the same elements of a compound. The polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal morphology, optical properties, electrical properties, stability, and solubility. Various factors, such as recrystallization solvent, crystallization rate, and storage temperature, may result in a single predominant crystal system.

[0039] In another embodiment, the compounds of the general formula may have chiral centers and / or axial asymmetry and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, single diastereomers and cis-trans isomers. Each chiral center or axial asymmetry independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomers of these compounds.

[0040] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) and C-14( 14 The deuterated pharmaceuticals may be labeled with radioisotopes such as 1,2-dihydrogen (C). As another example, deuterium may be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by general hydrogen and carbon. Compared to non-deuterated pharmaceuticals, deuterated pharmaceuticals generally have the advantages of reduced side effects, improved drug stability, enhanced efficacy, and extended in vivo half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

[0041] Explanation of terms

[0042] Unless otherwise specified, the terms used in the present invention, including those used in the specification and claims, are defined as follows. Please note that in this specification and the appended claims, the singular forms "a" and "an" include the plural meaning unless otherwise specified in the context. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance spectroscopy, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. As used herein, "or" or "and" means "and / or" unless otherwise specified.

[0043] Unless otherwise specified, "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched groups, having 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyls, particularly alkyls substituted with one or more halogens. Preferred alkyls are CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t is selected from Bu.

[0044] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic); partially unsaturated cycloalkyls may be referred to as "cycloalkenyls" if the carbocyclic ring contains at least one double bond, or "cycloalkynyls" if the carbocyclic ring contains at least one triple bond. The cycloalkyls may include monocyclic or polycyclic groups, as well as spirocycles (e.g., having 2, 3, or 4 fused rings). In some embodiments, the cycloalkyls are monocyclic. In some embodiments, the cycloalkyls are monocyclic or bicyclic. The ring carbon atoms of the cycloalkyls may be optionally oxidized to form oxo or sulfido groups. The cycloalkyls further include cycloalkylene. In some embodiments, the cycloalkyls include 0, 1, or 2 double bonds. In some embodiments, the cycloalkyls include 1 or 2 double bonds (partially unsaturated cycloalkyls). In some embodiments, the cycloalkyl may be fused with an aryl, heteroaryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the cycloalkyl may be fused with an aryl, cycloalkyl, and heterocycloalkyl. In some embodiments, the cycloalkyl may be fused with an aryl and a heterocycloalkyl. In some embodiments, the cycloalkyl may be fused with an aryl and a cycloalkyl. Examples of the cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norcamphanyl, norpinanyl, norcarnyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.

[0045] Unless otherwise specified, "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy, particularly alkoxy substituted with one or more halogens. Preferred alkoxy are OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0046] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" (or "halogenated") before a radical name indicates that the radical is partially or fully halogenated, i.e., substituted by F, Cl, Br or I, preferably F or Cl, in any combination.

[0047] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily occur, and the description includes instances in which the event or circumstance occurs and instances in which the event or circumstance does not occur.

[0048] The substituent "-O-CH2-O-" means that the two oxygen atoms in the substituent are attached to two adjacent carbon atoms in a heterocycloalkyl, aryl, or heteroaryl, for example: [ka]

[0049] When the number of a linker group is 0, such as -(CH2)0-, it means that the linker group is a single bond.

[0050] When one of the variables is selected from a chemical bond, it means that the two groups connected by this variable are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0051] The term "membered ring" includes any cyclic structure. The term "membered" is intended to refer to the number of main chain atoms that form the ring. For example, cyclohexyl, pyridinyl, pyranyl, and thiopyranyl are 6-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are 5-membered rings.

[0052] The term "moiety" refers to a specific portion or functional group of a molecule. A chemical moiety is generally considered to refer to a chemical substance contained in or attached to a molecule.

[0053] Solid wedge connections unless otherwise noted [ka] and wedge-shaped dashed bond [ka] represents the absolute configuration of a stereocenter, and a straight solid bond [ka] and straight dashed bond [ka] represents the relative configuration of the stereocenters. Wavy line [ka] is a solid wedge connection [ka] or wedge-shaped dashed bond [ka] or a wavy line [ka] is a straight solid line connection [ka] or straight dashed bond [ka] Represents.

[0054] Unless otherwise indicated, single or double bonds are [ka] It is expressed by:

[0055] Specific pharmaceutical and medical terms

[0056] The term "acceptable" as used herein means that a formulation component or active ingredient does not have an excessive and deleterious effect on the general health of the treated subject.

[0057] The terms "treatment", "course of treatment" and "treatment" as used herein include alleviating, inhibiting or ameliorating a disease symptom or condition, inhibiting the occurrence of a complication, improving or preventing the underlying metabolic syndrome, inhibiting the occurrence of a disease or condition (e.g., controlling the progression of a disease or condition), relieving a disease or condition, regressing a disease or condition, and alleviating complications caused by a disease or condition, or preventing or treating symptoms caused by a disease or condition. As used herein, a compound or pharmaceutical composition, when administered, can improve a disease, symptom or condition, and in particular can improve the severity, delay the onset, delay the progression, or shorten the duration of a disease. Fixed or episodic administration, or continuous or intermittent administration, can result from or be associated with administration.

[0058] "Active ingredient" refers to compounds of the general formula and pharma- ceutically acceptable inorganic or organic salts of compounds of the general formula. The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial asymmetry) and therefore may exist in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center independently produces two optical isomers, and all possible optical isomers, diastereomeric mixtures, and pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0059] As used herein, terms such as "compound," "composition," "agent," or "medicine or pharmaceutical agent" are used interchangeably and all refer to a compound or composition that, when administered to an individual (human or animal), is capable of eliciting a desired pharmacological and / or physiological response through local and / or systemic action.

[0060] The terms "administered, administering, or administration" as used herein refer to direct administration of a compound or composition, or administration of a prodrug, derivative, analog, etc. of an active compound.

[0061] Although the numerical ranges and parameters defining the broad scope of the present invention are approximations, the relevant values ​​set forth in certain embodiments are set forth herein as precisely as possible. However, any numerical value inherently contains a standard deviation that necessarily results from certain testing methods. Here, "about" generally means that the actual value is within a particular value or range ±10%, 5%, 1%, or 0.5%. Alternatively, the term "about" indicates that the actual numerical value is within an acceptable standard error of the mean value, as would be understood by one of ordinary skill in the art. Except in experimental examples or unless otherwise indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe amounts of materials, lengths of time, temperatures, operating conditions, proportions of amounts, etc.) are understood to be modified by the term "about". Thus, unless otherwise indicated, all numerical parameters set forth in this specification and the appended claims are approximations that may be varied as desired. At the very least, these numerical parameters should be interpreted as numerical values ​​obtained using the significant digits given or conventional rounding rules.

[0062] Scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art, unless otherwise defined herein. Furthermore, singular nouns used herein include their plurals, unless otherwise contradicted by context, and plural nouns used herein also include their singulars.

[0063] therapeutic use

[0064] The present invention provides methods for treating diseases, including but not limited to conditions in which PARP is implicated (eg, cancer), using compounds of the general formula or pharmaceutical compositions of the present invention.

[0065] In some embodiments, a method of treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of the general structural formula.In some embodiments, the cancer is mediated by PARP.In other embodiments, the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.

[0066] Route of administration

[0067] The compound of the present invention and its pharmaceutical acceptable salts can be prepared into various formulations containing a safe and effective amount of the compound of the present invention or its pharmaceutical acceptable salts and a pharmaceutical acceptable excipient or carrier, where "safe and effective amount" means the amount of compound that is sufficient to significantly improve the condition without causing serious adverse effects.The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject to be treated.

[0068] "Pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use, have sufficient purity, and have sufficiently low toxicity. As used herein, "compatible" means that the components of the composition are capable of being mixed with the compound of the present invention without significantly reducing the pharmaceutical effectiveness of the compound. Examples of pharmaceutically acceptable excipients or carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0069] The compounds of the present invention may be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous) or topically.

[0070] Solid dosage forms for oral administration include capsules, tablets, pills, pulvises, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or the following ingredients: (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarding agents such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, said dosage forms may further comprise buffering agents.

[0071] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials known in the art.These may contain opacifying agents, and the active compound or compounds in such compositions can be released in a certain part of the digestive tract in a delayed manner.The examples of embedding components that can be used include polymeric materials and wax-based materials.If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0072] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, etc. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0073] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0074] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methylate, and agar-agar, or mixtures of these substances.

[0075] Compositions for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0076] Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required as required.

[0077] The compound of the present invention may be administered alone or in combination with other pharma- ceutical acceptable compounds. When the pharmaceutical composition of the present invention is used, a safe and effective amount of the compound of the present invention is administered to the mammal (such as a human) to be treated, where the dosage is a pharma- ceutical effective dose. For a 60 kg human, the daily dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, the specific dosage also takes into account factors such as the route of administration and the patient's health condition, but these are well known to those skilled in the art.

[0078] The features described in the present invention or the features described above in the embodiments can be combined in any combination. All features disclosed herein can be used in any composition, and the various features disclosed herein can be replaced with any alternative features that provide the same, equivalent or similar purpose. Thus, unless otherwise specified, the features disclosed herein are merely generic examples of equivalent or similar features.

[0079] (Detailed Description)

[0080] Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions are described in detail as follows, which will make the contents of the present invention very clear. It should be understood that the following detailed description and examples are for reference purposes only. After reading the description of the present invention, those skilled in the art can make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present application as defined herein.

[0081] In all examples, 1 H-NMR spectra were recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts were expressed in δ (ppm); unless otherwise specified, 200–300 mesh silica gel was used for separation, and the ratio of eluents was by volume. EXAMPLES

[0082] Example 1: Synthesis of Compound 1 [ka]

[0083] Step 1: Synthesis of compound int_1-2: [ka]

[0084] To a solution of compound int_1-1 (5.00 g, 23.79 mmol) in dioxane (30 mL), selenium dioxide (3.96 g, 35.68 mmol) was added at room temperature, and the reaction was heated to 110° C. and stirred for 20 hours. After cooling, the reaction was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (100 mL). The combined filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate int_1-2. LC-MS(ESI):225[M+H] + .

[0085] Step 2: Synthesis of compound int_1-3: [ka]

[0086] To a solution of 60% sodium hydride (2.23 g, 55.76 mmol) in anhydrous tetrahydrofuran (25 mL), triethyl 2-phosphonobutyrate (14.07 g, 55.76 mmol) was slowly added dropwise with stirring at 0° C. After the dropwise addition was complete, the mixture was stirred at 0° C. for 10 min, slowly warmed to room temperature, heated to 40° C. and stirred for 5 min. The reaction was cooled to −78° C. and a solution of intermediate int_1-2 (5.00 g, 22.30 mmol) in anhydrous tetrahydrofuran (25 mL) was slowly added dropwise with stirring. The mixture was quenched by the addition of saturated aqueous ammonium chloride (100 mL), the reaction was concentrated under reduced pressure to remove most of the tetrahydrofuran, and extracted with ethyl acetate (150 mL×2). The organic phases were combined, washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate int_1-3 (a mixture of E / Z configurations). LC-MS(ESI):323[M+H] + .

[0087] Step 3: Synthesis of compounds int_1-4: [ka]

[0088] Intermediate int_1-3 (3.00 g, 9.31 mmol) and palladium on carbon (10%, water content 50%, 1.49 g) were mixed in ethanol (25 mL), the mixture was purged with hydrogen twice, and then the reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) at room temperature overnight. The mixture was filtered, the filtrate was concentrated under reduced pressure, a solution of hydrogen chloride in dioxane (4 M, 10 mL) was added, and the resulting mixture was stirred at room temperature for 0.5 h. Diethyl ether (100 mL) was added for dilution, the mixture was filtered, and the filter cake was washed with diethyl ether and dried under reduced pressure to give intermediate int_1-4. LC-MS(ESI):249[M+H] + .

[0089] Step 4: Synthesis of compounds int_1-5: [ka]

[0090] Intermediate int_1-4 (2.00 g, 8.06 mmol) was dissolved in dioxane (35 mL) at room temperature, 2,3-dichloro-5,6-dicyanobenzoquinone (2.01 g, 8.86 mmol) was added, and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, and saturated aqueous sodium bicarbonate (50 mL) was added, and the mixture was stirred for 1 hour, then filtered, and the filter cake was washed successively with water and diethyl ether. The filter cake was dried under reduced pressure to give intermediate int_1-5. LC-MS(ESI):247[M+H] + .

[0091] Step 5: Synthesis of compounds int_1-6: [ka]

[0092] Lithium aluminum hydride (16.24 mL, 16.24 mmol, 1M in THF) was added to a solution of intermediate int_1-5 (2.00 g, 8.12 mmol) in tetrahydrofuran (40 mL) under nitrogen atmosphere in an ice-water bath, and the reaction mixture was stirred at 0° C. for 1 h. To the reaction solution, water (1 mL), 15% aqueous sodium hydroxide solution (2 mL), and water (3 mL) were added successively with stirring. After stirring for 15 min, the reaction solution was filtered, and the filtrate was extracted with ethyl acetate (30 mL×4). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate int_1-6. LC-MS(ESI):205[M+H] + .

[0093] Step 6: Synthesis of compounds int_1-7: [ka]

[0094] To a solution of intermediate int_1-6 (2.00 g, 9.79 mmol) and N,N-dimethylformamide (71.58 mg, 0.979 mmol) in dichloromethane was added thionyl chloride (4.26 mL, 58.76 mmol) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 5 h and the reaction was concentrated under reduced pressure to give crude intermediate int_1-7, which was used directly in the next step without purification.

[0095] Step 7: Synthesis of compound 1: [ka]

[0096] Intermediate int_1-7 (crude product, 2.00 g), intermediate int_1-8 (2.21 g, 8.98 mmol), potassium iodide (298 mg, 1.80 mmol) and N,N-diisopropylethylamine (5.80 g, 44.91 mmol) were mixed in acetonitrile (25 mL) at room temperature, and the mixture was heated to 80 ° C. and stirred for 2 hours. After cooling the reaction solution, it was concentrated under reduced pressure to remove the organic solvent, water (100 mL) was added, and the mixture was made basic with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL × 4). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain compound 1. LC-MS(ESI):433[M+H] + . 1H NMR(400MHz,DMSO-d6) δ 11.84(s,1H),8.40(d,J=1.5Hz,1H),8.33(d,J=4.9Hz,1H),8.23(d,J=2.6Hz,1H),7.82(d,J=8.8Hz,1H),7.75(s,1H),7.62(s,1H) ),7.48-7.39(m,1H),3.65(s,2H),3.32-3.28(m,2H),2.90-2.79(m,1H),2.59-2.52(m,8H),1.20-1.12(m,3H),0.72-0.56(m,4H).

[0097] Example 2: Synthesis of Compound 2 [ka]

[0098] Intermediate int_1-7 (2.00 g), intermediate int_2-1 (2.50 g, 11.30 mmol), potassium iodide (298 mg, 1.80 mmol) and N,N-diisopropylethylamine (5.80 g, 44.91 mmol) were mixed in acetonitrile (25 mL) at room temperature, and the mixture was heated to 80 ° C. and stirred for 2 hours. After cooling the reaction solution, it was concentrated under reduced pressure to remove the organic solvent, water (100 mL) was added, and the mixture was made basic with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL × 4). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain compound 2. LC-MS(ESI):408[M+H] + .

[0099] Example 3: Synthesis of Compound 3 [ka]

[0100] Step 1: Synthesis of compound int_3-1: [ka]

[0101] A mixture of intermediate int_1-5 (3.00 g, 12.18 mmol) and phosphorus oxychloride (37.36 g, 243.64 mmol) was heated to 100° C. and stirred for 3 hours. After cooling the reaction mixture, it was concentrated under reduced pressure to remove phosphorus oxychloride, and the residue was poured into water (200 mL) and made basic with saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (60 mL×4). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and a crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate int_3-1. LC-MS(ESI):265[M+H] + .

[0102] Step 2: Synthesis of compound int_3-2 [ka]

[0103] Intermediate int_3-1 (2.00 g, 7.56 mmol) and sodium methoxide (816 mg, 15.11 mmol) were mixed in methylbenzene (30 mL) at room temperature, and the mixture was heated to 50° C. and stirred for 5 hours. After cooling, the reaction solution was poured into water (150 mL) and extracted with ethyl acetate (50 mL×4). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate int_3-2. LC-MS(ESI):261[M+H] + .

[0104] Step 3: Synthesis of compound int_3-3 [ka]

[0105] To a solution of intermediate int_3-2 (2.00 g, 7.68 mmol) in tetrahydrofuran (30 mL), methyllithium (1.5 M in THF, 7.68 mL, 11.53 mmol) was added under nitrogen atmosphere at −78° C. while cooling, and the reaction mixture was stirred at −78° C. for 1 h. The reaction was warmed to 0° C. and quenched by dropwise addition of saturated aqueous ammonium chloride solution (20 mL) while stirring, followed by addition of water (50 mL). The mixture was extracted with ethyl acetate (50 mL×4). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate int_3-3. LC-MS(ESI):231[M+H] + .

[0106] Step 4: Synthesis of compound int_3-4 [ka]

[0107] A mixture of intermediate int_3-3 (1.50 g, 6.94 mmol) and 6N hydrochloric acid (15 mL) was heated to 100° C. and stirred for 2 h. The reaction was cooled to 0° C. and basified with 15% aqueous sodium hydroxide solution to pH=6-7 with stirring. The mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to give intermediate int_3-4. LC-MS(ESI):217[M+H] + .

[0108] Step 5: Synthesis of compound int_3-5: [ka]

[0109] Sodium borohydride (350 mg, 9.25 mmol) was slowly added to a solution of intermediate int_3-4 (1.00 g, 4.62 mmol) in methanol (25 mL) in an ice-water bath, and the reaction mixture was stirred at 0° C. for 0.5 h, then warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to give the crude product. The crude product was separated and purified by silica gel chromatography to give intermediate int_3-5. LC-MS(ESI):219[M+H] + .

[0110] Step 6: Synthesis of compound int_3-6: [ka]

[0111] To a solution of intermediate int_3-5 (1.00 g, 4.58 mmol) and N,N-dimethylformamide (33 mg, 0.458 mmol) in dichloromethane (20 mL) was added thionyl chloride (3.27 g, 27.49 mmol) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 5 h and the reaction was concentrated under reduced pressure to give crude intermediate int_3-6, which was used directly in the next step without purification.

[0112] Step 7: Synthesis of compound 3 [ka]

[0113] Intermediate int_3-6 (1.00 g), intermediate int_3-7 (931 mg, 4.22 mmol), potassium iodide (140 mg, 0.845 mmol) and N,N-diisopropylethylamine (2.73 g, 21.12 mmol) were mixed in acetonitrile (20 mL) at room temperature, and the mixture was heated to 80 ° C. and stirred for 2 hours. After cooling the reaction solution, it was concentrated under reduced pressure to remove the organic solvent, water (100 mL) was added, and the mixture was made basic with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain compound 3. LC-MS(ESI):421[M+H] + .

[0114] Example 4: Synthesis of Compound 4 [ka]

[0115] Step 1: Synthesis of compound int_4-2: [ka]

[0116] To a solution of intermediate int_4-1 (1.00 g, 4.87 mmol) and N,N-dimethylformamide (36 mg, 0.487 mmol) in dichloromethane (20 mL) was added thionyl chloride (3.48 g, 29.24 mmol) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 5 h and the reaction was concentrated under reduced pressure to give crude intermediate int_4-2, which was used directly in the next step without purification.

[0117] Step 2: Synthesis of compound 4: [ka]

[0118] Intermediate int_4-2 (1.00 g), intermediate int_3-7 (985 mg, 4.47 mmol), potassium iodide (148 mg, 0.894 mmol) and N,N-diisopropylethylamine (2.89 g, 22.36 mmol) were mixed in acetonitrile (20 mL) at room temperature, and the mixture was heated to 80 ° C. and stirred for 2 hours. After cooling the reaction solution, it was concentrated under reduced pressure to remove the organic solvent, water (100 mL) was added, and the mixture was made basic with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain compound 4. LC-MS(ESI):408[M+H] + .

[0119] Example 5: Synthesis of Compound 5 [ka]

[0120] Step 1: Synthesis of compound int_5-2: [ka]

[0121] Intermediate int_5-1 (2.00 g, 7.78 mmol), triethylsilane (1.81 g, 15.56 mmol), triethylamine (2.36 g, 23.34 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (635 mg, 0.778 mmol) and anhydrous N,N-dimethylformamide (38 mL) were added to an autoclave at room temperature. After purging with carbon monoxide, the reaction was pressurized to 60 psi with carbon monoxide, heated to 110 °C and stirred for 12 h. After cooling the reaction to room temperature, the pressure was slowly released, the mixture was filtered, and the filtrate was added with saturated aqueous sodium bicarbonate (200 mL) and then extracted with dichloromethane (60 mL x 3). The organic phases were combined, washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate int_5-2. LC-MS(ESI):207[M+H] + .

[0122] Step 2: Synthesis of compound int_5-3: [ka]

[0123] Sodium borohydride (275 mg, 7.27 mmol) was slowly added to a solution of intermediate int_5-2 (1.00 g, 4.85 mmol) in methanol (20 mL) in an ice-water bath, and the reaction mixture was stirred at 0° C. for 0.5 h, then warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure, water (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate int_5-3. LC-MS(ESI):209[M+H] + .

[0124] Step 3: Synthesis of compound int_5-4: [ka]

[0125] To a solution of intermediate int_5-3 (1.00 g, 4.80 mmol) and N,N-dimethylformamide (35 mg, 0.480 mmol) in dichloromethane (20 mL) was added thionyl chloride (3.43 g, 28.82 mmol) dropwise with stirring at 0° C. The mixture was stirred at room temperature for 5 h and the reaction was concentrated under reduced pressure to give crude intermediate int_5-4, which was used directly in the next step without purification.

[0126] Step 4: Synthesis of compound 5: [ka]

[0127] Intermediate int_5-4 (1.00 g), intermediate int_3-7 (972 mg, 4.41 mmol), potassium iodide (146 mg, 0.882 mmol) and N,N-diisopropylethylamine (2.85 g, 22.06 mmol) were mixed in acetonitrile (20 mL) at room temperature, and the mixture was heated to 80° C. and stirred for 2 hours. After cooling the reaction solution, it was concentrated under reduced pressure to remove the organic solvent, water (100 mL) was added, and the mixture was made basic with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain compound 5. LC-MS(ESI):411[M+H] + . 1H NMR400MHz, CDCl3) δ 9.43(s,1H),8.20-7.95(m,2H),7.82(s,2H),7.15(d,J=8.8Hz,1H),4.74(t,J=5.8Hz,1H),3.4 9(s,2H),3.26(s,4H),3.01(d,J=5.1Hz,3H),2.58(s,4H),1.91(s,2H),1.13(t,J=7.4Hz,3H).

[0128] Examples 6 to 68: Synthesis of Compounds 6 to 68 Using different starting materials, the target compounds 6 to 68 in Table 1 can be obtained by the synthetic methods of General Reaction Schemes 1, 2, 3, 4 or 5, or by other routes.

[0129] [Table 1] TIFF2024514703000055.tif248168TIFF2024514703000056.tif72168

[0130] Example 69: Experiment on in vitro inhibition of the activity of poly(ADP-ribose) polymerase [PARP-1 enzyme] by the compounds of the invention Histones were coated onto 384-well plates overnight at 4°C, rinsed three times with PBST buffer, and blocked for 1 h at room temperature. After 1 h, the histones were rinsed another three times with PBST, DMSO, or serially diluted compounds, and a mixture containing PARP-1 enzyme and DNA was added, and the resulting mixture was incubated for 10 min at 25°C. After 10 min, NAD + The reaction was started by adding 100% ethanol. After 60 min at room temperature, the reaction solution was rinsed three times with PBST, and the level of poly / mono-ADP-ribose on histones was detected by adding a horseradish peroxidase (HRP)-conjugated poly / mono-ADP-ribose antibody. After 1 h of incubation at room temperature, HRP substrates ECLA and B were added, and chemiluminescence was quantified by Envision. The inhibition rate and IC 50 was calculated in comparison with the DMSO control. The results are shown in Table 2 below.

[0131] [Table 2]

[0132] +++ is IC 50 This means that the concentration is 10 nM or less. ++ is IC 50 This means that the concentration is 10 nM to 50 nM. + is IC 50 means that the concentration is greater than 50 nM.

[0133] As can be seen from the data in Table 2, the compounds of the present invention have good inhibitory activity against PARP-1.

[0134] Although specific embodiments of the present invention have been described above, those skilled in the art will understand that these embodiments are merely illustrative and that many changes or modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of general formula (1), or an isomer, crystal, pharma- ceutically acceptable salt, hydrate or solvate thereof. 【Chemistry 1】 (In general formula (1), R １ is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R ２ is H or (C1-C3) alkyl, R ３ is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl; n is 1 or 2; R ４ and R ５ represents two substituents on the cycloalkyl ring, each independently being H or F; X １ and X ２ are each independently CH or N.

2. The compound has the following structure: 【Chemistry 2】 or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

3. A compound of formula (2), or an isomer, crystal, pharma- ceutically acceptable salt, hydrate or solvate thereof. 【Chemistry 3】 (In general formula (2), R １ is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R ２ is H or (C1-C3) alkyl, X ３ and X ４ One of X is CH and the other is N; ５ is CR ６ or N, and R ６ is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl; or X ３ and X ４ are both CH, and X ５ is N, R ７ is H, (C1-C4) alkyl, or (C3-C4) cycloalkyl substituted with 0-2 F.

4. The compound has the following structure: 【Chemistry 4】 or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

5. A compound of formula (3), or an isomer, crystal, pharma- ceutically acceptable salt, hydrate or solvate thereof. 【Chemistry 5】 (In general formula (3), R １ is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R ３ is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl; R ７ is H, (C1-C4) alkyl, or (C3-C4) cycloalkyl substituted with 0-2 F.

6. The compound has the following structure: 【Chemistry 6】 or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

7. A compound of formula (4), or an isomer, crystal, pharma- ceutically acceptable salt, hydrate or solvate thereof. 【Chemistry 7】 (In general formula (4), R １ is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R ２ is H or (C1-C3) alkyl, R ３ is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl; R ７ is H, (C1-C4)alkyl, or (C3-C4)cycloalkyl substituted with 0-2 F; X １ and X ２ are each independently CH or N, １ and X ２ are not both N at the same time.)

8. The compound has the following structure: 【Chemistry 8】 or an isomer, crystalline form, pharma- ceutically acceptable salt, hydrate or solvate thereof.

9. A compound of formula (5), or an isomer, crystal, pharma- ceutically acceptable salt, hydrate or solvate thereof. 【Chemistry 9】 (In general formula (5), R １ is (C1-C4) alkyl, (C1-C4) fluoroalkyl, or (C3-C5) cycloalkyl; R ３ is H, F, Cl, (C1-C4) alkyl, or (C1-C4) fluoroalkyl; R ７ is H, (C1-C4)alkyl, or (C3-C4)cycloalkyl substituted with 0-2 F; X ６ is N.R. ８ , O or CR ９ R １０ and R ８ is H or (C1-C3) alkyl, R ９ and R １０ are each independently H, (C1-C3) alkyl, (C1-C3) fluoroalkyl, or (C3-C4) cycloalkyl.

10. The compound has the following structure: 【Chemistry 10】 10. The compound of claim 9, having one of the following structures:

11. A pharmaceutical composition comprising a pharma- ceutical acceptable excipient or carrier and, as an active ingredient, a compound according to any one of claims 1 to 10 or an isomer, crystalline form, pharma- ceutical acceptable salt, hydrate or solvate thereof.

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