CN116143700A - Phthalazinone compound, and preparation method and application thereof - Google Patents

Phthalazinone compound, and preparation method and application thereof Download PDF

Info

Publication number
CN116143700A
CN116143700A CN202211571163.6A CN202211571163A CN116143700A CN 116143700 A CN116143700 A CN 116143700A CN 202211571163 A CN202211571163 A CN 202211571163A CN 116143700 A CN116143700 A CN 116143700A
Authority
CN
China
Prior art keywords
acid
compound
cancer
oxo
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202211571163.6A
Other languages
Chinese (zh)
Other versions
CN116143700B (en
Inventor
宫平
秦铭泽
赵燕芳
刘亚婧
侯云雷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenyang Pharmaceutical University
Original Assignee
Shenyang Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenyang Pharmaceutical University filed Critical Shenyang Pharmaceutical University
Priority to CN202211571163.6A priority Critical patent/CN116143700B/en
Publication of CN116143700A publication Critical patent/CN116143700A/en
Application granted granted Critical
Publication of CN116143700B publication Critical patent/CN116143700B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a phthalazinone compound, a preparation method and application thereof, belongs to the technical field of medicines, and aims to provide a PARP inhibitor with better activity shown in a general formula I and a PARP/HDACs double-target inhibitor. The study found that most of the compounds had significant effects on PARPThe pharmacological activity screening shows that the compound provided by the invention has good anti-tumor activity and obvious inhibition effect on various human tumor cells, and can be used for preparing medicines for treating diseases caused by abnormal expression of PARP and/or HDAC, in particular medicines for treating and/or preventing cancers, neurodegenerative diseases, inflammations and the like.

Description

Phthalazinone compound, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of phthalazinone compounds or pharmaceutically acceptable salts thereof and application of a pharmaceutical composition containing the compounds.
Background
Poly ADP-ribose polymerase, PARP, a ribozyme, has the ability to catalyze the transfer of ADP-ribose to a target protein, and is involved in many cellular processes including gene regulation, chromatin remodeling, DNA repair, and apoptosis. Since 1963, PARP was first reported to be 50 years or more, and its important role has been paid a great attention to a wide range of scholars, and particularly, in recent years, research on the relationship between PARP and tumorigenesis and progress has been made in improving the therapeutic effect of tumors by using inhibition of PARP. It is currently known that the PARP family contains at least 18 molecular subtypes, of which PARP-1 was found earliest, most abundant in the PARP family and functions about 90% in the PARP family, and thus has been studied most thoroughly.
PARP-1 repairs single stranded damaged DNA mainly through a base-excision repair (BER) pathway. The BRAC1/2 gene plays a role in repairing DNA damage through a homologous recombination (homologous recombination, HR) pathway, and when the BRCA gene is mutated, the homologous recombination repair pathway has defects. At this time, base excision repair is blocked when PARP-1 function is inhibited, resulting in the formation of DNA Double Strand Breaks (DSBs), and in homologous recombination defective cells, only non-homologous end joining repair pathways can be diverted to cause chromosomal instability, cell cycle arrest and apoptosis, i.e., synthetic lethality (Synthetic lethality, SL). Based on synthetic lethal theory, PARP-1 inhibitor can generate synthetic lethal effect with homologous recombination repair defective tumor cells, but can not kill normal cells. The PARP-1 inhibitor not only can be independently used for treating homologous recombination defect tumors, but also can make tumor cells more sensitive to cytotoxic drugs (chemoradiotherapy drugs, platinum-type drugs, alkylating agents, topoisomerase inhibitors and the like) by inhibiting PARP-1 mediated DNA damage repair.
Histone deacetylases (histone deacetylase, HDACs) are a class of proteases that are ubiquitous in eukaryotic cells. Currently, HDACs inhibitor studies against cancer are mainly around Zn 2+ A dependent protease. Studies have shown that overexpression of HDACs is closely related to cancer, which disrupts the balance of histone acetylation levels, resulting in imbalance in gene expression, affecting cell proliferation and cell cycle regulation, and then resulting in cell canceration. HDACs inhibitors are a popular target in the field of tumor therapy in recent years, and can inhibit the differentiation of tumor cells, thereby inhibiting the growth of various tumor cells, and have the characteristics of higher tolerance and lower cytotoxicity.
A great deal of research shows that the inhibition of HDACs and PARP can enhance the killing effect on tumor cells, and in various tumor cells treated by PARPi and HDACi together, the synergistic inhibition effect on the tumor cells is observed in vivo and in vitro, so that the combined application of the two inhibitors can be used for improving the anti-tumor effect. Therefore, the design of a novel PARP/HDACs dual inhibitor for treating tumors is a potential strategy.
Disclosure of Invention
The invention aims at providing phthalazinone compounds shown in a general formula I or pharmaceutically acceptable salts thereof,
Figure SMS_1
wherein:
X 2 、X 3 、X 4 each independently is CR 3 ；
R 3 Selected from hydrogen, fluorine;
ring A is selected from
Figure SMS_2
n is 1 or 2;
R 2 selected from (C) 1 -C 8 ) Alkyl, said (C) 1 -C 8 ) Alkyl groups optionally being substituted by 1-3R 4 Substitution;
R 4 selected from trifluoromethyl, difluoromethyl, amino, hydroxy, phenyl, pyridyl, (C) 1 -C 4 ) Alkoxy, phenyl (C) 2 -C 4 ) Alkenyl group,
Figure SMS_3
Said phenyl, phenyl (C 2 -C 4 ) Alkenyl and pyridyl can optionally be +.>
Figure SMS_4
Or 1-3R 7 Substitution;
R 5 、R 6 each independently selected from hydrogen, hydroxy, (C) 1 -C 4 ) Alkyl, hydroxy (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl; said (C) 1 -C 4 ) Alkyl groups optionally being substituted by 1-3R 11 Substitution;
or R is 5 And R is 6 Together with the nitrogen atom to which they are attached, form a 5-6 membered nitrogen containing heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, said nitrogen containing heterocyclic ring optionally comprising 1-2 carbon-carbon double or triple bonds, said nitrogen containing heterocyclic ring optionally being substituted with 1-3R' S, which may be the same or different 10 Substituted, the ring carbon atom may be oxo;
R 11 selected from hydroxy groups, (C) 1 -C 6 ) Alkoxy, (C) 1 -C 6 ) An alkylamino group;
R 7 selected from hydrogen, halogen, trifluoromethyl, (C) 1 -C 4 ) Alkyl, amino, hydroxy, cyano;
R 10 selected from hydrogen, (C) 1 -C 4 ) Alkyl, hydroxy (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, hydroxy, amino, (C) 1 -C 4 ) An acyl group.
The invention preferably discloses phthalazinone compounds shown in a general formula I or pharmaceutically acceptable salts thereof, wherein,
R 2 selected from:
Figure SMS_5
the phthalazinone compound shown in the general formula I or pharmaceutically acceptable salt thereof is finally preferred to be any one of the following compounds:
Figure SMS_6
/>
Figure SMS_7
/>
Figure SMS_8
/>
Figure SMS_9
the phthalazinone compounds of the general formula I in the invention can form pharmaceutically acceptable salts with acids. The pharmaceutically acceptable salts include salts formed with inorganic acids, organic acids, alkali metal ions, the inorganic acids being selected from the group consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; the organic acid is selected from the group consisting of: fumaric acid, succinic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid; the alkali metal ions are selected from potassium ions, sodium ions and lithium ions.
"halogen" in the present invention means fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight or branched chain alkyl group; "cycloalkyl" refers to a substituted or unsubstituted cycloalkyl; "aryl" refers to phenyl or naphthyl that is unsubstituted or substituted; "heteroaryl" means a monocyclic or polycyclic ring system containing one or more heteroatoms selected from N, O, S, the ring system being aromaticSexual, such as imidazolyl, pyridyl, pyrazolyl, (1, 2, 3) -and (1, 2, 4) -triazolyl, furyl, thienyl;
Figure SMS_10
representing the substituent linkage.
The invention can contain phthalazinone compounds of the formula I or pharmaceutically acceptable salts thereof as active ingredients, and can be mixed with pharmaceutically acceptable carriers or excipients to prepare pharmaceutical compositions. The carrier or excipient comprises diluents, binders, wetting agents, disintegrants, lubricants, glidants, which are known in the art. Diluents include starch, dextrin, sucrose, dextrose, lactose, mannitol, sorbitol, xylitol, dibasic calcium phosphate; the wetting agent comprises water, ethanol, isopropanol, etc.; the binder comprises starch slurry, dextrin, syrup, mel, glucose solution, acacia pulp, gelatin slurry, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, and polyethylene glycol; the disintegrating agent comprises dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and sodium dodecyl sulfate; lubricants and glidants include talc, silicon dioxide, polyethylene glycol.
The pharmaceutical composition can be prepared into pharmaceutically acceptable dosage forms, including injection, tablet and capsule.
The phthalazinone compound or the pharmaceutically acceptable salt thereof is combined with other active ingredients, so that a better treatment effect is achieved.
The invention also provides application of phthalazinone compounds of the general formula I or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating cancers, neurodegenerative diseases and inflammations related to PARP enzyme and HDAC enzyme. The cancer is any one of breast cancer, pancreatic cancer, ovarian cancer, lung cancer, liver cancer, gastric cancer, colorectal cancer, cervical cancer, testicular cancer, melanoma, nasopharyngeal cancer, oral cancer, glioblastoma, bladder cancer, prostate cancer, esophageal cancer, brain tumor, reproductive system tumor, respiratory system tumor, lymphatic system tumor, digestive system tumor and skin tumor.
The present invention also provides the synthetic routes shown below (schemes 1-2), all of which are prepared by the means described in these synthetic routes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the final compounds of the present invention are prepared by methods described in these synthetic routes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. The R is 2 、X 2 、X 3 、X 4 Is a corresponding group in a corresponding position of a compound shown in a general formula I, wherein n=1 or 2.
Route 1:
Figure SMS_11
the substituted or substituted o-formylbenzoic acid is used as a starting material to react with dimethyl phosphite to prepare a phosphorus ylide intermediate 1; intermediate 1 is reacted by Wittig-Horner to obtain intermediate 2; intermediate 2 is subjected to cyano hydrolysis and cyclization reaction to prepare intermediate 3; intermediate 3 is subjected to condensation and Boc protection removal reaction to prepare intermediate 4; intermediate 4 is subjected to carbon disulfide addition to prepare intermediate 5; intermediate 5 and halogenated amine (amide or ester) undergo nucleophilic substitution reaction to prepare the target compound of formula II.
Route 2:
Figure SMS_12
taking the intermediate 3 as a raw material, and performing condensation and Boc removal protection reaction to obtain an intermediate 6; intermediate 6 is subjected to carbon disulfide addition to prepare intermediate 7; intermediate 7 is nucleophilic substituted with a haloamine (amide or ester) to produce the target compound of formula III.
The invention has the beneficial effects that:
the compound provided by the invention has stronger independent PARP inhibition effect and common PARP/HDAC inhibition effect, and can be used for preparing medicaments for treating diseases caused by abnormal expression of PARP and/or HDAC, in particular medicaments for treating and/or preventing cancers, neurodegenerative diseases, inflammations and the like.
The invention aims to develop and obtain a PARP inhibitor with better activity and a PARP/HDACs double-target inhibitor. Experiments show that most of the compounds have remarkable inhibitory activity on PARP, and part of the compounds have stronger inhibitory activity on PARP and HDACs, and pharmacological activity screening shows that the compounds provided by the invention have good anti-tumor activity, have remarkable inhibitory effect on various humanized tumor cells, and have further developed medicinal value.
Detailed Description
The examples are intended to illustrate, but not limit the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by using a Bruker AVANCE III or Bruker ARX-600 nuclear magnetic resonance instrument, and tetramethylsilane is used as an internal standard; the mass spectrum is measured by an Agilent 1100 four-level rod liquid chromatography-mass spectrometer; the reagents used are analytically pure or chemically pure.
Example 1: preparation of 2- (dimethylamino) ethyl-4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 1)
Step A: preparation of dimethyl (3-oxo-1, 3-dihydro-isobenzofuran-1-yl) phosphonate (intermediate 1)
Figure SMS_13
Dimethyl phosphite (16.5 mL,0.18 mol) was added dropwise to a solution of sodium methoxide (77.2 g,0.19 mol) in methanol (150 mL) at 0deg.C, and after the addition, o-formylbenzoic acid (22.5 g,0.15 mol) was added to the reaction mixture in portions over 20min, and the temperature was maintained below 5deg.C. The reaction solution was slowly warmed to 20℃and reacted for 2 hours. After completion of the reaction, methanesulfonic acid (13.6 mL,0.21 mol) was added dropwise to the reaction solution over 30min, the solvent was distilled off after the completion of the addition, the resulting white residue was dissolved in water (90 mL), extracted three times with methylene chloride (3X 70 mL), the organic layers were combined, the organic layers were backwashed twice with water (2X 20 mL), and dried over magnesium sulfate. Removing magnesium sulfate by suction filtration, evaporating filtrate, and freezing to obtain crystalline white25.8g of a coloured solid was used in the next step, in 71.2% yield, without purification, MS (ESI) m/z (%)] + 。
And (B) step (B): preparation of 2-fluoro-5- (3-oxo-1, (3H) -dihydro-isobenzofuranylidenemethyl) benzonitrile (intermediate 2 a)
Figure SMS_14
24.2g (0.1 mol) of intermediate 1 and 2-fluoro-5-formylbenzonitrile (0.1 mol) were dissolved in 200mL of tetrahydrofuran, and triethylamine (10 mL,0.1 mol) was slowly added dropwise over 25min, maintaining the temperature below 15 ℃. After the completion of the dropwise addition, the reaction solution was slowly warmed to 20℃and reacted for 1 hour. After the reaction was completed, most of the solvent was distilled off, the reaction solution was poured into 150mL of water and stirred continuously for 30 minutes, the solid was collected by suction filtration, washed with water twice (2X 20 mL), n-hexane twice (2X 20 mL), diethyl ether twice (2X 20 mL), and dried to give a white solid (E: Z4: 3), the yield was 91.2%, and the isomer was used in the next step without separation, MS (ESI) m/Z (%):264.35 [ M-H ]] - 。
According to the operation method of the step B, intermediates 2B-2d are respectively prepared
3-fluoro-5- (3-oxo-1, (3H) -dihydro-isobenzofuranylidenemethyl) benzonitrile (2 b): white solid, yield 89.2%, MS (ESI) m/z (%):264.09 [ M-H ]] - 。
4-fluoro-3- (3-oxo-1, (3H) -dihydro-isobenzofuranylidenemethyl) benzonitrile (2 c): white solid, yield 90.5%, MS (ESI) m/z (%):264.28 [ M-H ]] - 。
3- (3-oxo-1, (3H) -dihydro-isobenzofuranylidenemethyl) benzonitrile (2 d): white solid, yield 93.1%, MS (ESI) m/z (%):246.12 [ M-H ]] - 。
Step C: preparation of 2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoic acid (intermediate 3 a)
Figure SMS_15
130 to intermediate 2a (0.09 mol) under stirringTo the suspension of mL of water was added an aqueous NaOH solution (13N, 32 mL), and the temperature was raised to 90℃and the reaction was carried out for 1h. The reaction was cooled to 70℃and 80% hydrazine hydrate (65 mL,1.3 mol) was slowly added and the reaction was allowed to react at 70℃for 18h. After the reaction, the mixture was cooled to room temperature and acidified to pH 4 with 8N hydrochloric acid solution. Stirring was continued for 10min at room temperature, the reaction solution was suction filtered, the filter cake was washed successively with water (2X 40 mL) and diethyl ether (2X 30 mL), and dried to give a pale pink powder in 71% yield. 1 H NMR(600MHz,DMSO-d 6 )δ13.28(bs,1H),12.61(s,1H),8.28(dd,J＝7.9,1.0Hz,1H),7.99(d,J＝8.0Hz,1H),7.91(td,J＝7.9,1.3Hz,1H),7.86–7.81(m,2H),7.61–7.57(m,1H),7.25(dd,J＝10.7,8.5Hz,1H),4.37(s,2H).MS(ESI)m/z(％):297.24[M-H] - 。
According to the operation method of the step C, intermediates 3b-3d are respectively prepared
3-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoic acid (3 b): white solid, yield 69.2%. 1 H NMR(600MHz,DMSO-d 6 )δ13.30(bs,1H),12.62(s,1H),8.29–8.26(m,1H),8.00(d,J＝8.0Hz,1H),7.94–7.90(m,1H),7.87–7.83(m,1H),7.75–7.73(m,1H),7.54–7.48(m,2H),4.42(s,2H).MS(ESI)m/z(％):299.13[M+H] + 。
4-fluoro-3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoic acid (3 c): white solid, yield 70.1%. 1 H NMR(600MHz,DMSO-d 6 )δ13.02(s,1H),12.54(s,1H),8.29(d,J＝7.6Hz,1H),8.03(d,J＝8.0Hz,1H),7.97(t,J＝7.3Hz,1H),7.93–7.86(m,3H),7.34(t,J＝9.0Hz,1H),4.42(s,2H).MS(ESI)m/z(％):297.24[M-H] - 。
3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoic acid (3 d): white solid, yield 75.5%. 1 H NMR(600MHz,DMSO-d 6 )δ12.97(bs,1H),12.62(s,1H),8.29–8.26(m,1H),7.97(d,J＝8.0Hz,1H),7.91–7.87(m,2H),7.85–7.81(m,1H),7.79(d,J＝7.8Hz,1H),7.59(d,J＝7.7Hz,1H),7.44(t,J＝7.7Hz,1H),4.39(s,2H).MS(ESI)m/z(％):279.30[M-H] - 。
Step D: preparation of 4- (4-fluoro-3- (piperazine-1-carbonyl) benzyl) -2H-phthalazin-1-one (intermediate 4 a)
Figure SMS_16
Intermediate 3a (2.1 g,7.0 mmol), N-Boc piperazine (1.6 g,8.4 mmol), HBTU (3.2 g,8.4 mmol), triethylamine (1.4 g,14.0 mmol) were added to DMF (20 mL) and reacted at room temperature for 2h. After the reaction, pouring the reaction solution into water, continuously stirring for more than 1H, suction-filtering the suspension, and sequentially using cold DMF-H 2 O (1:1, 2X 5 mL), cold water (2X 5 mL), cold isopropanol (2X 5 mL) and cold diethyl ether (2X 5 mL) to give 3.1g of a white solid; HCl (6N, 15 mL) was added to a solution of the intermediate (3.1 g,6.5 mmol) prepared above in ethanol (7 mL) at room temperature, stirred at room temperature for 3h, the ethanol was distilled off, the aqueous solution was adjusted to pH10 with aqueous ammonia, extracted three times with dichloromethane (3X 10 mL), the organic layers were combined, backwashed once with 10mL of water, dried over anhydrous sodium sulfate, concentrated to give a white crystalline solid 2.1g in overall yield 85%, 1 H NMR(600MHz,DMSO-d 6 )δ12.59(s,1H),8.28–8.24(m,1H),7.99–7.94(m,1H),7.92–7.86(m,1H),7.86–7.80(m,1H),7.43–7.38(m,1H),7.34–7.30(m,1H),7.24–7.19(m,1H),4.32(s,2H),3.57–2.54(m,8H).MS(ESI)m/z(％):367.17[M+H] + 。
according to the operation method of the step D, intermediates 4b-4e and intermediate 6 are respectively prepared
4- (3-fluoro-5- (piperazine-1-carbonyl) benzyl) -2H-phthalazin-1-one (4 b): white solid, yield 76.2%, MS (ESI) m/z (%):367.74 [ M+H ]] + 。
4- (2-fluoro-5- (piperazine-1-carbonyl) benzyl) -2H-phthalazin-1-one (4 c): white solid, yield 72.5%, MS (ESI) m/z (%):367.23 [ M+H ]] + 。
4- (3- (piperazine-1-carbonyl) benzyl) -2H-phthalazin-1-one (4 d): white solid, yield 82.5%, 1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),8.31–8.21(m,1H),7.99–7.92(m,1H),7.91–7.79(m,2H),7.43–7.34(m,2H),7.32–7.26(m,1H),7.24–7.16(m,1H),4.35(s,2H),3.57–3.04(m,5H),2.78–2.54(m,4H).MS(ESI)m/z(％):349.02[M+H] + 。
4- (3- (1, 4-diazacycloheptane-1-carbonyl) -4-fluorobenzyl) -2H-phthalazin-1-one (4 e): pale yellow solid in 65.4% yield, 1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),8.26(d,J＝7.7Hz,1H),7.99–7.94(m,1H),7.92–7.86(m,1H),7.85–7.81(m,1H),7.47–7.37(m,2H),7.27–7.18(m,1H),4.33(s,2H),3.84–3.55(m,2H),3.31–2.77(m,6H),1.93–1.62(m,2H).MS(ESI)m/z(％):381.03[M+H] + 。
2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) -N- (piperidin-4-yl) benzamide (intermediate 6): intermediate 6 is prepared from intermediate 3a and 4-amino-N-Boc-piperidine as raw materials in a pale yellow solid with a yield of 66.8%, 1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.49(bs,1H),8.28–8.24(m,1H),8.00–7.97(m,1H),7.92–7.88(m,1H),7.85–7.81(m,1H),7.52–7.48(m,1H),7.47–7.42(m,1H),7.22–7.18(m,1H),4.33(s,2H),4.04–3.96(m,1H),3.26–1.67(m,8H).MS(ESI)m/z(％):381.35[M+H] + 。
step E: preparation of sodium 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (intermediate 5 a)
Figure SMS_17
Intermediate 4a (0.37 g,1 mmol), naOH (0.04 g,1 mmol), carbon disulfide (0.1 g,1 mmol) was dissolved in methanol (5 mL), reacted at room temperature for 4h, suction filtered to give 0.4g of pale yellow solid with a yield of 88.0%, MS (ESI) m/z (%):486.89 [ M+Na ]] + 。
According to the operation method of the step E, intermediates 5b-5E and intermediate 7 are respectively prepared
Sodium 4- (3-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (5 b): pale yellow solid, yield 84.5%, MS (ESI) m/z (%):486.83 [ M+Na ]] + 。
Sodium 4- (4-fluoro-3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (5 c): pale yellow solid in 85.3% yield, MS (ESI) m/z (%):486.83 [ M+Na ]] + 。
Sodium 4- (3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (5 d): pale yellow solid, collectedThe rate was 83.8%, and MS (ESI) m/z (%) was 468.87[ M+Na ]] + 。
Sodium 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) 1, 4-diazacycloheptane-1-carbodisulfate (5 e): light yellow solid, yield 75.8%, MS (ESI) m/z (%):500.88 [ M+Na ]] + 。
Sodium 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (intermediate 7): intermediate 7 was obtained as pale yellow solid in 82.8% yield, MS (ESI) m/z (%) 500.88[ M+Na ]] + 。
Step F: preparation of 2- (dimethylamino) ethyl-4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 1)
Figure SMS_18
Intermediate 5a (0.24 g,0.5 mmol), 2-dimethylaminoethyl chloride hydrochloride (0.08 g,0.5 mmol) and triethylamine (0.06 g,0.6 mmol) were dissolved in methanol (5 mL) and reacted at 50℃for 4h, after the reaction was completed, cooled to room temperature and suction filtered to give 0.23g of a white solid with a yield of 90%. 1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.7Hz,1H),7.96(d,J＝7.9Hz,1H),7.90(t,J＝7.3Hz,1H),7.84(t,J＝7.4Hz,1H),7.48–7.43(m,1H),7.39(d,J＝4.9Hz,1H),7.25(t,J＝8.9Hz,1H),4.34(s,2H),4.32–3.80(m,4H),3.76–3.69(m,2H),3.41–3.37(m,2H),3.35–3.33(m,2H),2.55–2.52(m,2H),2.18(s,6H).MS(ESI)m/z(％):514.39[M+H] + 。
According to the preparation method of the compound 1, the intermediates 5 and 7 are used as raw materials, and the compound 2-46 is obtained through the preparation method of the step F by substitution reaction with various small molecule halogenated amines (amides and esters).
Example 2: preparation of 2- (diethylamino) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 2)
Using intermediate 5a and 2-diethylamino chloroethane hydrochloride as raw materials, and preparing white solid according to step F, the yield is 86.4％。 1 H NMR(600MHz,CDCl 3 -d 6 )δ10.88(s,1H),8.43–8.39(m,1H),7.73–7.68(m,2H),7.67–7.63(m,1H),7.32–7.25(m,2H),6.98(t,J＝8.8Hz,1H),4.23(s,2H),4.23–3.74(m,6H),3.43–3.38(m,2H),3.38–3.30(m,2H),2.77–2.70(m,2H),2.64–2.53(m,4H),1.01(t,J＝6.8Hz,6H).MS(ESI)m/z:542.42[M+H] + 。
Example 3: preparation of 2- (pyrrolidin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 3)
Starting from intermediate 5a and N- (2-chloroethyl) pyrrolidine hydrochloride, step F gave a white solid in 83.5% yield. 1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.3Hz,1H),7.96(d,J＝7.6Hz,1H),7.92–7.87(m,1H),7.86–7.80(m,1H),7.50–7.43(m,1H),7.42–7.35(m,1H),7.25(t,J＝8.6Hz,1H),4.34(s,2H),4.34–3.80(m,4H),3.78–3.68(m,2H),3.49–3.42(m,2H),2.90–2.75(m,2H),2.69–2.60(m,2H),2.50(s,4H),1.73(s,4H).MS(ESI)m/z:540.25[M+H] + 。
Example 4: preparation of 2- (piperidin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 4)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.28–8.25(m,1H),7.95(d,J＝8.0Hz,1H),7.91–7.87(m,1H),7.83(t,J＝7.5Hz,1H),7.46(ddd,J＝7.7,5.0,2.1Hz,1H),7.38(dd,J＝6.4,2.1Hz,1H),7.25(t,J＝9.0Hz,1H),4.34(s,2H),4.34–3.78(m,4H),3.76–3.69(m,2H),3.45–3.35(m,2H),3.35–3.33(m,2H),2.56–2.51(m,2H),2.38(s,4H),1.48(s,4H),1.37(s,2H).MS(ESI)m/z:554.46[M+H] + 。
Example 5: preparation of 2- (4-methylpiperazin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 5)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.5Hz,1H),7.95(d,J＝8.0Hz,1H),7.91–7.88(m,1H),7.85–7.82(m,1H),7.46(ddd,J＝7.7,4.9,2.1Hz,1H),7.38(dd,J＝6.4,2.1Hz,1H),7.25(t,J＝9.0Hz,1H),4.34(s,2H),4.34–3.79(m,4H),3.77–3.68(m,2H),3.40(t,J＝7.1Hz,2H),3.35–3.33(m,2H),2.56(t,J＝7.1Hz,2H),2.49–2.23(m,8H),2.17(s,3H).MS(ESI)m/z:569.31[M+H] + 。
Example 6: preparation of 2-morpholinoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 6)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.4Hz,1H),7.96(d,J＝7.3Hz,1H),7.90(t,J＝6.6Hz,1H),7.84(t,J＝6.7Hz,1H),7.48–7.43(m,1H),7.41–7.35(m,1H),7.25(t,J＝8.5Hz,1H),4.34(s,2H),4.34–3.80(m,4H),3.77–3.70(m,2H),3.56(s,4H),3.45–3.39(m,2H),3.35–3.33(m,2H),2.60–2.55(m,2H),2.41(s,4H).MS(ESI)m/z:556.18[M+H] + 。
Example 7: preparation of 2- (dimethylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 7)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.7Hz,1H),7.96(d,J＝7.9Hz,1H),7.90(t,J＝7.3Hz,1H),7.83(t,J＝7.3Hz,1H),7.49–7.44(m,1H),7.43–7.38(m,1H),7.25(t,J＝8.9Hz,1H),4.34(s,2H),4.30(s,2H),4.34–3.84(m,4H),3.79–3.69(m,2H),3.38–3.34(m,2H),3.08(s,3H),2.84(s,3H).MS(ESI)m/z:550.10[M+Na] + 。
Example 8: preparation of 2- (diethylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 8)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.7Hz,1H),7.96(d,J＝8.1Hz,1H),7.93–7.88(m,1H),7.86–7.81(m,1H),7.49–7.44(m,1H),7.43–7.38(m,1H),7.25(t,J＝9.0Hz,1H),4.34(s,2H),4.32(s,2H),4.34–3.85(m,4H),3.81–3.67(m,2H),3.42(q,J＝7.0Hz,2H),3.38–3.34(m,2H),3.28(q,J＝7.0Hz,2H),1.20(t,J＝7.1Hz,3H),1.01(t,J＝7.0Hz,3H).MS(ESI)m/z:578.14[M+Na] + 。
Example 9: preparation of 2- (cyclopropylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 9)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.33–8.17(m,2H),8.00–7.94(m,1H),7.93–7.88(m,1H),7.86–7.80(m,1H),7.50–7.44(m,1H),7.43–7.37(m,1H),7.29–7.21(m,1H),4.34(s,2H),4.34–4.01(m,3H),3.96(s,2H),3.94–3.82(m,1H),3.80–3.68(m,2H),3.40–3.34(m,2H),2.64–2.58(m,1H),0.65–0.56(m,2H),0.46–0.33(m,2H).MS(ESI)m/z:562.14[M+Na] + 。
Example 10: preparation of 2- (cyclobutylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 10)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.42(d,J＝7.6Hz,1H),8.28–8.24(m,1H),7.96(d,J＝8.0Hz,1H),7.92–7.88(m,1H),7.85–7.81(m,1H),7.46(ddd,J＝7.8,4.9,2.1Hz,1H),7.40(dd,J＝6.4,2.0Hz,1H),7.25(t,J＝9.0Hz,1H),4.34(s,2H),4.34–4.03(m,3H),3.98(s,2H),3.95–3.80(m,1H),3.78–3.70(m,2H),3.38–3.33(m,2H),2.16–2.11(m,2H),1.92–1.85(m,2H),1.66–1.57(m,2H).MS(ESI)m/z:576.22[M+Na] + 。
Example 11: preparation of 2- (cyclopentylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 11)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.31–8.22(m,1H),8.18–8.09(m,1H),8.01–7.94(m,1H),7.93–7.87(m,1H),7.86–7.77(m,1H),7.51–7.43(m,1H),7.43–7.33(m,1H),7.31–7.18(m,1H),4.34(s,2H),4.34–3.82(m,7H),3.80–3.68(m,2H),3.40–3.35(m,2H),1.82–1.34(m,8H).MS(ESI)m/z:590.17[M+Na] + 。
Example 12: preparation of 2- (cyclohexylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 12)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.30–8.23(m,1H),8.07–8.01(m,1H),7.99–7.78(m,3H),7.49–7.37(m,2H),7.31–7.20(m,1H),4.34(s,2H),4.34–4.06(m,3H),3.99(s,2H),3.92–3.85(m,1H),3.78–3.70(m,2H),3.54–3.48(m,1H),3.35(m,2H),1.74–1.51(m,5H),1.24–1.07(m,5H).MS(ESI)m/z:604.19[M+Na] + 。
Example 13: preparation of 2-oxo-2- (pyrrolidin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 13)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.7Hz,1H),7.96(d,J＝8.0Hz,1H),7.90(t,J＝7.4Hz,1H),7.84(t,J＝7.5Hz,1H),7.48–7.43(m,1H),7.42–7.38(m,1H),7.25(t,J＝9.0Hz,1H),4.34(s,2H),4.33–4.24(m,1H),4.22(s,2H),4.19–3.99(m,2H),3.99–3.82(m,1H),3.79–3.68(m,2H),3.56(t,J＝6.8Hz,2H),3.38–3.35(m,2H),3.29(t,J＝6.9Hz,2H),1.91(p,J＝6.8Hz,2H),1.78(p,J＝6.8Hz,2H).MS(ESI)m/z:576.22[M+Na] + 。
Example 14: preparation of 2-oxo-2- (piperidin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 14)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.6Hz,1H),7.96(d,J＝7.8Hz,1H),7.92–7.88(m,1H),7.83(t,J＝7.2Hz,1H),7.48–7.43(m,1H),7.42–7.37(m,1H),7.25(t,J＝8.7Hz,1H),4.34(s,2H),4.32(s,2H),4.23–4.00(m,3H),3.96–3.87(m,1H),3.79–3.70(m,2H),3.52–3.46(m,2H),3.45–3.40(m,2H),3.39–3.35(m,2H),1.63–1.52(m,4H),1.46–1.39(m,2H).MS(ESI)m/z:590.11[M+Na] + 。
Example 15: preparation of 2-morpholino-2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 15)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.8Hz,1H),7.96(d,J＝8.0Hz,1H),7.90(t,J＝7.4Hz,1H),7.84(t,J＝7.5Hz,1H),7.48–7.44(m,1H),7.42–7.38(m,1H),7.25(t,J＝8.9Hz,1H),4.34(s,2H),4.33(s,2H),4.30–3.97(m,3H),3.96–3.81(m,1H),3.78–3.71(m,2H),3.65–3.60(m,2H),3.58–3.53(m,4H),3.46–3.42(m,2H),3.38–3.35(m,2H).MS(ESI)m/z:592.16[M+Na] + 。
Example 16: preparation of 2-thiomorpholino-2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 16)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.6Hz,1H),7.96(d,J＝7.8Hz,1H),7.90(t,J＝6.7Hz,1H),7.84(t,J＝7.2Hz,1H),7.48–7.44(m,1H),7.42–7.38(m,1H),7.25(t,J＝8.9Hz,1H),4.34(s,5H),4.19–4.03(m,2H),3.98–3.87(m,1H),3.83–3.79(m,2H),3.77–3.70(m,4H),2.74–2.70(m,2H),2.56–2.53(m,2H).MS(ESI)m/z:608.16[M+Na] + 。
Example 17: preparation of 2- (4-methylpiperazin-1-yl) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydrophthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 17)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.26(d,J＝7.7Hz,1H),7.96(d,J＝7.8Hz,1H),7.90(t,J＝7.2Hz,1H),7.83(t,J＝7.2Hz,1H),7.48–7.44(m,1H),7.40(d,J＝4.9Hz,1H),7.25(t,J＝8.9Hz,1H),4.34(s,2H),4.32(s,2H),4.31–3.84(m,4H),3.78–3.70(m,2H),3.56–3.51(m,2H),3.47–3.42(m,2H),3.38–3.34(m,2H),2.38–2.33(m,2H),2.27–2.23(m,2H),2.18(s,3H).MS(ESI)m/z:605.28[M+Na] + 。
Example 18: preparation of 2- (piperidin-1-yl) ethyl 4- (3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 18)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),8.26(d,J＝7.7Hz,1H),7.96(d,J＝8.0Hz,1H),7.89(t,J＝7.4Hz,1H),7.84(d,J＝7.5Hz,1H),7.46–7.37(m,3H),7.29(d,J＝7.3Hz,1H),4.36(s,2H),4.36–3.81(m,4H),3.78–3.58(m,2H),3.48–3.36(m,4H),2.59–2.52(m,2H),2.49–2.30(m,4H),1.53–1.44(m,4H),1.41–1.34(m,2H).MS(ESI)m/z:536.21[M+H] + 。
Example 19: preparation of 2- (4-methylpiperazin-1-yl) ethyl 4- (3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 19)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),8.26(d,J＝7.9Hz,1H),7.95(d,J＝8.0Hz,1H),7.89(t,J＝7.6Hz,1H),7.83(t,J＝7.5Hz,1H),7.43(d,J＝7.8Hz,1H),7.41–7.37(m,2H),7.31–7.27(m,1H),4.36(s,2H),4.36–3.77(m,4H),3.75–3.55(m,2H),3.45–3.35(m,4H),2.59–2.53(m,2H),2.49–2.21(m,8H),2.16(s,3H).MS(ESI)m/z:551.26[M+H] + 。
Example 20: preparation of 2- (cyclopentylamino) -2-oxoethyl 4- (3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 20)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),8.33–8.21(m,1H),8.19–8.09(m,1H),8.02–7.77(m,3H),7.50–7.34(m,3H),7.34–7.25(m,1H),4.36(s,2H),4.33–3.82(m,7H),3.81–3.59(m,2H),3.55–3.37(m,2H),1.83–1.57(m,4H),1.53–1.34(m,4H).MS(ESI)m/z:572.12[M+Na] + 。
Example 21: preparation of 2- (cyclohexylamino) -2-oxoethyl 4- (3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 21)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),8.32–8.22(m,1H),8.09–8.01(m,1H),8.00–7.93(m,1H),7.92–7.86(m,1H),7.86–7.79(m,1H),7.47–7.36(m,3H),7.34–7.26(m,1H),4.36(s,2H),4.36–3.84(m,7H),3.79–3.62(m,2H),3.56–3.40(m,3H),1.76–1.63(m,4H),1.57–1.50(m,1H),1.29–1.25(m,1H),1.22–1.08(m,4H).MS(ESI)m/z:587.17[M+Na] + 。
Example 22: preparation of 2- (piperidin-1-yl) ethyl 4- (3-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 22)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),8.27(d,J＝7.8Hz,1H),7.97(d,J＝8.0Hz,1H),7.91(t,J＝7.4Hz,1H),7.84(t,J＝7.5Hz,1H),7.31(d,J＝9.6Hz,1H),7.22(s,1H),7.16(d,J＝8.4Hz,1H),4.39(s,2H),4.36–3.78(m,4H),3.76–3.60(m,2H),3.48–3.34(m,4H),2.61–2.51(m,2H),2.49–2.28(m,4H),1.56–1.43(m,4H),1.43–1.32(m,2H).MS(ESI)m/z:554.20[M+H] + 。
Example 23: preparation of 2- (4-methylpiperazin-1-yl) ethyl 4- (3-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 23)
1 H NMR(600MHz,DMSO-d 6 )δ12.65(s,1H),8.29(d,J＝7.7Hz,1H),7.98(d,J＝8.0Hz,1H),7.93–7.89(m,1H),7.87–7.83(m,1H),7.34–7.31(m,1H),7.25(s,1H),7.20–7.17(m,1H),4.40(s,2H),4.37–4.15(m,2H),4.09–3.84(m,2H),3.78–3.65(m,2H),3.45–3.42(m,2H),3.42–3.38(m,2H),2.59(t,J＝7.1Hz,2H),2.57–2.37(m,8H),2.26(s,3H).MS(ESI)m/z:569.24[M+H] + 。
Example 24: preparation of 2- (cyclopentylamino) -2-oxoethyl 4- (3-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 24)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),8.27(d,J＝7.8Hz,1H),8.14(d,J＝6.9Hz,1H),7.98(d,J＝8.0Hz,1H),7.91(t,J＝7.4Hz,1H),7.84(t,J＝7.4Hz,1H),7.31(d,J＝9.5Hz,1H),7.23(s,1H),7.17(d,J＝8.3Hz,1H),4.39(s,2H),4.34–4.05(m,3H),4.02–3.87(m,4H),3.76–3.63(m,2H),3.48–3.37(m,2H),1.82–1.73(m,2H),1.67–1.58(m,2H),1.53–1.44(m,2H),1.42–1.34(m,2H).MS(ESI)m/z:590.05[M+Na] + 。
Example 25: preparation of 2- (cyclohexylamino) -2-oxoethyl 4- (3-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 25)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),8.33–8.21(m,1H),8.09–7.81(m,4H),7.37–7.13(m,3H),4.39(s,2H),4.33–3.87(m,6H),3.78–3.61(m,2H),3.55–3.38(m,3H),1.75–1.61(m,4H),1.58–1.50(m,1H),1.30–1.25(m,1H),1.22–1.05(m,4H).MS(ESI)m/z:604.19[M+Na] + 。
Example 26: preparation of 2- (piperidin-1-yl) ethyl 4- (4-fluoro-3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 26)
1 H NMR(600MHz,DMSO-d 6 )δ12.55(s,1H),8.28(d,J＝7.8Hz,1H),8.00(d,J＝8.0Hz,1H),7.95(t,J＝7.5Hz,1H),7.87(t,J＝7.5Hz,1H),7.45–7.37(m,2H),7.31(t,J＝9.0Hz,1H),4.39(s,2H),4.34–3.76(m,4H),3.74–3.56(m,2H),3.49–3.34(m,4H),2.62–2.51(m,2H),2.49–2.28(m,4H),1.55–1.43(m,4H),1.42–1.33(m,2H).MS(ESI)m/z:554.65[M+H] + 。
Example 27: preparation of 2- (4-methylpiperazin-1-yl) ethyl 4- (4-fluoro-3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 27)
1 H NMR(600MHz,DMSO-d 6 )δ12.55(s,1H),8.34–8.23(m,1H),8.04–7.92(m,2H),7.91–7.83(m,1H),7.46–7.36(m,2H),7.35–7.26(m,1H),4.39(s,2H),4.32–3.80(m,4H),3.74–3.58(m,2H),3.45–3.36(m,4H),2.59–2.55(m,2H),2.48–2.24(m,8H),2.17(s,3H).MS(ESI)m/z:570.27[M+H] + 。
Example 28: preparation of 2- (cyclopentylamino) -2-oxoethyl 4- (4-fluoro-3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 28)
1 H NMR(600MHz,DMSO-d 6 )δ12.55(s,1H),8.35–8.22(m,1H),8.19–8.09(m,1H),8.04–7.92(m,2H),7.91–7.83(m,1H),7.49–7.37(m,2H),7.36–7.26(m,1H),4.39(s,2H),4.32–3.86(m,7H),3.76–3.57(m,2H),3.56–3.39(m,2H),1.83–1.71(m,2H),1.67–1.57(m,2H),1.53–1.45(m,2H),1.42–1.33(m,2H).MS(ESI)m/z:589.98[M+Na] + 。
Example 29: preparation of 2- (cyclohexylamino) -2-oxoethyl 4- (4-fluoro-3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 29)
1 H NMR(600MHz,DMSO-d 6 )δ12.55(s,1H),8.36–8.21(m,1H),8.09–7.92(m,3H),7.92–7.81(m,1H),7.51–7.24(m,3H),4.39(s,2H),4.31–3.88(m,6H),3.76–3.60(m,2H),3.55–3.39(m,3H),1.77–1.62(m,4H),1.57–1.49(m,1H),1.31–1.26(m,1H),1.22–1.07(m,4H).MS(ESI)m/z:604.13[M+Na] + 。
Example 30: preparation of 2- (piperidin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) -1, 4-diazacycloheptane-1-carbodisulfate (Compound 30)
MS(ESI)m/z:568.92[M+H] + 。
Example 31: preparation of 2- (4-methylpiperazin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydrophthalazin-1-yl) methyl) benzoyl) -1, 4-diazacycloheptane-1-carbodisulfate (Compound 31)
MS(ESI)m/z:583.13[M+H] + 。
Example 32: preparation of 2- (cyclopentylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) -1, 4-diazacycloheptane-1-carbodisulfate (Compound 32)
MS(ESI)m/z:604.51[M+Na] + 。
Example 33: preparation of 2- (cyclohexylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) -1, 4-diazacycloheptane-1-carbodisulfate (Compound 33)
MS(ESI)m/z:618.27[M+Na] + 。
Example 34: preparation of 2- (dimethylamino) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 34)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.35–8.21(m,2H),8.01–7.94(m,1H),7.92–7.79(m,2H),7.57–7.40(m,2H),7.25–7.15(m,1H),5.20–5.07(m,1H),4.48–4.38(m,1H),4.33(s,2H),4.21–4.10(m,1H),3.60–3.44(m,2H),3.37–3.26(m,2H),2.51–2.46(m,2H),2.17(s,6H),2.00–1.86(m,2H),1.57–1.43(m,2H).MS(ESI)m/z:528.02[M+Na] + 。
Example 35: preparation of 2- (diethylamino) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 35)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.39–8.19(m,2H),8.03–7.79(m,3H),7.60–7.38(m,2H),7.28–7.13(m,1H),5.24–5.02(m,1H),4.50–4.38(m,1H),4.33(s,2H),4.23–4.07(m,1H),3.59–3.45(m,2H),3.36–3.28(m,2H),2.78–2.51(m,6H),2.01–1.88(m,2H),1.57–1.43(m,2H),1.00(s,6H).MS(ESI)m/z:556.38[M+H] + 。
Example 36: preparation of 2- (pyrrolidin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 36)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.35–8.22(m,2H),8.01–7.94(m,1H),7.93–7.80(m,2H),7.57–7.49(m,1H),7.48–7.41(m,1H),7.24–7.16(m,1H),5.22–5.02(m,1H),4.47–4.37(m,1H),4.33(s,2H),4.20–4.11(m,1H),3.58–3.49(m,2H),3.48–3.41(m,2H),3.01–2.56(m,6H),1.99–1.90(m,2H),1.82–1.69(m,4H),1.55–1.46(m,2H).MS(ESI)m/z:554.46[M+H] + 。
Example 37: preparation of 2- (piperidin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 37)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.38–8.19(m,2H),8.03–7.79(m,3H),7.61–7.38(m,2H),7.28–7.13(m,1H),5.23–5.01(m,1H),4.52–4.38(m,1H),4.33(s,2H),4.22–4.08(m,1H),3.58–3.39(m,4H),2.65–2.50(m,6H),2.00–1.88(m,2H),1.60–1.36(m,8H).MS(ESI)m/z:568.35[M+H] + 。
Example 38: preparation of 2-morpholinoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 38)
1 H NMR(600MHz,DMSO-d 6 )δ12.59(s,1H),8.30(d,J＝7.7Hz,1H),8.26(d,J＝7.7Hz,1H),7.97(d,J＝8.0Hz,1H),7.91–7.88(m,1H),7.85–7.81(m,1H),7.53(dd,J＝6.6,2.0Hz,1H),7.44(ddd,J＝7.3,4.5,2.1Hz,1H),7.22–7.18(m,1H),5.17–5.10(m,1H),4.45–4.39(m,1H),4.33(s,2H),4.18–4.13(m,1H),3.58–3.54(m,4H),3.54–3.45(m,2H),3.39(t,J＝7.0Hz,2H),2.56(t,J＝7.2Hz,2H),2.45–2.37(m,4H),1.98–1.90(m,2H),1.53–1.47(m,2H).MS(ESI)m/z:570.20[M+H] + 。
Example 39: preparation of 2- (diethylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 39)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.34(d,J＝7.7Hz,1H),8.29–8.23(m,1H),7.98(d,J＝8.0Hz,1H),7.92–7.87(m,1H),7.83(t,J＝7.5Hz,1H),7.56–7.50(m,1H),7.44(ddd,J＝7.6,4.7,2.3Hz,1H),7.23–7.17(m,1H),5.15–5.02(m,1H),4.52–4.38(m,1H),4.33(s,2H),4.29(s,2H),4.21–4.11(m,1H),3.64–3.46(m,2H),3.42(q,J＝7.1Hz,2H),3.27(q,J＝7.0Hz,2H),2.02–1.89(m,2H),1.57–1.47(m,2H),1.20(t,J＝7.1Hz,3H),1.01(t,J＝7.1Hz,3H).MS(ESI)m/z:592.22[M+Na] + 。
Example 40: preparation of 2-oxo-2- (pyrrolidin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 40)
1 H NMR(600MHz,DMSO-d 6 )δ12.59(s,1H),8.33(d,J＝7.4Hz,1H),8.26(d,J＝7.7Hz,1H),7.98(d,J＝8.0Hz,1H),7.89(t,J＝7.5Hz,1H),7.83(t,J＝7.5Hz,1H),7.55–7.51(m,1H),7.47–7.41(m,1H),7.20(t,J＝9.2Hz,1H),5.14–5.01(m,1H),4.50–4.40(m,1H),4.33(s,2H),4.19(s,2H),4.18–4.13(m,1H),3.61–3.47(m,4H),3.29(t,J＝6.8Hz,2H),1.99–1.87(m,4H),1.78(p,J＝6.8Hz,2H),1.56–1.48(m,2H).MS(ESI)m/z:590.11[M+Na] + 。
Example 41: preparation of 2-oxo-2- (piperidin-1-yl) ethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 41)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.33(d,J＝7.5Hz,1H),8.26(d,J＝7.8Hz,1H),7.98(d,J＝8.0Hz,1H),7.89(t,J＝7.4Hz,1H),7.83(t,J＝7.5Hz,1H),7.55–7.51(m,1H),7.46–7.42(m,1H),7.20(t,J＝9.2Hz,1H),5.12–5.05(m,1H),4.49–4.41(m,1H),4.33(s,2H),4.29(s,2H),4.20–4.13(m,1H),3.58(s,2H),3.50–3.47(m,2H),3.45–3.39(m,2H),2.00–1.90(m,2H),1.62–1.48(m,6H),1.45–1.40(m,2H).MS(ESI)m/z:604.19[M+Na] + 。
Example 42: preparation of 2-morpholino-2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 42)
1 H NMR(600MHz,DMSO-d 6 )δ12.59(s,1H),8.34(d,J＝7.6Hz,1H),8.26(d,J＝7.7Hz,1H),7.98(d,J＝8.0Hz,1H),7.89(t,J＝7.3Hz,1H),7.83(t,J＝7.5Hz,1H),7.55–7.51(m,1H),7.46–7.42(m,1H),7.20(t,J＝9.3Hz,1H),5.12–5.05(m,1H),4.48–4.41(m,1H),4.33(s,2H),4.30(s,2H),4.19–4.14(m,1H),3.64–3.60(m,2H),3.60–3.51(m,6H),3.46–3.43(m,2H),1.98–1.89(m,2H),1.56–1.48(m,2H).MS(ESI)m/z:606.11[M+Na] + 。
Example 43: preparation of 2- (cyclopropylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 43)
1 H NMR(600MHz,DMSO-d 6 )δ12.59(s,1H),8.33(d,J＝7.6Hz,1H),8.26(d,J＝7.8Hz,1H),8.23–8.20(m,1H),7.98(d,J＝8.0Hz,1H),7.91–7.88(m,1H),7.83(t,J＝7.2Hz,1H),7.53(dd,J＝6.6,1.9Hz,1H),7.44(ddd,J＝7.3,4.6,2.2Hz,1H),7.22–7.18(m,1H),5.11–5.05(m,1H),4.44–4.38(m,1H),4.33(s,2H),4.18–4.13(m,1H),3.94(s,2H),3.58–3.48(m,2H),2.63–2.59(m,1H),1.98–1.91(m,2H),1.52(q,J＝9.9Hz,2H),0.63–0.58(m,2H),0.43–0.37(m,2H).MS(ESI)m/z:576.16[M+Na] + 。
Example 44: preparation of 2- (cyclobutylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 44)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.40(d,J＝7.2Hz,1H),8.33(d,J＝7.4Hz,1H),8.26(d,J＝7.7Hz,1H),7.98(d,J＝7.9Hz,1H),7.89(t,J＝7.4Hz,1H),7.83(t,J＝7.4Hz,1H),7.59–7.48(m,1H),7.47–7.40(m,1H),7.20(t,J＝9.2Hz,1H),5.18–4.99(m,1H),4.46–4.37(m,1H),4.33(s,2H),4.22–4.09(m,2H),3.96(s,2H),3.64–3.43(m,2H),2.20–2.07(m,2H),2.00–1.83(m,4H),1.66–1.47(m,4H).MS(ESI)m/z:590.11[M+Na] + 。
Example 45: preparation of 2- (cyclopentylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 45)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.33(d,J＝7.5Hz,1H),8.26(d,J＝7.8Hz,1H),8.11(d,J＝7.0Hz,1H),7.98(d,J＝8.0Hz,1H),7.89(t,J＝7.5Hz,1H),7.83(t,J＝7.5Hz,1H),7.57–7.49(m,1H),7.47–7.40(m,1H),7.20(t,J＝9.2Hz,1H),5.14–5.03(m,1H),4.47–4.37(m,1H),4.33(s,2H),4.19–4.11(m,1H),4.03–3.97(m,1H),3.96(s,2H),3.61–3.46(m,2H),2.01–1.88(m,2H),1.83–1.70(m,2H),1.68–1.58(m,2H),1.57–1.43(m,4H),1.43–1.32(m,2H).MS(ESI)m/z:604.13[M+Na] + 。
Example 46: preparation of 2- (cyclohexylamino) -2-oxoethyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 46)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),8.33(d,J＝7.5Hz,1H),8.26(d,J＝7.8Hz,1H),8.02(d,J＝7.7Hz,1H),7.98(d,J＝8.0Hz,1H),7.89(t,J＝7.5Hz,1H),7.83(t,J＝7.5Hz,1H),7.55–7.51(m,1H),7.46–7.42(m,1H),7.20(t,J＝9.2Hz,1H),5.15–5.02(m,1H),4.48–4.37(m,1H),4.33(s,2H),4.19–4.12(m,1H),3.97(s,2H),3.60–3.47(m,3H),2.00–1.89(m,2H),1.74–1.63(m,4H),1.56–1.49(m,3H),1.27–1.21(m,2H),1.19–1.10(m,3H).MS(ESI)m/z:618.15[M+Na] + 。
Example 47: preparation of 4- (hydroxyamino) -4-oxobutyl-4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 47)
Intermediate 5a (0.24 g,0.5 mmol), ethyl 4-bromobutyrate (0.12 g,0.6 mmol) and triethylamine (0.06 g,0.6 mmol) were dissolved in methanol (5 mL) and reacted at 50 ℃ for 4h, after the reaction was completed, cooled to room temperature, concentrated in vacuo and column chromatographed to give ethyl 4- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-thiocarbonyl) butyrate as a white solid, 0.25g, 90% yield.
Intermediate 4- ((4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-thiocarbonyl) ethyl butyrate (0.25 g,0.45 mmol), DBU (0.04 g,0.23 mmol) and aqueous hydroxylamine (0.27 g,8.2 mmol) were dissolved in methanol (5 mL), reacted for 3h at 40 ℃, cooled to room temperature after reaction completion, diluted with water (5 mL), adjusted to pH6 with 2N HCl, extracted (3X 5 mL) with DCM: iPrOH (3:1.) the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a pale red solid, 0.15g, 62% yield.
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),10.42(s,1H),8.72(s,1H),8.27(d,J＝6.7Hz,1H),7.98–7.93(m,1H),7.93–7.87(m,1H),7.86–7.81(m,1H),7.49–7.43(m,1H),7.42–7.37(m,1H),7.25(t,J＝7.5Hz,1H),4.34(s,3H),4.18–4.01(m,2H),3.93–3.81(m,1H),3.77–3.69(m,2H),3.40–3.34(m,2H),3.29–3.21(m,2H),2.13–2.02(m,2H),1.90–1.82(m,2H)； 13 CNMR(151MHz,DMSO-d 6 )δ196.29,168.71,164.66,159.87,157.76,156.13,145.27,135.27,133.96,132.41,132.36,132.04,129.55,129.52,128.38,126.56,125.94,123.84,123.72,116.55,116.41,45.82,41.40,36.94,36.18,31.77,24.92.MS(ESI)m/z(％):566.17[M+Na] + 。
The compounds of examples 48-63 were prepared from intermediates 5 and 7 and various small molecule haloesters according to the procedure for the preparation of example 47.
Example 48: preparation of 5- (hydroxyamino) -5-oxopentyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 48)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),10.36(s,1H),8.69(s,1H),8.32–8.23(m,1H),8.02–7.77(m,3H),7.52–7.35(m,2H),7.30–7.20(m,1H),4.34(s,2H),4.34––3.81(m,4H),3.79–3.63(m,2H),3.40–3.34(m,2H),3.30–3.20(m,2H),2.07–1.89(m,2H),1.72–1.47(m,4H).MS(ESI)m/z:580.19[M+Na] + 。
Example 49: preparation of 6- (hydroxyamino) -6-oxohexyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 49)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),10.35(s,1H),8.68(s,1H),8.27(d,J＝7.7Hz,1H),7.96(d,J＝7.9Hz,1H),7.90(t,J＝7.4Hz,1H),7.84(t,J＝7.4Hz,1H),7.48–7.43(m,1H),7.41–7.37(m,1H),7.25(t,J＝8.9Hz,1H),4.34(s,2H),4.34–3.80(m,4H),3.78–3.68(m,2H),3.35–3.32(m,2H),3.24(t,J＝7.3Hz,2H),1.95(t,J＝7.2Hz,2H),1.62(p,J＝7.3Hz,2H),1.55–1.47(m,2H),1.39–1.30(m,2H).MS(ESI)m/z:594.08[M+Na] + 。
Example 50: preparation of 7- (hydroxyamino) -7-oxoheptyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 50)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),10.33(s,1H),8.66(s,1H),8.35–8.20(m,1H),8.00–7.79(m,3H),7.51–7.33(m,2H),7.31–7.19(m,1H),4.34(s,2H),4.34–3.80(m,4H),3.80–3.64(m,2H),3.39–3.33(m,2H),3.27–3.18(m,2H),2.03–1.83(m,2H),1.68–1.21(m,8H).MS(ESI)m/z:608.29[M+Na] + 。
Example 51: preparation of 4- (hydroxycarbamoyl) benzyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 51)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),11.20(s,1H),9.04(s,1H),8.31–8.20(m,1H),7.99–7.79(m,3H),7.74–7.64(m,2H),7.52–7.41(m,3H),7.41–7.36(m,1H),7.29–7.21(m,1H),4.61(s,2H),4.34(s,2H),4.34–3.80(m,4H),3.78–3.66(m,2H),3.38–3.34(m,2H).MS(ESI)m/z:614.05[M+Na] + 。
Example 52: (E) Preparation of (E) -4- (3-hydroxyamino) -3-oxoprop-1-en-1-ylbenzyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydrophthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 52)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),10.79(s,1H),9.06(s,1H),8.32–8.22(m,1H),7.98–7.80(m,3H),7.55–7.36(m,7H),7.29–7.21(m,1H),6.53–6.38(m,1H),4.58(s,2H),4.34(s,2H),4.34–3.82(m,4H),3.79–3.67(m,2H),3.45–3.35(m,2H).MS(ESI)m/z:640.23[M+Na] + 。
Example 53: preparation of 6- (hydroxyamino) -6-oxohexyl 4- (3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 53)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),10.35(s,1H),8.67(s,1H),8.27(d,J＝7.5Hz,1H),7.96(d,J＝7.5Hz,1H),7.91–7.86(m,1H),7.86–7.80(m,1H),7.45–7.37(m,3H),7.33–7.26(m,1H),4.36(s,2H),4.36–3.84(m,4H),3.76–3.62(m,2H),3.51–3.37(m,2H),3.24(t,J＝7.0Hz,2H),1.95(t,J＝7.0Hz,2H),1.68–1.57(m,2H),1.55–1.46(m,2H),1.38–1.29(m,2H).MS(ESI)m/z:576.03[M+Na] + 。
Example 54: preparation of 7- (hydroxyamino) -7-oxoheptyl 4- (3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 54)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),10.33(s,1H),8.65(s,1H),8.26(d,J＝7.7Hz,1H),7.96(d,J＝7.9Hz,1H),7.89(t,J＝7.3Hz,1H),7.83(t,J＝7.4Hz,1H),7.45–7.35(m,3H),7.29(d,J＝7.3Hz,1H),4.36(s,2H),4.36–3.80(m,4H),3.78–3.58(m,2H),3.47–3.35(m,2H),3.23(t,J＝7.1Hz,2H),1.93(t,J＝7.1Hz,2H),1.67–1.57(m,2H),1.51–1.45(m,2H),1.38–1.32(m,2H),1.28–1.25(m,2H).MS(ESI)m/z:589.98[M+Na] + 。
Example 55: preparation of 6- (hydroxyamino) -6-oxohexyl 4- (3-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 55)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),10.35(s,1H),8.68(s,1H),8.35–8.20(m,1H),8.03–7.82(m,3H),7.36–7.13(m,3H),4.39(s,2H),4.39–3.83(m,4H),3.76–3.62(m,2H),3.48–3.37(m,2H),3.29–3.19(m,2H),2.03–1.89(m,2H),1.68–1.58(m,2H),1.56–1.47(m,2H),1.38–1.30(m,2H).MS(ESI)m/z:594.02[M+Na] + 。
Example 56: preparation of 7- (hydroxyamino) -7-oxoheptyl 4- (3-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 56)
1 H NMR(600MHz,DMSO-d 6 )δ12.61(s,1H),10.34(s,1H),8.66(s,1H),8.27(d,J＝7.6Hz,1H),7.98(d,J＝7.7Hz,1H),7.91(t,J＝7.1Hz,1H),7.85(t,J＝7.2Hz,1H),7.31(d,J＝9.1Hz,1H),7.23(s,1H),7.17(d,J＝8.3Hz,1H),4.39(s,2H),4.35–4.13(m,2H),4.07–3.83(m,2H),3.76–3.62(m,2H),3.46–3.36(m,2H),3.24(t,J＝7.1Hz,2H),1.94(t,J＝7.1Hz,2H),1.66–1.58(m,2H),1.51–1.45(m,2H),1.39–1.32(m,2H),1.28–1.25(m,2H).MS(ESI)m/z:608.23[M+Na] + 。
Example 57: preparation of 6- (hydroxyamino) -6-oxohexyl 4- (4-fluoro-3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 57)
1 H NMR(600MHz,DMSO-d 6 )δ12.55(s,1H),10.34(s,1H),8.67(s,1H),8.37–8.20(m,1H),8.07–7.79(m,3H),7.50–7.24(m,3H),4.39(s,2H),4.31–3.84(m,4H),3.75–3.57(m,2H),3.53–3.37(m,2H),3.28–3.20(m,2H),2.05–1.84(m,2H),1.69–1.57(m,2H),1.56–1.46(m,2H),1.40–1.28(m,2H).MS(ESI)m/z:594.27[M+Na] + 。
Example 58: preparation of 7- (hydroxyamino) -7-oxoheptyl 4- (4-fluoro-3- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) piperazine-1-carbodisulfate (Compound 58)
1 H NMR(600MHz,DMSO-d 6 )δ12.55(s,1H),10.34(s,1H),8.66(s,1H),8.28(d,J＝7.3Hz,1H),8.04–7.93(m,2H),7.91–7.83(m,1H),7.46–7.36(m,2H),7.31(t,J＝8.1Hz,1H),4.39(s,2H),4.34–3.81(m,4H),3.76–3.57(m,2H),3.52–3.36(m,2H),3.28–3.19(m,2H),2.00–1.88(m,2H),1.67–1.57(m,2H),1.52–1.44(m,2H),1.39–1.32(m,2H),1.29–1.24(m,2H).MS(ESI)m/z:608.16[M+Na] + 。
Example 59: preparation of 6- (hydroxyamino) -6-oxohexyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) -1, 4-diazacycloheptane-1-carbodisulfate (Compound 59)
MS(ESI)m/z:607.97[M+Na] + 。
Example 60: preparation of 7- (hydroxyamino) -7-oxoheptyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzoyl) -1, 4-diazepane-1-carbodisulfate (Compound 60)
MS(ESI)m/z:622.05[M+Na] + 。
Example 61: preparation of 6- (hydroxyamino) -6-oxohexyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 61)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),10.34(s,1H),8.67(s,1H),8.35–8.22(m,2H),7.98(d,J＝7.7Hz,1H),7.89(t,J＝7.2Hz,1H),7.83(t,J＝7.2Hz,1H),7.58–7.49(m,1H),7.49–7.40(m,1H),7.20(t,J＝9.1Hz,1H),5.22–5.06(m,1H),4.49–4.37(m,1H),4.33(s,2H),4.20–4.11(m,1H),3.59–3.44(m,2H),3.26–3.17(m,2H),2.03–1.85(m,4H),1.65–1.58(m,2H),1.55–1.46(m,4H),1.37–1.30(m,2H).MS(ESI)m/z:608.03[M+Na] + 。
Example 62: preparation of 7- (hydroxyamino) -7-oxoheptyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 62)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),10.34(s,1H),8.66(s,1H),8.31(d,J＝7.4Hz,1H),8.26(d,J＝7.7Hz,1H),7.98(d,J＝7.8Hz,1H),7.89(t,J＝7.3Hz,1H),7.83(t,J＝7.3Hz,1H),7.56–7.51(m,1H),7.47–7.41(m,1H),7.20(t,J＝9.2Hz,1H),5.21–5.07(m,1H),4.48–4.38(m,1H),4.33(s,2H),4.21–4.09(m,1H),3.56–3.44(m,2H),3.25–3.16(m,2H),1.98–1.88(m,4H),1.65–1.57(m,2H),1.52–1.44(m,4H),1.38–1.32(m,2H),1.28–1.24(m,2H).MS(ESI)m/z:622.05[M+Na] + 。
Example 63: preparation of 4- (hydroxycarbamoyl) benzyl 4- (2-fluoro-5- ((4-oxo-3, 4-dihydro-phthalazin-1-yl) methyl) benzamide) piperidine-1-carbodisulfate (Compound 63)
1 H NMR(600MHz,DMSO-d 6 )δ12.60(s,1H),11.20(s,1H),9.03(s,1H),8.34–8.24(m,2H),8.00–7.94(m,1H),7.92–7.87(m,1H),7.85–7.79(m,1H),7.69(d,J＝7.5Hz,2H),7.55–7.51(m,1H),7.49–7.38(m,3H),7.23–7.17(m,1H),5.17–5.06(m,1H),4.59(s,2H),4.44–4.36(m,1H),4.33(s,2H),4.20–4.13(m,1H),3.60–3.48(m,2H),1.99–1.90(m,2H),1.56–1.46(m,2H).MS(ESI)m/z:628.07[M+Na] + 。
Investigation of the biological Activity of the Compounds of the invention
Assays for inhibiting PARP-1 Activity by Compounds
The assay for measuring PARP-1 kinase activity is based on an enzyme-linked immunosorbent assay (ELISA). The specific operation is as follows:
a histone coated 384-well plate was prepared, 25 μl of histone solution was added to each well, and incubated overnight at 4 ℃. PBST buffer, blocking buffer and assay buffer were prepared and histone coated 384-well plates were washed 3 times with PBST buffer. Blocking was performed with 50. Mu.L of blocking buffer for 1h at room temperature. Plates were washed 3 times with PBST buffer. 1000x compound was prepared in the source plate. mu.L of the compound was transferred from the source plate to a 96 well intermediate plate, shaken at 1000rpm and centrifuged for 1min. Transfer 5 μl DMSO/compound into each well. PARP-1 and DNA mixtures were incubated at 25℃for 10min. 10. Mu.L of PARP-1 was added&DNA was incubated with the compound for 10min at room temperature and 10. Mu.L of DNA was added to the minimum control of the assay plate. 10 μL 2.5XNAD was added to each well + And incubated at 25℃for 60min. Plates were washed 3 times with PBST buffer. mu.L of anti-poly/mono ADP ribose rabbit monoclonal antibody was added. Incubate for 1.5h at room temperature and wash the plates 3 times with PBST buffer. mu.L of diluent (1:2000 in blocking buffer) anti-rabbit IgG, HRP antibody was added. Incubate for 1h at room temperature, then wash the plates 3 times with PBST buffer. mu.L of a mixture of Femto-ECL substrate A and Femto-ECL substrate B (1:1) was added. Chemiluminescence was read immediately on Envision. Calculation of IC of example Compounds against PARP-1 kinase 50 The data are shown in Table 1.
TABLE 1
Figure SMS_19
/>
Figure SMS_20
Compounds inhibit HDAC-1 Activity assay
The assay for measuring HDAC-1 kinase activity is based on an enzyme-linked immunosorbent assay (ELISA). The specific operation is as follows:
1 Xassay buffer (modified Tris buffer) was prepared. Compounds were transferred to assay plates by Echo550 in 100% dmso. Enzyme solutions were prepared in 1x assay buffer. Trypsin and Ac peptide substrates were added to 1x assay buffer to make a substrate solution. Transfer 15. Mu.L of enzyme solution to assay plate. For low controls, transfer of 15 μl1x assay buffer is required. To each well 10 μl of substrate solution was added to start the reaction. Plates were read on Paradigm with 355nm excitation and 460nm emission kinetics. The inhibition data for the HDAC-1 kinase by the example compounds are shown in Table 2.
TABLE 2
Figure SMS_21
/>
Figure SMS_22
In vitro antitumor cell Activity
The phthalazinone compounds of the formula I are subjected to in vitro activity screening for inhibiting human breast cancer cells MDA-MB-436, human breast cancer cells MCF-7 and human breast cancer cells MDA-MB-231.
After resuscitating and passaging 2-3 times for stabilization, the cells were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digests into a centrifuge tube, the culture broth is then added to terminate digestion. Centrifuging the centrifuge tube at 800r/min for 10min, removing the supernatant, adding 5mL of culture solution, blowing and beating uniformly mixed cells, sucking 10 mu L of cell suspension, adding into a cell counting plate for counting, and adjusting the cell concentration to 104 cells/hole. Except that the A1 well was blank, no cells were added, and 100. Mu.L of the cell suspension was added to the 96-well plate. The 96-well plate was placed in an incubator for cultivation for 24 hours.
The sample was dissolved in 50. Mu.L of dimethyl sulfoxide, and then an appropriate amount of culture solution was added to dissolve the sample into 2mg/mL of a liquid medicine, and then the sample was diluted to 20, 4, 0.8, 0.16, 0.032. Mu.g/mL in a 24-well plate.
3 wells were added at each concentration, with two rows and two columns surrounding the well, which had greater environmental impact, and were used only with blank wells. The 96-well plate was placed in an incubator for cultivation for 96 hours.
The medicated culture solution in the 96-well plate was discarded, the cells were washed twice with Phosphate Buffered Saline (PBS), 100. Mu.L of MTT (0.5 mg/mL) was added to each well, and after 4 hours in the incubator, the MTT solution was discarded, and 100. Mu.L of dimethyl sulfoxide was added. The surviving cells and MTT reaction product A are fully dissolved by oscillating on a magnetic oscillator, and the result is measured in an enzyme-labeled instrument. Drug IC can be determined by the Bliss method 50 Values.
The results of the compounds inhibiting the activities of human breast cancer cells MDA-MB-436, MCF-7 and MDA-MB-231 are shown in Table 3.
TABLE 3 Table 3
Figure SMS_23
/>
Figure SMS_24
/>
Figure SMS_25
From the above test results, it is clear that the compounds of formula I to be protected according to the present invention have high level of inhibitory activity against PARP and/or HDAC, and good in vitro anti-tumor cell proliferation activity.
While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims (9)

1. A phthalazinone compound or a pharmaceutically acceptable salt thereof, wherein the phthalazinone compound has the structural formula:
Figure FDA0003988102370000011
wherein:
X 2 、X 3 、X 4 each independently is CR 3 ；
R 3 Selected from hydrogen, fluorine;
ring A is selected from
Figure FDA0003988102370000012
n is 1 or 2;
R 2 selected from (C) 1 -C 8 ) Alkyl, said (C) 1 -C 8 ) Alkyl groups optionally being substituted by 1-3R 4 Substitution;
R 4 selected from trifluoromethyl, difluoromethyl, amino, hydroxy, phenyl, pyridyl, (C) 1 -C 4 ) Alkoxy, phenyl (C) 2 -C 4 ) Alkenyl group,
Figure FDA0003988102370000013
Said phenyl, phenyl (C 2 -C 4 ) Alkenyl and pyridyl can optionally be +.>
Figure FDA0003988102370000014
Or 1-3R 7 Substitution;
R 5 、R 6 each independently selected from hydrogen, hydroxy, (C) 1 -C 4 ) Alkyl, hydroxy (C) 1 -C 4 ) Alkyl, (C) 3 -C 6 ) Cycloalkyl; said (C) 1 -C 4 ) Alkyl groups optionally being substituted by 1-3R 11 Substitution;
or R is 5 And R is 6 Together with the nitrogen atom to which they are attached, form a 5-6 membered nitrogen containing heterocyclic ring containing 1-3 heteroatoms selected from N, O and S, said nitrogen containing heterocyclic ringThe heterocyclic ring may optionally include 1 to 2 carbon-carbon double or triple bonds, and the nitrogen-containing heterocyclic ring may optionally be substituted with 1 to 3R's, which may be the same or different 10 Substituted, the ring carbon atom may be oxo;
R 11 selected from hydroxy groups, (C) 1 -C 6 ) Alkoxy, (C) 1 -C 6 ) An alkylamino group;
R 7 selected from hydrogen, halogen, trifluoromethyl, (C) 1 -C 4 ) Alkyl, amino, hydroxy, cyano;
R 10 selected from hydrogen, (C) 1 -C 4 ) Alkyl, hydroxy (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) Alkoxy, hydroxy, amino, (C) 1 -C 4 ) An acyl group.
2. The phthalazinone compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in formula I, R 2 Selected from:
Figure FDA0003988102370000015
/>
Figure FDA0003988102370000021
3. the phthalazinone compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the phthalazinone compound of formula i is any one of the following compounds:
Figure FDA0003988102370000022
/>
Figure FDA0003988102370000031
/>
Figure FDA0003988102370000041
/>
Figure FDA0003988102370000051
4. the phthalazinone compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein said pharmaceutically acceptable salt is a salt of said phthalazinone compound with an inorganic acid selected from the group consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; the organic acid is selected from the group consisting of: fumaric acid, succinic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid; the alkali metal ions are selected from potassium ions, sodium ions and lithium ions.
5. A pharmaceutical composition comprising the phthalazinone compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, in admixture with a pharmaceutically acceptable carrier or excipient; the carrier or excipient is one or more of diluent, adhesive, wetting agent, disintegrating agent, lubricant and glidant; the diluent is one or more of starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol and calcium hydrophosphate; the wetting agent is one or more of water, ethanol and isopropanol; the adhesive is one or more of starch slurry, dextrin, syrup, honey, glucose solution, acacia pulp, gelatin pulp, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose and polyethylene glycol; the disintegrating agent is one or more of dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch and sodium dodecyl sulfate; the lubricant and the glidant are one or more of talcum powder, silicon dioxide and polyethylene glycol; the pharmaceutical composition can be prepared into pharmaceutically acceptable dosage forms, and the dosage forms are selected from injection, tablets and capsules.
6. Use of a phthalazinone compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention and/or treatment of cancer, neurodegenerative diseases or inflammation associated with PARP enzyme and HDAC enzyme.
7. Use of the pharmaceutical composition of claim 5 for the preparation of a medicament for the prevention and/or treatment of cancer, neurodegenerative diseases or inflammation associated with PARP enzyme and HDAC enzyme.
8. The use according to claim 6 or 7, wherein the cancer is any one of breast cancer, pancreatic cancer, ovarian cancer, lung cancer, liver cancer, stomach cancer, colorectal cancer, cervical cancer, testicular cancer, melanoma, nasopharyngeal cancer, oral cancer, glioblastoma, bladder cancer, prostate cancer, esophageal cancer, brain tumor, tumor of the reproductive system, tumor of the respiratory system, tumor of the lymphatic system, tumor of the digestive system, and tumor of the skin.
9. A process for the preparation of a phthalazinone compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising the following synthetic route:
the R is 2 、X 2 、X 3 、X 4 Is a corresponding group in a corresponding position of a compound shown in a general formula I, wherein n=1 or 2;
route 1:
Figure FDA0003988102370000061
the substituted or substituted o-formylbenzoic acid is used as a starting material to react with dimethyl phosphite to prepare a phosphorus ylide intermediate 1; intermediate 1 is reacted by Wittig-Horner to obtain intermediate 2; intermediate 2 is subjected to cyano hydrolysis and cyclization reaction to prepare intermediate 3; intermediate 3 is subjected to condensation and Boc protection removal reaction to prepare intermediate 4; intermediate 4 is subjected to carbon disulfide addition to prepare intermediate 5; intermediate 5 reacts with halogenated amine, halogenated amide or halogenated ester through nucleophilic substitution reaction to prepare target compound of formula II;
route 2:
Figure FDA0003988102370000071
taking the intermediate 3 as a raw material, and performing condensation and Boc removal protection reaction to obtain an intermediate 6; intermediate 6 is subjected to carbon disulfide addition to prepare intermediate 7; intermediate 7 reacts with halogenated amine, halogenated amide or halogenated ester through nucleophilic substitution reaction to prepare target compound of formula III.
CN202211571163.6A 2022-12-08 2022-12-08 Phthalazinone compound, and preparation method and application thereof Active CN116143700B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211571163.6A CN116143700B (en) 2022-12-08 2022-12-08 Phthalazinone compound, and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211571163.6A CN116143700B (en) 2022-12-08 2022-12-08 Phthalazinone compound, and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN116143700A true CN116143700A (en) 2023-05-23
CN116143700B CN116143700B (en) 2024-06-28

Family

ID=86351601

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202211571163.6A Active CN116143700B (en) 2022-12-08 2022-12-08 Phthalazinone compound, and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN116143700B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898377A (en) * 2012-02-14 2013-01-30 南京圣和药业有限公司 Novel phthalazinone derivatives and uses thereof
CN102898378A (en) * 2012-11-16 2013-01-30 江苏先声药业有限公司 Phthalazinone derivatives and application thereof
CN110194762A (en) * 2018-02-27 2019-09-03 中国科学院上海药物研究所 Phthalazines ketones derivant, preparation method and use
CN110845425A (en) * 2019-11-07 2020-02-28 合肥工业大学 Phthalazine derivative and preparation method and application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898377A (en) * 2012-02-14 2013-01-30 南京圣和药业有限公司 Novel phthalazinone derivatives and uses thereof
CN102898378A (en) * 2012-11-16 2013-01-30 江苏先声药业有限公司 Phthalazinone derivatives and application thereof
CN110194762A (en) * 2018-02-27 2019-09-03 中国科学院上海药物研究所 Phthalazines ketones derivant, preparation method and use
CN110845425A (en) * 2019-11-07 2020-02-28 合肥工业大学 Phthalazine derivative and preparation method and application thereof

Also Published As

Publication number Publication date
CN116143700B (en) 2024-06-28

Similar Documents

Publication Publication Date Title
CA3049141C (en) N-[4-fluoro-5-[[(2s,4s)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide as oga inhibitor
JP6141568B1 (en) Novel pyrazolo [3,4-d] pyrimidine compound or salt thereof
KR100618074B1 (en) Benzamide derivatives and their use as cytokine inhibitors
EP2799437B1 (en) Quinoline and cinnoline derivatives and use thereof
CN108314677B (en) EZH2 inhibitor and application thereof
US20030004158A1 (en) Nitrogen containing heterocyclic quinoline compounds
SK135597A3 (en) Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases
JP2010508288A (en) Heterocyclic amide compounds useful as kinase inhibitors
CZ300293B6 (en) Novel amide derivatives, process of their preparation and pharmaceutical composition in which they are comprised
CZ20013276A3 (en) Novel amide derivatives, process of their preparation and pharmaceutical composition in which they are comprised
JPWO2005080392A1 (en) Pyrazoloquinolone derivatives and uses thereof
EP1012147B1 (en) O-substituted hydroxycumaranone derivatives as antitumor and antimetastatic agents
JP2000143635A (en) Arterialization inhibitor
CA2536313A1 (en) Fused pyrimidine derivative and use thereof
CN106632181A (en) Aurone mannich base compound and preparation method and application thereof
EP2733144B1 (en) Novel compound having parp inhibitory activity
CA2724003A1 (en) Novel n-(2-amino-phenyl)-acrylamides
JP2002537285A (en) Acylated aminoacetonitriles as cysteine protease inhibitors
CN116143700B (en) Phthalazinone compound, and preparation method and application thereof
JP2003231633A (en) Medicinal composition
AU2020424661B2 (en) Disubstituted adamantyl derivative or pharmaceutically acceptable salt thereof, and pharmaceutical composition for suppressing cancer growth comprising same as active ingredient
US20040176594A1 (en) Nitrogenous heterocyclic compounds
KR102576102B1 (en) Probe for detecting uch37 and uses thereof
CN117229264A (en) Aryl Schiff base compound containing 2-aminopyrimidine structure and application thereof
NZ754849B2 (en) N-[4-fluoro-5-[[(2s,4s)-2-methyl-4-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]-1-piperidyl]methyl]thiazol-2-yl]acetamide as oga inhibitor

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant