WO2018228474A1 - 聚(adp-核糖)聚合酶抑制剂、制备方法及用途 - Google Patents

聚(adp-核糖)聚合酶抑制剂、制备方法及用途 Download PDF

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WO2018228474A1
WO2018228474A1 PCT/CN2018/091268 CN2018091268W WO2018228474A1 WO 2018228474 A1 WO2018228474 A1 WO 2018228474A1 CN 2018091268 W CN2018091268 W CN 2018091268W WO 2018228474 A1 WO2018228474 A1 WO 2018228474A1
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compound
formula
minutes
cancer
mobile phase
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PCT/CN2018/091268
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English (en)
French (fr)
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张富尧
袁洪顺
神小明
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上海时莱生物技术有限公司
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Priority to EP18817795.0A priority Critical patent/EP3640245B1/en
Priority to US16/622,395 priority patent/US11072596B2/en
Priority to JP2019568695A priority patent/JP2020523361A/ja
Publication of WO2018228474A1 publication Critical patent/WO2018228474A1/zh

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    • 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
    • C07D401/10—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 carbon chain containing aromatic 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to a poly(ADP-ribose) polymerase inhibitor, a preparation method and use thereof.
  • PARP Poly(ADP-ribose) polymerase
  • PARP-1 inhibitors can be used as sensitizers to improve the efficacy of anticancer drugs.
  • Chemotherapy or radiotherapy drugs inhibit or kill cells by destroying the structure of the DNA of tumor cells, and tumor cells can be damaged by PARP-1.
  • DNA cells are repaired to produce resistance to chemotherapeutic drugs, so PARP-1 inhibitor drugs can be combined with chemotherapeutic drugs to cope with drug resistance, thereby reducing the dose and improving the efficacy. Additional studies have shown that the use of PARP-1 inhibitor alone can kill DNA repair-deficient cancer cells, particularly BRCA-1/2 deletion or mutant cancer cells.
  • PARP-1 inhibitors have become one of the hotspots in the development of cancer drugs, and the reliability and feasibility of this target have been confirmed.
  • Facebook's Olaparib trade name Lynparza
  • Pfizer's Rucaparib and Tesaro's Niraparib were approved by the FDA for treatment after chemotherapy, and other research drugs such as Talazoparib and Veliparib were in clinical trials.
  • the compound of the present invention has strong PARP inhibitory activity and can be used for treating diseases associated with PARP such as cancer, inflammatory diseases and the like.
  • the present invention provides a compound of formula I, a pharmaceutically acceptable salt, isomer or mixture thereof, solvate, polymorph, stable isotope derivative or prodrug thereof. ;
  • R a is selected from hydrogen, hydrazine, fluorine, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted cycloalkyl;
  • R b is selected from hydrogen, deuterium, substituted or unsubstituted C 1-6 alkyl or substituted or unsubstituted cycloalkyl;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from hydrogen, hydrazine or fluorine, and when R a is hydrogen, R 1 , R 2 And at least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is deuterium or fluorine;
  • R a is hydrogen
  • n is 1
  • R 9 is a 5-position fluorine
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are not hydrogen at the same time;
  • R a is hydrogen
  • m is not 0, and R 7 is fluorine
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are not hydrogen at the same time;
  • n is the number of R 7 and is 0, 1, 2, 3 or 4;
  • n is the number of R 9 and is 0, 1, 2 or 3.
  • R b is hydrogen or deuterium.
  • R a is selected from the group consisting of hydrazine, fluorine or a substituted or unsubstituted C 1-6 alkyl group; and R 7 , R 8 , R 9 , m and n are as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 contain at least one fluorene or fluorine, and R 7 , R 8 , R 9 , m and n are as defined above.
  • R a is selected from the group consisting of hydrazine, fluorine or a substituted or unsubstituted C 1-6 alkyl group.
  • the structure of the compound of Formula I is a compound of Formula I-4:
  • R a is methyl, fluorine or hydrazine
  • R 7a , R 7b , R 8 , R 9a , R 9b and R 9c are each independently hydrogen or fluorine.
  • the R a may be fluorine or hydrazine, and may also be fluorine.
  • the R 7b may be hydrogen.
  • the R 8 may be hydrogen.
  • the R 9a may be hydrogen.
  • the R 9c may be hydrogen.
  • the R a is methyl, fluoro or fluorene
  • the R 7a , R 7b , R 8 , R 9a R 9b and R 9c are each independently hydrogen or fluorine, and at most only two fluorines.
  • the R a is methyl, fluorine or hydrazine
  • the R 8 is hydrogen
  • the R 7b , R 9a and R 9c are each independently hydrogen or fluorine, and at most one fluorine
  • R 7a and R 9b are each independently hydrogen or fluorine.
  • the R a is fluorine or deuterium
  • the R 8 , R 9a and R 9c are hydrogen
  • R 7b , R 7a and R 9b are each independently hydrogen or fluorine, and when said R 7b is fluorine, said R 9b is fluorine.
  • the R a is fluorine or deuterium
  • the R 7b , R 8 , R 9a and R 9c are hydrogen
  • the R 7a and R 9b are each independently hydrogen or fluorine.
  • the R a is fluorine
  • the R 7b , R 8 , R 9a and R 9c are hydrogen
  • R 7a and R 9b are each independently hydrogen or fluorine.
  • the compound of formula I is selected from any of the following structures:
  • a compound of formula I can be obtained from compound 101 under the following chiral resolution conditions;
  • the chiral splitting conditions may include:
  • the chiral column is Chrialpak AS-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 6.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at an RT of 10.7 minutes or 11.6 minutes.
  • the compound of Formula I may be a chiral compound of Compound 101 having a corresponding RT value of 5.8 minutes or 7.7 minutes under the following test conditions;
  • the detecting conditions may include:
  • the chiral column is Chrialpak AS-H 4.6mm x 250mm;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 1.0 mL/min
  • the detection wavelength was UV 210 nm.
  • a compound of formula I can be obtained under compound chiral resolution conditions for compound 102;
  • the chiral splitting conditions may include:
  • the chiral column is Chrialpak AS-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 6.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at an RT of 12.2 minutes or 10.8 minutes.
  • the compound of Formula I can be obtained under the following chiral resolution conditions for Compound 103;
  • the chiral splitting conditions may include:
  • the chiral column is Chrialpak AS-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 6.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at an RT of 15.2 minutes or 13.4 minutes.
  • a compound of formula I can be obtained under compound chiral resolution conditions for compound 104;
  • the chiral splitting conditions may include:
  • the chiral column is Chrialpak AS-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 6.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at an RT of 12.3 minutes or 10.9 minutes.
  • a compound of formula I can be obtained under compound chiral resolution conditions for compound 105;
  • the chiral splitting conditions may include:
  • the chiral column is CHIRALCEL OD-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 3.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at RT of 20.5 minutes or 23.8 minutes.
  • the compound of Formula I can be a chiral compound of Compound 105 having a corresponding RT value of 15.02 minutes or 16.71 minutes under the following test conditions;
  • the detecting conditions may include:
  • the chiral column is CHIRALCEL OD-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 0.5 mL/min
  • the detection wavelength was UV 210 nm.
  • a compound of formula I can be obtained under compound chiral resolution conditions for compound 106;
  • the chiral splitting conditions may include:
  • the chiral column is CHIRALCEL OD-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 3.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at RT of 22.5 minutes or 24.5 minutes.
  • a compound of formula I can be obtained as compound 107 under the following chiral resolution conditions;
  • the chiral splitting conditions may include:
  • the chiral column is CHIRALCEL OD-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 3.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at an RT of 24.3 minutes or 26.8 minutes.
  • a compound of formula I can be obtained under compound chiral resolution conditions for compound 108;
  • the chiral splitting conditions may include:
  • the chiral column is CHIRALCEL OD-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 3.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at RT of 21.3 minutes or 23.3 minutes.
  • a compound of formula I can be obtained under compound chiral resolution conditions for compound 109;
  • the chiral splitting conditions may include:
  • the chiral column is Chrialpak AS-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 6.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at an RT of 13.6 minutes or 15.8 minutes.
  • the compound of Formula I may be a chiral compound of Compound 109 having a corresponding RT value of 8.9 minutes or 11.3 minutes under the following test conditions;
  • the detecting conditions may include:
  • the chiral column is Chrialpak AS-H 4.6mm x 250mm;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 1.0 mL/min
  • the detection wavelength was UV 210 nm.
  • a compound of Formula I can be obtained under compound chiral resolution conditions for Compound 110;
  • the chiral splitting conditions may include:
  • the chiral column is Chrialpak AS-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 6.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at an RT of 16.7 minutes or 14.2 minutes.
  • a compound of formula I can be obtained as compound 111 under the following chiral resolution conditions;
  • the chiral splitting conditions may include:
  • the chiral column is Chrialpak AS-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 6.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at an RT of 18.7 minutes or 16.9 minutes.
  • a compound of formula I can be obtained from compound 112 under the following chiral resolution conditions;
  • the chiral splitting conditions may include:
  • the chiral column is Chrialpak AS-H 10mm x 250mm, 5 ⁇ m;
  • the column temperature is 40 ° C;
  • Mobile phase A is 0.1% DEA in Hexane, and the percent is volume percent;
  • Mobile phase B is ethanol
  • the flow rate is 6.0 mL/min
  • the detection wavelength is UV 210nm
  • the compound represented by the formula (I) was collected separately at an RT of 15.8 minutes or 14.2 minutes.
  • the present invention also provides a process for the preparation of a compound of the formula I, which comprises the steps of:
  • X is a halogen
  • R 0 is an amine protecting group
  • R a , R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , m and n The definition is as described above.
  • the X may be bromine.
  • the R 0 may be a tert-butyl group.
  • the reagent for providing basic conditions may be a basic alkaline reagent for the reaction in the field, including an organic base and an inorganic base, and the organic base may be lithium hexamethyldisilazide.
  • the organic base may be lithium hexamethyldisilazide.
  • N,N-diisopropylethylamine potassium t-butoxide, sodium t-butoxide, lithium t-butoxide, tetrabutylammonium fluoride and N-methylmorpholine.
  • the inorganic base may be potassium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium fluoride, cesium carbonate, lithium carbonate, potassium phosphate, sodium hydride and potassium hydride.
  • One or more eg potassium carbonate).
  • the metal catalyst may be a conventional catalyst for such a reaction in the art, such as cuprous iodide, cuprous bromide, cuprous chloride, copper powder, cuprous oxide, copper oxide, bromine.
  • a conventional catalyst for such a reaction in the art such as cuprous iodide, cuprous bromide, cuprous chloride, copper powder, cuprous oxide, copper oxide, bromine.
  • copper, copper chloride, copper acetate, cuprous acetate, copper trifluoroacetate, copper trifluorosulfonate and ferric chloride for example, cuprous iodide).
  • the reagent for providing acidic conditions may be a conventional acidic reagent for the reaction in the field, including an organic acid and an inorganic acid, and the organic acid may be trifluoroacetic acid, methanesulfonic acid or trifluorocarbon.
  • the organic acid may be trifluoroacetic acid, methanesulfonic acid or trifluorocarbon.
  • the inorganic acid may be one or more of hydrochloric acid, sulfuric acid, sulfonic acid, phosphoric acid, and metaphosphoric acid (for example, methanesulfonic acid).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the compound of the formula I, a pharmaceutically acceptable salt thereof, an isomer or a mixture thereof, a solvate, and more A crystalline form, a stable isotope derivative or prodrug, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention also provides the compound of the formula I, a pharmaceutically acceptable salt, an isomer thereof or a mixture thereof, a solvate, a polymorph, a stable isotope derivative or a prodrug, Or the use of the pharmaceutical composition for the preparation of a medicament for preventing, alleviating and/or treating a disease which can be alleviated by a PARP inhibitor.
  • the present invention also provides the compound of the formula I, a pharmaceutically acceptable salt, an isomer thereof or a mixture thereof, a solvate, a polymorph, a stable isotope derivative or a prodrug, Or the use of the pharmaceutical composition described in the preparation of a PARP inhibitor.
  • the present invention also provides the compound of the formula I, a pharmaceutically acceptable salt, an isomer thereof or a mixture thereof, a solvate, a polymorph, a stable isotope derivative or a prodrug, Or the pharmaceutical composition is prepared for the prevention, alleviation and/or treatment of cancer, inflammatory diseases, vascular diseases, stroke, renal failure, diabetes, Parkinson's disease, septic shock, neurotoxicity, ischemic shock Or use in drugs for injury, transplant rejection, reperfusion injury, retinal damage, UV-induced skin damage, viral infection or multiple sclerosis.
  • the present invention also provides the compound of the formula I, a pharmaceutically acceptable salt, an isomer thereof or a mixture thereof, a solvate, a polymorph, a stable isotope derivative or a prodrug, Or the use of the pharmaceutical composition as an adjunct to the preparation of a cancer treatment or a medicament for enhancing the treatment of cancer by radiotherapy and/or chemotherapy.
  • the present invention also provides the compound of the formula I, a pharmaceutically acceptable salt, an isomer thereof or a mixture thereof, a solvate, a polymorph, a stable isotope derivative or a prodrug, Or the use of the pharmaceutical composition for the preparation of a medicament for treating cancer, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (such as glioma), nasopharyngeal carcinoma, Esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (such as colon cancer, rectal cancer, etc.), lung cancer (such as small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, terminally differentiated cancer, etc.), kidney cancer, skin Cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, bone cancer, osteosarcoma, seminoma, testicular tumor, uter
  • the present invention also provides the compound of the formula I, a pharmaceutically acceptable salt, an isomer thereof or a mixture thereof, a solvate, a polymorph, a stable isotope derivative or a prodrug, Or the use of the pharmaceutical composition for the preparation of a medicament for treating cancer, wherein the cancer may be selected from the group consisting of a solid tumor, acute or chronic leukemia, lymphoma, central nervous system cancer, brain cancer, blood-borne cancer, peritoneum Cancer, gastric cancer, lung cancer, cancer lacking homologous recombination-dependent DNA double-strand break repair activity, defective or mutant phenotype on BRCA-1 or BRCA2 (such as breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer).
  • the cancer may be selected from the group consisting of a solid tumor, acute or chronic leukemia, lymphoma, central nervous system cancer, brain cancer, blood-borne cancer, peritoneum Cancer, gastric cancer, lung cancer, cancer lacking homologous recombination-dependent DNA
  • the compound of the formula I a pharmaceutically acceptable salt, an isomer thereof or a mixture thereof, a solvate, a polymorph, a stable isotope derivative or a prodrug, or the drug
  • the composition may be used in combination with another one or more anticancer agents selected from the group consisting of alkylating agents, platinum drugs, topoisomerase inhibitors, metabolic antagonists, alkaloids, antibody drugs, hormones.
  • Anticancer agents proteasome inhibitors, HDAC inhibitors, CDK kinase inhibitors, VEGFR or EGFR inhibitors, m-TOR inhibitors, PI3K kinase inhibitors, B-Raf inhibitors, PARP inhibitors, c-Met kinase inhibition Agent, ALK kinase inhibitor, AKT inhibitor, ABL inhibitor, FLT3 inhibitor, PD-1 mAb or PD-L1 monoclonal antibody.
  • the present invention also provides the compound of the formula I, a pharmaceutically acceptable salt, an isomer thereof or a mixture thereof, a solvate, a polymorph, a stable isotope derivative or a prodrug, Or use of the pharmaceutical composition for the preparation of a medicament for treating cancer, wherein the medicament may be used in combination with another one or more anticancer agents, the anticancer agent being selected from an alkylating agent (cyclophosphorus) Amide, hydrochloric acid mustard, dibromomannitol, carmustine, dacarbazine, melphalan, etc., platinum drugs (eg cisplatin, carboplatin, thioplatin, nedaplatin, oxaliplatin, Lobaplatin, etc., topoisomerase inhibitors (topotecan, irinotecan, rupidine, ixacetac, letoticon, gimathycan, difluentic), metabolic antagonists For example, methotrex
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight or branched chain groups of 1 to 20 carbon atoms.
  • An alkyl group of 1 to 10 carbon atoms is preferred, more preferably 1 to 8 carbon atoms, and non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl, t-butyl , sec-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethyl Propyl, 1-ethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,
  • the alkyl group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, preferably one or more groups, independently selected from alkyl, halo, hydroxy. , mercapto, cyano, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkane An oxy group, a cycloalkyl fluorenyl group, a heterocycloalkyl fluorenyl group, an oxo group, an amino group, a halogenated alkyl group, a hydroxyalkyl group, a carboxyl group or a carboxylate group.
  • alkyl and its prefix are used herein, both straight-chain and branched saturated carbon bonds are included.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms, most preferably Non-limiting examples of including 3 to 6 carbon atoms, monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexyl Dienyl, cycloheptyl, cyclooctyl and the like.
  • Non-limiting examples of polycyclic cycloalkyl groups include, but are not limited to, spiro, fused, and bridged cycloalkyl groups.
  • the cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from the group consisting of alkyl, halogen, hydroxy, decyl, cyano, alkenyl, alkyne.
  • halogen means fluoro, chloro, bromo or iodo, preferably bromo or iodo.
  • Substituted means that one or more hydrogen or deuterium atoms in the group, preferably from 1 to 5 hydrogen or deuterium atoms, are independently substituted with each other by a corresponding number of substituents.
  • “Pharmaceutically acceptable salt” refers to a biological group capable of retaining the free base without other toxic side effects, which may be an acidic group, a basic group or an amphoteric group, and non-limiting examples include, but are not limited to: Acid salts include hydrochloride, hydrobromide, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, coke Phosphate, nitrate, acetate, propionate, citrate, octoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate , succinate, suberate, benzoate, methyl benzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, besylate, (D,L
  • the pharmaceutically acceptable salt thereof may further include an alkali metal salt (for example, a sodium salt or a potassium salt), an alkaline earth metal salt (for example, a calcium salt or a magnesium salt), and an organic base salt (for example). Alkyl aromatic amino acids, amino acids, etc.).
  • an alkali metal salt for example, a sodium salt or a potassium salt
  • an alkaline earth metal salt for example, a calcium salt or a magnesium salt
  • an organic base salt for example. Alkyl aromatic amino acids, amino acids, etc.
  • Solvate means an aggregate (or associate) formed by one or more solvent molecules with a compound of the invention.
  • Solvents of the solvate formed include, but are not limited to, water, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetic acid, and the like.
  • Polymorph refers to a different solid crystalline phase of a compound of the invention produced in the solid state by the presence of two or more different molecular arrangements, which may exist as a single crystalline or polymorphic mixture.
  • stable isotope derivative means an isotope-substituted derivative obtained by substituting a hydrogen atom of any one of the compounds of the present invention with 1 to 5 atomic atoms, or an isotope obtained by substituting one or three C 14 atoms for any carbon atom.
  • Prodrug means a compound that can be converted to a biologically active compound of the invention under physiological conditions (eg, in vivo) or by solvolysis, and is understood to be a pharmaceutically acceptable metabolic precursor.
  • the prodrug may be inactive or less active than the active parent compound, but may be rapidly converted in vivo to produce the parent compound of the invention, which may improve its solubility in animals as well as certain metabolic properties, including, for example, amino protecting groups, A carboxyl protecting group, a phospholipid, or the like.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipient.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active ingredient to exert biological activity.
  • isomers means a stereoisomer comprising: an enantiomer and a diastereomer, and a cis-trans isomer is one of the diastereomers.
  • the isomers of the present compounds may be their enantiomers, diastereomers, and any mixtures thereof, including the formation of free or salt forms.
  • the reagents and starting materials used in the present invention are commercially available.
  • the positive progress of the present invention is that the compound of the present invention has strong PARP inhibitory activity and can be used for the treatment of diseases associated with PARP such as cancer, inflammatory diseases and the like.
  • Figure 1 shows the inhibitory effect of the control group, Compound Example 23 and Niraparib on the tumor volume of MDA-MB-436 cells.
  • the structure of all compounds of the invention can be determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ is reported in units of 10 -6 (ppm).
  • the NMR measuring instrument was performed on a Bruker AVANCE-400 spectrometer.
  • the deuterated solvents tested were deuterated chloroform (CDCl 3 ), deuterated methanol (MeOD), deuterated dimethyl sulfoxide (DMSO-d 6 ), and the internal standard was tetramethylsilane (TMS).
  • MS mass spectra
  • HPLC purity was determined by an Agilent high performance liquid chromatograph Agilent 1260/1220 chromatograph (Agilent Zorbax Bonus RP 3.5 ⁇ m x 4.6 mm x 150 mm or Boston pHlex ODS 4.6 mm x 150 mm x 3 ⁇ m).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai, Yantai Xinnuo Chemical HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used for thin layer chromatography (TLC) is 2.5x 5cm, 0.2mm ⁇ 0.25mm, thin layer.
  • the pre-TLC purification product has a specification of 1 mm or 0.4 mm to 0.5 mm and 20 x 20 cm.
  • the instrument used in the fast separator is Gela Technologies MP200, and the column size is generally Flash column silica-CS (12g ⁇ 330g).
  • the chiral test column models are CHIRALCEL OD-H, OJ-H or CHIRALPAK AD-H, AS-H 4.6mm X 250mm X 5 ⁇ m, preparative column type CHIRALCEL OD-H, OJ-H or CHIRALPAK AD-H, AS -H 10mm X 250mm X 5 ⁇ m,
  • Known starting materials of the present invention can be synthesized by or according to methods known in the art, or from suppliers Sigma Aldrich, ACROS, Alfa Aesar, TCI, Belling, Anne Chemical, Suiyuan Chemical, Maclean, Companies such as Siyan Chemical purchased the proceeds.
  • Anhydrous solvents such as anhydrous tetrahydrofuran, anhydrous dichloromethane, anhydrous N,N-dimethylacetamide and the like are all purchased from the above chemical companies.
  • the reaction is generally carried out under a nitrogen or argon atmosphere.
  • the nitrogen or argon atmosphere means that the reaction flask is connected to a balloon of nitrogen or argon having a volume of about 1 L and subjected to three pumping displacements.
  • reaction temperature is room temperature, and the temperature is 15 to 25 °C.
  • the reaction in the examples is generally monitored by LCMS or TLC.
  • the LCMS instrument is described above.
  • the developing solvent system used in TLC is generally: dichloromethane and methanol, petroleum ether and ethyl acetate, dichloromethane and acetic acid. Ester, petroleum ether and system of dichloromethane, ethyl acetate and methanol, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount (0.1% to 10%) of a base (for example, triethylamine or 37% ammonia, etc.) or acid (such as acetic acid, etc.) are adjusted.
  • a base for example, triethylamine or 37% ammonia, etc.
  • acid such as acetic acid, etc.
  • the purified compound is prepared by Prep-TLC, column chromatography or Agela preparation system.
  • the elution solvent system is generally: dichloromethane and methanol, petroleum ether and ethyl acetate, dichloromethane and ethyl acetate, petroleum ether and dichloromethane.
  • a base for example, triethylamine or 28% aqueous ammonia, etc.
  • an acid may be added. (for example, acetic acid, etc.) to adjust.
  • PE petroleum ether
  • Prep-HPLC preparation high performance liquid chromatography.
  • the third step 3-(4-bromophenyl)-3-deuteropiperidin-2-one
  • reaction mixture was quenched with 100 mL of water, ethyl acetate (200 mL ⁇ 2), and the organic phase was concentrated.
  • the residue was mixed with 30 mL of concentrated hydrochloric acid and 60 mL of methanol at 40 to 45 ° C After reacting for 30 minutes, the reaction solution was diluted with water, and then neutralized with a 2N aqueous NaOH solution to pH to 8 to 9 and extracted with ethyl acetate, and concentrated to give a crude 3-(4-bromophenyl)-3-indole piperidine, 6.0 g, yield 90%.
  • Step 5 tert-butyl 3-(4-bromophenyl)-3-deuteropiperidin-1-carboxylate
  • Step 6 3-(4-(7-(tert-Butylcarbamoyl)-2H-indazol-2-yl)phenyl)-3-deuteropiperidin-1-carboxylic acid tert-butyl ester
  • reaction solution was cooled to room temperature, quenched with 50 mL of water, extracted with MTBE (200 mL ⁇ 2), and dissolved in citric acid water. Washing, drying and concentrating to give the crude foamy 3-(4-(7-(tert-butylcarbamoyl)-2H-indazol-2-yl)phenyl)-3-indolepiperidin-1-carboxylic acid tert-butyl
  • the crude product was separated by HPLC to obtain a preparation liquid, about 400 mL of the separation liquid, and neutralized to pH 8 to 9 with 1N NaOH, and then ethyl acetate (400 mL) ⁇ 2) Extraction, and concentration to give a crude product (yield: 2-(4-(3-fluoropiperidin-3-yl)phenyl)-2H-carbazole-7-carboxamide 114 mg.
  • the above crude product was heated to complete dissolution with 64 mg of p-toluenesulfonic acid in ethanol, and the ethanol was concentrated. The residue was purified by THF, filtered and dried to yield 110 mg of p-toluenesulfonate.
  • Example 1 The racemic compound obtained in Example 1 was separated and separated by a chiral column Chrialpak AS-H (10 mm x 250 mm, 5 ⁇ m) at a column temperature of 40 ° C and a mobile phase A of 0.1% DEA in Hexane (v/v).
  • the mobile phase B was ethanol, the running time was 30 minutes, the gradient was mobile phase A/mobile phase B (50/50, v/v), the flow rate was 6.0 mL/min, and the detection wavelength was UV 210 nm, which was 10.7 minutes at RT.
  • tert-Butyl 3-(4-bromophenyl)-3-hydroxypiperidine-1-carboxylate (26.0 g, 0.074 mol) was dissolved in anhydrous dichloromethane (500 mL) at 20 to 25 ° C. Under the protection, it was cooled to -78 ° C, and DAST (57.0 g, 0.353 mol) was added dropwise to the reaction system. The temperature during the dropwise addition was not more than -75 ° C, and the mixture was stirred for 2 hours. LC-MS showed that the raw materials disappeared. The reaction system was quenched by adding 100 mL of water, and the pH was adjusted to 7-8 with 2M aq. NaOH.
  • the third step 3-(4-(7-(tert-butylcarbamoyl)-2H-indazol-2-yl)phenyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester
  • the racemic compound obtained in Example 22 was separated and separated by a chiral column CHIRALCEL OD-H (10 mm x 250 mm, 5 ⁇ m) at a column temperature of 40 ° C and a mobile phase A of 0.1% DEA in Hexane (v/v).
  • the mobile phase B was ethanol, the running time was 35 minutes, the gradient was mobile phase A/mobile phase B (60/40, v/v), the flow rate was 3.0 mL/min, and the detection wavelength was UV 210 nm, respectively at RT for 20.5 minutes.
  • tert-Butyl 3-(4-bromophenyl)-3-methylpiperidine-1-carboxylate (15.0 g, 42.3 mmol) was dissolved in DMSO (180 mL) at 20-25 ° C, respectively. NaH (2.2 g, 55.0 mmol) was heated to 40-45 ° C and stirred for 30 minutes. Then, a solution of iodomethane (6.3 g, 44.4 mmol) in DMSO (20 mL) was added dropwise to the reaction system, and the addition was completed. Stirring was continued for 30 minutes at ⁇ 45°C. LCMS showed the disappearance of the starting material.
  • Step 4 tert-butyl 3-(4-bromophenyl)-3-methylpiperidine-1-carboxylate
  • Step 5 3-(4-(7-(tert-Butylcarbamoyl)-2H-indazol-2-yl)phenyl)-3-deuteropiperidin-1-carboxylic acid tert-butyl ester
  • Example 44 The above-described racemic compound was subjected to resolution separation by a chiral column to obtain a R configuration product (Example 44) and an S configuration product (Example 45) in a single configuration.
  • Example 43 The racemic compound obtained in Example 43 was separated and separated by a chiral column Chrialpak AS-H (10 mm x 250 mm, 5 ⁇ m) at a column temperature of 40 ° C and a mobile phase A of 0.1% DEA in Hexane (v/v).
  • the mobile phase B was ethanol, the running time was 30 minutes, the gradient was mobile phase A/mobile phase B (50/50, v/v), the flow rate was 6.0 mL/min, and the detection wavelength was UV 210 nm, which was 13.6 minutes at RT.
  • Multi-function microplate reader SpectraMax M5 Microplate Reader (Molecular Devices)
  • the 1.1PARP1 Colorimetric Assay Kit contains:
  • 1x PBS Take a packet of PBS powder and add 1L of deionized water to dissolve completely;
  • 1x PARP assay buffer Dilute 10x PARP assay buffer in 1:10 with deionized water to obtain 1x PARP assay buffer.
  • the compound was dissolved in DMSO and diluted to 100 ⁇ M for use.
  • the 100 ⁇ M compound stock solution was diluted to 10 ⁇ M with 1 ⁇ PARP assay buffer, and then the compound was serially diluted 3-fold with 1 ⁇ PARP assay buffer containing 10% DMSO to obtain a series of concentrations of the compound for use. 5 ⁇ L of the diluted compound (total volume 50 ⁇ L) was added to each well, such that the final concentration of the compound was 1 ⁇ M starting at a series of 3-fold dilutions.
  • reaction solution was prepared in a ratio of 2.5 ⁇ L of 10x PARP buffer + 2.5 ⁇ L of 10x PARP Assay mixture + 5 ⁇ L of Activated DNA + 15 ⁇ L of deionized water per well, and 25 ⁇ L of the reaction solution was added to each well (see Table 1).
  • OD 450 nm was read on a microplate reader by adding 100 ⁇ L of 2 M H 2 SO 4 per well.
  • the inhibition rate is calculated using the following formula:
  • Inhibition rate (ODsample-OD0%) / (OD100% - OD0%) ⁇ 100%
  • ODsample the OD value of the sample test well
  • OD100% OD value of the whole live control well.
  • the PARP-1 kinase inhibitory activity of the compound of the present invention is determined by the above experimental method, and the in vitro enzymatic inhibitory activity (IC 50 ) of the compound is measured as shown in the following Table 2: + represents 10-100 ⁇ m, ++ represents 1-10 ⁇ m, ++ + indicates 0.5-1 ⁇ m, ++++ indicates 0.1-0.5 ⁇ m, and +++++ indicates ⁇ 0.1 ⁇ m.
  • SD rats were used as test animals, and the drug concentration in plasma at different times after intravenous administration and intragastric administration of the compound of the example was determined by LC/MS/MS method to study the pharmacokinetics of the compound of the present invention in rats. Learn behavior and evaluate its pharmacokinetic characteristics.
  • the rats were sacrificed by jugular vein puncture at different time points from 0.083-24 h before and after administration. K2-EDTA was anticoagulated, centrifuged, and plasma was taken and stored at -70 °C until LC/MS/MS analysis.
  • Test Compound Stock Solution A certain amount of the compound powder of the example was accurately weighed and diluted to 10 mM with DMSO, respectively.
  • Buffer 100 mM potassium phosphate buffer, pH 7.4; 10 nM MgCl 2 .
  • NADPH ⁇ -nicotinamide adenine dinucleotide phosphate reduced form, tetrasodium salt, NADPH ⁇ 4Na, supplier: sigma, catalog number 616.
  • Liver microsomes human liver microsomes, Corning Cat No. 452117; rat liver microsomes, Xenotech Cat No. R1000; mouse liver microsomes, Xenotech Cat No. M1000; dog liver microsomes, Xenotech Cat No. D1000; Crab monkey liver microsomes, Corning Cat No. 452413, final formulated to a concentration of 0.5 mg protein/mL.
  • Formulation Stop Solution A cold acetonitrile solution containing 100 ng/mL Tolbutamide and 100 ng/mL Labetalol as an internal standard.
  • a 680 [mu]L/well microsome solution was dispensed to a 96-well plate according to Platemap, and as a spare, the mixture of microsome solution and compound was incubated at 37[deg.] C. for about 10 minutes.
  • each component in the incubation medium contained: 0.5 mg protein/mL microsomes, 1 ⁇ M test compound, 1 ⁇ M ginseng, 0.99% methanol, and 0.01% DMSO.
  • the sampling plate is shaken for about 10 minutes.
  • the sample was centrifuged at 4000 rpm for 20 min at 4 °C.
  • Example 23 The compound of Example 23 and niraparib of the present invention were analyzed in accordance with the above procedures, and the results are shown in Table 4 below.
  • mice BALB/c nude mice, 6-8 weeks old, weighing 18-22 g, female, provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal certificate number: 20130016001914.
  • IVC independent air supply system
  • Each cage animal information card indicates the number of animals in the cage, gender, strain, date of receipt, dosing schedule, experiment number, group, and start date of the experiment. All cages, litter and drinking water are sterilized prior to use. Cage, feed and drinking water are changed twice a week.
  • Human breast cancer MDA-MB-436 cells (ATCC, Manassas, Virginia, Cat. No. ATCC-HTB-130) in vitro monolayer culture, culture conditions of RPMI1640 medium plus 10% fetal bovine serum, 37 ° C5 % CO 2 incubator culture. Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, after the number reaches the requirement, the cells are collected, counted, and inoculated. 0.2 mL (1 ⁇ 107) MDA-MB-436 cells (with matrigel, volume ratio of 1:1) were subcutaneously inoculated into the right back of each mouse, and the group was administered at an average tumor volume of 157 mm 3 . .
  • the dosage and administration schedule are shown in Table 5.
  • the tumor volume subcutaneously in nude mice was measured 2-3 times a week, the rats were weighed, and data were recorded.
  • the administration volume is 10 mg/mL.
  • TGI (%) (1-T/C) ⁇ 100%.
  • Example 23 The inhibitory effects of the control group, Example 23 and niraparib on the tumor volume of MDA-MB-436 cells are shown in Table 6 and Figure 1.
  • Example 23 and niraparib had a very strong inhibitory effect on the tumor growth of the MDA-MB-436 cell nude mouse model at a dose of 50 mg/kg and continuous PO administration for 18 days.
  • the antitumor activity of the inventive compound Example 23 was stronger than that of the positive control niraparib, the administration was stopped at 18 days and the observation was continued until 39 days, and it was found that the compound Example 23 and niraparib can continue to inhibit the growth of the tumor, and the compound of the present invention Example 23
  • the anti-tumor effect of the observation period was significantly stronger than that of the positive control niraparib, and the compound of Example 23 of the present invention was able to completely regress the tumor in some animals, and the compound of Example 23 gave the tumor completely disappeared at a rate of 50%, while the positive control
  • the ratio of test animals in which niraparib completely abolished the tumor was zero.
  • CYP1A2 ⁇ -naphthoflavone
  • CYP2C9 sulfaphenazole
  • CYP2C19 omeprazole
  • CYP3A4 ketoconazole
  • CYP2D6 quinidine.
  • CYP1A2 Phenacetin at 30 ⁇ M
  • CYP2C9 Diclofenac at 10 ⁇ M
  • CYP2C19 S-Mephenytoin at 35 ⁇ M
  • CYP3A4 Midazolam at 5 ⁇ M and Testosterone at 80 ⁇ M
  • CYP2D6 Bufuralol at 10 ⁇ M.
  • 100 mM K-buffer 9.5 mL of Stock A and 40.5 mL of Stock B were mixed, diluted to 500 mL with Milli-Q ultrapure water, and then buffered to pH 7.4 with KOH or H 3 PO 4 .
  • test plate Incubate the test plate at 37 ° C: 3A4 for 5 minutes, 1A2, 2C9 and 2D6 for 10 minutes each, and 2C19 for 45 minutes;
  • X is the logarithm of the concentration.
  • Y is the concentration of the inhibitor in response to high to low.
  • the inhibitory IC 50 of the compounds of the invention against various subtypes of human liver microsomal CYP450 enzyme is shown in Table 7 below.
  • CHO-hERG cells were cultured in a 175 cm 2 flask, and the cell density was increased to 60-80%. The culture solution was removed, washed once with 7 mL of PBS (Phosphate Buffered Saline phosphate buffer), and then digested with 3 mL of Detachin.
  • PBS Phosphate Buffered Saline phosphate buffer
  • Single-cell high-impedance sealing and whole-cell patterning were all done automatically by the Qpatch instrument. After obtaining the whole-cell recording mode, the cells were clamped at -80 mV before giving a 5 second +40 mV depolarization stimulus. First, give a 50-millisecond -50 mV preamplifier, then repolarize to -50 mV for 5 seconds, then back to -80 mV. This voltage stimulation was applied every 15 seconds, and the extracellular fluid was recorded for 5 minutes after recording for 2 minutes, and then the administration process was started. The compound concentration was started from the lowest test concentration, and each test concentration was given for 2.5 minutes. After all the concentrations were continuously administered, the administration was given. Positive control compound 3 ⁇ M Cisapride. Test at least 3 cells (n ⁇ 3) for each concentration.
  • the experimental reagents used were purchased from Sigma, with a purity of >98%;

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Abstract

本发明公开了一种如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药。本发明的化合物具有较强的PARP抑制活性，可用于治疗与PARP相关的疾病，如癌症、炎症疾病等。

Description

聚(ADP-核糖)聚合酶抑制剂、制备方法及用途
本申请要求申请日为2017年6月14日的中国专利申请CN201710454485.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种聚(ADP-核糖)聚合酶抑制剂、制备方法及用途。
背景技术
聚腺苷二磷酸核糖聚合酶(poly(ADP-ribose)polymerase，PARP)是真核生物细胞中的一类核酶，涉及多种细胞过程，如与DNA损伤修复、基因组稳定性和程序性细胞死亡等密切相关，于1963年首次被报道，PARP家族至少含有18种亚型，它们具有不同的结构和细胞功能，包括PARP-1、PARP-2、PARP-4、Tankyrase-1和2和其它PARP-3～16。PARP由四个结构域组成，包括DNA结合域、半胱天冬酶切域、自身修饰域和催化域。其中PARP-1最先被发现，尽管PARP-1和PARP-2结构相似，但是DNA损伤修复的过程大部分是由PARP-1来完成，所以PARP抑制剂药物研究主要集中于PARP-1抑制剂上。
多种类型的癌症细胞比常规细胞更加依赖于PARP，使得PARP抑制剂药物成为癌症治疗中最为吸引力的靶标。PARP-1抑制剂可以作为增敏剂来提高抗癌药物的疗效，化疗或放疗药物是通过破坏肿瘤细胞的DNA的结构来抑制或杀死细胞，而肿瘤细胞可以通过PARP-1对受损的DNA细胞进行修复，从而对化疗药物产生耐药性，所以PARP-1抑制剂药物可以联合化疗药物来应对耐药性，从而可以降低药量和提高疗效的效果。另外研究表明单独使用PARP-1抑制剂可以杀死DNA修复缺陷型癌细胞，特别是BRCA-1/2缺失或者突变型癌细胞。
基于多年来对PARP抑制剂的研究，目前PARP-1抑制剂已经成为癌症药物研发的热点之一，而且已经证实该靶点的可靠和可行性。阿斯利康公司的奥拉帕利(Olaparib)，商品名Lynparza，于2014年先后被EMA和FDA批准，用于BRCA基因突变相关的晚期卵巢癌化疗后的单药治疗。随后辉瑞的Rucaparib和Tesaro的Niraparib相继被FDA批准上市用于化疗后的患者治疗，除此之外其它在研药物如Talazoparib、Veliparib等都处于临床实验阶段。近期这些研究结果也证实了PARP抑制剂用于BRCA基因缺失或者突变相关的癌症的治疗方面具有巨大优势。
发明内容
本发明的目的是提供一种聚(ADP-核糖)聚合酶抑制剂、制备方法及用途。本发明的化合物具有较强的PARP抑制活性，可用于治疗与PARP相关的疾病，如癌症、炎症疾病等。
第一方面，本发明提供一种如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药；
Figure PCTCN2018091268-appb-000001
其中，
R a选自氢、氘、氟、取代或未取代的C 1-6烷基或者取代或未取代的环烷基；
R b选自氢、氘、取代或未取代的C 1-6烷基或者取代或未取代的环烷基；
R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9各自独立地选自氢、氘或氟，且当R a为氢时，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9中至少有一个为氘或氟；
当R a为氢，n为1，且R 9为5位氟时，R 1、R 2、R 3、R 4、R 5、R 6和R 8不同时为氢；
当R a为氢，m不为0，且R 7为氟时，R 1、R 2、R 3、R 4、R 5、R 6和R 8不同时为氢；
m为R 7的数目，且为0、1、2、3或4；
n为R 9的数目，且为0、1、2或3。
在本发明的一个优选例中，R b为氢或氘。
在本发明的一个优选例中，所述的如通式I所示的化合物的结构如下：
Figure PCTCN2018091268-appb-000002
其中，R a选自氘、氟或者取代或未取代的C 1-6烷基；R 7、R 8、R 9、m和n的定义如上所述。
在本发明的一个优选例中，所述的如通式I所示的化合物的结构如下：
Figure PCTCN2018091268-appb-000003
其中，R 1、R 2、R 3、R 4、R 5和R 6中至少含有一个氘或氟，R 7、R 8、R 9、m和n的定义如上所述。
在本发明的一个优选例中，所述的如通式I所示的化合物的结构如下：
Figure PCTCN2018091268-appb-000004
其中，R a选自氘、氟或者取代或未取代的C 1-6烷基。
在本发明的一些方案中，所述的如通式I所示的化合物的结构为如通式I-4所示的化合物：
Figure PCTCN2018091268-appb-000005
其中，R a为甲基、氟或氘；
R 7a、R 7b、R 8、R 9a、R 9b和R 9c各自独立地为氢或氟。
所述的如通式I-4所示的化合物中，所述的R a可为氟或氘，还可为氟。
所述的如通式I-4所示的化合物中，所述的R 7b可为氢。
所述的如通式I-4所示的化合物中，所述的R 8可为氢。
所述的如通式I-4所示的化合物中，所述的R 9a可为氢。
所述的如通式I-4所示的化合物中，所述的R 9c可为氢。
在本发明的一些方案中，所述的如通式I-4所示的化合物中，所述的R a为甲基、氟或氘，所述的R 7a、R 7b、R 8、R 9a、R 9b和R 9c各自独立地为氢或氟，且至多只有两个氟。
在本发明的一些方案中，所述的如通式I-4所示的化合物中，所述的R a为甲基、氟 或氘，所述的R 8为氢；所述的R 7b、R 9a和R 9c各自独立地为氢或氟，且至多只有一个氟；所述的R 7a和R 9b各自独立地为氢或氟。
在本发明的一些方案中，所述的如通式I-4所示的化合物中，所述的R a为氟或氘，所述的R 8、R 9a和R 9c为氢，所述的R 7b、R 7a和R 9b各自独立地为氢或氟，且当所述的R 7b为氟时，所述的R 9b为氟。
在本发明的一些方案中，所述的如通式I-4所示的化合物中，所述的R a为氟或氘，所述的R 7b、R 8、R 9a和R 9c为氢，所述的R 7a和R 9b各自独立地为氢或氟。
在本发明的一些方案中，所述的如通式I-4所示的化合物中，所述的R a为氟，所述的R 7b、R 8、R 9a和R 9c为氢，所述的R 7a和R 9b各自独立地为氢或氟。
在本发明的一个优选例中，所述的如通式I所示的化合物选自以下任一结构：
Figure PCTCN2018091268-appb-000006
Figure PCTCN2018091268-appb-000007
Figure PCTCN2018091268-appb-000008
Figure PCTCN2018091268-appb-000009
Figure PCTCN2018091268-appb-000010
Figure PCTCN2018091268-appb-000011
Figure PCTCN2018091268-appb-000012
Figure PCTCN2018091268-appb-000013
Figure PCTCN2018091268-appb-000014
Figure PCTCN2018091268-appb-000015
Figure PCTCN2018091268-appb-000016
在本发明的一些方案中，如通式I所示的化合物可为化合物101在以下手性拆分条 件下得到；
Figure PCTCN2018091268-appb-000017
所述的手性拆分条件可包括：
手性柱为Chrialpak AS-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为6.0mL/min；
检测波长为UV 210nm；
在RT为10.7分钟或11.6分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物101中在以下检测条件下对应RT值为5.8分钟或7.7分钟的手性化合物；
Figure PCTCN2018091268-appb-000018
所述的检测条件可包括：
手性柱为Chrialpak AS-H 4.6mm x 250mm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为1.0mL/min；
检测波长为UV 210nm。
在本发明的一些方案中，如通式I所示的化合物可为化合物102在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000019
所述的手性拆分条件可包括：
手性柱为Chrialpak AS-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为6.0mL/min；
检测波长为UV 210nm；
在RT为12.2分钟或10.8分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物103在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000020
所述的手性拆分条件可包括：
手性柱为Chrialpak AS-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为6.0mL/min；
检测波长为UV 210nm；
在RT为15.2分钟或13.4分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物104在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000021
所述的手性拆分条件可包括：
手性柱为Chrialpak AS-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为6.0mL/min；
检测波长为UV 210nm；
在RT为12.3分钟或10.9分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物105在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000022
所述的手性拆分条件可包括：
手性柱为CHIRALCEL OD-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝60/40，比例为体积比；
流速为3.0mL/min；
检测波长为UV 210nm；
在RT为20.5分钟或23.8分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物105中在以下检测条件下对应RT值为15.02分钟或16.71分钟的手性化合物；
Figure PCTCN2018091268-appb-000023
所述的检测条件可包括：
手性柱为CHIRALCEL OD-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝60/40，比例为体积比；
流速为0.5mL/min；
检测波长为UV 210nm。
在本发明的一些方案中，如通式I所示的化合物可为化合物106在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000024
所述的手性拆分条件可包括：
手性柱为CHIRALCEL OD-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝60/40，比例为体积比；
流速为3.0mL/min；
检测波长为UV 210nm；
在RT为22.5分钟或24.5分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物107在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000025
所述的手性拆分条件可包括：
手性柱为CHIRALCEL OD-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝60/40，比例为体积比；
流速为3.0mL/min；
检测波长为UV 210nm；
在RT为24.3分钟或26.8分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物108在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000026
所述的手性拆分条件可包括：
手性柱为CHIRALCEL OD-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝60/40，比例为体积比；
流速为3.0mL/min；
检测波长为UV 210nm；
在RT为21.3分钟或23.3分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物109在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000027
所述的手性拆分条件可包括：
手性柱为Chrialpak AS-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为6.0mL/min；
检测波长为UV 210nm；
在RT为13.6分钟或15.8分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物109中在以下检测条件下对应RT值为8.9分钟或11.3分钟的手性化合物；
Figure PCTCN2018091268-appb-000028
所述的检测条件可包括：
手性柱为Chrialpak AS-H 4.6mm x 250mm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为1.0mL/min；
检测波长为UV 210nm。
在本发明的一些方案中，如通式I所示的化合物可为化合物110在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000029
所述的手性拆分条件可包括：
手性柱为Chrialpak AS-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为6.0mL/min；
检测波长为UV 210nm；
在RT为16.7分钟或14.2分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物111在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000030
所述的手性拆分条件可包括：
手性柱为Chrialpak AS-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为6.0mL/min；
检测波长为UV 210nm；
在RT为18.7分钟或16.9分钟分别收集得到所述的如通式(I)所示的化合物。
在本发明的一些方案中，如通式I所示的化合物可为化合物112在以下手性拆分条件下得到；
Figure PCTCN2018091268-appb-000031
所述的手性拆分条件可包括：
手性柱为Chrialpak AS-H 10mm x 250mm，5μm；
柱温为40℃；
流动相A为0.1％DEA in Hexane，百分号为体积百分比；
流动相B为乙醇；
梯度为流动相A/流动相B＝50/50，比例为体积比；
流速为6.0mL/min；
检测波长为UV 210nm；
在RT为15.8分钟或14.2分钟分别收集得到所述的如通式(I)所示的化合物。
即使采用其他手性拆分、纯化方法或检测方法，只要能在本发明所记载的手性分离或检测方法下相应保留时间下得到手性单一的化合物即落入本发明的保护范围内。
第二方面，本发明还提供一种如通式I所示的化合物的制备方法，其包括如下步骤：
Figure PCTCN2018091268-appb-000032
a1)将通式I-A所示的化合物与通式I-B所示的化合物在碱性和金属催化剂条件下进行偶联反应得到通式I-C所示的化合物；
b1)将通式I-C所示的化合物在酸性条件下脱去保护基得到如通式I所示的化合物；
其中X为卤素，R 0为胺基保护基，R a、R b、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、m和n的定义如上所述。
所述的如通式I所示的化合物的制备方法中，所述的X可为溴。
所述的如通式I所示的化合物的制备方法中，所述的R 0可为叔丁基。
所述的步骤a1中，提供碱性条件的试剂可为本领域该类反应常规的碱性试剂，包括有机碱和无机碱类，所述的有机碱类可为六甲基二硅基氨基锂、六甲基二硅基氨基钠、六甲基二硅基氨基钾、二异丙基氨基锂、正丁基锂、仲丁基锂、三乙胺、吡啶、2,6-二甲基吡啶、N,N-二异丙基乙基胺、叔丁醇钾、叔丁醇钠、叔丁醇锂、四丁基氟化铵和N-甲 基吗啡啉中的一种或多种。所述的无机碱类可为碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾、氢氧化锂、氟化铯、碳酸铯、碳酸锂、磷酸钾、氢化钠和氢化钾中的一种或多种(例如碳酸钾)。
所述的步骤a1中，所述的金属催化剂可为本领域该类反应的常规催化剂，例如碘化亚铜、溴化亚铜、氯化亚铜、铜粉、氧化亚铜、氧化铜、溴化铜、氯化铜、醋酸铜、醋酸亚铜、三氟醋酸铜、三氟磺酸铜和三氯化铁中的一种或多种(例如碘化亚铜)。
所述的步骤b1中，提供酸性条件的试剂可为本领域该类反应常规的酸性试剂，包括有机酸和无机酸类，所述的有机酸类可为三氟乙酸、甲烷磺酸、三氟甲磺酸、对甲苯磺酸、苯磺酸、三氯乙酸、甲酸、乙酸和草酸中的一种或多种。所述的无机酸类可为盐酸、硫酸、磺酸、磷酸和偏磷酸中的一种或多种(例如甲烷磺酸)。
第三方面，本发明提供一种药物组合物，其包括有效量的所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，以及药学上可接受的载体、稀释剂或赋形剂。
本发明还提供了所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者所述的药物组合物在制备用于预防、缓解和/或治疗可通过PARP抑制剂减轻疾病的药物中的应用。
本发明还提供了所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者所述的药物组合物在制备PARP抑制剂中的应用。
本发明还提供了所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者所述的药物组合物在制备用于预防、缓解和/或治疗癌症、炎症性疾病、血管疾病、中风、肾衰竭、糖尿病、帕金森氏病、感染性休克、神经毒性、缺血性休克或损伤、移植排斥、再灌注损伤、视网膜损伤、UV-诱导的皮肤损伤、病毒感染或多发性硬化症的药物中的应用。
本发明还提供了所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者所述的药物组合物在制备癌症治疗中的辅助药物或者用于强化放疗和/或化疗对癌症的治疗的药物中的应用。
本发明还提供了所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者所述的药物组合物在制备治疗癌症的药物中的应用，其中所述的癌症选自乳腺癌、卵巢癌、前列腺癌、 黑色素癌、脑瘤(例如神经胶质瘤)、鼻咽癌、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌(例如结肠癌、直肠癌等)、肺癌(例如小细胞肺癌、非小细胞肺癌、鳞形细胞癌、末分化癌等)、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤、肉瘤、脂肪肉瘤、骨软骨瘤、骨癌、骨肉瘤、精原细胞瘤、睾丸肿瘤、子宫瘤(例如子宫颈癌、子宫内膜癌等)、头颈肿瘤(例如喉癌、咽癌、舌癌等)、多发性骨髓瘤、恶性淋巴瘤(例如网状细胞肉瘤、篱淋巴肉瘤、霍奇金淋巴瘤、套细胞淋巴瘤等)、真性红细胞增多症、白血病(例如急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等)、甲状腺肿瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、胆管癌、绒毛膜上皮癌或儿科肿瘤(例如成神经细胞瘤、胚胎睾丸癌、视网膜母细胞瘤等)。
本发明还提供了所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者所述的药物组合物在制备治疗癌症的药物中的用途，其中所述的癌症可选自实体瘤、急性或慢性白血病、淋巴瘤、中枢神经系统癌症、脑癌、血源性癌症、腹膜癌、胃癌、肺癌、缺乏同源重组依赖性DNA双链断裂修复活性的癌症、BRCA-1或BRCA2上缺陷性或突变表型的癌症(如乳腺癌、卵巢癌、前列腺癌和胰腺癌)。
所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者所述的药物组合物可以与另外一种或多种抗癌剂联合使用，所述的抗癌剂选自烷化剂、铂类药物、拓扑异构酶抑制剂、代谢拮抗剂、生物碱、抗体药物、激素抗癌剂、蛋白酶体抑制剂、HDAC抑制剂、CDK激酶抑制剂、VEGFR或EGFR抑制剂、m-TOR抑制剂、PI3K激酶抑制剂、B-Raf抑制剂、PARP抑制剂、c-Met激酶抑制剂、ALK激酶抑制剂、AKT抑制剂、ABL抑制剂、FLT3抑制剂、PD-1单抗或PD-L1单抗。
本发明还提供了所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者所述的药物组合物在制备治疗癌症的药物中的用途，其中所述的药物可以与另外一种或多种抗癌剂联合使用，所述的抗癌剂选自烷化剂(环磷酰胺、盐酸氮芥、二溴甘露醇、卡莫司汀、达卡巴嗪、美法仑等)、铂类药物(例如顺铂、卡铂、环硫铂、奈达铂、奥沙利铂、洛铂等)、拓扑异构酶抑制剂(拓扑替康、伊力替康、卢比替康、伊沙替康、勒托替康、吉马替康、二氟替康)、代谢拮抗剂(例如甲氨蝶呤、5-氟尿嘧啶、卡培他滨、培美曲塞等)、生物碱(例如多西他赛、紫杉醇、长春碱等)、抗体药物(曲妥单抗、帕曲妥单抗、贝伐单抗等)、激素抗癌剂(例如亮丙瑞林、度他雄胺、地塞米松等)、蛋白酶体抑制剂(硼砂佐 米、艾莎佐米、来那度胺等)、CDK激酶抑制剂(palbociclib、ribociclib等)、VEGFR或EGFR抑制剂(阿法替尼、伊马替尼、吉非替尼、厄洛替尼等)、m-TOR抑制剂(依维莫司、西罗莫司等)、PI3K激酶抑制剂(艾拉利司等)、B-Raf抑制剂(索拉菲尼、维罗菲尼、瑞伐菲尼等)、其它PARP抑制剂(olaparib、niraparib等)、HDAC抑制剂(西达苯胺、帕比司他、伏立诺他等)c-Met激酶抑制剂(克唑替尼)、ALK激酶抑制剂(色瑞替尼、阿来替尼等)、AKT抑制剂(哌立福新等)、ABL抑制剂、FLT3抑制剂、PD-1单抗(Opdivo、Keytruda等)或PD-L1单抗(Atezolizumab)。
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义：
术语“烷基”是指饱和的脂肪族烃基团，包括1～20个碳原子的直链或支链基团。优选1～10个碳原子的烷基，更优选1～8个碳原子，非限制实施例包括但不限于：甲基、乙基、正丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、正己基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1,1,2-三甲基丙基、1-乙基-2-甲基丙基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、3,4-二甲基戊基、2-乙基戊基、3-乙基戊基、幸基、壬基、癸基、十一烷基、十二烷基，以及它们的各种异构体等。烷基可以是取代的或未取代的，当被取代时可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个基团，独立地选自烷基、卤素、羟基、巯基、氰基、烯基、炔基、烷氧基、烷巯基、烷基氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷巯基、杂环烷巯基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基等。当“烷基”和其前缀在此处使用，都包含直链和支链的饱和碳键。
术语“环烷基”是指饱和或部分不饱和单环或多环环状取代基，包括3～20个碳原子，优选3～12个碳原子，更优选3～10个碳原子，最优选包括3～6个碳原子，单环环烷基的非限制实施例包括但不限于：环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基等。多环环烷基的非限制实施例包括但不限于螺环、稠环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，所述取代基优选为一个或多个基团，独立地选自烷基、卤素、羟基、巯基、氰基、烯基、炔基、烷氧基、烷巯基、烷基氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷巯基、杂环烷巯基、氧代基、氨基、卤代烷基、羟烷基、羧基或羧酸酯基等。
术语“卤素”是指氟、氯、溴或碘，优选溴或碘。
“取代的”是指基团中的一个或多个氢或氘原子，优选为1～5个氢或氘原子彼此独立地被相应数目的取代基所取代。
“药学上可接受的盐”是指能够保留游离碱的生物有效性而无其它毒副作用的，它可以是酸性基团、碱性基团或两性基团，非限制实施例包括但不限于：酸性盐包括盐酸盐、氢溴酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、硝酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、甲酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、苯甲酸盐、甲基苯甲酸盐、邻苯二甲酸盐、马来酸盐、甲磺酸盐、对甲苯磺酸盐、苯磺酸盐、(D,L)-酒石酸、柠檬酸盐、马来-酸盐、(D,L-)苹果酸盐、富马酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、谷氨酸盐、天冬氨酸盐、三氟甲磺酸盐、扁桃体酸盐、抗败血酸盐、水杨酸盐等。当本发明化合物含有酸性基团是，其药学上可接受的盐还可以包括：碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如钙盐或镁盐)、有机碱盐(例如烷基芳香基氨类、氨基酸等)。
“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的聚集体(或缔合物)。形成的溶剂化物的溶剂包括，但不限于：水、二甲亚砜、甲醇、乙醇、异丙醇、乙酸等。
“多晶型物”是指本发明的化合物在固态状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相，它可以存在单一晶型或多晶型混合物。
“稳定的同位素衍生物”是指本发明的化合物任意的氢原子被1～5氘原子取代所得到的同位素取代衍生物、或任意的碳原子被1～3个C 14原子取代所得到的同位素取代衍生物、或任意的氧原子被1～3个O 18原子取代所得到的同位素衍生物。
“前药”表示可在生理学条件下(例如体内)或通过溶剂分解而被转化成本发明的生物活性化合物的化合物，可以理解为药学上可接受的代谢前体。前药可以为非活性物质或者比活性母体化合物活性小，但是可以在体内迅速转化产生本发明的母体化合物，可以改善其在动物体内的溶解度以及某些代谢特性，前药包括例如氨基保护基、羧基保护基、磷脂类等。
“药物组合物”是指含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其它化学组分的混合物，以及其它组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收而发挥生物活性。
“异构体”是指立体异构体，包括：对映异构体和非对映异构体，顺反异构体是非对映异构体的一种。本分明的化合物中的异构体可以是其对映异构体、非对映异构体以 及它们的任意混合物，包括游离或成盐的形成存在。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写，除非另有说明，都以它们通常使用的、公认的缩写为准，或参考IUPAC-IUBC Commission on Biochemical Nomenclature(参见Biochem.1972,11,942-944)。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的化合物具有较强的PARP抑制活性，可用于治疗与PARP相关的疾病，如癌症、炎症疾病等。
附图说明
图1为对照组、化合物实施例23和Niraparib对MDA-MB-436细胞肿瘤体积的抑制作用
具体实施方式
下面通过实施例进一步描述本说明，但这些实施例并非限制本发明的范围。
本发明实施例中未注明具体条件的实验方法，通常按照常规方法和条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
本发明所有化合物的结构可通过核磁共振(NMR)或质谱(MS)来确定。NMR位移(δ)以10 -6(ppm)的单位记录。NMR的测定仪器是Bruker AVANCE-400光谱仪进行。测试的氘代溶剂为氘代氯仿(CDCl 3)、氘代甲醇(MeOD)、氘代二甲基亚砜(DMSO-d 6)，内标为四甲基硅烷(TMS)。
低分辨率质谱(MS)是由Agilent 6120quadruple LCMS质谱仪测定。
HPLC纯度的测定是由安捷伦高效液相色谱仪Agilent 1260/1220色谱仪(Agilent Zorbax Bonus RP 3.5μm×4.6mm×150mm或Boston pHlex ODS 4.6mm×150mm×3μm)。
本发明化合物及其中间体的纯化可以使用常规的制备级HPLC、硅胶板、柱色谱或使用快速分离仪进行分离纯化。
薄层层析硅胶板使用烟台黄海、烟台新诺化工的HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是2.5x 5cm，0.2mm～0.25mm，薄层层析分离法(pre-TLC)纯化产品采用的的规格是1mm或者0.4mm～0.5mm，20x 20cm。
柱色谱(硅胶柱层析)一般使用的规格是100～200目或200～300目或300～400目。
快速分离仪使用的仪器型号是Agela Technologies MP200，色谱柱规格一般为Flash column silica-CS(12g～330g)。
制备级HPLC(Pre-HPLC)使用的仪器是Gilson GX-281，柱子型号：Welch ultimate XB-C18 21.2mm X 250mm X 10μm。
手性测试柱的型号为CHIRALCEL OD-H、OJ-H或者CHIRALPAK AD-H、AS-H 4.6mm X 250mm X 5μm，制备柱型号为CHIRALCEL OD-H、OJ-H或者CHIRALPAK AD-H、AS-H 10mm X 250mm X 5μm，
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或从供应商Sigma Aldrich、ACROS、Alfa Aesar、TCI、百灵威、安耐吉化学、韶远化学、麦克林、思言化学等公司购买所得。
无水溶剂例如无水四氢呋喃、无水二氯甲烷、无水N,N-二甲基乙酰胺等都购自上述化学公司。
实施例中无特殊说明，反应一般是在氮气或氩气氛围中进行，氮气或氩气氛围是指反应瓶连接一个约1L容积大小的氮气或者氩气的气球并进行三次抽气置换。
实施例中无特殊说明，反应的温度为室温，温度为15～25℃。
实施例中的反应一般采用LCMS或者TLC进行监测，其中LCMS仪器见上所述，TLC所使用的展开剂体系一般为：二氯甲烷和甲醇、石油醚和乙酸乙酯、二氯甲烷和乙酸乙酯、石油醚和二氯甲烷、乙酸乙酯和甲醇等体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量(0.1％～10％)的碱(例如三乙胺或37％的氨水等)或酸(例如醋酸等)进行调节。
纯化化合物采用的Prep-TLC、柱层析或者Agela制备体系，洗脱溶剂体系一般为：二氯甲烷和甲醇、石油醚和乙酸乙酯、二氯甲烷和乙酸乙酯、石油醚和二氯甲烷、乙酸乙酯和甲醇等体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量(0.1％～10％)的碱(例如三乙胺或28％的氨水等)或酸(例如醋酸等)进行调节。
本发明的缩写词具有以下含义：
DMAc：N,N-二甲基乙酰胺
DMSO：二甲亚砜
MTBE：甲基叔丁基醚
THF：四氢呋喃
PE：石油醚
EA：乙酸乙酯
DAST：二乙胺基三氟化硫
(Boc) 2O：二碳酸二叔丁酯
NaHCO 3：碳酸氢钠
NaOH：氢氧化钠
NaH：氢化钠
DEA：二乙胺
Hexane：正己烷
RT：保留时间
SFC：超临界流体色谱
TLC：Thin layer chromatography
Prep-TLC：preparation thin layer chromatography
Prep-HPLC：preparation high performance liquid chromatography。
实施例1：
2-(4-(3-氘哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
Figure PCTCN2018091268-appb-000033
第一步：乙基2-(4-溴苯基)-5-((叔丁氧基羰基)氨基)戊酸乙酯
Figure PCTCN2018091268-appb-000034
室温下，将2-(4-溴苯基)乙酸乙酯(24.3g，0.1mol)溶于DMSO(60mL)中，分批加入60％NaH(4.3g，0.107mol)，加料完毕，搅拌20分钟，滴加(3-溴丙基)氨基甲酸叔丁酯(21.4g，0.09mol)的DMSO(60mL)溶液，滴加完毕，加热至40～45℃，并搅拌反应2小时，TLC显示有新物质生成，仍有少量原料(TLC条件：EA：PE＝1:10)向反应体系中加入100mL氯化铵溶液，对其进行淬灭，乙酸乙酯萃取(300mL+100mL)， 有机相干燥浓缩得粗品37.0g，将上述粗品混合100～200目硅胶进行柱层析(洗脱条件：石油醚梯度洗脱至乙酸乙酯：石油醚1:4)，得中间体乙基2-(4-溴苯基)-5-((叔丁氧基羰基)氨基)戊酸乙酯为油状物18.0g，收率45％。
MS(ESI),m/z,300.0[M-100] +.
1H NMR(400MHz,CDCl 3)δ(ppm)7.48–7.43(m,2H),7.22–7.17(m,2H),4.52(s,1H),4.13(dd,J＝13.6,7.1Hz,2H),3.52(s,1H),3.13(s,2H),2.07(s,1H),1.87–1.73(m,1H),1.47–1.37(m,4H),1.22(t,J＝7.1Hz,3H).
第二步：3-(4-溴苯基)哌啶-2-酮
Figure PCTCN2018091268-appb-000035
向乙基2-(4-溴苯基)-5-((叔丁氧基羰基)氨基)戊酸乙酯(45.0g，0.11mol)的200mL乙醇中滴加2M的盐酸乙醇溶液(200mL)，滴加完毕，搅拌反应30分钟，LC-MS显示原料消失，浓缩，将获得残留物混合碳酸钾(23.0g，0.15mol)，于乙醇(500mL)中加热回流18h，LC-MS显示原料消失，浓缩掉大部分乙醇，残留物混合200mL水，用6N的盐酸调节pH至1～2，用乙酸乙酯萃取(500mL×2),干燥，浓缩，残留物用石油醚打浆得白色固体，真空干燥得3-(4-溴苯基)哌啶-2-酮，23.7g，收率：83％。
MS(ESI),m/z,254.0[M+H] +.
1H NMR(400MHz,MeOD)δ(ppm)7.53–7.42(m,2H),7.23–7.13(m,2H),3.64(dd,J＝8.2,6.2Hz,1H),3.49–3.35(m,2H),2.19(tdd,J＝8.7,6.1,2.6Hz,1H),1.96–1.75(m,3H).
第三步：3-(4-溴苯基)-3-氘代哌啶-2-酮
Figure PCTCN2018091268-appb-000036
将3-(4-溴苯基)哌啶-2-酮(7.6g，30mmol)混于氘代甲醇(100g)中，氮气保护下，加热至40～45℃，加入甲醇钠(3.2g，60mmol)，并在40～45℃下反应16h，LCMS检测显示氘代率90％，将反应液冷却至20～25℃，加入100mL氯化铵溶液淬灭，用乙酸乙酯(100mL×2)萃取，干燥，浓缩得粗品，用石油醚打浆过滤得白色固体为3-(4-溴苯基)-3-氘代哌啶-2-酮7.0g，收率92％，LCMS分析氘代率92％，核磁显示氘代率94％。
MS(ESI),m/z,255.0[M+H] +.
1H NMR(400MHz,MeOD)δ(ppm)7.46(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,2H),3.38(dd,J＝12.6,7.0Hz,2H),2.15(d,J＝3.6Hz,1H),1.97–1.70(m,3H).
第四步：3-(4-溴苯基)-3-氘代哌啶
Figure PCTCN2018091268-appb-000037
将3-(4-溴苯基)-3-氘代哌啶-2-酮(7.0g，27.5mmol)溶于四氢呋喃(140mL)中，冷却至0～5℃，分批加入硼氢化钠(3.15g，82.9mmol)，并搅拌反应30分钟，加入乙醇，并搅拌反应30分钟，滴加三氟化硼乙醚(11.7g，82.9mmol)，滴加完毕，自然升温至20～25℃，并搅拌反应18h，LCMS显示大部分原料消失，将反应液用100mL水淬灭，乙酸乙酯(200mL×2)萃取，有机相浓缩干，残留物混合30mL浓盐酸和60mL甲醇，40～45℃下反应30分钟，反应液加水稀释，再用2N NaOH水溶液中和至pH至8～9，乙酸乙酯萃取，干燥浓缩得粗品3-(4-溴苯基)-3-氘代哌啶，6.0g，收率90％。
MS(ESI),m/z,241.0[M+H] +.
第五步：3-(4-溴苯基)-3-氘代哌啶-1-甲酸叔丁酯
Figure PCTCN2018091268-appb-000038
20～25℃，将3-(4-溴苯基)-3-氘代哌啶(1.1g，3.3mmol)、1N NaOH(10mL)的MTBE(20mL)溶液中，加入Boc 2O(0.73g，3.3mmol)，加料完毕搅拌1h，加入50mL MTBE，收集有机相，干燥，浓缩得粗品3-(4-溴苯基)-3-氘代哌啶-1-甲酸叔丁酯1.22g，收率95％。
MS(ESI),m/z,241.0[M+H] +.
第六步：3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯
Figure PCTCN2018091268-appb-000039
20～25℃，将3-(4-溴苯基)-3-氘代哌啶-1-甲酸叔丁酯(1.0g，3mmol)、N-叔丁基-1H-吲唑-7-甲酰胺(0.65g，3mmol)、碳酸钾(1.2g，9mmol)、溴化亚铜(0.1g，0.7mmol) 和8-羟基喹啉(0.1g，0.68mmol)混于DMAc(30mL)中，置换氮气保护，110～120℃搅拌反应18h，LCMS显示有部分的原料剩余，有产物生成，反应液冷却至室温，加入50mL水淬灭，MTBE(200mL×2)萃取，有机相用柠檬酸水溶于洗涤，干燥浓缩得泡沫状粗品3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯，1.6g，直接用于下一步。
第七步：2-(4-(3-氘代哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
Figure PCTCN2018091268-appb-000040
将3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯混于甲苯(3mL)中，室温加入甲烷磺酸(6mL)，加料完毕，升温至40～45℃，搅拌反应30分钟，LCMS显示原料消失，有产物生成，加水稀释，用2N NaOH水溶液中和pH至8～9，乙酸乙酯(100mL×2)萃取，干燥浓缩得粗品1.1g，上述粗品通过HPLC分离获得制备液，制备分离液约400mL，用1N NaOH中和pH至8～9，再用乙酸乙酯(400mL×2)萃取，干燥浓缩得粗品2-(4-(3-氟哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺114mg。上述粗品可与64mg对甲苯磺酸在乙醇中加热至完全溶解，浓缩掉乙醇，残留物用四氢呋喃打浆，过滤，干燥得对甲苯磺酸盐产品110mg。
MS(ESI),m/z,322.2[M+H] +.
1H NMR(400MHz,MeOD)δ(ppm)9.00(s,1H),8.18(dd,J＝7.0,0.8Hz,1H),8.05(t,J＝9.1Hz,3H),7.74(d,J＝8.2Hz,2H),7.53(d,J＝8.6Hz,2H),7.34–7.17(m,3H),3.48(d,J＝12.3Hz,2H),3.22–3.01(m,2H),2.37(s,3H),2.09(d,J＝10.1Hz,2H),1.99–1.80(m,2H).
实施例2和3：
(R或S)-2-(4-(3-氘代哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
Figure PCTCN2018091268-appb-000041
将实施例1得到的消旋体化合物用手性柱Chrialpak AS-H(10mm x 250mm，5μm)进行拆分分离，柱温40℃，流动相A为0.1％DEA in Hexane(v/v)，流动相B为乙醇，运行时间为30分钟，梯度为流动相A/流动相B(50/50，v/v)，流速为6.0mL/min，检测波长为UV 210nm，分别在RT为10.7分钟(实施例2化合物)和11.6分钟(实施例3化 合物)进行收集分离得到两个单一构型的化合物，经手性柱Chrialpak AS-H(4.6mm x 250mm)检测，柱温40℃，流动相A为0.1％DEA in Hexane(v/v)，流动相B为乙醇，运行时间为20分钟，梯度为流动相A/流动相B(50/50)，流速为1.0mL/min，检测波长为UV 210nm，第一个单一构型化合物为实施例2，RT 5.8min，ee值99％和第二个单一构型化合物为实施例3，RT 7.7min，ee值99％。
实施例4-21：
按照实施例1～3的合成方法并采用相应的起始原料，制备得到实施例4～21的化合物如下表格：
Figure PCTCN2018091268-appb-000042
Figure PCTCN2018091268-appb-000043
Figure PCTCN2018091268-appb-000044
实施例22：
2-(4-(3-氟哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
Figure PCTCN2018091268-appb-000045
第一步：3-(4-溴苯基)-3-羟基哌啶-1-羧酸叔丁酯
Figure PCTCN2018091268-appb-000046
20～25℃条件下将1-溴-4-碘苯(29.0g，0.10mol)溶于无水四氢呋喃(500mL)中，氮气保护下冷却至-78℃，向反应体系中滴加2.5M正丁基锂溶液(45mL)，滴加过程中控制温度不超过-75℃，滴加完毕搅拌15分钟，继续向反应体系中滴加3-氧代哌啶-1-甲酸叔丁酯的四氢呋喃溶液(19.5g，50mL THF)，滴加过程中控制温度不超过-75℃，滴加完毕搅拌30分钟，TLC显示原料1-溴-4-碘苯基本消失(EA:PE＝1:4，254nm)，向反应体系中加入100mL氯化铵水溶液淬灭，乙酸乙酯萃取(300mL×2)，有机相水洗干燥浓缩得粗品35g，柱层析得3-(4-溴苯基)-3-羟基哌啶-1-羧酸叔丁酯，19.0g产品，收率51.9％(柱分离条件：石油醚洗脱至EA：PE＝1：4)。
MS(ESI),m/z,283.0[M-72] +.
第二步：3-(4-溴苯基)-3-氟哌啶-1-甲酸叔丁酯
Figure PCTCN2018091268-appb-000047
20～25℃条件下将3-(4-溴苯基)-3-羟基哌啶-1-羧酸叔丁酯(26.0g，0.074mol)溶于无水二氯甲烷(500mL)中，氮气保护下冷却至-78℃，向反应体系中滴加DAST(57.0g，0.353mol)，滴加过程中控制温度不超过-75℃，滴加完毕搅拌2小时，LC-MS显示原料消失，向反应体系中加入100mL水淬灭，用2M aq.NaOH调节pH至7～8，收集有机相， 水相再用二氯甲烷(300mL)萃取，合并有机相，有机相水洗干燥浓缩得粗品21.5g，柱层析得产品3-(4-溴苯基)-3-氟哌啶-1-甲酸叔丁酯，12.5g，收率47.8％(柱分离条件：石油醚洗脱至EA：PE＝1：10)。
MS(ESI),m/z,283.0[M-74] +.
1H NMR(400MHz,CDCl 3)δ(ppm)7.52(t,J＝10.4Hz,2H),7.32–7.24(m,2H),4.17(dd,J＝23.5,16.4Hz,2H),3.35–2.69(m,2H),2.27–1.86(m,3H),1.57–1.33(m,9H).
第三步：3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氟哌啶-1-甲酸叔丁酯
Figure PCTCN2018091268-appb-000048
20～25℃条件下将3-(4-溴苯基)-3-氟哌啶-2-酮(2.45g，6.8mmol)、N-叔丁基-1H-吲唑-7-甲酰胺(1.5g，6.8mmol)、碳酸钾(2.95g，20.5mmol)、溴化亚铜(0.2g，1.5mmol)和8-羟基喹啉(0.2g，1.36mmol)混于DMAc(60mL)中，置换氮气保护，加热至110～120℃搅拌反应18h，LCMS显示有部分的原料剩余。将反应液冷却至室温，加入50mL水淬灭，MTBE(500mL×2)萃取，有机相用柠檬酸水溶于洗涤，干燥浓缩得泡沫状粗品3.5g，上述粗品柱层析(PE至EA/PE＝3:2)得产品3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氟哌啶-1-甲酸叔丁酯，1.56g。
MS(ESI),m/z,283.0[M-43] +.
1H NMR(400MHz,CDCl 3)δ(ppm)9.31(s,1H),8.57(s,1H),8.29(d,J＝7.0Hz,1H),7.90(dd,J＝34.5,8.3Hz,3H),7.64(d,J＝8.5Hz,2H),7.38–7.12(m,2H),4.34(d,J＝58.7Hz,2H),3.46–2.69(m,2H),2.33–1.95(m,4H),1.84–1.37(m,21H).
第四步：2-(4-(3-氟哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
Figure PCTCN2018091268-appb-000049
20～25℃条件下将3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氟哌啶-1-甲酸叔丁酯(0.68g，1.4mmol)混于甲苯(1.5mL)中，慢慢加入甲烷磺酸(3mL)，加料完毕，升温至30～35℃，搅拌反应30分钟，将反应液加水稀释，用2N NaOH水溶液中和pH至8～9，乙酸乙酯(200mL×2)萃取，干燥浓缩得粗品2-(4-(3-氟哌啶-3-基)苯基)-2H- 吲唑-7-甲酰胺，600mg，Pre-HPLC制备分离得产品的三氟醋酸盐，370mg。
MS(ESI),m/z,339.2[M+H] +.
1H-NMR(400MHz,MeOD)δ(ppm)9.02(s,1H),8.21–8.12(m,3H),8.02(dd,J＝8.4,0.9Hz,1H),7.72(d,J＝8.8Hz,2H),7.27(dd,J＝8.4,7.1Hz,1H),3.75–3.39(m,3H),3.22(td,J＝12.5,2.6Hz,1H),2.26(s,4H).
实施例23和24：
(R或S)-2-(4-(3-氟哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
Figure PCTCN2018091268-appb-000050
将实施例22得到的消旋体化合物用手性柱CHIRALCEL OD-H(10mm x 250mm，5μm)进行拆分分离，柱温40℃，流动相A为0.1％DEA in Hexane(v/v)，流动相B为乙醇，运行时间为35分钟，梯度为流动相A/流动相B(60/40，v/v)，流速为3.0mL/min，检测波长为UV 210nm，分别在RT为20.5分钟(实施例23化合物)和23.8分钟(实施例24化合物)进行收集分离得到两个单一构型的化合物，经手性柱CHIRALCEL OD-H(4.6mm x 250mm)检测，柱温40℃，流动相A为0.1％DEA in Hexane(v/v)，流动相B为乙醇，运行时间为25分钟，梯度为流动相A/流动相B(60/40)，流速为0.5mL/min，检测波长为UV 210nm，第一个单一构型化合物为实施例23，RT 15.02min，ee值99％和第二个单一构型化合物为实施例24，RT 16.71min，ee值99％。
实施例25-42：
按照实施例22～24的合成方法并采用相应的起始原料，制备得到实施例25-42的化合物如下表格：
Figure PCTCN2018091268-appb-000051
Figure PCTCN2018091268-appb-000052
Figure PCTCN2018091268-appb-000053
Figure PCTCN2018091268-appb-000054
实施例43：
2-(4-(3-甲基哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
Figure PCTCN2018091268-appb-000055
第一步：3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯
Figure PCTCN2018091268-appb-000056
20～25℃条件下，将3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯(15.0g，42.3mmol)溶于DMSO(180mL)中，分别加入60％NaH(2.2g，55.0mmol)，加料完毕升温至40～45℃并搅拌30分钟，继续向反应体系中滴加碘甲烷(6.3g，44.4mmol)的DMSO(20mL)溶液，滴加完毕，40～45℃继续搅拌30分钟，LCMS显示原料消失，向反应体系中加入氯化铵水溶液(150mL)淬灭，乙酸乙酯萃取(200mL×2)，有机相水洗(100mL×2)，干燥浓缩得粗品3-(4-溴苯基)-3-甲基哌啶-2-酮，16.0g，收率99％。
MS(ESI),m/z,314.0[M-55] +.
1H NMR(400MHz,CDCl 3)δ(ppm)7.51–7.44(m,2H),7.24–7.18(m,2H),3.71(ddd,J＝12.9,8.5,5.7Hz,1H),3.49–3.40(m,1H),2.39(ddd,J＝14.1,4.8,4.1Hz,1H),1.96(ddd,J＝14.1,11.0,5.1Hz,1H),1.88–1.68(m,2H),1.56(s,9H),1.50(s,3H).
第二步：3-(4-溴苯基)-3-甲基哌啶-2-酮
Figure PCTCN2018091268-appb-000057
20～25℃条件下将3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯(16.0g，0.044mol)混于乙醇(200mL)中，慢慢滴加盐酸乙醇(200mL)，加料完毕，搅拌反应30分钟，将反应体系浓缩干，浓缩残留物用aq.NaHCO 3游离，乙酸乙酯(500mL×2)萃取，有机相干燥浓缩得产品3-(4-溴苯基)-3-甲基哌啶-2-酮11.0g，收率95％。
MS(ESI),m/z,268.0[M+H] +.
第三步：3-(4-溴苯基)-3-甲基哌啶
Figure PCTCN2018091268-appb-000058
20～25℃将3-(4-溴苯基)-3-甲基哌啶-2-酮(11.5g，43mmol)溶于四氢呋喃(250mL)中，冷却至0～5℃，分批加入硼氢化钠(4.9g，130mmol)，并搅拌反应30分钟，加入乙醇(6.0g，130mmol)，并搅拌反应30分钟，滴加三氟化硼乙醚(19.0g，130mmol)，滴加完毕，自然升温至20～25℃，并搅拌反应18h，，向反应液中加入60mL浓盐酸，并搅拌30分钟，LCMS显示反应完成，向反应液中加入50mL水，加入2M NaOH溶液条件pH至8～9；用乙酸乙酯(500mL×2),有机相水洗，干燥浓缩得粗品3-(4-溴苯基)-3-甲基哌啶，10.0g，收率91.7％。
MS(ESI),m/z,254.0[M+H] +.
第四步：3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯
Figure PCTCN2018091268-appb-000059
20～25℃条件下，将3-(4-溴苯基)-3-甲基哌啶(3.0g，11.8mmol)、1N NaOH(18mL) 和MTBE(100mL)混合，搅拌均匀，加入Boc 2O(2.6g，11.9mmol)，加料完毕搅拌1h，反应液加入100mL MTBE，收集有机相，干燥，浓缩得粗品3-(4-溴苯基)-3-甲基哌啶-1-甲酸叔丁酯，3.6g，收率86.1％。
MS(ESI),m/z,298.0[M-55] +.
第五步：3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯
Figure PCTCN2018091268-appb-000060
20～25℃，将3-(4-溴苯基)-3-氘代哌啶(2.56g，7.2mmol)、N-叔丁基-1H-吲唑-7-甲酰胺(1.56g，7.2mmol)、碳酸钾(3.0g，21.7mmol)、溴化亚铜(0.2g，1.48mmol)和8-羟基喹啉(0.2g，1.36mmol)混于DMAc(60mL)中，氮气置换保护保护并加热至110～120℃搅拌反应18h，LCMS显示有部分的原料剩余，有产物生成，将反应液冷却至升温，加入50mL水淬灭，MTBE(200mL×2)萃取，有机相用柠檬酸水溶于洗涤，干燥浓缩得泡沫状粗品3.5g，上述粗品柱层析分离纯化(石油醚洗脱至EA/PE＝3:2)得产品3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯，1.8g，收率47％。
MS(ESI),m/z,435.0[M-100] +.
第六步：2-(4-(3-甲基哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
Figure PCTCN2018091268-appb-000061
20～25℃条件下将3-(4-(7-(叔丁基氨基甲酰基)-2H-吲唑-2-基)苯基)-3-氘代哌啶-1-甲酸叔丁酯(1.0g，2mmol)混于甲苯(2mL)中，慢慢加入甲烷磺酸(4mL)，加料完毕，升温至30～35℃，搅拌反应30分钟，LCMS显示原料消失，有产物生成，将反应液加水稀释，用aq.NaOH中和pH至8～9，乙酸乙酯(100mL×2)萃取，干燥浓缩得粗品750mg，HPLC制备分离得产品2-(4-(3-甲基哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺的三氟醋酸盐，470mg。
MS(ESI),m/z,335.2[M+H] +.
1H-NMR(400MHz,MeOD)δ(ppm)8.94(s,1H),8.21–7.96(m,4H),7.69(d,J＝8.8Hz,2H),7.27(dd,J＝8.3,7.1Hz,1H),3.74(d,J＝13.1Hz,1H),3.53-3.29(m,2H),3.20- 3.17(m,1H),2.41(t,J＝13.0Hz,1H),1.94(d,J＝12.1Hz,3H),1.42(s,3H).
实施例44和45：
(R或S)-2-(4-(3-甲基哌啶-3-基)苯基)-2H-吲唑-7-甲酰胺
Figure PCTCN2018091268-appb-000062
将上述消旋体化合物用手性柱进行拆分分离，得到单一构型的R构型产物(实施例44)和S构型产物(实施例45)。
将实施例43得到的消旋体化合物用手性柱Chrialpak AS-H(10mm x 250mm，5μm)进行拆分分离，柱温40℃，流动相A为0.1％DEA in Hexane(v/v)，流动相B为乙醇，运行时间为30分钟，梯度为流动相A/流动相B(50/50，v/v)，流速为6.0mL/min，检测波长为UV 210nm，分别在RT为13.6分钟(实施例44化合物)和15.8分钟(实施例45化合物)进行收集分离得到两个单一构型的化合物，经手性柱Chrialpak AS-H(4.6mm x250mm)检测，柱温40℃，流动相A为0.1％DEA in Hexane(v/v)，流动相B为乙醇，运行时间为20分钟，梯度为流动相A/流动相B(50/50)，流速为1.0mL/min，检测波长为UV 210nm，第一个单一构型化合物为实施例44，RT 8.9min，ee值99％和第二个单一构型化合物为实施例45，RT 11.3min，ee值99％。
实施例46-63：
按照实施例43～45的合成方法并采用相应的起始原料，制备得到实施例46～63的化合物如下表格：
Figure PCTCN2018091268-appb-000063
Figure PCTCN2018091268-appb-000064
Figure PCTCN2018091268-appb-000065
Figure PCTCN2018091268-appb-000066
生物测试实施例：
实验例1 PARP激酶活性的测定
PARP1激酶活性通过以下的方法进行测试：
本实验中使用的材料和仪器：
多功能酶标仪SpectraMax M5 Microplate Reader(Molecular Devices)
PARP1 Colorimetric Assay Kit(BPS，Cat#80580)
PBS(Life Technologies，Cat#003000)
Tween-20(Sigma，Cat#P9416-100mL)
H 2SO 4(国药，Cat#10021618)
实验方法和步骤
1.PARP1Colorimetric Assay
1.1PARP1 Colorimetric Assay Kit包含：
PARP1 5μg
5x histone mixture 1mL
10x assay mixture containing biotinylated substrate 300μL
10x PARP assay buffer 1mL
Blocking buffer 25mL
Activated DNA 500μL
Streptavidin-HRP 100μL
Colorimetric HRP substrate 10mL
96孔板一块
1.2试剂配制：
1x PBS：取一包PBS粉末加入1L去离子水充分溶解；
PBST：1x PBS中加入Tween-20；
2M H 2SO 4：用去离子水稀释H 2SO 4至2M；
1x PARP assay buffer：用去离子水按照1:10的比例稀释10x PARP assay buffer得到1x PARP assay buffer。
1.3化合物稀释
化合物用DMSO溶解、稀释至100μM备用。
测试时，用1x PARP assay buffer稀释100μM化合物储液至10μM，然后用含有10％DMSO的1x PARP assay buffer依次3倍梯度稀释化合物，得到一系列浓度的化合物备用。每反应孔加入5μL稀释好的化合物(总体积50μL)，这样化合物终浓度为1μM起始3倍稀释的一系列浓度。
1.4反应步骤
1.4.1包被
1)用1x PBS按照1:5的比例稀释5x histone mixture得到1x的包被液；
2)每孔加入50μL稀释好的包被液4℃包被过夜；
3)弃去包被液，每孔200μL PBST buffer洗涤3次；
4)每孔加入200μL Blocking buffer，室温孵育90min；
5)弃去blocking buffer，用PBST洗涤3次；
1.4.2 PARP1反应实验
1)按照每孔2.5μL 10x PARP buffer+2.5μL 10x PARP Assay mixture+5μL Activated DNA +15μL去离子水的比例制备反应液，每孔加入反应液25μL(参见表1)。
2)向样品测试孔中加入5μL稀释好的化合物，全活对照孔和空白孔中加入等体积的含10％DMSO的1x PARP buffer。
表1
  全活对照孔 样品测试孔 空白孔
10x PARP buffer 2.5μL 2.5μL 2.5μL
10x Assay mixture 2.5μL 2.5μL 2.5μL
Activated DNA 5μL 5μL 5μL
去离子水 15μL 15μL 15μL
稀释好的待测化合物 - 5μL -
含10％DMSO的1x PARP buffer 5μL - 5μL
1x PARP buffer - - 20μL
PARP1(2.5ng/μL) 20μL 20μL -
总体积 50μL 50μL 50μL
3)向空白孔中加入20μL的1x PARP buffer。
4)冰上解冻PARP1，用1x PARP buffer稀释至2.5ng/μL，向除空白孔外的所有反应孔中加入20μL稀释好的PARP1，混匀，室温反应1h。
5)弃去反应液，用PBST洗涤3次。
1.4.3检测
1)用Blocking buffer按照1:50的比例稀释Streptavidin-HRP，向所有孔中加入50μL稀释好的Streptavidin-HRP，室温孵育30min。
3)弃去HRP，用PBST洗涤3次。
4)每孔加入100μL的colorimetric HRP substrate，室温反应20min。
5)每孔加入100μL的2M H 2SO 4在酶标仪上读取OD 450nm。
2.计算抑制率及IC 50
抑制率用以下公式计算：
抑制率＝(ODsample-OD0％)/(OD100％-OD0％)×100％
ODsample：样品测试孔的OD值；
OD0％：空白孔的OD值；
OD100％：全活对照孔的OD值。
本发明化合物的PARP-1激酶抑制活性通过以上的实验方法进行测定，测得化合物体外酶学抑制活性(IC 50)见下表2：+表示10-100μm，++表示1-10μm，+++表示0.5-1μm，++++表示0.1-0.5μm，+++++表示<0.1μm。
表2 本发明化合物的PARP-1激酶活性
化合物编号 PARP1 化合物编号 PARP1 化合物编号 PARP1
1 +++++ 21 +++++ 41 ++++
2 +++++ 22 +++++ 42 ++++
3 +++++ 23 +++++ 43 ++++
4 +++++ 24 +++++ 44 ++++
5 +++++ 25 +++++ 45 ++++
6 +++++ 26 +++++ 46 ++++
7 +++++ 27 +++++ 47 ++++
8 +++++ 28 +++++ 48 ++++
9 +++++ 29 +++++ 49 ++++
10 ++++ 30 +++++ 50 ++++
11 ++++ 31 ++++ 51 ++++
12 ++++ 32 ++++ 52 +++
13 ++++ 33 ++++ 53 +++
14 ++++ 34 ++++ 54 +++
15 ++++ 35 ++++ 55 ++++
16 +++++ 36 ++++ 56 ++++
17 +++++ 37 ++++ 57 ++++
18 +++++ 38 ++++ 58 ++++
19 +++++ 39 ++++ 59 ++++
20 +++++ 40 ++++ 60 ++++
61 ++++ 62 ++++ niraparib +++++
实验例2 实施例2、23和24化合物的大鼠药代动力学测定
1.实验摘要
以SD大鼠为受试动物，应用LC/MS/MS法测定大鼠静注和灌胃给予实施例化合物后不同时刻血浆中的药物浓度，以研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。
2.实验方案
2.1供试药品：
本发明实施例3、23、24和阳性对照niraparib化合物
2.2供试动物
健康成年雄性SD(Sprague-Dawley)大鼠，每个供试化合物各3只，6-9周龄，体重250±50g，购自上海斯莱克实验动物有限责任公司。
2.3供试药物配制
称取适量样品，加入0.5％Methocel/2％tween 80至终体积，配制2mg/mL用于灌胃给药。
2.4供试药品给药
雄性SD大鼠每个供试化合物各三只，禁食一夜后给予灌胃给药，剂量为10mg/kg。
3.实验操作
在给药前和后0.083-24h不同时间点与大鼠经颈静脉穿刺取血，K2-EDTA抗凝，离心，取血浆，-70℃冷冻保存直至LC/MS/MS分析。
4.药代动力学数据结果
本发明化合物的大鼠药代参数见下表3。
表3 本发明化合物的大鼠药代动力学参数
Figure PCTCN2018091268-appb-000067
结果表明，实施例3化合物和实施例24化合物的暴露量明显高于阳性化合物(niraparib)，实施例23化合物的T 1/2显著大于阳性化合物(niraparib)。
实施例3 本发明化合物实施例23体外代谢稳定性评价
本发明化合物的体外肝微粒体稳定性的评价通过以下的方法进行测试：
测试化合物储备液的配制：准确称取一定量的实施例化合物粉末，用DMSO分别溶解稀释至10mM。
缓冲液：100mM磷酸钾缓冲液，pH 7.4；10nM MgCl 2。
NADPH：β-烟酰胺腺嘌呤二核苷酸磷酸盐还原形式，四钠盐，NADPH·4Na，供应商：sigma，目录号为616。
肝微粒体：人肝微粒体，Corning Cat No.452117；大鼠肝微粒体，Xenotech Cat No.R1000；小鼠肝微粒体，Xenotech Cat No.M1000；狗肝微粒体，Xenotech Cat No.D1000；食蟹猴肝微粒体，Corning Cat No.452413，最终配制浓度为0.5mg protein/mL。
配制终止液：包含100ng/mL Tolbutamide和100ng/mL Labetalol作为内标的冷乙腈溶液。
化合物稀释：
1.中间溶液：用495μL甲醇(浓度：100μM，99％MeOH)稀释5μL的储备溶液(10mM)中的化合物或对照物。
2.操作溶液：用450μL 100mM的磷酸钾缓冲液(浓度：10μM，9.9％MeOH)将中间溶液中稀释至50μL。
实验步骤：
1.除基质空白外，向所有平板(T0，T5，T10，T20，T30，T60，NCF60)添加10μL化合物或对照工作溶液/孔。
2.根据Platemap将680μL/孔微粒体溶液分配至96孔板，作为备用，在37℃下孵育微粒体溶液和化合物的混合物约10分钟。
3.向NCF60中加入10μL100mM磷酸钾缓冲液/孔，37℃孵育，启动定时器。
4.预热后，根据platemap分配90μL/孔d的NADPH再生系统至96孔板备用，然后加入10μL/孔到每个平板上开始反应。孵育培养基中各组分的最终浓度包含：0.5mg protein/mL的微粒体，1μM测试化合物，1μM阳参，0.99％的甲醇和0.01％的DMSO。
5. 37℃孵育，启动定时器。
6.加300μL/孔的上述配制的终止液(4℃冷却)终止反应。
7.采样板晃动约10分钟。
8.样品在4℃下以4000转/分离心20min。
9.离心时，用300μL的HPLC水负载8个新的96孔板，然后转移100μL的上清液进行混合，然后进行LC/MS/MS检测。
10.数据分析：通过LC-MS/MS系统检测相应化合物及内标的峰面积，按下式计算化合物的T 1/2:
Figure PCTCN2018091268-appb-000068
Figure PCTCN2018091268-appb-000069
对本发明化合物实施例23和niraparib按照上述步骤进行分析，结果如下表4所示。
表4 实施例化合物体外肝微粒体代谢稳定性的测试结果
Figure PCTCN2018091268-appb-000070
11.实验结果：如表4所示，本发明化合物23在人肝微粒体、狗肝微粒体和食蟹猴肝微粒体实验中都表现出了优异的代谢稳定性。
实施例4 本发明化合物实施例23在小鼠MDA-MB-436模型上的药效学研究
4.1实验动物
BALB/c裸小鼠，6-8周龄，体重18-22克，雌性，由上海西普尔-必凯实验动物有限公司提供，动物合格证号：20130016001914。
4.2饲养条件
动物到达后在实验环境饲养3-7天后方开始实验。动物在SPF级动物房以IVC(独立送风系统)笼具饲养(每笼4只)。每笼动物信息卡注明笼内动物数目，性别，品系，接收日期，给药方案，实验编号，组别以及实验开始日期。所有笼具、垫料及饮水在使用前均灭菌。笼具、饲料及饮水每周更换两次。
4.3肿瘤细胞接种方法
人乳腺癌MDA-MB-436细胞(ATCC,马纳萨斯,弗吉尼亚州,货号：ATCC-HTB-130)体外单层培养，培养条件为RPMI1640培养基中加10％胎牛血清，37℃5％CO 2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求后，收取细胞，计数，接种。将0.2mL(1×107个)MDA-MB-436细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到157mm 3时开始分组给药。
4.4供试样品配制
量取80mL去离子水到合适的容器中，称取2.5g MethylCellulose，搅拌状态下缓慢加入到去离子水中，搅拌至均一，吸取10mL Tween 80，加入到溶液中，搅拌至均一，继续加去离子水至500mL，搅拌至均一，即得Vehicle溶媒。称取适量的实施例23的对甲苯磺酸盐，加入适量的上述vehicle溶媒，涡旋至均匀。
4.5供试药品给药
给药剂量和给药方案见表5。每周测2-3次裸小鼠皮下的瘤体积，称量鼠重，记录数据。
表5
Figure PCTCN2018091268-appb-000071
注：给药体积为10mg/mL。
4.6分析评价
实验评价指标：采用肿瘤生长抑制率TGI(％)或相对肿瘤增殖率T/C(％)进行评价，其中T为实验组，C为对照组。
相对肿瘤增殖率T/C(％)的计算：若T>T 0，T/C(％)＝(T-T 0)/(C-C 0)×100％，若T<T 0，T/C(％)＝(T-T 0)/T 0×100％其中T、C为实验结束时的肿瘤体积；T 0、C 0为实验开始时的肿瘤体积。
肿瘤生长抑制率TGI(％)的计算：TGI(％)＝(1-T/C)×100％。
评价标准：T/C(％)>40(即TGI(％)<60％)为无效；T/C(％)≤40(即TGI(％)≥60％)为有效，并经过统计学处理P<0.05为有效。
4.7药效实验结果
对照组、实施例23和niraparib对MDA-MB-436细胞肿瘤体积的抑制作用如表6和 图1所示。
表6 本发明化合物实施例23对MDA-MB-436细胞肿瘤体积的抑制作用
Figure PCTCN2018091268-appb-000072
结果表明：本发明化合物实施例23和niraparib在剂量为50mg/kg，连续PO给药18天的情况下，对MDA-MB-436细胞裸鼠模型的肿瘤生长具有非常强的抑制作用，而且本发明化合物实施例23的抑瘤活性强于阳性对照niraparib，在18天停止给药并继续观察至39天，发现化合物实施例23和niraparib能继续抑制肿瘤的生长，而且本发明化合物实施例23在观察期的抑瘤效果明显强于阳性对照niraparib，而且本发明化合物实施例23能够使得部分动物的肿瘤发生完全消退，化合物实施例23使得肿瘤完全消失的受试动物比率为50％，而阳性对照niraparib使得肿瘤完全消失的受试动物比率为0。
实施例5 本发明化合物实施例23对人肝微粒体CYP450酶的抑制作用评价
本发明化合物对人源6种亚型的CYP450酶的抑制作用评价通过以下的实验方法进行测定：
各亚型参比化合物：CYP1A2：α-萘黄酮；CYP2C9：磺胺苯吡唑；CYP2C19：奥美拉唑；CYP3A4：酮康唑；CYP2D6：奎尼丁。
底物浓度：CYP1A2:Phenacetin at 30μM；CYP2C9:Diclofenac at 10μM；CYP2C19:S-Mephenytoin at 35μM；CYP3A4:Midazolam at 5μM and Testosterone at 80μM；CYP2D6:Bufuralol at 10μM.
实验步骤：
1.预热0.1M的磷酸钾缓冲液(K-buffer)，pH为7.4；
100mM K-buffer：将9.5mL的Stock A和40.5mL的Stock B进行混匀，用Milli-Q超纯水稀释至500mL，然后用KOH或者H 3PO 4将缓冲液滴定至pH为7.4。
Stock A(1M磷酸二氢钾)：将136.5g磷酸二氢钾溶于1L Milli-Q超纯水；
Stock B(1M磷酸氢二钾)：将174.2g磷酸氢二钾溶于1L Milli-Q超纯水。
2.在96孔板中准备测试化合物和参比抑制剂(400×)的浓度梯度；
2.1.取8μL 10mM的测试化合物至12μL的乙腈中，并混匀；
2.2.为CYP1A2、CYP2C9和CYP2D6配制抑制剂的标液：12μL1mMα-萘黄酮+10μL 40mM磺胺苯吡唑+10μL10mM奎尼丁+8μL DMSO；
2.3.为CYP3A4和CYP2C19配置单独的抑制剂标液：8μL DMSO+12μL CAN；
2.4.在DMSO/ACN(v/v:40:60)混合液中进行3倍梯度稀释；
3.准备4×NADPH辅酶(将66.7mg ANDPH溶于10mL 0.1MK-buffer，PH＝7.4)；
4.准备4×底物浓度(每个亚型需2mL)，添加HLM时需在冰上操作；
5.在冰上准备0.2mg/mL的HLM溶液(10μL 20mg/mL至990μL0.1M K-buffer)。
6.将0.2mg/mL的HLM加至测试孔中，每孔400μL，然后将梯度稀释的400×测试化合物加至对应孔中；
7.将0.2mg/mL的HLM加至测试孔中，每孔200μL，然后将梯度稀释的参考抑制剂加至对应孔中，步骤6、7都需在冰上操作；
8.将96孔测试板置于冰上，往测试板里加入如下溶液(复孔)：
8.1.混于在0.2mg/mL HLM溶液中加入30μL的测试化合物和参考化合物(见步骤6和7)；
8.2.加入15μL 4×底物溶液(见步骤4)；
9.将96孔测试板和NADPH溶液在37℃预孵育5分钟；
10.往96孔测试板中加入15μL/孔预热的8mM NADPH溶液(见步骤3)以引发反应；
11.将测试板置于37℃孵育：3A4孵育5分钟，1A2、2C9和2D6各孵育10分钟，2C19孵育45分钟；
12.加入120μL/孔含有内参的ACN以终止反应；
13.淬灭后，用振荡器(IKA，MTS 2/4)振板10分钟(600转/分钟)，然后离心15分钟(Thermo Multifuge×3R)。
14.将50μL来自每个孔的上清液转移到含有50μL超纯水(Millipore，ZMQS50F01)的96孔样品板中，用于LC/MS分析。
数据分析：使用GraphPad Prism 5.0或Xlfit模型205基于数据计算使用以下公式进行曲线拟合以计算IC 50：
Figure PCTCN2018091268-appb-000073
X是浓度的对数.Y是响应于从高到低的抑制剂浓度。
本发明化合物对人肝微粒体CYP450酶各亚型的抑制IC 50见下表7。
表7
Figure PCTCN2018091268-appb-000074
结果表明：本发明化合物实施例23对CYP4506个主要亚型的抑制半衰期均大于10μM，说明该化合物在CYP450酶代谢方面具有较好的安全性。
实施例6 本发明化合物实施例23的hERG钾离子通道抑制活性测试
本发明化合物对人源6种亚型的CYP450酶的抑制作用评价通过以下的实验方法进行测定：
6.1细胞准备
CHO-hERG细胞培养于175cm 2的培养瓶中，待细胞密度生长到60～80％，移走培养液，用7mL PBS(Phosphate Buffered Saline磷酸盐缓冲液)洗一遍，然后加入3mL Detachin消化。
待消化完全后加入7mL培养液中和，然后离心，吸走上清液，再加入5mL培养液重悬，以确保细胞密度为2～5×10 6/mL。
6.2溶液配制(如表8所示)
表8 细胞内液和外液的组成成分
Figure PCTCN2018091268-appb-000075
Figure PCTCN2018091268-appb-000076
6.3电生理记录过程
单细胞高阻抗封接和全细胞模式形成过程全部由Qpatch仪器自动完成，在获得全细胞记录模式后，细胞钳制在-80毫伏，在给予一个5秒的+40毫伏去极化刺激前，先给予一个50毫秒的-50毫伏前置电压，然后复极化到-50毫伏维持5秒，再回到-80毫伏。每15秒施加此电压刺激，记录2分钟后给予细胞外液记录5分钟，然后开始给药过程，化合物浓度从最低测试浓度开始，每个测试浓度给予2.5分钟，连续给完所有浓度后，给予阳性对照化合物3μM Cisapride。每个浓度至少测试3个细胞(n≥3)。
6.4化合物准备
将20mM的化合物母液用细胞外液进行稀释，取5μL 20mM的化合物母液加入2495μL细胞外液，500倍稀释至40μM，然后在含0.2％DMSO的细胞外液中依次进行3倍连续稀释得到需要测试的最终浓度。最高测试浓度为40μM，依次分别为40，13.33，4.44，1.48，0.49，0.16μM共6个浓度。最终测试浓度中的DMSO含量不超过0.2％，此浓度的DMSO对hERG钾通道没有影响。
6.5数据分析
实验数据由XLFit软件进行分析。
6.6质量控制
环境：湿度20～50％，温度22～25℃；
试剂：所用实验试剂购买于Sigma公司，纯度>98％；
报告中的实验数据必须满足以下标准：
全细胞封接阻抗>100MΩ
尾电流幅度>400pA
药理学参数：多浓度Cisapride对hERG通道的抑制效应设为阳性对照。
6.7实验结果
本发明化合物实施例23对hERG电流的抑制结果如下表9。
表9
Figure PCTCN2018091268-appb-000077
结果表明：本发明化合物实施例23对于心脏hERG钾离子通道的抑制半衰期大于40μM，说明基本没有抑制作用。
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 (16)

  1. 一种如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药；
    Figure PCTCN2018091268-appb-100001
    其中，
    R a选自氢、氘、氟、取代或未取代的C 1-6烷基或者取代或未取代的环烷基；
    R b选自氢、氘、取代或未取代的C 1-6烷基或者取代或未取代的环烷基；
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9各自独立地选自氢、氘或氟，且当R a为氢时，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9中至少有一个为氘或氟；
    当R a为氢，n为1，且R 9为5位氟时，R 1、R 2、R 3、R 4、R 5、R 6和R 8不同时为氢；
    当R a为氢，m不为0，且R 7为氟时，R 1、R 2、R 3、R 4、R 5、R 6和R 8不同时为氢；
    m为R 7的数目，且为0、1、2、3或4；
    n为R 9的数目，且为0、1、2或3。
  2. 如权利要求1所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于，R b为氢或氘。
  3. 如权利要求1所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于：
    Figure PCTCN2018091268-appb-100002
    其中，R a选自氘、氟或者取代或未取代的C 1-6烷基；R 7、R 8、R 9、m和n的定义如权利要求1中所述。
  4. 如权利要求1所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其 混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于：所述的如通式I所示的化合物的结构如下：
    Figure PCTCN2018091268-appb-100003
    其中，R 1、R 2、R 3、R 4、R 5和R 6中至少含有一个氘或氟，R 7、R 8、R 9、m和n的定义如权利要求1中所述。
  5. 如权利要求1所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于：所述的如通式I所示的化合物的结构如下：
    Figure PCTCN2018091268-appb-100004
    其中，R a选自氘、氟或者取代或未取代的C 1-6烷基。
  6. 如权利要求1所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于：所述的如通式I所示的化合物的结构如下：
    Figure PCTCN2018091268-appb-100005
    其中，R a为甲基、氟或氘；
    R 7a、R 7b、R 8、R 9a、R 9b和R 9c各自独立地为氢或氟。
  7. 如权利要求6所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于：所述的R a为氟或氘；
    和/或，所述的R 7b为氢；
    和/或，所述的R 8为氢；
    和/或，所述的R 9a为氢；
    和/或，所述的R 9c为氢。
  8. 如权利要求1所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于：所述的如通式I所示的化合物选自以下任一结构：
    Figure PCTCN2018091268-appb-100006
    Figure PCTCN2018091268-appb-100007
    Figure PCTCN2018091268-appb-100008
    Figure PCTCN2018091268-appb-100009
    Figure PCTCN2018091268-appb-100010
    Figure PCTCN2018091268-appb-100011
    Figure PCTCN2018091268-appb-100012
    Figure PCTCN2018091268-appb-100013
    Figure PCTCN2018091268-appb-100014
    Figure PCTCN2018091268-appb-100015
    Figure PCTCN2018091268-appb-100016
  9. 如权利要求1所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其 混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，其特征在于，所述的如通式I所示的化合物为化合物101在手性拆分条件1下在RT为10.7分钟或11.6分钟分别收集得到；
    Figure PCTCN2018091268-appb-100017
    或，所述的如通式I所示的化合物为化合物102在手性拆分条件1下在RT为12.2分钟或10.8分钟分别收集得到；
    Figure PCTCN2018091268-appb-100018
    或，所述的如通式I所示的化合物为化合物103在手性拆分条件1下在RT为15.2分钟或13.4分钟分别收集得到；
    Figure PCTCN2018091268-appb-100019
    或，所述的如通式I所示的化合物为化合物104在手性拆分条件1下在RT为12.3分钟或10.9分钟分别收集得到；
    Figure PCTCN2018091268-appb-100020
    或，所述的如通式I所示的化合物为化合物105在手性拆分条件2下在RT为20.5分钟或23.8分钟分别收集得到；
    Figure PCTCN2018091268-appb-100021
    或，所述的如通式I所示的化合物为化合物106在手性拆分条件2下在RT为22.5分钟或24.5分钟分别收集得到；
    Figure PCTCN2018091268-appb-100022
    或，所述的如通式I所示的化合物为化合物107在手性拆分条件2下在RT为24.3分钟或26.8分钟分别收集得到；
    Figure PCTCN2018091268-appb-100023
    或，所述的如通式I所示的化合物为化合物108在手性拆分条件2下在RT为21.3分钟或23.3分钟分别收集得到；
    Figure PCTCN2018091268-appb-100024
    或，所述的如通式I所示的化合物为化合物109在手性拆分条件1下在RT为13.6分钟或15.8分钟分别收集得到；
    Figure PCTCN2018091268-appb-100025
    或，所述的如通式I所示的化合物为化合物110在手性拆分条件1下在RT为16.7 分钟或14.2分钟分别收集得到；
    Figure PCTCN2018091268-appb-100026
    或，所述的如通式I所示的化合物为化合物111在手性拆分条件1下在RT为18.7分钟或16.9分钟分别收集得到；
    Figure PCTCN2018091268-appb-100027
    或，所述的如通式I所示的化合物为化合物112在手性拆分条件1下在RT为15.8分钟或14.2分钟分别收集得到；
    Figure PCTCN2018091268-appb-100028
    所述的手性拆分条件1包括：
    手性柱为Chrialpak AS-H 10mm x 250mm，5μm；
    柱温为40℃；
    流动相A为0.1％DEA in Hexane，百分号为体积百分比；
    流动相B为乙醇；
    梯度为流动相A/流动相B＝50/50，比例为体积比；
    流速为6.0mL/min；
    检测波长为UV 210nm；
    所述的手性拆分条件2包括：
    手性柱为CHIRALCEL OD-H 10mm x 250mm，5μm；
    柱温为40℃；
    流动相A为0.1％DEA in Hexane，百分号为体积百分比；
    流动相B为乙醇；
    梯度为流动相A/流动相B＝60/40，比例为体积比；
    流速为3.0mL/min；
    检测波长为UV 210nm。
  10. 一种如通式I所示的化合物的制备方法，其特征在于，其包括如下步骤：
    Figure PCTCN2018091268-appb-100029
    a1)将通式I-A所示的化合物与通式I-B所示的化合物在碱性和金属催化剂条件下进行偶联反应得到通式I-C所示的化合物；
    b1)将通式I-C所示的化合物在酸性条件下脱去保护基得到如通式I所示的化合物；
    其中，X为卤素，R 0为胺基保护基，R a、R b、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、m和n的定义如权利要求1-9中任一项所述。
  11. 一种药物组合物，其包括有效量的如权利要求1-9中任一项所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，以及药学上可接受的载体、稀释剂或赋形剂。
  12. 如权利要求1-9中任一项所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者如权利要求11所述的药物组合物在制备用于预防、缓解和/或治疗可通过PARP抑制剂减轻疾病的药物中的应用。
  13. 如权利要求12所述的应用，其特征在于：如权利要求1-9中任一项所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者如权利要求11所述的药物组合物用于制备预防、缓解和/或治疗癌症、炎症性疾病、血管疾病、中风、肾衰竭、糖尿病、帕金森氏病、感染性休克、神经毒性、缺血性休克或损伤、移植排斥、再灌注损伤、视网膜损伤、UV-诱导的皮肤损伤、病毒感染或多发性硬化症的药物。
  14. 如权利要求12所述的应用，其特征在于：如权利要求1-9中任一项所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者如权利要求11所述的药物组合物用于制备癌症治疗中的辅助药物或者用于强化放疗和/或化疗对癌症的治疗药物。
  15. 如权利要求1-9中任一项所述的如通式I所示的化合物、其药学上可接受的盐、异构体或其混合物形式、溶剂化物、多晶型物、稳定的同位素衍生物或前药，或者如权 利要求11所述的药物组合物在制备治疗癌症的药物中的应用，其中所述的癌症选自实体瘤、急性或慢性白血病、淋巴瘤、中枢神经系统癌症、脑癌、血源性癌症、腹膜癌、胃癌、肺癌、缺乏同源重组依赖性DNA双链断裂修复活性的癌症、BRCA-1或BRCA2上缺陷性或突变表型的癌症。
  16. 如权利要求15所述的应用，其特征在于：所述的药物与另外一种或多种抗癌剂联合使用，所述的抗癌剂选自烷化剂、铂类药物、拓扑异构酶抑制剂、代谢拮抗剂、生物碱、抗体药物、激素抗癌剂、蛋白酶体抑制剂、HDAC抑制剂、CDK激酶抑制剂、VEGFR或EGFR抑制剂、m-TOR抑制剂、PI3K激酶抑制剂、B-Raf抑制剂、PARP抑制剂、c-Met激酶抑制剂、ALK激酶抑制剂、AKT抑制剂、ABL抑制剂、FLT3抑制剂、PD-1单抗或PD-L1单抗。
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