Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
• • 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
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines 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
  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• • 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
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • 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
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • 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
  • C07D401/14—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 three or more hetero rings
• • 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

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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