Piperazine-containing parp inhibitors, methods of making and medical uses thereof

Abstract

This invention provides a class of PARP inhibitors containing piperazine structures, their preparation methods, and their pharmaceutical uses. Specifically, it provides novel compounds and / or pharmaceutically acceptable salts thereof as shown in general formulas (1), (2), (3), (4), and (5), as well as compositions containing compounds and / or pharmaceutically acceptable salts thereof as shown in general formulas (1), (2), (3), (4), and (5), their preparation methods, and their use as PARP inhibitors in the preparation of antitumor drugs.

Description

[0001] This application claims priority to Chinese application CN202110439238.4, filed on April 22, 2021. The full text of the aforementioned Chinese application is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of medicinal chemistry, and more specifically, to novel compounds with poly(ADP-ribose) polymerase (PARP) inhibitory activity, their preparation methods, 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. Using nicotinamide adenine dinucleotide (NAD+) as a substrate, it catalyzes the formation of ADP-ribose units or their polymers (PARs) on specific amino acid residues of itself or other proteins, modifying proteins through PAR modification and thereby regulating protein degradation and function. The PARP family consists of seven isoenzymes, including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), end-anchored polymerases 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 PARP family contains many enzymes, PARP-1 is responsible for more than 90% of intracellular ADP-ribosylation (PAR). PARPs play important roles in chromosome structure regulation, gene transcription, DNA replication and recombination, and DNA repair. Among them, PARP-1 promotes ADP-ribosylation and polymerization in DNA repair, initiates DNA repair, and regulates the recruitment and levels of DNA repair proteins.

[0004] When tumor cell DNA is damaged by chemotherapy drugs or ionizing radiation, PARP-1 is rapidly activated, using NAD+ as a substrate to synthesize large amounts of PAR at the DNA damage site, modifying histones. It then recruits DNA repair proteins, initiating DNA repair. PARP-1 is primarily involved in the repair of single-stranded DNA breaks (SSBs). When PARP-1 is inhibited by PARP inhibitors, SSBs cannot be repaired. During S-phase DNA replication, SSBs are converted into double-strand breaks (DSBs), and inhibition of PARP-1 function leads to the accumulation of DSBs within the cell. The body repairs DSBs mainly through two mechanisms: homologous recombination (HR) and non-homologous end joining (NHEJ). Homologous recombination repair is the primary mechanism for S-phase DSB repair and has high reliability. BRCA1 and BRCA2 play important roles in homologous recombination repair. The loss of BRCA1 and BRCA2 restricts DSB repair. Studies have found BRCA1 / 2 mutations in ovarian, breast, and prostate cancers, and cancer cells lacking BRCA1 and BRCA2 are particularly sensitive to PARP inhibitors. This may be because PARP inhibitors inhibit PARP-1, inducing DSB (dysplasia of the stem cell), and due to the lack of BRCA1 / 2, repair is hindered, leading to cell death. Therefore, PARP inhibitors have shown good clinical efficacy in treating BRCA1 / 2-deficient tumors. Besides being used as monotherapy, PARP inhibitors can also be used in combination with chemotherapy and radiotherapy drugs to achieve the goal of reducing dosage and improving efficacy. Olaparib was the first PARP inhibitor approved for marketing. With the continuous expansion of the indications for PARP inhibitors, their application is also deepening, not only focusing on tumors but also showing some effectiveness in stroke, myocardial ischemia, inflammation, and diabetes.

[0005] While efforts to develop PARP inhibitors for the treatment of cancer and other diseases are ongoing, these inhibitors lack specificity for PARP family proteins, have significant toxic side effects, and are prone to drug resistance. Therefore, the development of specific, highly active PARP-1 inhibitors has important clinical value. Summary of the Invention

[0006] This invention provides a compound of general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0007]

[0008] In general formula (1):

[0009] R 1It is (C1-C4)alkyl, (C1-C4)fluoroalkyl, or (C3-C5)cycloalkyl;

[0010] R 2 It is H or (C1-C3) alkyl;

[0011] R 3 It can be H, F, Cl, (C1-C4)alkyl, or (C1-C4)fluoroalkyl;

[0012] n is 1 or 2;

[0013] R 4 and R 5 Represents two substituents on the cycloalkyl ring, each independently being H or F; and

[0014] X 1 X 2 Each can be CH or N independently.

[0015] In another specific embodiment of the present invention, the compound of general formula (1) has one of the following structures:

[0016]

[0017]

[0018] This invention provides a compound of general formula (2) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0019]

[0020] In general formula (2):

[0021] R 1 It is (C1-C4)alkyl, (C1-C4)fluoroalkyl, or (C3-C5)cycloalkyl;

[0022] R 2 It is H or (C1-C3) alkyl;

[0023] X 3 and X 4 One is CH, the other is N, and X 5 For CR 6 Or N, R 6 It is H, F, Cl, (C1-C4)alkyl or (C1-C4)fluoroalkyl; or X 3 and X 4 Both are CH, X 5 For N; and

[0024] R 7It is H, (C1-C4) alkyl, or (C3-C4) cycloalkyl substituted with 0-2 F atoms.

[0025] In another specific embodiment of the present invention, the compound of general formula (2) has one of the following structures:

[0026]

[0027] This invention provides a compound of general formula (3) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0028]

[0029] In general formula (3):

[0030] R 1 It is (C1-C4)alkyl, (C1-C4)fluoroalkyl, or (C3-C5)cycloalkyl;

[0031] R 3 It is H, F, Cl, (C1-C4)alkyl or (C1-C4)fluoroalkyl; and

[0032] R 7 It is H, (C1-C4) alkyl, or (C3-C4) cycloalkyl substituted with 0-2 F atoms.

[0033] In another specific embodiment of the present invention, the compound of general formula (3) has one of the following structures:

[0034]

[0035] This invention provides a compound of general formula (4) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0036]

[0037] In general formula (4):

[0038] R 1 It is (C1-C4)alkyl, (C1-C4)fluoroalkyl, or (C3-C5)cycloalkyl;

[0039] R 2 It is H or (C1-C3) alkyl;

[0040] R 3 It can be H, F, Cl, (C1-C4)alkyl, or (C1-C4)fluoroalkyl;

[0041] R 7It is H, (C1-C4) alkyl, or (C3-C4) cycloalkyl substituted with 0-2 F atoms; and

[0042] X 1 X 2 Each can be CH or N independently, but X 1 and X 2 They are not both N.

[0043] In another specific embodiment of the present invention, the compound of general formula (4) has one of the following structures:

[0044]

[0045]

[0046] This invention provides a compound of general formula (5) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0047]

[0048] In general formula (5):

[0049] R 1 It is (C1-C4)alkyl, (C1-C4)fluoroalkyl, or (C3-C5)cycloalkyl;

[0050] R 3 It can be H, F, Cl, (C1-C4)alkyl, or (C1-C4)fluoroalkyl;

[0051] R 7 It is H, (C1-C4) alkyl, or (C3-C4) cycloalkyl substituted with 0-2 F atoms; and

[0052] X 6 For NR 8 O or CR 9 R 10 R 8 H or (C1-C3) alkyl, R 9 and R 10 Each of them is independently H, (C1-C3)alkyl, (C1-C3)fluoroalkyl, or (C3-C4)cycloalkyl.

[0053] In another specific embodiment of the present invention, the compound of general formula (5) has one of the following structures:

[0054]

[0055] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a diluent and / or an excipient, and a compound of the general formula (1)-(5) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0056] Another object of the present invention is to provide the use of the compounds of general formulas (1)-(5) of the present invention, or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical compositions thereof, in the preparation of medicaments for the treatment, regulation or prevention of PARP-related diseases.

[0057] Another object of the present invention is to provide a method for treating, modulating or preventing PARP-mediated diseases, including administering to a subject a therapeutically effective amount of a compound of formula (1)-(5) of the present invention, or any isomer thereof, crystal form thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.

[0058] It should be understood that the foregoing general description of the invention and the following detailed description are exemplary and illustrative, and are intended to provide further explanation of the claimed invention.

[0059] Compound Synthesis

[0060] The preparation methods of the general formula compounds of the present invention are described in detail below, but these specific methods do not constitute any limitation on the present invention.

[0061] The compounds of the general formula described above can be synthesized using standard synthetic techniques or known techniques combined with the methods described herein. Furthermore, the solvents, temperatures, and other reaction conditions mentioned herein can be varied. Starting materials used for the synthesis of the compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using known techniques and starting materials, including those discovered in March, ADVANCED ORGANIC CHEMISTRY 4. th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd The method described in Ed. (Wiley 1999) can be used to prepare compounds by employing appropriate reagents and by introducing different groups into the molecular formulas provided herein.

[0062] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the explanations below. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art. On the other hand, the present invention also provides a method for preparing the compound of the general formula (1), wherein the general formula compound can be prepared using the following general reaction procedures 1-5:

[0063] General reaction process 1

[0064]

[0065] Compounds of general formula (1) can be prepared according to general reaction procedure 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 the general reaction flow 1, compound 1-1 reacts with thionyl chloride to generate compound 1-2, and compound 1-2 undergoes a substitution reaction with 1-3 to generate the target compound 1-4.

[0066] General reaction process 2

[0067]

[0068] The compound of general formula (2) can be prepared according to general reaction procedure 2, wherein R 1 R 2 R 7 X 3 X 4 and X 5 As defined above. As shown in general reaction flow 2, compound 2-1 reacts with thionyl chloride to generate compound 2-2, and compound 2-2 undergoes a substitution reaction with 2-3 to generate the target compound 2-4.

[0069] General reaction process 3

[0070]

[0071] Compounds of general formula (3) can be prepared according to general reaction procedure 3, wherein R 1 R 3 and R 7As defined above. As shown in the general reaction flow 3, compound 3-1 reacts with phosphorus oxychloride to generate compound 3-2, compound 3-2 reacts with sodium methoxide to generate compound 3-3, compound 3-3 reacts with lithium methyl at low temperature to generate compound 3-4, compound 3-4 reacts with hydrochloric acid to generate compound 3-5, compound 3-5 is reduced with a reducing agent to generate 3-6, 3-6 reacts with thionyl chloride to generate compound 3-7, and compound 3-7 undergoes a substitution reaction with 3-8 to generate the target compound 3-9.

[0072] General reaction process 4

[0073]

[0074] Compounds of general formula (4) can be prepared according to general reaction procedure 4, wherein R 1 R 2 R 3 R 7 X 1 and X 2 As defined above. As shown in the general reaction flow 4, compound 4-1 reacts with thionyl chloride to generate compound 4-2, and compound 4-2 undergoes a substitution reaction with 4-3 to generate the target compound 4-4.

[0075] General reaction process 5

[0076]

[0077] Compounds of general formula (5) can be prepared according to general reaction procedure 5, wherein R 1 R 3 R 7 and X 6 As defined above. As shown in the general reaction flow 5, compound 5-1 undergoes a carbonylation reaction in the presence of a reducing agent (e.g., triethylsilane) to give compound 5-2. Compound 5-2 is reduced with a reducing agent to generate 5-3. Compound 5-3 reacts with thionyl chloride to generate compound 5-4. Compound 5-4 undergoes a substitution reaction with 5-5 to generate the target compound 5-6.

[0078] Further forms of the compound

[0079] "Pharmaceutical acceptable" here means that a substance, such as a carrier or diluent, will not destroy the biological activity or properties of a compound and is relatively non-toxic. For example, when given to an individual, a substance will not cause unwanted biological effects or interact with any of its components in a harmful manner.

[0080] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the administered organism and does not diminish the compound's biological activity and properties. In some specific respects, pharmaceutically acceptable salts are obtained by reacting compounds of a general formula with acids, such as inorganic acids like hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, and carbonic acid; organic acids like 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 like aspartic acid and glutamic acid.

[0081] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is ethanol, an alcohol is formed. Solvates of general formula compounds are readily prepared or formed according to the methods described herein. For example, hydrates of general formula compounds are readily prepared by recrystallization from a mixture of water and an organic solvent, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds mentioned herein can exist in both non-solventized and solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solventized form.

[0082] In other specific embodiments, the general formula compound is prepared in various forms, including but not limited to amorphous, pulverized, and nano-particle forms. Furthermore, the general formula compound includes crystalline forms and can also be polymorphic. Polymorphs comprise different lattice arrangements of the same elemental composition of the compound. Polymorphs typically exhibit different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvents, crystallization rates, and storage temperatures may cause a single crystal form to dominate.

[0083] In another aspect, the general formula compounds may possess chiral centers and / or axial chirality, and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers, as well as cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of this invention. This invention implies the inclusion of all such isomeric forms of these compounds.

[0084] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium.3 H), Iodine-125 ( 125 I) and C-14 14 C). For example, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs generally have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0085] the term

[0086] Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0087] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, etc. i Pr、 n Pr、 i Bu、 n Bu or t Bu.

[0088] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic). A partially unsaturated cycloalkyl group may be referred to as "cycloalkenyl" if the carbon ring contains at least one double bond, or as "cycloynyl" if the carbon ring contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The cycloforming carbon atom of the cycloalkyl group may optionally be oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, the cycloalkyl group may be fused with aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl and heterocyclic alkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norcamphenyl, norpinel, norcarel, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and so on.

[0089] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, particularly those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, etc. i- PrO, n- PrO, i- BuO、 n- BuO or t- BuO.

[0090] Unless otherwise specified, "halogen" (or halogenated group) means fluorine, chlorine, bromine or iodine. The term "halogenated" (or "halogen substituted") appearing before the group name indicates that the group is partially or completely halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0091] "Optional" or "optionally" means that the event or condition described below may, but is not required, occur, and the description includes both the scenario in which the event or condition occurs and the scenario in which the event or condition does not occur.

[0092] The substituent "-O-CH2-O-" indicates that the two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocyclic alkyl, aryl, or heteroaryl group. For example:

[0093] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a single bond.

[0094] When one of the variables is selected as a chemical bond, it means that the two groups connected are directly linked. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0095] The term "membered ring" includes any ring structure. The term "membered" refers to the number of skeleton atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thioranyl are six-membered rings, while cyclopentyl, pyrroleyl, furanyl, and thiophenyl are five-membered rings.

[0096] The term "fragment" refers to a specific part or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.

[0097] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0098] Unless otherwise stated, use Indicates a single bond or a double bond.

[0099] Specific pharmaceutical and medical terminology

[0100] The term “acceptable,” as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for general therapeutic purposes.

[0101] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndromes; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; alleviating a disease or symptom; reducing complications arising from a disease or symptom; or preventing or treating signs arising from a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, may improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether administered regularly or intermittently, continuously or intermittently, it may be attributable to or related to the administration.

[0102] "Active ingredient" refers to the compound represented by the general formula, and pharmaceutically acceptable inorganic or organic salts of the compound of the general formula. The compounds of the present invention may contain one or more asymmetric centers (chiral or axially chiral), and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers. The asymmetric centers that may exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention means including all such isomeric forms of these compounds.

[0103] The terms “compound,” “composition,” “agent,” or “medicine or medicament” may be used interchangeably here, and all refer to a compound or composition that, when applied to an individual (human or animal), can induce a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0104] The term “administered, administering, or administration” here refers to the direct application of the compound or composition described herein, or the application of a prodrug, derivative, or analog of the active compound.

[0105] While the numerical ranges and parameters used to define the broader scope of this invention are approximate values, the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any value inevitably contains standard deviations due to individual test methods. Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "approximately" may mean that the actual value falls within the acceptable standard error of the mean, as determined by those skilled in the art. Except for experimental examples, or unless explicitly stated otherwise, it is understood that all ranges, quantities, values, and percentages used herein (e.g., to describe material usage, duration, temperature, operating conditions, quantity ratios, and others similar) are modified with "approximately". Therefore, unless otherwise stated, the numerical parameters disclosed in this specification and the accompanying claims are approximate values ​​and are subject to change as needed. At a minimum, these numerical parameters should be understood as the indicated significant digits and values ​​obtained using general rounding.

[0106] Unless otherwise defined in this specification, scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. Furthermore, unless conflicting with the context, singular nouns used herein include their plural forms, and vice versa.

[0107] Therapeutic uses

[0108] This invention provides methods for treating diseases using compounds or pharmaceutical compositions of the general formula of this invention, including but not limited to conditions involving PARP (e.g., cancer).

[0109] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need 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 a hematologic malignancy and a solid tumor, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial carcinoma, prostate cancer, liver cancer, ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all metastatic cancers.

[0110] route of administration

[0111] The compounds of this invention and their pharmaceutically acceptable salts can be formulated into various preparations, comprising, within a safe and effective range, the compounds of this invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective range of the compound is determined based on the age, condition, and duration of treatment of the patient.

[0112] "Pharmaceutically acceptable excipients or carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0113] When applying the compounds of this invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0114] Solid dosage forms for oral administration include capsules, tablets, pills, powders, 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 with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0115] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0116] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, 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.

[0117] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0118] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0119] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous 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.

[0120] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0121] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of this invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0122] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used with any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features. Detailed Implementation

[0123] The following description will elaborate on the specific aspects, characteristics, and advantages of the aforementioned compounds, methods, and pharmaceutical compositions, making the content of this invention readily apparent. It should be understood that the detailed descriptions and examples described below are specific embodiments and are for reference only. After reading this description, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by this application.

[0124] In all embodiments, 1 H-NMR was recorded using a Varian Mercury 400 NMR spectrometer, and chemical shifts are expressed as δ (ppm). Unless otherwise specified, the silica gel used for separation was 200-300 mesh, and all eluent ratios were by volume.

[0125] Example 1: Synthesis of Compound 1

[0126]

[0127] Step 1: Synthesis of compound int_1-2:

[0128]

[0129] At room temperature, selenium dioxide (3.96 g, 35.68 mmol) was added to a dioxane (30 mL) solution of compound int_1-1 (5.00 g, 23.79 mmol). The reaction mixture was heated to 110 °C and stirred for 20 hours. After cooling, the mixture was filtered through a diatomaceous earth filter, and the filter cake was washed with ethyl acetate (100 mL). The filtrates were combined, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate int_1-2.

[0130] LC-MS (ESI): 225 [M+H] + .

[0131] Step 2: Synthesis of compound int_1-3:

[0132]

[0133] Triethyl-2-butylpropene (14.07 g, 55.76 mmol) was slowly added dropwise to a 25 mL solution of anhydrous tetrahydrofuran containing 2.23 g, 55.76 mmol of 60% sodium hydride while stirring at 0 °C. After the addition was complete, stirring was continued at 0 °C for 10 minutes, then slowly raised to room temperature, and then heated to 40 °C while stirring for 5 minutes. The reaction mixture was cooled to -78 °C, and a 25 mL solution of anhydrous tetrahydrofuran containing 5.00 g, 22.30 mmol of intermediate int_1-2 was slowly added dropwise while stirring. The reaction was quenched with 100 mL of saturated ammonium chloride aqueous solution, concentrated under reduced pressure to remove most of the tetrahydrofuran, and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with 50 mL of water and 50 mL of saturated brine, 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).

[0134] LC-MS (ESI): 323 [M+H] + .

[0135] Step 3: Synthesis of compounds int_1-4:

[0136]

[0137] Intermediate int_1-3 (3.00 g, 9.31 mmol) and palladium on carbon (10%, 50% water content, 1.49 g) were mixed in ethanol (25 mL). After purging with hydrogen twice, the reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere (hydrogen balloon). The mixture was filtered, and the filtrate was concentrated under reduced pressure. A dioxane solution of hydrogen chloride (4 M, 10 mL) was added, and the mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with diethyl ether (100 mL), filtered, and the filter cake was washed with diethyl ether and dried under reduced pressure to obtain intermediate int_1-4.

[0138] LC-MS (ESI): 249 [M+H] + .

[0139] Step 4: Synthesis of compounds int_1-5:

[0140]

[0141] At room temperature, intermediate int_1-4 (2.00 g, 8.06 mmol) was dissolved in dioxane (35 mL) solution, and 2,3-dichloro-5,6-dicyanobenzoquinone (2.01 g, 8.86 mmol) was added. The reaction mixture was heated under reflux for 3 hours. The organic solvent was removed by concentration under reduced pressure, and saturated sodium bicarbonate aqueous solution (50 mL) was added. The mixture was stirred for 1 hour, filtered, and the filter cake was washed successively with water and ether. The filter cake was dried under reduced pressure to give intermediate int_1-5.

[0142] LC-MS (ESI): 247 [M+H] + .

[0143] Step 5: Synthesis of compounds int_1-6:

[0144]

[0145] Under nitrogen protection and ice-water bath cooling, lithium aluminum hydride (16.24 mL, 16.24 mmol, 1 M in THF) was added to a tetrahydrofuran (40 mL) solution of intermediate int_1-5 (2.00 g, 8.12 mmol). The reaction mixture was stirred at 0 °C for 1 hour. While stirring, water (1 mL), 15% sodium hydroxide solution (2 mL), and water (3 mL) were added sequentially to the reaction mixture. After stirring for 15 minutes, the mixture 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate int_1-6.

[0146] LC-MS (ESI): 205 [M+H] + .

[0147] Step 6: Synthesis of compounds int_1-7:

[0148]

[0149] Thionyl chloride (4.26 mL, 58.76 mmol) was added dropwise to a dichloromethane solution of intermediate int_1-6 (2.00 g, 9.79 mmol) and N,N-dimethylformamide (71.58 mg, 0.979 mmol) under stirring at 0 °C. The mixture was stirred at room temperature for 5 hours, and the reaction solution was concentrated under reduced pressure to obtain crude intermediate int_1-7, which was used directly in the next reaction without purification.

[0150] Step 7: Synthesis of Compound 1:

[0151]

[0152] At room temperature, intermediates int_1-7 (crude product 2.00 g), 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), and the mixture was heated to 80 °C and stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure to remove the organic solvent, and water (100 mL) was added. The solution was then alkalized with a saturated sodium bicarbonate aqueous solution. Extraction was performed 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain compound 1.

[0153] LC-MS (ESI): 433 [M+H] + .

[0154] 1 H NMR (400MHz, DMSO-d6) δ11.84(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)

[0155] Example 2: Synthesis of Compound 2

[0156]

[0157] At room temperature, intermediates int_1-7 (2.00 g), 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), and the mixture was heated to 80 °C and stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure to remove the organic solvent, and water (100 mL) was added. The solution was then alkalized with a saturated sodium bicarbonate aqueous solution. Extraction was performed 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain compound 2.

[0158] LC-MS (ESI): 408 [M+H]+ .

[0159] Example 3: Synthesis of Compound 3

[0160]

[0161] Step 1: Synthesis of compound int_3-1:

[0162]

[0163] 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 was concentrated under reduced pressure to remove phosphorus oxychloride. The residue was then poured into water (200 mL) and alkalized with a saturated sodium bicarbonate solution. Extraction was performed 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate int_3-1.

[0164] LC-MS (ESI): 265 [M+H] + .

[0165] Step 2: Synthesis of compound int_3-2:

[0166]

[0167] Intermediate int_3-1 (2.00 g, 7.56 mmol) and sodium methoxide (816 mg, 15.11 mmol) were mixed in toluene (30 mL) at room temperature and heated to 50 °C with stirring for 5 hours. After cooling, the reaction mixture 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate int_3-2.

[0168] LC-MS (ESI): 261 [M+H] + .

[0169] Step 3: Synthesis of compound int_3-3:

[0170]

[0171] Under nitrogen protection and cooling to -78°C, methyllithium (1.5M in THF, 7.68 mL, 11.53 mmol) was added to a tetrahydrofuran (30 mL) solution of intermediate int_3-2 (2.00 g, 7.68 mmol). The reaction mixture was stirred at -78°C for 1 hour. The reaction solution was heated to 0°C, and quenched dropwise with saturated ammonium chloride aqueous solution (20 mL) while stirring. Water (50 mL) was then added, and 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate int_3-3.

[0172] LC-MS (ESI): 231 [M+H] + .

[0173] Step 4: Synthesis of compound int_3-4:

[0174]

[0175] 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 hours. The reaction mixture was cooled to 0 °C and alkalized to pH 6–7 with 15% sodium hydroxide aqueous solution while stirring. Extraction was performed 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, yielding intermediate int_3-4.

[0176] LC-MS (ESI): 217 [M+H] + .

[0177] Step 5: Synthesis of compound int_3-5:

[0178]

[0179] Sodium borohydride (350 mg, 9.25 mmol) was slowly added to a methanol (25 mL) solution of intermediate int_3-4 (1.00 g, 4.62 mmol) under ice-water bath cooling. The reaction mixture was stirred at 0 °C for 0.5 hours, then heated to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and water (100 mL) was added. Extraction was performed 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate int_3-5.

[0180] LC-MS (ESI): 219 [M+H]+ .

[0181] Step 6: Synthesis of compound int_3-6:

[0182]

[0183] Thionyl chloride (3.27 g, 27.49 mmol) was added dropwise 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) with stirring at 0 °C. The mixture was stirred at room temperature for 5 hours, and the reaction solution was concentrated under reduced pressure to obtain crude intermediate int_3-6, which was used directly in the next reaction without purification.

[0184] Step 7: Synthesis of Compound 3:

[0185]

[0186] At room temperature, intermediates int_3-6 (1.00 g), 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), and the mixture was heated to 80 °C and stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure to remove the organic solvent, and water (100 mL) was added. The solution was then alkalized with a saturated sodium bicarbonate aqueous solution. Extraction was performed 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain compound 3.

[0187] LC-MS (ESI): 421 [M+H] + .

[0188] Example 4: Synthesis of Compound 4

[0189]

[0190] Step 1: Synthesis of compound int_4-2:

[0191]

[0192] Thionyl chloride (3.48 g, 29.24 mmol) was added dropwise 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) with stirring at 0 °C. The mixture was stirred at room temperature for 5 hours, and the reaction solution was concentrated under reduced pressure to obtain crude intermediate int_4-2, which was used directly in the next reaction without purification.

[0193] Step 2: Synthesis of Compound 4:

[0194]

[0195] At room temperature, intermediates int_4-2 (1.00 g), 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), and the mixture was heated to 80 °C and stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure to remove the organic solvent, and water (100 mL) was added. The solution was then alkalized with a saturated sodium bicarbonate aqueous solution. Extraction was performed 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain compound 4.

[0196] LC-MS (ESI): 408 [M+H] + .

[0197] Example 5: Synthesis of Compound 5

[0198]

[0199] Step 1: Synthesis of compound int_5-2:

[0200]

[0201] At room temperature, 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(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (635 mg, 0.778 mmol), and anhydrous N,N-dimethylformamide (38 mL) were added to a high-pressure reactor. After purging with carbon monoxide, the reactor was pressurized to 60 psi with carbon monoxide and heated to 110 °C with stirring for 12 hours. The reaction mixture was cooled to room temperature, the pressure was slowly released, and the mixture was filtered. A saturated sodium bicarbonate aqueous solution (200 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (60 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate int_5-2.

[0202] LC-MS (ESI): 207 [M+H] + .

[0203] Step 2: Synthesis of compound int_5-3:

[0204]

[0205] Sodium borohydride (275 mg, 7.27 mmol) was slowly added to a methanol (20 mL) solution of intermediate int_5-2 (1.00 g, 4.85 mmol) under ice-water bath cooling. The reaction mixture was stirred at 0 °C for 0.5 hours, then heated to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and water (100 mL) was added. Extraction was performed 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain intermediate int_5-3.

[0206] LC-MS (ESI): 209 [M+H] + .

[0207] Step 3: Synthesis of compound int_5-4:

[0208]

[0209] Thionyl chloride (3.43 g, 28.82 mmol) was added dropwise 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) with stirring at 0 °C. The mixture was stirred at room temperature for 5 hours, and the reaction solution was concentrated under reduced pressure to obtain crude intermediate int_5-4, which was used directly in the next reaction without purification.

[0210] Step 4: Synthesis of Compound 5:

[0211]

[0212] At room temperature, intermediates int_5-4 (1.00 g), 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), and the mixture was heated to 80 °C and stirred for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure to remove the organic solvent, and water (100 mL) was added. The solution was then alkalized with a saturated sodium bicarbonate aqueous solution. Extraction was performed 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, yielding the crude product. The crude product was purified by silica gel chromatography to obtain compound 5.

[0213] LC-MS (ESI): 411 [M+H] + .

[0214] 1 H NMR (400MHz, CDCl3) δ9.43(s,1H),8.20–7.95(m,2H),7.82(s,2H),7.15(d,J=8.8Hz,1H),4.74(t,J=5.8 Hz,1H),3.49(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)

[0215] Example 6-68 Synthesis of compound 6-68

[0216] Using the synthetic methods described in the general reaction procedures 1, 2, 3, 4 or 5 above, or by adopting other routes and using different starting materials, the target compounds 6-68 in Table 1 can be obtained.

[0217] Table 1

[0218]

[0219]

[0220]

[0221] Example 69: In vitro assay to inhibit the activity of the compound of the present invention against poly(ADP-ribose) polymerase [PARP-1 enzyme].

[0222] Histones were coated onto 384-well plates and incubated overnight at 4°C. After washing three times with PBST buffer, the plates were blocked at room temperature for 1 hour. After 1 hour, the plates were washed three more times with PBST, and DMSO or serially diluted compounds were added, along with a mixture containing PARP-1 enzyme and DNA. The plates were incubated at 25°C for 10 minutes. After 10 minutes, NAD+ was added. + Initiate the reaction. After reacting at room temperature for 60 minutes, wash three times with PBST, add a poly / mono-ADP ribose antibody conjugated with horseradish peroxidase (HRP), and detect the level of poly / mono-ADP ribose on histones. After incubating at room temperature for 1 hour, add HRP substrates ECL A and B, and perform quantitative chemiluminescence using Envision. Calculate the percentage of inhibition and IC50 of the compounds compared to the control group DMSO. 50 The results are shown in Table 2 below.

[0223] Table 2. Inhibitory activity of the compounds of the present invention against PARP-1 (IC50) 50 ,nM)

[0224] compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> 1 0.54nM 2 +++ 3 +++ 4 +++ 5 1.7nM 6 ++ 7 ++ 8 ++ 9 ++ 10 ++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 ++ 28 ++ 29 ++ 30 ++ 31 ++ 32 ++ 33 +++ 34 +++ 35 +++ 36 +++

[0225] 37 ++ 38 ++ 39 ++ 40 ++ 41 ++ 42 ++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 +++ 49 +++ 50 +++ 51 ++ 52 ++ 53 ++ 54 +++ 55 ++ 56 +++ 57 +++ 58 +++ 59 ++ 60 ++ 61 +++ 62 ++ 63 +++ 64 +++ 65 ++ 66 ++ 67 +++ 68 +++

[0226] +++ indicates IC 50 Less than or equal to 10 nM

[0227] ++ indicates IC 50 10 nM to 50 nM

[0228] + indicates IC 50 Greater than 50 nM.

[0229] As can be seen from the data in Table 2, the compounds of the present invention have good inhibitory activity against PARP-1.

[0230] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of formula (1) or a pharmaceutically acceptable salt thereof: In general formula (1): R 1 It is (C1-C4)alkyl or (C1-C4)fluoroalkyl; R 2 For H; R 3 It can be H, F, Cl, (C1-C4)alkyl, or (C1-C4)fluoroalkyl; n is 1; R 4 and R 5 Represents two substituents on the cycloalkyl ring, each independently being H or F; X 1 For N; and, X 2 For CH.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has any of the following structures: and 。 3. A compound of formula (1) or a pharmaceutically acceptable salt thereof: In general formula (1): R 1 It is (C1-C4)alkyl or (C1-C4)fluoroalkyl; R 2 For H; R 3 For H; n is 1; R 4 and R 5 Represents two substituents on the cycloalkyl ring, each independently being H or F; X 1 For CH; and, X 2 Let N be the number of elements in the array.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound has any of the following structures: and 。 5. A pharmaceutical composition, characterized in that, It contains a pharmaceutically acceptable excipient or carrier, and a compound or a pharmaceutically acceptable salt thereof as any one of claims 1-4 as an active ingredient.

6. Use of a compound as described in any one of claims 1-4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 5, in the preparation of a medicament for treating poly(ADP-ribose) polymerase-related diseases.

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