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WO2023138541A1 - 吡啶酰胺类parp抑制剂、及其制备方法和医药用途 - Google Patents

吡啶酰胺类parp抑制剂、及其制备方法和医药用途 Download PDF

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Publication number
WO2023138541A1
WO2023138541A1 PCT/CN2023/072425 CN2023072425W WO2023138541A1 WO 2023138541 A1 WO2023138541 A1 WO 2023138541A1 CN 2023072425 W CN2023072425 W CN 2023072425W WO 2023138541 A1 WO2023138541 A1 WO 2023138541A1
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Prior art keywords
alkyl
pharmaceutically acceptable
general formula
cycloalkyl
compound
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PCT/CN2023/072425
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English (en)
French (fr)
Inventor
谢雨礼
吕永聪
吴应鸣
钱立晖
Original Assignee
微境生物医药科技(上海)有限公司
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Priority to CN202380015606.XA priority Critical patent/CN118434725A/zh
Publication of WO2023138541A1 publication Critical patent/WO2023138541A1/zh

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    • 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
    • A61K31/498—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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 specifically relates to a class of pyridine amide PARP inhibitors, a preparation method and a medical application thereof.
  • PARP Poly(ADP-ribose) polymerase
  • PARP Poly(ADP-ribose) polymerase
  • NAD+ nicotinamide adenine dinucleotide
  • PARP family consists of 7 isozymes, including PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), tankyrases such as PARP-5 (TANK-1, TANK-2, and TANK-3), PARP-7, and PARP-10 [de la Lastra CA.
  • PARP-1 is responsible for more than 90% of ADP-ribosylation (PAR) in cells.
  • PARPs play an important role in regulation of chromosome structure, gene transcription, DNA replication and recombination, and DNA repair.
  • PARP-1 promotes ADP-ribosylation and polymerization in DNA repair, initiates DNA repair and regulates the recruitment and level of DNA repair proteins.
  • PARP-1 When the DNA of tumor cells 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 site of DNA damage and modify histones. DNA repair proteins are then recruited to initiate DNA repair. PARP-1 is primarily involved in the repair of single-strand DNA breaks (SSBs). When PARP-1 is inhibited by PARP inhibitors, SSBs cannot be repaired. During S-phase DNA replication, SSBs are converted into double strand breaks (DSBs, Double strand breaks). Inhibiting the function of PARP-1 leads to the accumulation of intracellular DSBs.
  • SSBs single-strand DNA breaks
  • the body repairs DSBs mainly through two methods: homologous recombination (HR) and non-homologous DNA end joining (NHEJ, Non-Homologous End Joining), among which homologous recombination repair is the main method of DSB repair in S phase, and the repair reliability is high.
  • BRCA1 and BRCA2 play an important role in homologous recombination repair. Loss 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 It has good clinical effect in the treatment of BRCA1/2-deficient tumors.
  • 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 is the first PARP inhibitor approved for marketing. As the indications of PARP inhibitors continue to expand, 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 technical problem to be solved by the present invention is that current PARP inhibitors lack certain specificity to PAPR family proteins, have non-negligible toxic and side effects, and are prone to drug resistance. Therefore, the present invention provides pyridine amide PARP inhibitors, a preparation method and a medical application thereof.
  • the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • X 1 and X 2 are each independently CH or N;
  • R 1 is H, (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy, wherein said (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy can be substituted by one or more of the following groups: -H, halogen;
  • R 2 is halogen or (C1-C4) alkyl
  • R 3 is -H, halogen or (C1-C4) alkyl, wherein said (C1-C4) alkyl can be substituted by one or more of the following groups: -H, halogen;
  • R is -H, (C1-C4) alkyl or (C3-C6) cycloalkyl, wherein said (C1-C4) alkyl or (C3-C6) cycloalkyl may be substituted by one or more of the following groups: -H, -D, halogen; or
  • R 4 is -CD 3 or (C3-C6)cycloalkyl, wherein the (C3-C6)cycloalkyl can be substituted by one or more of the following groups: -H, halogen.
  • R is H , (C1-C3) alkyl, (C3-C4) cycloalkyl or (C1-C3) alkoxy, wherein the (C1-C3) alkyl, (C3-C4) cycloalkyl or (C1-C3) alkoxy can be substituted by one or more of the following groups: H or F.
  • R 1 is H, -CH 3 , -CH 2 CH 3 , -OMe, -OCF 3 , -OCHF 2 , -OCH 2 F or -OEt, preferably -CH 3 , -CH 2 CH 3 , or -OMe.
  • R 2 is F, Cl or (C1-C3) alkyl.
  • R 2 is F, Cl, -Me or -Et, preferably F, Cl, -Me.
  • R 3 is H, halogen or (C1-C3) alkyl, wherein the (C1-C3) alkyl can be substituted by one or more of the following groups: H or F.
  • R 3 is H, F, Cl, -Me, -CH 2 CH 3 , Preferably H, F, Cl, -Me or
  • R 4 is -H, (C1-C3) alkyl or (C3-C4) cycloalkyl, wherein the (C1-C3) alkyl or (C3-C4) cycloalkyl can be substituted by one or more of the following groups: -H, -D or -F.
  • R 4 is H, -CH 3 , -CD 3 , -CH 2 CH 3 , Preferably -CH 3 , -CD 3 , More preferably -CH 3 , -CD 3 , More preferably -CH 3 , more preferably -CD 3 , more preferably more preferably
  • R 4 is -CD 3 , (C3-C4)cycloalkyl, wherein the (C3-C4)cycloalkyl can be substituted by one or more of the following groups: H or F.
  • the present invention provides a compound represented by general formula (2) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • X 1 and X 2 are each independently CH or N;
  • R 1 is H, (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy, wherein said (C1-C4) alkyl, (C3-C6) cycloalkyl or (C1-C4) alkoxy can be substituted by one or more of the following groups: -H, halogen;
  • R 3 is -H, halogen or (C1-C4)alkyl, wherein the (C1-C4)alkyl may be substituted by one or more of the following groups: -H, halogen.
  • the compound of the present invention has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of the present invention or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.
  • Another object of the present invention is to provide the compound of the present invention or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical compositions for the purposes of preparing medicines for treating, regulating or preventing diseases related to PARP.
  • said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.
  • Another object of the present invention is also to provide a method for treating, regulating or preventing related diseases mediated by PARP, comprising administering to a subject a therapeutically effective amount of the indicated compound of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PRO Methods in TECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
  • 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, etc., are not limited to those explained below.
  • Compound of the present invention The compound can also optionally be prepared by combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed 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 (1) can be prepared using the following general reaction scheme 1:
  • Compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , R 3 , R 4 , X 1 and X 2 are as defined above. As shown in general reaction scheme 1, compound 1-1 reacts with thionyl chloride to generate compound 1-2, and compound 1-2 undergoes substitution reaction with 1-3 to generate target compound (1).
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively nontoxic, i.e., does not cause unwanted biological effects or interact in a deleterious manner with any of the components it contains when administered to an individual.
  • pharmaceutically acceptable salt refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and that does not abolish the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound of formula with an acid or base including, but not limited to, the acids and bases found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1 st Ed., (Wiley, 2002).
  • references to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In summary, for purposes of the compounds and methods provided herein, the solvated forms Considered equivalent to the unsolvated form.
  • compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms.
  • the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.
  • the compounds of general formula (1) may exhibit chiral centers and/or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers.
  • Each chiral center or axial chirality will independently give rise to 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 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 compounds.
  • compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs usually have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and prolonging the half-life of drugs in vivo. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
  • alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, 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 means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic) that may be referred to as “cycloalkenyl” if the carbocycle contains at least one double bond, or "cycloalkynyl” if the carbocycle contains at least one triple bond.
  • Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic. in some embodiments In, cycloalkyl is monocyclic or bicyclic.
  • Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form oxo or thioxo.
  • Cycloalkyl also includes cycloalkylene.
  • cycloalkyl groups contain 0, 1, or 2 double bonds.
  • the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl).
  • cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinenyl, norcarenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and the like.
  • alkoxy means 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 OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substitution
  • appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I, preferably F or Cl, in any combination.
  • the 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 ring structure.
  • member is meant to indicate the number of skeletal 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. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys represents the absolute configuration of a stereocenter
  • straight solid line key and straight dashed keys Indicates the relative configuration of the stereocenter
  • a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
  • treatment include alleviating, inhibiting or ameliorating a symptom or condition of a disease; inhibiting the development of complications; ameliorating or preventing an underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition;
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axichiral) and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to 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 invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition refers to a compound or composition that, when administered to an individual (human or animal), is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering refers to direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound.
  • the present invention provides methods for treating diseases using compounds of the general formula or pharmaceutical compositions of the present invention, including but not limited to conditions involving PARP (such as cancer, ischemic disease, ischemia-reperfusion injury, inflammation, nerve injury, vascular disease and diabetes, etc.).
  • PARP such as cancer, ischemic disease, ischemia-reperfusion injury, inflammation, nerve injury, vascular disease and diabetes, etc.
  • a method for treating cancer comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of the general formula to an individual in need.
  • the cancer is mediated by PARP.
  • the cancer is a blood cancer and a solid tumor, 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 made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the range of safe and effective amounts and pharmaceutically acceptable excipients or carriers.
  • safe and effective amount refers to: the amount of the compound is sufficient to obviously improve the condition without producing serious side effects.
  • the safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipients or carriers” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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.), polyhydric alcohols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid, magnesium stearate
  • the compounds of the present invention When the compounds of the present invention are administered, they can 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 the following ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; Potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; In capsules, tablets and pills, the dosage form may also contain
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, 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 used 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 used 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
  • 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, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, 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 vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound 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 which 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 applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, and for a person with a body weight of 60kg, the daily dosage is usually 1 to 2000mg, preferably 50-1000mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
  • methyl 5-bromo-6-methylpyridine-2-carboxylate (6.5g, 28mmol), tert-butyl piperazine-1-carboxylate (8.4g, 45mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (II) (879mg, 1.05mmol ) and cesium carbonate (19.6 g, 60 mmol) were mixed in 1,4-dioxane (60 mL). The reaction solution was heated to 110°C and stirred for 6 hours.
  • the intermediate int_1-2 (6.00g, 17.91mmol) was dissolved in methanol (120mL) at room temperature, cyclopropylamine (2.04g, 35.8mmol) was added, and stirred overnight at room temperature.
  • the reaction solution was concentrated to remove the organic solvent, and the residue was purified by recrystallization (dichloromethane/petroleum ether) to obtain a pale yellow intermediate int_1-3.
  • the target compound 2-52 in Table 1 can be obtained by using the synthesis method of the above-mentioned Example 1, or using other similar routes and using different raw materials.
  • Example 53 The compound of the present invention inhibits the activity of poly (ADP-ribose) polymerase [PARP-1 enzyme] in vitro
  • Histones were coated on a 384-well plate overnight for 4 nights, washed three times with PBST buffer, and blocked for 1 hour at room temperature. After 1 hour, rinse again three times with PBST, 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 start the reaction. After reacting at room temperature for 60 minutes, rinse with PBST three times, add poly/mono-ADP ribose antibody conjugated with horseradish peroxidase (HRP), and detect the level of poly/mono-ADP ribose on histone.
  • HRP horseradish peroxidase
  • +++ means IC 50 less than or equal to 10nM
  • Example 54 The compound of the present invention inhibits the proliferation of MDA-MB-436 cells in vitro

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Abstract

本发明公开了一种吡啶酰胺类PARP抑制剂、及其制备方法和医药用途。具体的，涉及一种如通式(1)所示的新化合物和/或其药学上可接受的盐，以及含有如通式(1)所示化合物的组合物和/或其药学上可接受的盐，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

吡啶酰胺类PARP抑制剂、及其制备方法和医药用途
本申请要求申请日为2022年1月20日的中国专利申请202210067335.X、2022年3月1日的中国专利申请202210206331.5、2022年6月7日的中国专利申请202210642141.8及2022年11月25日的中国专利申请202211494319.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学领域，更具体而言，涉及一类吡啶酰胺类PARP抑制剂、及其制备方法和医药用途。
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
本发明要解决的技术问题是目前PARP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。为此，本发明提供了吡啶酰胺类PARP抑制剂、及其制备方法和医药用途。
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：
通式(1)中：
X1、X2各自独立地为CH或N；
R1为H、(C1-C4)烷基、(C3-C6)环烷基或(C1-C4)烷氧基，其中所述(C1-C4)烷基、(C3-C6)环烷基或(C1-C4)烷氧基可被1个或多个以下基团取代：-H、卤素；
R2为卤素或(C1-C4)烷基；
R3为-H、卤素或(C1-C4)烷基，其中所述(C1-C4)烷基可被1个或多个以下基团取代：-H、卤素；
X2为N时，R4为-H、(C1-C4)烷基或(C3-C6)环烷基，其中所述(C1-C4)烷基或(C3-C6)环烷基可被1个或多个以下基团取代：-H、-D、卤素；或
X2为CH时，R4为-CD3或(C3-C6)环烷基，其中所述(C3-C6)环烷基可被1个或多个以下基团取代：-H、卤素。
在另一优选例中，其中所述通式(1)中，R1为H、(C1-C3)烷基、(C3-C4)环烷基或(C1-C3)烷氧基，其中所述(C1-C3)烷基、(C3-C4)环烷基或(C1-C3)烷氧基可被1个或多个以下基团取代：H或F。
在另一优选例中，其中所述通式(1)中，R1为H、-CH3、-CH2CH3、 -OMe、-OCF3、-OCHF2、-OCH2F或-OEt，优选为-CH3、-CH2CH3、 或-OMe。
在另一优选例中，其中所述通式(1)中，R2为F、Cl或(C1-C3)烷基。
在另一优选例中，其中所述通式(1)中，R2为F、Cl、-Me或-Et，优选为F、Cl、-Me。
在另一优选例中，其中所述通式(1)中，R3为H、卤素或(C1-C3)烷基，其中所述(C1-C3)烷基可被1个或多个以下基团取代：H或F。
在另一优选例中，其中所述通式(1)中，R3为H、F、Cl、-Me、-CH2CH3、优选为H、F、Cl、-Me或
在另一优选例中，其中所述通式(1)中，X2为N时，R4为-H、(C1-C3)烷基或(C3-C4)环烷基，其中所述(C1-C3)烷基或(C3-C4)环烷基可被1个或多个以下基团取代：-H、-D或-F。
在另一优选例中，其中所述通式(1)中，X2为N时，R4为H、-CH3、-CD3、-CH2CH3、 优选为-CH3、-CD3、更优选为-CH3、-CD3、更优选为-CH3，更优选为-CD3，更优选为更优选为
在另一优选例中，其中所述通式(1)中，X2为CH时，R4为-CD3、(C3-C4)环烷基，其中所述(C3-C4)环烷基可被1个或多个以下基团取代：H或F。
在另一优选例中，其中所述通式(1)中，X2为CH时，R4为-CD3、 优选为-CD3、
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：
通式(2)中：
X1、X2各自独立地为CH或N；
R1为H、(C1-C4)烷基、(C3-C6)环烷基或(C1-C4)烷氧基，其中所述(C1-C4)烷基、(C3-C6)环烷基或(C1-C4)烷氧基可被1个或多个以下基团取代：-H、卤素；
R3为-H、卤素或(C1-C4)烷基，其中所述(C1-C4)烷基可被1个或多个以下基团取代：-H、卤素。
在本发明的另一具体实施例中，本发明化合物具有以下结构之一：


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，以及本发明所述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所述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用途。其中，所述的疾病优选癌症，所述癌症为血液癌和实体瘤。
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(1)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(1)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 4th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd 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(1)化合物可采用下列一般反应流程1制备：
一般反应流程1
通式(1)化合物可根据一般反应流程1制备，其中R1、R2、R3、R4、X1和X2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通式化合物(1)。
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或碱反应获得，其中所述的酸或碱包括，但不限于发现于Stahl和Wermuth，Handbook of Pharmaceutical Salts:Properties,Selection,and Use 1st Ed.，(Wiley,2002)中的酸和碱。
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(1)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(1)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(1)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(1)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(1)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CH3、CH3CH2、CF3、CHF2、CF3CH2、CF3(CH3)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代基。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OCH3、OCF3、CHF2O、CF3CH2O、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。
除非另有规定，可以理解词语“包含”，或其变体如“包括”或“含有”是指包括所述的元素或整数，或者元素或整数的组，但不排除任意其他的元素或整数，或者元素或整数的组。
取代基“-O-CH2-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：
当一个连接基团的数量为0时，比如-(CH2)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，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型， 用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键
除非另有说明，用表示单键或双键。
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(1)所示化合物，以及通式(1)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、缺血性疾病、缺血-再灌注损伤、炎症、神经损伤、血管疾病和糖尿病等)。
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)、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
步骤1：化合物int_1-2的合成:
在氮气保护下，将5-溴-6-甲基吡啶-2-羧酸甲酯(6.5g,28mmol)、哌嗪-1-甲酸叔丁酯(8.4g,45mmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(879mg,1.05mmol)和碳酸铯(19.6g,60mmol)混合于1,4-二氧六环(60mL)中。反应液加热至110℃搅拌6小时。冷却后，加水(100mL)稀释，用乙酸乙酯(200mL×3)萃取，合并有机相。有机相经过水(100mL)以及饱和氯化钠水溶液(100mL)洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂，残余物经硅胶色谱法分离纯化得中间体int_1-2。
LC-MS(ESI):336[M+H]+。
步骤2：化合物int_1-3的合成:
在室温下，将中间体int_1-2(6.00g,17.91mmol)溶于甲醇(120mL)中，加入环丙胺(2.04g,35.8mmol)，室温搅拌过夜。将反应液浓缩除去有机溶剂，残余物经重结晶(二氯甲烷/石油醚)纯化得淡黄色中间体int_1-3。
LC-MS(ESI):361[M+H]+。
步骤3：化合物int_1-4的合成:
在室温下，将中间体int_1-3(6.30g,17.50mmol)溶于二氯甲烷(15mL)中。在0℃ 下，滴加三氟乙酸(15mL)，搅拌0.5小时。用饱和碳酸氢钠水溶液(30mL)淬灭，二氯甲烷(50mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤。滤液减压浓缩除去有机溶剂，残余物经重结晶(二氯甲烷/石油醚)纯化得黄色中间体int_1-4。
LC-MS(ESI):261[M+H]+。
步骤4：化合物1的合成:
在室温下，将中间体int_1-5(35mg,0.157mmol)溶于二氯甲烷(3mL)中，加入N,N-二甲基甲酰胺(1滴)和二氯亚砜(0.1mL)，室温搅拌2小时。减压浓缩干，残余物用乙腈(3mL)溶解，加入N,N-二异丙基乙基胺(59mg,0.456mmol)和中间体int_1-4(41mg,0.157mmol)，反应液加热至70℃搅拌15小时。冷却后减压浓缩，残留物经C18反相色谱法分离纯化得到化合物1。
LC-MS(ESI):465[M+H]+。
实施例2-52化合物2-52的合成
使用上述实施例1的合成方法，或者采用其他类似路线，采用不同原料，可以得到表1中目标化合物2-52。
表1



实施例53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IC50。结果见下列表2。
表2.本发明化合物对PARP-1的抑制活性(IC50,nM)
+++表示IC50小于或等于10nM
++表示IC50为10nM至50nM
+表示IC50大于50nM
实施例54本发明化合物体外抑制MDA-MB-436细胞增殖实验
1200个每孔的MDA-MB-436细胞种于96孔低吸附板，过夜贴壁后，加入梯度稀释的化合物，继续孵育10天后，通过CTG检测细胞的ATP水平，评价细胞生长。与DMSO组对比，计算化合物抑制生长的百分率及IC50。具体结果见下表3。
表3.本发明化合物对MDA-MB-436细胞的抑制活性(IC50,nM)
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 (17)

  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：

    通式(1)中：
    X1、X2各自独立地为CH或N；
    R1为H、(C1-C4)烷基、(C3-C6)环烷基或(C1-C4)烷氧基，其中所述(C1-C4)烷基、(C3-C6)环烷基或(C1-C4)烷氧基可被1个或多个以下基团取代：-H、卤素；
    R2为卤素或(C1-C4)烷基；
    R3为-H、卤素或(C1-C4)烷基，其中所述(C1-C4)烷基可被1个或多个以下基团取代：-H、卤素；
    X2为N时，R4为-H、(C1-C4)烷基或(C3-C6)环烷基，其中所述(C1-C4)烷基或(C3-C6)环烷基可被1个或多个以下基团取代：-H、-D、卤素；或
    X2为CH时，R4为-CD3或(C3-C6)环烷基，其中所述(C3-C6)环烷基可被1个或多个以下基团取代：-H、卤素。
  2. 如权利要求1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，其中所述通式(1)中，R1为-H、(C1-C3)烷基、(C3-C4)环烷基或(C1-C3)烷氧基，其中所述(C1-C3)烷基、(C3-C4)环烷基或(C1-C3)烷氧基可被1个或多个以下基团取代：-H或-F。
  3. 如权利要求2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，其中所述通式(1)中，R1为-H、-CH3、-CH2CH3、 -OMe、-OCF3、-OCHF2、-OCH2F或-OEt， 优选为-CH3、-CH2CH3、或-OMe。
  4. 如权利要求1-3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，其中所述通式(1)中，R2为-F、-Cl或(C1-C3)烷基。
  5. 如权利要求4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，其中所述通式(1)中，R2为-F、-Cl、-Me或-Et，优选为-F、-Cl、-Me。
  6. 如权利要求1-5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，其中所述通式(1)中，R3为-H、卤素或(C1-C3)烷基，其中所述(C1-C3)烷基可被1个或多个以下基团取代：-H或-F。
  7. 如权利要求6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，其中所述通式(1)中，R3为-H、-F、-Cl、-Me、-CH2CH3、优选为-H、-F、-Cl、-Me或
  8. 如权利要求1-7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，其中所述通式(1)中，X2为N时，R4为-H、(C1-C3)烷基或(C3-C4)环烷基，其中所述(C1-C3)烷基或(C3-C4)环烷基可被1个或多个以下基团取代：-H、-D或-F。
  9. 如权利要求8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，其中所述通式(1)中，X2为N时，R4为H、-CH3、-CD3、-CH2CH3、 优选为-CH3、-CD3、更优 选为-CH3、-CD3、更优选为-CH3，更优选为-CD3，更优选为更优选为
  10. 如权利要求1-7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，其中所述通式(1)中，X2为CH时，R4为-CD3、(C3-C4)环烷基，其中所述(C3-C4)环烷基可被1个或多个以下基团取代：H或F。
  11. 如权利要求10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，其中所述通式(1)中，X2为CH时，R4为-CD3、 优选为-CD3、
  12. 如权利要求1-11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，其中所述化合物具有以下结构之一：
  13. 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：

    通式(2)中：
    X1、X2各自独立地为CH或N；
    R1为H、(C1-C4)烷基、(C3-C6)环烷基或(C1-C4)烷氧基，其中所述(C1-C4)烷基、(C3-C6)环烷基或(C1-C4)烷氧基可被1个或多个以下基团取代：-H、卤素；
    R3为-H、卤素或(C1-C4)烷基，其中所述(C1-C4)烷基可被1个或多个以下基团取代：-H、卤素。
  14. 如权利要求13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，其中所述化合物具有以下结构之一：
  15. 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1-14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。
  16. 一种如权利要求1-14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15所述的药物组合物在制备治疗、调节和/或预防与聚(ADP-核糖)聚合酶(PARP)相关的疾病药物中的用途。
  17. 如权利要求16所述的用途，其中所述的疾病是癌症，所述癌症是血液癌和实体瘤。
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