WO2022222921A1 - 含哌嗪结构的parp抑制剂、其制备方法及医药用途 - Google Patents

含哌嗪结构的parp抑制剂、其制备方法及医药用途 Download PDF

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WO2022222921A1
WO2022222921A1 PCT/CN2022/087652 CN2022087652W WO2022222921A1 WO 2022222921 A1 WO2022222921 A1 WO 2022222921A1 CN 2022087652 W CN2022087652 W CN 2022087652W WO 2022222921 A1 WO2022222921 A1 WO 2022222921A1
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compound
alkyl
pharmaceutically acceptable
general formula
cycloalkyl
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PCT/CN2022/087652
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English (en)
French (fr)
Inventor
谢雨礼
吕永聪
钱立晖
樊后兴
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微境生物医药科技(上海)有限公司
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Priority to BR112023021383A priority Critical patent/BR112023021383A2/pt
Priority to EP22791028.8A priority patent/EP4328224A1/en
Priority to CN202280029738.3A priority patent/CN117279916A/zh
Priority to MX2023012361A priority patent/MX2023012361A/es
Priority to CA3213029A priority patent/CA3213029A1/en
Priority to AU2022261011A priority patent/AU2022261011A1/en
Priority to KR1020237038365A priority patent/KR20230175225A/ko
Priority to JP2023564639A priority patent/JP2024514703A/ja
Publication of WO2022222921A1 publication Critical patent/WO2022222921A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and more particularly, relates to a new compound with poly(ADP-ribose) polymerase (PARP) inhibitory effect, a preparation method thereof, and use of the compound in the preparation of antitumor drugs.
  • PARP poly(ADP-ribose) polymerase
  • PARP Poly (ADP-ribose) polymerase
  • PARP nicotinamide adenine dinucleotide
  • NAD+ nicotinamide adenine dinucleotide
  • PARP family consists of 7 isozymes, including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), tankyrase such as PARP-5 (TANK-1, TANK-2 and TANK) -3), PARP-7 and PARP-10 [de la Lastra CA.
  • PARP-1 is responsible for more than 90% of ADP-ribosylation (PAR) in cells.
  • PARPs play important roles in the regulation of chromosome structure, gene transcription, DNA replication and recombination, and DNA repair.
  • PARP-1 is involved in DNA repair, promoting ADP-ribosylation and polymerization, initiating DNA repair and regulating the recruitment and level of DNA repair proteins.
  • PARP-1 When tumor cell DNA is damaged by chemotherapeutic drugs or ionizing radiation, PARP-1 is quickly activated and uses NAD+ as a substrate to synthesize a large amount of PAR at the DNA damage and modify histones. It then recruits DNA repair proteins to initiate DNA repair. PARP-1 is mainly involved in the repair of single-strand DNA breaks (SSBs). When PARP-1 is inhibited by PARP inhibitor, SSB cannot be repaired. During DNA replication in S phase, SSB is converted into double-strand break (DSB, Double strand break), inhibiting the function of PARP-1 leads to intracellular DSB. accumulate.
  • SSBs single-strand DNA breaks
  • the body repairs DSBs mainly in two ways: homologous recombination (HR) and non-homologous DNA end joining (NHEJ, Non-Homologous End Joining).
  • Homologous recombination repair is the main way of DSB repair in S phase, and Repair reliability is high.
  • BRCA1 and BRCA2 play important roles in homologous recombination repair. Deletion of BRCA1 and BRAC2 results in restricted DSB repair. Studies have found that BRCA1/2 mutations are found in ovarian cancer, breast cancer, and prostate cancer, and cancer cells with BRCA1 and 2 deletions are particularly sensitive to PARP inhibitors.
  • PARP inhibitors In addition to single drug use, PARP inhibitors can also be used in combination with chemotherapy drugs and radiotherapy drugs, so as to achieve the purpose of reducing the dose and improving the efficacy.
  • Olaparib was the first PARP inhibitor approved for marketing. With the continuous expansion of the indications of PARP inhibitors, the application of PARP inhibitors is also deepening, not only around tumors, but also has certain effects on stroke, myocardial ischemia, inflammation and diabetes.
  • the present invention provides a compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • 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 1 or 2;
  • R4 and R5 represent two substituents on the cycloalkyl ring, each independently H or F;
  • X 1 and X 2 are each independently CH or N.
  • the compound of general formula (1) has one of the following structures:
  • the present invention provides a compound represented by the general formula (2) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 1 is (C1-C4) alkyl, (C1-C4) fluoroalkyl or (C3-C5) cycloalkyl;
  • R 2 is H or (C1-C3) alkyl
  • One of X 3 and X 4 is CH, the other is N, X 5 is CR 6 or N, and R 6 is H, F, Cl, (C1-C4) alkyl or (C1-C4) fluoroalkyl; or both X3 and X4 are CH and X5 is N; and
  • R7 is H, (C1-C4)alkyl or (C3-C4)cycloalkyl substituted with 0-2 Fs.
  • the compound of general formula (2) has one of the following structures:
  • the present invention provides a compound represented by the general formula (3) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 1 is (C1-C4) alkyl, (C1-C4) fluoroalkyl or (C3-C5) cycloalkyl;
  • R3 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 Fs.
  • the compound of general formula (3) has one of the following structures:
  • the present invention provides a compound represented by the general formula (4) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • 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 Fs;
  • X 1 and X 2 are each independently CH or N, but X 1 and X 2 are not N at the same time.
  • the compound of general formula (4) has one of the following structures:
  • the present invention provides a compound represented by the general formula (5) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • 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 Fs;
  • X 6 is NR 8 , O or CR 9 R 10
  • 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.
  • the compound of general formula (5) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising pharmaceutically acceptable carriers, diluents and/or excipients, and the compounds of the general formulae (1)-(5) of the present invention, or their respective Isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.
  • Yet another object of the present invention provides the compounds represented by the general formulae (1)-(5) of the present invention, or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or Use of the above-mentioned pharmaceutical composition for preparing a medicine for treating, regulating or preventing PARP-related diseases.
  • Another object of the present invention also provides a method for treating, regulating or preventing PARP-mediated diseases, comprising administering to a subject a therapeutically effective amount of the compounds represented by the general formulae (1)-(5) of the present invention , or each of its isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical compositions.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula can be prepared by using the following general reaction schemes 1-5:
  • Embodiments of compounds of general formula ( 1 ) can be prepared according to general reaction scheme 1 , wherein R1, R2, R3 , R4, R5 , X1, X2 and n are as defined above. As shown in general reaction scheme 1, compound 1-1 reacts with thionyl chloride to form compound 1-2, and compound 1-2 and 1-3 undergo a substitution reaction to form target compound 1-4.
  • Embodiments in compounds of general formula ( 2 ) can be prepared according to general reaction scheme 2 , wherein R1, R2, R7 , X3 , X4 and X5 are as defined above. As shown in general reaction scheme 2, compound 2-1 reacts with thionyl chloride to form compound 2-2, and compound 2-2 undergoes substitution reaction with 2-3 to form target compound 2-4.
  • Embodiments of compounds of general formula (3) can be prepared according to general reaction scheme 3 , wherein R1, R3 and R7 are as defined above.
  • 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 methyl lithium at low temperature
  • Compound 3-4 is generated, compound 3-4 is reacted with hydrochloric acid to generate compound 3-5, compound 3-5 is reduced with a reducing agent to generate compound 3-6, compound 3-6 reacts with thionyl chloride to generate compound 3-7, compound Substitution reaction between 3-7 and 3-8 produces the target compound 3-9.
  • 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 are as defined above.
  • compound 4-1 reacts with thionyl chloride to form compound 4-2, and compound 4-2 undergoes a substitution reaction with 4-3 to form target compound 4-4.
  • Embodiments of compounds of general formula (5) can be prepared according to general reaction scheme 5, wherein R 1 , R 3 , R 7 and X 6 are as defined above.
  • compound 5-1 is subjected to carbonyl intercalation reaction in the presence of a reducing agent (such as: triethylsilylhydrogen) to obtain compound 5-2, and compound 5-2 is reduced with a reducing agent to form 5-3, compound 5-3 reacts with thionyl chloride to generate compound 5-4, and compound 5-4 undergoes substitution reaction with 5-5 to generate target compound 5-6.
  • a reducing agent such as: triethylsilylhydrogen
  • “Pharmaceutically acceptable” as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
  • pharmaceutically acceptable salt refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting compounds of the general formula with acids, such as inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, nitric, carbonic, formic, acetic, propionic , 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, p-toluenesulfonic acid and other organic acids And acidic amino acids such as aspartic acid and glutamic acid.
  • acids such as inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric,
  • references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of the general formula are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of the general formula is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the compounds of the general formula are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms.
  • compounds of the general formula include crystalline forms and may also be used as polymorphic forms.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • compounds of the general formula may have chiral centers and/or axial chirality, and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers form, and in the form of cis-trans isomers.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as 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.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, 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 , iPr , nPr , iBu , nBu or tBu .
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and if the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl” alkenyl", or if the carbocycle contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”.
  • Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic.
  • the cycloalkyl group is monocyclic or bicyclic.
  • the ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form oxo or thiol groups.
  • Cycloalkyl also includes cycloalkylene.
  • the cycloalkyl group contains 0, 1 or 2 double bonds.
  • cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups).
  • cycloalkyl groups can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused to aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexane and the like.
  • alkoxy refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH3 , OCF3, CHF2O , CF3CH2O , i - PrO, n- PrO , i- BuO, n- BuO or t- BuO.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen-substituted appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.
  • Substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any cyclic structure.
  • membered is meant to denote the number of backbone atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific portion or functional group of a molecule.
  • a chemical moiety is generally considered to be a chemical entity contained in or attached to a molecule.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • treatment include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.
  • Active ingredient refers to the compound represented by the general formula, as well as the 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 centers or axial chirality) and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers.
  • the number of asymmetric centers that can exist depends 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 diastereomeric mixtures, as well as 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.
  • composition a compound capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides methods of treating diseases, including, but not limited to, conditions involving PARP (eg, cancer) using compounds of the general formulae or pharmaceutical compositions of the present invention.
  • diseases including, but not limited to, conditions involving PARP (eg, cancer) using compounds of the general formulae or pharmaceutical compositions of the present invention.
  • PARP eg, cancer
  • methods for cancer treatment comprising administering to an individual in need thereof an effective amount of any of the foregoing pharmaceutical compositions comprising a compound of formula.
  • the cancer is mediated by PARP.
  • 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.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity .
  • “Compatibility” as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carrier moieties are 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose,
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • 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.
  • Dosage forms for topical administration of the compounds of this 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 if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • Triethyl 2-butylpropene 14.07 g, 55.76 mmol was slowly added dropwise to a solution of 60% sodium hydride (2.23 g, 55.76 mmol) in dry tetrahydrofuran (25 mL) with stirring at 0°C. After the dropping was completed, stirring was continued at 0° C. for 10 minutes, and after slowly rising to room temperature, the mixture was heated to 40° C. and stirred for 5 minutes. The reaction solution 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 intermediate int_1-3 (3.00 g, 9.31 mmol), palladium carbon (10%, 50% water, 1.49 g) were mixed in ethanol (25 mL), and after replacing the hydrogen for 2 times, the reaction mixture was placed under a hydrogen atmosphere (hydrogen balloon) Stir overnight at room temperature. The mixture was filtered, the filtrate was concentrated under reduced pressure, a solution of hydrogen chloride in dioxane (4M, 10 mL) was added, and the mixture was stirred at room temperature for 0.5 hours. Diethyl ether (100 mL) was added to dilute, filtered, and the filter cake was washed with ether and dried under reduced pressure to obtain intermediate int_1-4.
  • the intermediate int_1-4 (2.00 g, 8.06 mmol) was dissolved in a solution of dioxane (35 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (2.01 g) was added. , 8.86 mmol), the reaction mixture was heated to reflux for 3 hours. The organic solvent was removed by concentration under reduced pressure, saturated aqueous sodium bicarbonate solution (50 mL) was added, the mixture was stirred for 1 hour, filtered, and the filter cake was washed with water and ether in turn. The filter cake was dried under reduced pressure to obtain intermediate int_1-5.
  • lithium tetrahydroaluminum (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), and the reaction mixture was Stir at 0°C for 1 hour.
  • intermediate int-1-7 (crude 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) were mixed with , 44.91 mmol) was mixed in acetonitrile (25 mL), 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 basified with saturated aqueous sodium bicarbonate solution. Extract with ethyl acetate (30 mL ⁇ 4).
  • 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) in acetonitrile (25 mL), 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 basified with saturated aqueous sodium bicarbonate solution. Extract with ethyl acetate (30 mL ⁇ 4).
  • 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) in acetonitrile (20 mL), 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 basified with a saturated aqueous sodium bicarbonate solution. Extract with ethyl acetate (30 mL ⁇ 3).
  • the target compounds 6-68 in Table 1 can be obtained.
  • Example 69 The compound of the present invention inhibits the activity of poly(ADP-ribose) polymerase [PARP-1 enzyme] in vitro
  • Histones were coated on 384-well plates overnight at 4°C, washed three times with PBST buffer, and blocked for 1 hour at room temperature. After 1 hour, rinse again with PBST three times, add DMSO or serially diluted compounds, and a mixture containing PARP-1 enzyme and DNA, and incubate at 25°C for 10 minutes. After 10 minutes, NAD + was added to initiate the reaction. After 60 minutes of reaction at room temperature, PBST was rinsed three times, and poly/mono-ADP ribose antibody conjugated with horseradish peroxidase (HRP) was added to detect the level of poly/mono-ADP ribose on histones. After 1 hour incubation at room temperature, HRP substrates ECL A and B were added and Envision quantified chemiluminescence. Compounds were calculated as percent inhibition and IC50 compared to the control DMSO. The results are shown in Table 2 below.
  • +++ means IC50 less than or equal to 10nM

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Abstract

提供了一类含哌嗪结构的PARP抑制剂、其制备方法及医药用途。具体的，提供了一种如通式(1)、(2)、(3)、(4)和(5)所示的化合物和/或其药学上可接受的盐，以及含有如通式(1)、(2)、(3)、(4)和(5)所示化合物和/或其药学上可接受的盐的组合物，制备方法和其作为PARP抑制剂在抗肿瘤药物制备中的用途。

Description

含哌嗪结构的PARP抑制剂、其制备方法及医药用途
本申请要求申请日为2021年4月22日的中国申请CN202110439238.4的优先权。本申请引用上述中国申请的全文。
技术领域
本发明属涉及药物化学领域，更具体而言，涉及具有聚(ADP-核糖)聚合酶(PARP)抑制作用的新化合物及其制备方法和该类化合物在抗肿瘤药物制备中的用途。
背景技术
聚(ADP-核糖)聚合酶(PARP)大多数真核细胞中均有表达，它以烟酰胺腺嘌呤二核苷酸(NAD+)为底物在自身或其他蛋白特定氨基酸残基上催化ADP-核糖单元或其聚合物(PAR)的形成，对蛋白进行PAR修饰，进而调控蛋白的降解和功能。PARP家族由7种同工酶组成，包括PARP-1、PARP-2、PARP-3、PARP-4(Vault-PARP)、端锚聚合酶如PARP-5(TANK-1、TANK-2和TANK-3)、PARP-7和PARP-10[de la Lastra CA.等人，Curr Pharm Des.，13(9)，933～962，2007]。尽管PARP家族的酶种类众多，但PARP-1负责了细胞内90％以上的ADP-核糖基化(PAR)。PARPs在包括染色体结构调控，基因转录，DNA复制和重组，以及DNA修复中发挥了重要的作用。其中PARP-1在DNA修复中，促进ADP-核糖基化和聚合，启动DNA修复并调控DNA修复蛋白的招募和水平。
当肿瘤细胞DNA受到化疗药物或电离辐射等损伤时，PARP-1很快被激活，以NAD+为底物，在DNA损伤处合成大量PAR，修饰组蛋白。继而招募DNA修复蛋白，启动DNA修复。PARP-1主要参与单链DNA断裂(SSB)的修复。当PARP-1被PARP抑制剂所抑制之后，SSB无法修复，在S期DNA复制过程中，SSB被转化成双链断裂(DSB,Double strand break)，抑制PARP-1的功能导致细胞内DSB的蓄积。机体对DSB的修复主要通过两种方式：同源重组(HR)和非同源的DNA末端链接(NHEJ,Non-Homologous End Joining)，其中同源重组修复是S期DSB修复的主要方式，且修复可靠性高。BRCAl和BRCA2在同源重组修复中发挥着重要的作用。BRCA1和BRAC2的缺失导致DSB修复受限。研究发现，在卵巢癌、乳腺癌、前列腺癌中，都发现BRCA1/2的突变，而BRCA1、2缺失的癌症细胞对PARP抑制剂尤为敏感。这可能源于PAPR抑制剂抑制PARP-1，诱发DSB，而由于BRCA1/2的缺失，修复受阻，进而诱发细胞死亡。为此，PARP抑制剂在临床上治疗BRCA1/2缺陷的肿瘤具有良好的效果。PARP抑制剂除了可以单药使用之外，还可以与化疗药物、放疗药物联用，从而达到降低剂量和提高疗效的目的。奥拉帕尼是第一个被批准上市的PARP抑制剂。随着PARP抑制剂的适应症不断扩展，PARP抑制剂的应用也在不断的深入，不仅仅围绕肿瘤，还对中风、心肌缺血、炎症和糖尿病有一定 的效果。
虽然开发PARP抑制剂用于治疗癌症和其他疾病的努力一直正在进行，但这类抑制剂对PAPR家族蛋白缺乏一定的特异性，具有不可忽视的毒副反应，易产生耐药性。因此，开发特异性的高活性PARP-1抑制剂具有重要的临床价值。
发明内容
本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022087652-appb-000001
通式(1)中：
R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
R 2为H或(C1-C3)烷基；
R 3为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；
n为1或2；
R 4和R 5代表环烷基环上的两个取代基，各自独立地为H或F；和
X 1、X 2各自独立地为CH或N。
在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：
Figure PCTCN2022087652-appb-000002
Figure PCTCN2022087652-appb-000003
本发明提供了一种通式(2)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022087652-appb-000004
通式(2)中：
R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
R 2为H或(C1-C3)烷基；
X 3和X 4中一个为CH、另外一个为N，X 5为CR 6或N，R 6为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；或者X 3和X 4都为CH，X 5为N；和
R 7为H、(C1-C4)烷基或被0-2个F取代的(C3-C4)环烷基。
在本发明的另一具体实施例中，通式(2)化合物具有以下结构之一：
Figure PCTCN2022087652-appb-000005
本发明提供了一种通式(3)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022087652-appb-000006
通式(3)中：
R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
R 3为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；和
R 7为H、(C1-C4)烷基或被0-2个F取代的(C3-C4)环烷基。
在本发明的另一具体实施例中，通式(3)化合物具有以下结构之一：
Figure PCTCN2022087652-appb-000007
本发明提供了一种通式(4)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022087652-appb-000008
通式(4)中：
R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
R 2为H或(C1-C3)烷基；
R 3为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；
R 7为H、(C1-C4)烷基或被0-2个F取代的(C3-C4)环烷基；和
X 1、X 2各自独立地为CH或N，但X 1和X 2不同时为N。
在本发明的另一具体实施例中，通式(4)化合物具有以下结构之一：
Figure PCTCN2022087652-appb-000009
Figure PCTCN2022087652-appb-000010
本发明提供了一种通式(5)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
Figure PCTCN2022087652-appb-000011
通式(5)中：
R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
R 3为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；
R 7为H、(C1-C4)烷基或被0-2个F取代的(C3-C4)环烷基；和
X 6为NR 8、O或CR 9R 10，R 8为H或(C1-C3)烷基，R 9和R 10各自独立地为H、(C1-C3)烷基、(C1-C3)氟代烷基或(C3-C4)环烷基。
在本发明的另一具体实施例中，通式(5)化合物具有以下结构之一：
Figure PCTCN2022087652-appb-000012
本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释 剂和/或赋形剂，以及本发明通式(1)-(5)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
本发明的再一个目的提供了本发明的通式(1)-(5)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与PARP相关疾病的药物中的应用。
本发明的再一个目的还提供治疗、调节或预防与PARP介导的相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)-(5)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。
化合物的合成
下面具体地描述本发明通式化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的通式化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式(1)所示化合物的制备方法，其中通式化合物可采用下列一般反应流程1-5制备：
一般反应流程1
Figure PCTCN2022087652-appb-000013
通式(1)化合物的实施方式可根据一般反应流程1制备，其中R 1、R 2、R 3、R 4、R 5、X 1、X 2和n如上文中所定义。如一般反应流程1所示，化合物1-1与氯化亚砜反应生成化合物1-2，化合物1-2与1-3发生取代反应生成目标化合物1-4。
一般反应流程2
Figure PCTCN2022087652-appb-000014
通式(2)化合物中的实施方式可根据一般反应流程2制备，其中R 1、R 2、R 7、X 3、X 4和X 5如上文中所定义。如一般反应流程2所示，化合物2-1与氯化亚砜反应生成化合物2-2，化合物2-2与2-3发生取代反应生成目标化合物2-4。
一般反应流程3
Figure PCTCN2022087652-appb-000015
通式(3)化合物的实施方式可根据一般反应流程3制备，其中R 1、R 3和R 7如上文中所定义。如一般反应流程3所示，化合物3-1和三氯氧磷反应生成化合物3-2，化合物3-2与甲醇钠反应生成化合物3-3，化合物3-3与甲基锂在低温下反应生成化合物3-4，化合物3-4在盐酸作用下生成化合物3-5，化合物3-5用还原剂还原生成3-6，化合物3-6与氯化亚砜反应生成化合物3-7，化合物3-7与3-8发生取代反应生成目标化合物3-9。
一般反应流程4
Figure PCTCN2022087652-appb-000016
通式(4)化合物的实施方式可根据一般反应流程4制备，其中R 1、R 2、R 3、R 7、X 1和X 2如上文中所定义。如一般反应流程4所示，化合物4-1与氯化亚砜反应生成化合物4-2，化合物4-2与4-3发生取代反应生成目标化合物4-4。
一般反应流程5
Figure PCTCN2022087652-appb-000017
通式(5)化合物的实施方式可根据一般反应流程5制备，其中R 1、R 3、R 7和X 6如上文中所定义。如一般反应流程5所示，化合物5-1在还原剂(如：三乙基硅氢)存在下进行插羰反应得到化合物5-2，化合物5-2用还原剂还原生成5-3，化合物5-3与氯化亚砜反应生成化合物5-4，化合物5-4与5-5发生取代反应生成目标化合物5-6。
化合物的进一步形式
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、碳酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，通式化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式化合物包括结晶型，也可以作为多晶型。多晶型包括 化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，通式化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH 2、CF 3(CH 3)CH、 iPr、 nPr、 iBu、 nBu或 tBu。
除非另有规定，“环烷基”是指非芳香族烃环系统(单环、双环或多环)，如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫离子基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一 些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环已二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。
除非另有规定，“烷氧基”指通过醚氧原子键合到分子其余部分的烷基。代表性的烷氧基为具有1-6个碳原子的烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基。如本文所用，“烷氧基”包括未取代和取代的烷氧基，尤其是被一个或多个卤素所取代的烷氧基。优选的烷氧基选自OCH 3、OCF 3、CHF 2O、CF 3CH 2O、 i-PrO、 n-PrO、 i-BuO、 n-BuO或 t-BuO。
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
取代基“-O-CH 2-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如：
Figure PCTCN2022087652-appb-000018
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为单键。
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。
术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。
除非另有说明，用楔形实线键
Figure PCTCN2022087652-appb-000019
和楔形虚线键
Figure PCTCN2022087652-appb-000020
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022087652-appb-000021
和直形虚线键
Figure PCTCN2022087652-appb-000022
表示立体中心的相对构型，用波浪线
Figure PCTCN2022087652-appb-000023
表示楔形实线键
Figure PCTCN2022087652-appb-000024
或楔形虚线键
Figure PCTCN2022087652-appb-000025
或用波浪线
Figure PCTCN2022087652-appb-000026
表示直形实线键
Figure PCTCN2022087652-appb-000027
或直形虚线键
Figure PCTCN2022087652-appb-000028
除非另有说明，用
Figure PCTCN2022087652-appb-000029
表示单键或双键。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制 疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。
“活性成分”指通式所示化合物，以及通式化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。
治疗用途
本发明提供了使用本发明通式化合物或药物组合物治疗疾病的方法，包括但不限于涉及PARP的病况(例如癌症)。
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效 量的任何前述的包括结构通式化合物的药物组合物。在一些实施例中，癌症由PARP介导。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于白血病、乳腺癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、前列腺癌、肝癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022087652-appb-000030
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除 了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
具体实施方式
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
实施例1化合物1的合成
Figure PCTCN2022087652-appb-000031
步骤1：化合物int_1-2的合成:
Figure PCTCN2022087652-appb-000032
在室温下，将二氧化硒(3.96g,35.68mmol)加入到化合物int_1-1(5.00g,23.79mmol)的二氧六环(30mL)溶液中，反应液加热到110℃搅拌20小时。反应液冷却后，垫硅藻土过滤，滤饼用乙酸乙酯(100mL)洗。合并滤液，减压浓缩，残余物经硅胶色谱法分离纯化得中间体int_1-2。
LC-MS(ESI):225[M+H] +。
步骤2：化合物int_1-3的合成:
Figure PCTCN2022087652-appb-000033
在0℃搅拌下，将三乙基2-丁基丙烯酯(14.07g,55.76mmol)缓慢滴加到60％氢化钠(2.23g,55.76mmol)的无水四氢呋喃(25mL)溶液中。滴完后继续在0℃下搅拌10分钟，缓慢升到室温后，再加热到40℃搅拌5分钟。将反应液冷却到-78℃，在搅拌下将中间体int_1-2(5.00g,22.30mmol)的无水四氢呋喃(25mL)溶液缓慢滴入。加入饱和氯化铵水溶液(100mL)淬灭，减压浓缩除掉大部分四氢呋喃，用乙酸乙酯(150mL×2)萃取。合并有机相用水(50mL)洗，饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩，残留物经硅胶色谱法分离纯化得到中间体int_1-3(E/Z构型的混合 物)。
LC-MS(ESI):323[M+H] +。
步骤3：化合物int_1-4的合成:
Figure PCTCN2022087652-appb-000034
将中间体int_1-3(3.00g,9.31mmol)，钯碳(10％,含水50％,1.49g)混合于乙醇(25mL)中，置换氢气2次后，反应混合物在氢气氛围(氢气球)下室温搅拌过夜。将混合物过滤，滤液减压浓缩，加入氯化氢的二氧六环溶液(4M,10mL)，室温搅拌0.5小时。加入乙醚(100mL)稀释，过滤，滤饼用乙醚洗，减压干燥得到中间体int_1-4。
LC-MS(ESI):249[M+H] +。
步骤4：化合物int_1-5的合成:
Figure PCTCN2022087652-appb-000035
在室温下，将中间体int_1-4(2.00g,8.06mmol)，溶于二氧六环(35mL)溶液中，加入2,3-二氯-5,6-二氰基苯醌(2.01g,8.86mmol)，反应混合物加热回流3小时。减压浓缩除去有机溶剂，加入饱和碳酸氢钠水溶液(50mL)，混合物搅拌1小时后，过滤，滤饼依次用水和乙醚洗。滤饼减压干燥得到中间体int_1-5。
LC-MS(ESI):247[M+H] +。
步骤5：化合物int_1-6的合成:
Figure PCTCN2022087652-appb-000036
在氮气保护及冰水浴冷却下，将四氢铝锂(16.24mL,16.24mmol,1M in THF)加入到中间体int_1-5(2.00g,8.12mmol)的四氢呋喃(40mL)溶液中，反应混合物在0℃下搅拌1小时。搅拌下往反应液中依次加入水(1mL)，15％氢氧化钠溶液(2mL)， 水(3mL)。搅拌15分钟后，过滤，滤液用乙酸乙酯(30mL×4)萃取。合并有机相，并用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体int_1-6。
LC-MS(ESI):205[M+H] +。
步骤6：化合物int_1-7的合成:
Figure PCTCN2022087652-appb-000037
在0℃搅拌下，将氯化亚砜(4.26mL,58.76mmol)滴加到中间体int_1-6(2.00g,9.79mmol)和N,N-二甲基甲酰胺(71.58mg,0.979mmol)的二氯甲烷溶液中。混合物在室温搅拌5小时，将反应液减压浓缩得到粗品中间体int_1-7，未经纯化直接用于下一步反应。
步骤7：化合物1的合成:
Figure PCTCN2022087652-appb-000038
在室温下，将中间体int_1-7(粗品2.00g)、中间体int_1-8(2.21g,8.98mmol)、碘化钾(298mg,1.80mmol)和N,N-二异丙基乙胺(5.80g,44.91mmol)混合于乙腈(25mL)中，混合物加热至80℃搅拌2小时。将反应液冷却后，减压浓缩除去有机溶剂，加入水(100mL)，用饱和碳酸氢钠水溶液碱化。用乙酸乙酯(30mL×4)萃取。合并有机相，并用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到化合物1。
LC-MS(ESI):433[M+H] +。
1H NMR(400MHz,DMSO-d 6)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)
实施例2化合物2的合成
Figure PCTCN2022087652-appb-000039
在室温下，将中间体int_1-7(2.00g)、中间体int_2-1(2.50g,11.30mmol)、碘化钾(298mg,1.80mmol)和N,N-二异丙基乙胺(5.80g,44.91mmol)混合于乙腈(25mL)中，混合物加热至80℃搅拌2小时。将反应液冷却后，减压浓缩除去有机溶剂，加入水(100mL)，用饱和碳酸氢钠水溶液碱化。用乙酸乙酯(30mL×4)萃取。合并有机相，并用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到化合物2。
LC-MS(ESI):408[M+H] +。
实施例3化合物3的合成
Figure PCTCN2022087652-appb-000040
步骤1：化合物int_3-1的合成:
Figure PCTCN2022087652-appb-000041
将中间体int_1-5(3.00g,12.18mmol)和三氯氧磷(37.36g,243.64mmol)的混合物 加热至100℃搅拌3小时。将反应液冷却后，减压浓缩除去三氯氧磷，再将残留物倒入水(200mL)中，用饱和碳酸氢钠水溶液碱化。用二氯甲烷(60mL×4)萃取。合并有机相，并用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体int_3-1。
LC-MS(ESI):265[M+H] +。
步骤2：化合物int_3-2的合成:
Figure PCTCN2022087652-appb-000042
在室温下，将中间体int_3-1(2.00g,7.56mmol)和甲醇钠(816mg,15.11mmol)混合于甲苯(30mL)中，混合物加热至50℃搅拌5小时。将反应液冷却后，倒入水(150mL)中，用乙酸乙酯(50mL×4)萃取。合并有机相，并用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体int_3-2。
LC-MS(ESI):261[M+H] +。
步骤3：化合物int_3-3的合成:
Figure PCTCN2022087652-appb-000043
在氮气保护及-78℃冷却下，将甲基锂(1.5M in THF,7.68mL,11.53mmol)加入到中间体int_3-2(2.00g,7.68mmol)的四氢呋喃(30mL)溶液中，反应混合物在-78℃下搅拌1小时。将反应液升温至0℃，搅拌下滴入饱和氯化氨水溶液(20mL)淬灭，再加入水(50mL)，用乙酸乙酯(50mL×4)萃取。合并有机相，并用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体int_3-3。
LC-MS(ESI):231[M+H] +。
步骤4：化合物int_3-4的合成:
Figure PCTCN2022087652-appb-000044
将中间体int_3-3(1.50g,6.94mmol)和6N盐酸(15mL)的混合物加热至100℃搅拌2小时。将反应液冷却至0℃，搅拌下用15％氢氧化钠水溶液碱化至pH＝6～7。用乙酸乙酯(30mL×3)萃取。合并有机相，并用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到中间体int_3-4。
LC-MS(ESI):217[M+H] +。
步骤5：化合物int_3-5的合成:
Figure PCTCN2022087652-appb-000045
在冰水浴冷却下，将硼氢化钠(350mg,9.25mmol)缓慢加入到中间体int_3-4(1.00g,4.62mmol)的甲醇(25mL)溶液中，反应混合物在0℃下搅拌0.5小时后，升到室温搅拌2小时。减压浓缩，加入水(100mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，并用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体int_3-5。
LC-MS(ESI):219[M+H] +。
步骤6：化合物int_3-6的合成:
Figure PCTCN2022087652-appb-000046
在0℃搅拌下，将氯化亚砜(3.27g,27.49mmol)滴加到中间体int_3-5(1.00g,4.58mmol)和N,N-二甲基甲酰胺(33mg,0.458mmol)的二氯甲烷(20mL)溶液中。混合物在室温搅拌5小时，将反应液减压浓缩得到粗品中间体int_3-6，未经纯化直接用于下一步反应。
步骤7：化合物3的合成:
Figure PCTCN2022087652-appb-000047
在室温下，将中间体int_3-6(1.00g)、中间体int_3-7(931mg,4.22mmol)、碘化钾(140mg,0.845mmol)和N,N-二异丙基乙胺(2.73g,21.12mmol)混合于乙腈(20mL)中，混合物加热至80℃搅拌2小时。将反应液冷却后，减压浓缩除去有机溶剂，加入水(100mL)，用饱和碳酸氢钠水溶液碱化。用乙酸乙酯(30mL×3)萃取。合并有机相，并用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到化合物3。
LC-MS(ESI):421[M+H] +。
实施例4化合物4的合成
Figure PCTCN2022087652-appb-000048
步骤1：化合物int_4-2的合成:
Figure PCTCN2022087652-appb-000049
在0℃搅拌下，将氯化亚砜(3.48g,29.24mmol)滴加到中间体int_4-1(1.00g,4.87mmol)和N,N-二甲基甲酰胺(36mg,0.487mmol)的二氯甲烷(20mL)溶液中。混合物在室温搅拌5小时，将反应液减压浓缩得到粗品中间体int_4-2，未经纯化直接用于下一步反应。
步骤2：化合物4的合成:
Figure PCTCN2022087652-appb-000050
在室温下，将中间体int_4-2(1.00g)、中间体int_3-7(985mg,4.47mmol)、碘化钾(148mg,0.894mmol)和N,N-二异丙基乙胺(2.89g,22.36mmol)混合于乙腈(20mL)中，混合物加热至80℃搅拌2小时。将反应液冷却后，减压浓缩除去有机溶剂，加入水(100mL)，用饱和碳酸氢钠水溶液碱化。用乙酸乙酯(30mL×3)萃取。合并有机相， 并用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到化合物4。
LC-MS(ESI):408[M+H] +。
实施例5化合物5的合成
Figure PCTCN2022087652-appb-000051
步骤1：化合物int_5-2的合成:
Figure PCTCN2022087652-appb-000052
在室温下，将中间体int_5-1(2.00g,7.78mmol)、三乙基硅烷(1.81g,15.56mmol)、三乙胺(2.36g,23.34mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(635mg,0.778mmol)和无水N,N-二甲基甲酰胺(38mL)加入到高压反应釜中，置换一氧化碳后，用一氧化碳加压到60psi，加热到110℃搅拌12小时。将反应液冷却到室温后，缓慢释放压力，过滤，往滤液中加入饱和碳酸氢钠水溶液(200mL)，用二氯甲烷(60mL×3)萃取。合并有机相，并用饱和食盐水(100mL×2)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体int_5-2。
LC-MS(ESI):207[M+H] +。
步骤2：化合物int_5-3的合成:
Figure PCTCN2022087652-appb-000053
在冰水浴冷却下，将硼氢化钠(275mg,7.27mmol)缓慢加入到中间体int_5-2(1.00 g,4.85mmol)的甲醇(20mL)溶液中，反应混合物在0℃下搅拌0.5小时后，升到室温搅拌2小时。减压浓缩，加入水(100mL)，用乙酸乙酯(30mL×3)萃取。合并有机相，并用饱和食盐水(50mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到中间体int_5-3。
LC-MS(ESI):209[M+H] +。
步骤3：化合物int_5-4的合成:
Figure PCTCN2022087652-appb-000054
在0℃搅拌下，将氯化亚砜(3.43g,28.82mmol)滴加到中间体int_5-3(1.00g,4.80mmol)和N,N-二甲基甲酰胺(35mg,0.480mmol)的二氯甲烷(20mL)溶液中。混合物在室温搅拌5小时，将反应液减压浓缩得到粗品中间体int_5-4，未经纯化直接用于下一步反应。
步骤4：化合物5的合成:
Figure PCTCN2022087652-appb-000055
在室温下，将中间体int_5-4(1.00g)、中间体int_3-7(972mg,4.41mmol)、碘化钾(146mg,0.882mmol)和N,N-二异丙基乙胺(2.85g,22.06mmol)混合于乙腈(20mL)中，混合物加热至80℃搅拌2小时。将反应液冷却后，减压浓缩除去有机溶剂，加入水(100mL)，用饱和碳酸氢钠水溶液碱化。用乙酸乙酯(30mL×3)萃取。合并有机相，并用饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂得到粗产品。粗产品经硅胶色谱法分离纯化得到化合物5。
LC-MS(ESI):411[M+H] +。
1H NMR(400MHz,CDCl 3)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＝5.8Hz,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)
实施例6-68化合物6-68的合成
使用上述一般反应流程1、2、3、4或5的合成方法，或者采用其他路线，用不同原 料，可以得到表1中目标化合物6-68。
表1
Figure PCTCN2022087652-appb-000056
Figure PCTCN2022087652-appb-000057
Figure PCTCN2022087652-appb-000058
实施例69本发明化合物体外抑制聚(ADP-核糖)聚合酶[PARP-1酶]活性实验
将组蛋白包被于384孔板上4度过夜，用PBST缓冲液漂洗三次后，室温封闭1小时。1小时后，再次用PBST漂洗三次，加入DMSO或者梯度稀释的化合物，和含有PARP-1酶和DNA的混合物，在25℃下孵育10分钟。10分钟后，加入NAD +启动反应。室温反应60分钟后，PBST漂洗三次，加入偶联了辣根过氧化酶(HRP)的poly/mono-ADP ribose抗体，检测组蛋白上poly/mono-ADP ribose的水平。室温孵育1小时后，加入HRP底物ECL A和B，Envision定量化学发光。与对照组DMSO相比，计算化合物抑制百分比以及IC 50。结果见下列表2。
表2.本发明化合物对PARP-1的抑制活性(IC 50,nM)
化合物 IC 50 化合物 IC 50 化合物 IC 50 化合物 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 +++
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 +++
+++表示IC 50小于或等于10nM
++表示IC 50为10nM至50nM
+表示IC 50大于50nM。
从表2数据可知，本发明化合物对PARP-1有较好的抑制活性。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (12)

  1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2022087652-appb-100001
    通式(1)中：
    R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
    R 2为H或(C1-C3)烷基；
    R 3为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；
    n为1或2；
    R 4和R 5代表环烷基环上的两个取代基，各自独立地为H或F；和
    X 1、X 2各自独立地为CH或N。
  2. 如权利要求1所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2022087652-appb-100002
    Figure PCTCN2022087652-appb-100003
  3. 一种如通式(2)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2022087652-appb-100004
    通式(2)中：
    R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
    R 2为H或(C1-C3)烷基；
    X 3和X 4中一个为CH、另外一个为N，X 5为CR 6或N，R 6为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；或者X 3和X 4都为CH，X 5为N；和
    R 7为H、(C1-C4)烷基或被0-2个F取代的(C3-C4)环烷基。
  4. 如权利要求3所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2022087652-appb-100005
  5. 一种如通式(3)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2022087652-appb-100006
    通式(3)中：
    R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
    R 3为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；和
    R 7为H、(C1-C4)烷基或被0-2个F取代的(C3-C4)环烷基。
  6. 如权利要求5所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶 剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2022087652-appb-100007
  7. 一种如通式(4)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2022087652-appb-100008
    通式(4)中：
    R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
    R 2为H或(C1-C3)烷基；
    R 3为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；
    R 7为H、(C1-C4)烷基或被0-2个F取代的(C3-C4)环烷基；和
    X 1、X 2各自独立地为CH或N，但X 1和X 2不同时为N。
  8. 如权利要求7所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2022087652-appb-100009
    Figure PCTCN2022087652-appb-100010
  9. 一种如通式(5)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：
    Figure PCTCN2022087652-appb-100011
    通式(5)中：
    R 1为(C1-C4)烷基、(C1-C4)氟代烷基或(C3-C5)环烷基；
    R 3为H、F、Cl、(C1-C4)烷基或(C1-C4)氟代烷基；
    R 7为H、(C1-C4)烷基或被0-2个F取代的(C3-C4)环烷基；和
    X 6为NR 8、O或CR 9R 10，R 8为H或(C1-C3)烷基，R 9和R 10各自独立地为H、(C1-C3)烷基、(C1-C3)氟代烷基或(C3-C4)环烷基。
  10. 如权利要求9所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：
    Figure PCTCN2022087652-appb-100012
  11. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-10中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。
  12. 一种如权利要求1-10中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求11所述的药物组合物在制备治疗聚(ADP-核糖)聚合酶相关疾病药物中的应用。
PCT/CN2022/087652 2021-04-22 2022-04-19 含哌嗪结构的parp抑制剂、其制备方法及医药用途 WO2022222921A1 (zh)

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WO2023046158A1 (zh) * 2021-09-26 2023-03-30 张文燕 氮杂喹啉酮类化合物及其医药用途
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