WO2020173328A1 - Dérivé de pyrrole et son procédé de préparation et son application - Google Patents

Dérivé de pyrrole et son procédé de préparation et son application Download PDF

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WO2020173328A1
WO2020173328A1 PCT/CN2020/075626 CN2020075626W WO2020173328A1 WO 2020173328 A1 WO2020173328 A1 WO 2020173328A1 CN 2020075626 W CN2020075626 W CN 2020075626W WO 2020173328 A1 WO2020173328 A1 WO 2020173328A1
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methyl
pyrrol
phenyl
ethyl
pyrrole
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陈亚东
陆涛
姜飞
马宇
李红玫
卞媛媛
崔勇
李慧丽
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China Pharmaceutical University
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    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic 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
    • A61K31/4523—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to pyrrole derivatives and their preparation methods and applications, especially their use as BET protein inhibitors.
  • tumors have become one of the main causes of human deaths worldwide.
  • Tumors generally have the characteristics of low overall cure rate and high recurrence rate. Therefore, prevention, treatment and suppression of tumor recurrence are of important scientific research value. Realizing tumor prevention and cure is quite urgent and challenging.
  • Bromodoma i ns are conserved protein domains that can specifically recognize acetylated lysine residues in histones.
  • BRDs exist in different proteins and play a key regulatory role in chromatin assembly and gene transcription.
  • BRDs small molecule inhibitors can interfere with the specific binding of BRDs domain to acetylated lysine, thereby blocking or partially blocking the role of acetylated lysine in gene transcription and regulating chromatin structure.
  • BRDs have been proven to be highly adaptable targets, and small molecule inhibitors acting on BRDs also have broad application prospects in the treatment of diseases, which has further enhanced the understanding of BRDs and related diseases by scientific researchers.
  • BRDs have become popular drug targets, and the biological functions and disease indications of human BRDs family members have also been elaborated.
  • BRDs inhibitors aimed at drug discovery.
  • These small molecule inhibitors have two main applications: First, these molecules can be used as chemical probes to explore the biological functions of BRDs in chromatin signaling pathways and transcriptional activation and silencing processes; Secondly, these molecules can treat various humans The potential of the disease.
  • the translational research of BRDs small molecule inhibitors is currently mainly focused on the T family, which includes BRD2, BRD3, BRD4 and BRDT.
  • BET inhibitors The emergence of new ⁇ T inhibitors will advance the understanding of transcriptional regulation in the context of diseases, and may be used as new epigenetic therapeutic drugs to treat many clinical diseases, such as cancer, inflammatory diseases, autoimmune diseases and cardiovascular diseases Diseases etc.
  • the compounds that enter clinical research are mainly triazines, quinolinones and pyridopyrroles.
  • the above types of inhibitors are relatively simple in structure, and the PK properties and in vitro properties of the compounds are not very ideal. Therefore, the present invention hopes to develop a novel structure core BET inhibitors to prevent and treat diseases related to this protein pathway.
  • the present invention provides a new type of core structure of T T. It is found that this type of compound has good activity and exhibits excellent drug-making properties. Summary of the invention
  • the present invention designs and synthesizes pyrrole derivatives and their preparation methods and applications by studying the crystal structure model of BET protein and summarizing the structure-activity relationship of BET.
  • the pharmacological test results show that the compound of the present invention has good BET protein inhibitory activity, Has good application prospects.
  • R 1 represents argon, halogen, alkyl, haloalkyl, heterocycloalkyl, cycloalkyl;
  • R 2 and R 3 are each independently selected from halogen, cyano, aryl, Het, R 5 , -COR 5 , -C0NHR 5 , -C0NR 5 Het, -G0R 5 Het, -G00R 5 , -GOOHet, -NHR 5 , -NH (CH 2 ) 1HD Het, -NH (CH 2 ),- 10 OR 5 > -NH (CH 2 ),- 10 NR 5 2> -NHC00R 5 , -NHCOOHet, -NHCONHR 5 , -NHCONHHet, -OR 5 , -0 (CH 2 ),- 10 NR 6 2> -0 (CH 2 ),- 10 Het or -0 (CHUR 5 ;
  • R 4 represents halogen, cyano, Het, R 5 , -COR 5 , -C0NR 5 Het, -G0R 5 Het, -GONHHet, -COOHet, -NHR 5 , -NH (CH 2 ),- 10 Het. -NH (CH 2 ),- 10 OR 5 > -NH (CH 2 ),-, o NR 5 2> -NHC00R 5 , -NHCOOHet, -NHCONHR 5 , -NHCONHHet, -OR 5 , -0 (CH 2 ),- 10 NR 5 2 , -(Kcm Hd Het or -(KCHJ HO OR 5 ;
  • X represents N, CNHR 5 , GNHGOR 5 , GNHHet, CNHCOHet;
  • Z means NR 5 ;
  • A represents alkenyl, alkynyl, biphenyl, cycloalkyl, cycloheteroalkyl, aryl ring or Het.
  • the biphenyl, aryl, diarylamino or Het may be optionally substituted with the following groups: halogen , -CN, -0H, -GF 3 , 0GF 3 , -OR 5 , -SH, -SR 5 , -NH 2 , -NHR 5 , -NR 5 2 , -NHC0R 5 , -NHS0 2 R 5 , -NRS0 2 R 5 , -COR% -C00R 5 , -G0NHR 5 , -CON (R 5 2 ), -CONH (CH 2 ),- 10 N (R 5 2 ), -C0NR 5 2 , -CON (R 5 2 ) 0, -CONH (CH 2 ) ,_i o N (R 5 2
  • B represents a single bond, 0, S, NH, NR 5 , NHR 5 , OR 5 , SR% R 5 , where R 5 represents a hydrogen atom, an alkyl group, a haloalkyl group, a heterocycloalkyl group, or a cycloalkyl group;
  • the aryl group is a carbocyclic ring containing phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, and the phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl group can be optionally substituted with 1, 2 or 3
  • the substituents are independently selected from the group consisting of hydrogen, alkyl, cyano, self-substituted alkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, Diarylalkyl, phenyl-containing carbocyclic ring, naphthyl-containing carbocyclic ring, acenaphthyl-containing carbocyclic ring, tetrahydronaphthyl-containing carbocyclic ring or Het;
  • the Het is selected from the group consisting of pyrrolidinyl, pyrrolyl, bitoyl, imidazolyl, pyranyl, morpholinyl, phenenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole Monocyclic heterocyclic ring of quinolinyl, pyrazinyl, pyrimidinyl, pipenoyl, substituted piperazinyl, pyrazinyl or pyridazinyl; or selected from quinolinyl, quinoxalinyl, indino, and benzimidazole Group, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxanyl, benzothienyl, 2, 3 -dihydrobenzoL&] [1, 4] Dioxanyl or benzo IV] [1, 3] Dioxolane bicyclic heterocycle; each
  • the halogen is selected from fluorine, chlorine or bromine.
  • Z means NR 5 ;
  • R 1 represents hydrogen cycloalkyl group ⁇ Hyun, Su supplier, alkyl, substituted alkyl, heterocycloalkyl having 3 to 7 carbon atoms, or 3 to 7 carbon atoms.
  • 2-(5-methyl-3-phenyl-1 //pyrrol-2-yl) -1 benzo[J] imidazole (1-1), 2-(4-ethyl-5 -Methyl-3-phenyl-1//pyrrol-2-yl)-1//benzo[o]imidazole (1-2), 1-(5-(benzo[o!l thiazole-2- Group) -2 -methyl-4 -phenyl-1 //pyrrol-3-yl) ethyl-1-one (1-3), 1-(5-(1 //benzo[o!l imidazole-2 -Yl)-2 -methyl-4-phenyl-1//pyrrol-3-yl)ethan-1-one (1-4), ethyl 5-(1//benzo[o] imidazole-2- Group)-2-methyl-4-phenyl-1//pyrrole-3-carboxylate (1-5), 5-(// ⁇ benzo
  • Ethyl-1 ketone (Bu87), 1 - ⁇ 5-[5-(2,4-dimethylpiperidin-1-yl)-1//benzo
  • the pharmaceutically acceptable salt includes the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, and diastereomer
  • the method for preparing the compound represented by the general formula ( ⁇ ) or its mixture or its acceptable salt is prepared by continuous reaction using ethyl acetoacetate derivative or aminoaryl ethyl ketone derivative as starting material .
  • a pharmaceutical composition in which the active ingredient is a compound of the general formula (1) or a mixture or acceptable salt thereof.
  • the above-mentioned pharmaceutical composition is used in the preparation of products for preventing or treating clinical diseases related to BRD protein.
  • the clinical conditions associated with BRD protein are rheumatoid arthritis, gouty arthritis melanoma, liver cancer, kidney cancer, acute leukemia, multiple myeloma, lymphoma, non-small cell lung cancer, prostate cancer, and Adenocarcinoma, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, gastrointestinal cancer or mesothelioma.
  • the ligand was serially diluted from 150
  • i I was then incubated for 60 minutes under dark conditions, and then read the light intensity using PHERAstar FSplate reader (B MG Labtech, Germany) equipment, the excitation/emission wavelengths were 680/570, respectively nm.
  • the compound experiment results are shown in the following table:
  • BRD4 IC 50 (nM) BRD4 IC 50 (nM)% (2 uM) a % (2 uM)
  • the MTT method was used to determine the inhibitory effect on the leukemia cell line MV4-11 tumor cell line.
  • the MTT method utilizes the NADP-related dehydrogenase in the mitochondria of living cells to reduce exogenous MTT into insoluble blue-purple crystals (Formazan), which are deposited in cells, while dead cells have no such function. Then use dimethyl sulfoxide (DKIS0) or triple solution (10% SDS-5% isobutanol-0.01mol/LHGL) to dissolve the purple crystals in the cells, and measure its OD with an enzyme-linked immunoassay at a wavelength of 570nm The value indirectly reflects the amount of living cells.
  • DKIS0 dimethyl sulfoxide
  • triple solution 10% SDS-5% isobutanol-0.01mol/LHGL
  • the biological activity test results show that the compound provided by the present invention has a BET protein inhibitory effect.
  • the compounds of the present invention can be used to treat various solid organ cancers, including melanoma, liver cancer, kidney cancer, lung cancer, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, testicular cancer, and bone cancer.
  • Cancer, brain cancer, esophageal cancer, gastrointestinal cancer, soft tissue tumor, blood cancer, lymphoma, etc., which can be caused by Cancer and inflammation mediated by BET protein may also be cancers that do not rely on the above-mentioned mechanisms. Therefore, the present invention proposes that the compound of the present invention can be used for the preparation of anticancer drugs.
  • liver microsomes of different species was determined by HPLC-MS.
  • HPLC-MS/MS method Incubate the mixture of microsome solution and compound at 37 ° C for a certain period of time, add phosphate buffer to NGF60 and incubate the frozen mixture of Tolbutamide and Labetalol (1:1) for different periods of time. reaction. The supernatant was obtained by centrifugation and analyzed by LG-MS/MS. The data was analyzed by first order kinetics to calculate T1/2 and GL.
  • MLM mimouse liver microsomes
  • RLM rat liver microsomes
  • DLM dog liver microsomes
  • CLM monkey liver microsomes
  • HLM human liver microsomes
  • Wuxi AppTec Co., Ltd. adds 10
  • Rat 0.209 3.32 1043 1878 a The control drug, midazolam is a fast-metabolizing sedative drug.
  • I -18, I -19 and I -30 all show strong in vitro metabolic stability, and the metabolic half-lives of the four species are better than the positive control Midazolam (Midazolam).
  • the half-life of ⁇ -19 in human and rat liver microsomes is as high as 199.3 min and 66.4 min, respectively, and the clearance rate is as low as 7.0 ul/min/mg and 20.9 ul/min/mg, respectively. It has better metabolic stability, longer half-life and lower clearance rate.
  • the in vitro activity test of BET protein shows that the compound provided by the present invention has significant BET protein binding ability.
  • the compounds provided by the present invention can be used to prevent or treat diseases related to BET protein inhibitors In particular, in tumor drugs.
  • the above method for preparing the compound represented by the general formula (1) or its mixture or its acceptable salt is prepared by continuous reaction with ethyl acetoacetate derivative or aminoaryl ethyl ketone derivative as starting material .
  • Step 1 Ethyl acetoacetate derivative (1-a) of general formula is glacial acetic acid solvent, add sodium nitrite, powder and acetyl derivative (1-b) and stir at room temperature for 8 hours, then heat the reaction to obtain compound ( 1-c).
  • Step 2 The compound of general formula (1-c) is heated and decarboxylated under strong base conditions to obtain compound (1-d), where the strong base includes: NaOH and K0H.
  • Step 3 The general formula aminoaryl ethyl ketone derivative (1-e) and acetyl derivative (1-b) are heated in absolute ethanol to obtain compound (1-d).
  • Step 4 General formula °Pyrroles (1-d) Under the condition of chlorooxyphosphonium, the Vi Ismeier-Haack reaction occurs to obtain compound (1-e).
  • Step 5 Compound (1-g) obtained by nucleophilic reaction of general formula nitrobenzene derivative (1-f) under basic conditions.
  • Step 6 Substitute the general formula to obtain the nitrobenzene derivative (1-g). Under the conditions of iron powder, ammonium chloride or palladium carbon and hydrogen, a reduction reaction occurs to obtain the compound (1-h).
  • Step 7 The compound (1-e) and compound (1 ⁇ h) of general formula are heated under the conditions of metabisulfurous acid and nitrogen to obtain the target compound (1-x).
  • the invention belongs to the field of medicinal chemistry, and specifically relates to pyrrole derivatives and their preparation methods and applications.
  • ethyl acetoacetate derivatives and aminoaryl ethyl ketone derivatives are used as starting materials to obtain pyrrole derivatives ( ⁇ ) through continuous reactions.
  • the preparation method route is relatively short, and the route is in eight steps. Or it is simpler within eight steps, the raw materials are more common and easy to obtain, and the preparation method has better applicability.
  • the p- pyrrole derivatives are a new class of BET protein inhibitors, with excellent protein activity and anti-tumor cell proliferation activity. At the same time, it has very good druggability, stable metabolism of liver microsomes, long half-life and low clearance rate. During the preparation process, it was found that this type of compound has good water solubility and has potential as an oral anti-tumor drug.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • S NMR shift
  • DMSO-d 6 neon-substituted dimethyl sulfoxide
  • CDG1 3 deuterated chloroform
  • CD 3 0D deuterated methanol
  • TMS tetramethylsilane
  • the thin layer chromatography silicon limb board uses Yantai Huanghai HSGF254 or Qingdao GF254 silicon limb board.
  • the silicon rubber sheet used in thin layer chromatography (TLC) adopts a size of 0.15mm ⁇ 0.2mm.
  • Thin layer chromatography is used for separation and purification products.
  • the specification is 0.4mm-0.5.
  • Cylindrical chromatography generally uses Yantai Huanghai baby limb 200 ⁇ -300 mesh silica gel as a carrier.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (6 "306
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon of approximately volume.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the hydrogenation reaction is usually evacuated, filled with argon, and repeated three times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature to 20 ° C ⁇ 30 ° C.
  • the monitoring of the reaction process in the examples adopts thin layer chromatography (TLC), the developing reagent used in the reaction, the eluent system of column chromatography used to purify the compound, the developing reagent system of thin layer chromatography and the rapid purification preparation
  • Liquid phase 1B C bonded phase separation column system includes: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: ethyl acetate/two Chloroform system, E: ethyl acetate/dichloromethane/n-hexane, F: methanol/water system, G: methanol/water/methylamine aqueous system, H: acetonitrile/water system, the volume ratio of the solvent is based on the compound It can be adjusted according to its polarity, and it can also be adjusted by adding a small amount of basic or acidic reagents
  • reaction solution was slowly poured into 200 mL ice water, extracted with dichloromethane (100 mL ⁇ 3), the organic phase was collected, washed with 200 mL saturated brine, dried with anhydrous sodium sulfate, and allowed to stand.
  • the preparation method is similar to the third step in implementation 1: 5-methyl-3-phenyl-1-pyrrole-2-formaldehyde (l-1c) is prepared similarly, with 2-methyl-4-phenyl-1//
  • the raw material of ethyl pyrrole-3-carboxylate (l-1a) was 3 g (13.10 mmol), and 2.66 g of white solid was finally purified, and the yield was 79.33%.
  • the preparation method is similar to the fourth step in implementation 1: 2-(5-methyl-3-phenyl-1//pyrrol-2-yl)-1//benzo[oOimidazole (1-1) is prepared similarly to 2-Methyl-4-phenyl-1//pyrrole-3-carboxylic acid ethyl ester (1-1 a) and o-phenylenediamine raw materials, the dosage is 150 mg (0.58 mmol), and the final purification is a white solid 103 mg, the yield was 51.10%. MS m/s (ESI) [M+H] + : 346.2.
  • Ethyl 5-(1//benzo[o!limidazol-2-yl)-2-methyl-4-phenyl-1//pyrrole-3-carboxylate (I -5) 500 mg (1 ⁇ 45 mmol) was dissolved in 10 mL of methanol, stirred at room temperature, and then 4 mL of 2 mmol/mL sodium hydroxide aqueous solution was added. TLG detects the end of the reaction, and adjusts the reaction solution to neutral or weakly acidic with dilute hydrochloric acid.
  • reaction solution was poured into 100 mL water, extracted with ethyl acetate (50 mL ⁇ 3), combined the organic phases, washed with 100 mL saturated brine, dried with anhydrous sodium sulfate, and allowed to stand. Filter, evaporate the solvent under reduced pressure, and use silica gel column chromatography to purify with system A to obtain 372 mg of white solid to white solid with a yield of 81.46%.
  • the preparation method and implementation 7 5-(1//benzo[o!limidazol-2-yl)-(2-(diethylamino)ethyl)-2-methyl-4-phenyl-1 //The preparation of pyrrole-3-carboxamide (I-7) is similar, with 5-(//benzo[dimidazol-2-yl)-2-methyl-4-phenyl-1//pyrrole-3- Carboxylic acid (1-6) and 4-methyl-1-piperazine ethylamine are used as raw materials, and the dosage of 1-6 is 80 mg (0.25 mmol).
  • Preparation method and implementation 7 5-(1//benzo[oOimidazole-2-yl)-A (2-(diethylamino)ethyl)-2-methyl-4-phenyl-1//
  • the preparation of pyrrole-3-formamide (I-7) is similar, with 5-(//benzo[c/]imidazol-2-yl)-2-methyl-4-phenyl-1//pyrrole-3- Carboxylic acid (I-6) and 1-methylpiperidine-4-amine are used as raw materials, and the dosage is 100 mg (0.32 mmol).
  • the final 18 G bonded phase separation column is used for rapid purification to prepare the liquid phase.
  • the elution system obtained 74 mg of white solid with a yield of 57.2%. 0 MS m/s (ESI) [M+H] + : 414.2.
  • the first step 4-acetyl-5-methyl-3 -(1-methyl-1 //pyrazole-4-yl) -1 //pyrrole-2-ethyl carboxylate (M1a)
  • the preparation method is similar to the first step of implementation 2: 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (I -2a), with 3-(1- Methyl-1 //pyr-4-yl)-3-oxopropionate ethyl ester and acetylacetone were used as raw materials, the dosage was 800 mg (4.01 mmol), and 900 mg of white solid was finally obtained with a yield of 82.6%. MS m/s (ESI) _] + : 276.2 c
  • the second step 1-(2-methyl-4-(1-methyl-1 H-pyrazole-4-yl) -1 H-pyrrol-3-yl) ethyl-1-one (11 b)
  • the preparation method is similar to the second step of implementation 2: 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (1-2a) is similar to the preparation of 4-acetyl-5 -Methyl-3 -(1-methyl-1 //pyrazole-4-yl) -1 //pyrrole-2-carboxylic acid ethyl ester (-11a) as the raw material, the dosage is 850 mg (3.10 mmol) Finally, 489 mg of white solid was obtained with a yield of 77.8%. MS m/s (ESI) [M+H] + : 204.3.
  • the preparation method of the brewing (l-11c) is similar to the third step: the preparation of 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-formaldehyde (1-2c), with 1- (2 -Methyl-4 -(1-methyl-1 H-pyrazol-4-yl) -1 H-pyrrol-3-yl) ethyl-1-one (
  • the sixth step 1-(2-methyl-4 -(1-methyl-1 //pyrazol-4-yl) -5-(5-(4-methylpiperazine-1-yl) -1 // Benzo
  • the preparation method is the same as that of Example 2.
  • the third step: 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxaldehyde The preparation of (
  • the preparation method is similar to the preparation of the fourth step: 1-1 in Example 1, using M2b and 4-(4-methylpiperazin-1-yl)benzene_1,2-diamine (-11e) as raw materials,
  • the feeding amount I-12b was 200 mg (0.87 mmol)
  • a white solid was separated and purified by an 18 C bonded phase separation column for rapid purification to prepare a liquid phase with an F elution system to obtain 89 mg of a white solid with a yield of 24.7%.
  • the preparation method is similar to the first step of Example 12:
  • the preparation of l-12a is similar to the preparation of 2-amino-1-(cheap-2-yl)ethan-1-one and acetylacetone as raw materials, and the charging amount is 2-amino- 1-(furan-2-yl)ethan-1-one hydrochloride was used as the raw material, the dosage was 500 mg (3.09 mmol), and 293 mg of white solid was finally obtained with a yield of 50.2%.
  • the second step 4-Acetyl-3-(Zan-2-yl)-5-methyl-1H-pyrrole aldehyde (-13b)
  • the preparation method is similar to the third step of Example 2:
  • -2c) is similar, with 1-2a as the raw material, and the amount of charge is 250 mg (1.32 mmol), 240 mg of white solid was finally obtained, with a yield of 83.8%.
  • the preparation method is similar to the fourth step of Example 1:
  • the preparation of 1-1 is similar to that of I-13b and 4-(4-methylpiperopyr-1-yl)benzene-1,2-diamine (1-1e)
  • the dosage of M3b was 200 mg (0.90 mmol)
  • the 18 G bonded phase separation column for rapid purification to prepare the liquid phase was separated and purified by the F elution system to obtain 110 mg of white solid with a yield of 30.1%.
  • the first step 1 -(2-methyl-4-(naphthalene-1-yl)-1 H-pyrrole-3-yl)ethan-1-one (l-14a)
  • the preparation method is similar to the first step of Example 12:
  • the preparation of 1-12a is similar, with 2-amino-1-(squeak-2-yl)ethan-1-one and acetone as raw materials, and the charging amount is 2-amino.
  • -1-(2-yl)ethan-1-one hydrochloride was used as the raw material, the dosage was 500 mg (2.26 mmol), and 408 mg of white solid was finally obtained with a yield of 72.7%.
  • the second step 4-acetyl-5-methyl-3-(naphthalene-1-yl)-1 H-pyrrole-2-formaldehyde (l-14b)
  • the preparation method is similar to the third step of Example 2:
  • -2c) is similar, M4a is the raw material, and the charging amount is 350 mg (1.40 mmol), 260 mg of white solid was finally obtained, with a yield of 66.9%.
  • the preparation method is similar to the fourth step of Example 1:
  • the preparation of 1-1 is similar to that of 1-14b and 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine (11e) as The raw material, the feeding amount BU13b is 200 mg (0.72 mmol), and finally the white solid 61 mg is obtained by rapid purification and preparation of the liquid phase 18 C bonded phase separation column with F elution system to obtain 61 mg of white solid.
  • the yield is 18.5%.
  • the preparation method is similar to that of Example 12, the first step: the preparation of -12a, 2-amino-1-(cheap-2-yl)ethan-1-one and acetylacetone are used as raw materials, and the charging amount is 2-amino-1 -(Furan-2-yl)ethan-1-one hydrochloride was used as the raw material, the dosage was 500 mg (2.25 mmol), and finally 366 mg of white solid was obtained with a yield of 65.2%. MS m/s (ESI): 251.3 [M+H] + .
  • the second step 4-Acetyl-5-methyl-3-(Quilin-7-yl) -1H-pyrrole-2-formaldehyde (I 15b)
  • the preparation method and Example 2 The third step: 4- Ethyl-5-methyl-3-phenyl-1H-**pyrrole-2-formic acid (l-2c) was prepared similarly, with I-15a as the raw material, and the dosage was 350 mg (1.40 mmol), and the final product was obtained White solid 210 mg, yield 54_ 2%.
  • Example 1 Step four 1-1 prepared similar to I -15b and 4- (4 - Juan Yue-l-a-l-yl) benzene-1,2 - diamine (BU 11e)
  • the dosage of M5b was 200 mg (0.71 mmol)
  • the white solid 72 mg was obtained by rapid purification and preparation of the liquid phase 18 C bonded phase separation column with F elution system, with a yield of 21.6%.
  • the preparation method is similar to the first step of Example 12: the preparation of -12a, 2-amino-1-(1 Z/ ⁇ -3-yl)ethan-1-one hydrochloride and acetylacetone are used as raw materials.
  • 2-Amino-1-(furan-2-yl)ethane-1-unitary hydrochloride was used as the raw material, and the feed amount was 800 mg (2.55 mmol).
  • 366 mg of white solid was obtained, with a yield of 63.1%.
  • Step 2 4 -Yichouji-
  • the preparation method is similar to the third step of Example 2:
  • the preparation of 4-ethyl-5-methyl-3-phenyl-1//pyrrole-2-formaldehyde (l-2c) is similar, M6a is the raw material and the amount of feed It was 350 mg (1.47 mmol), and 194 mg of white solid was finally obtained, with a yield of 49-8%.
  • Example 1 Step four 1-1 prepared similar to I -16b and 4- (4 - Juan Yue-l-a-l-yl) benzene-1,2 - diamine (BU 11e)
  • the dosage of M6b was 150 mg (0.56 mmol)
  • a white solid 84 mg was obtained by rapid purification and preparation of the liquid phase with an 18 C bonded phase separation column and F elution system.
  • the yield was 33.2%.
  • the preparation method is similar to the fourth step of Example 1:
  • the preparation of I1 is similar to that of I3c and 1,2,4-triphenylamine 0-3c) as raw materials, and the dosage I3c is 200 mg (1.10 rrmol) for final use.
  • the 18 G bonded phase separation column for rapid purification and preparation of liquid phase was separated and purified by F elution system to obtain 129 mg of white solid with a yield of 35.7%.
  • the first step 1- (3, 4 -Dinitrophenyl) -4 -Melin (l-18a)
  • the preparation method is similar to the fourth step: 2-(5-methyl-3-phenyl-1 // pyrrolidin-2-yl) -1 // benzo[ ⁇ /] imidazole (1-1) preparation is similar to I3c and 4-(4-morpholin-1-yl)benzene-1,2-diamine (M1e) are used as raw materials, and the dosage I3c is 150 mg (0.65 mmol).
  • the final liquid phase 1B is prepared by rapid purification . G bonded phase separation column was separated and purified with F elution system to obtain 100 mg of white solid with a yield of 37.8%. MS m/s (ESI) [M+H] + : 401.3.
  • the preparation method is similar to the fourth step: 2-(5-methyl-3-phenyl-1 // pyrrolidin-2-yl) -1 // benzo[oO imidazole (1-1) preparation is similar to the preparation 3c and 4-(4-/V methylpiperazin-1-yl)benzene-1,2-diamine (I11e) are used as raw materials, and the dosage of I3c is 150 mg (0.65 rrmol), which is finally prepared by rapid purification The liquid phase 18 G bonded phase separation column was separated and purified with F elution system to obtain 138 mg of white solid with a yield of 50.8%. MS m/s (ESI) [M+H] + : 414.3.
  • Example 21 _ 1 (5 - (5 _ ((2- (dimethylamino) ethyl) amino) benzo ⁇ 1 _ [_ oO taste Jun 2 - yl) - 2 - methyl - phenyl - 1 // pyrrolidin -3-base) ethyl-1-one (21)
  • the third step 1-(5- (5-((2-(Dimethylamino)ethyl)amino)-1// ⁇ benzo[0(
  • the preparation method is similar to the fourth step: 2-(5-methyl-3-phenyl-1 // pyrrolidin-2-yl) -1 // benzo
  • the preparation method and implementation 7 5-(1//benzo[oil taste Jun-2-yl)-A (2-(diethylhelium) ethyl) -2-methyl-4-phenyl- 1 //
  • the preparation of pyrrole-3 -carboxamide (I-7) is similar, I-17 and acetic acid are used as raw materials, and the dosage I-17 is 100 mg (0.30 mmol), and finally the 18 G bonded phase is separated by rapid purification to prepare the liquid phase.
  • the column was eluted with F to obtain 88 mg of a white solid with a yield of 78.5%.
  • the preparation method is similar to the preparation of the second and third steps of 1-2c in Example 2, with 2-amino-1-(4-fluorophenyl)ethan-1-one and acetylacetone as starting materials, and the dosage is 500 mg (2.64 mmol), 200 mg of white solid was finally obtained, and the two-step yield was 31_3%.
  • the preparation method is similar to the fourth step of Example 1:
  • the preparation of 1-1 is similar to that of 1-23b and 4-(4-morpholin-1-yl)benzene-1,2-diamine (-18b) as raw materials.
  • the feed amount I23b was 150 mg (0.61 mmol), and finally a white solid 88 mg was obtained by rapid purification and preparation of the liquid phase with an 18 C bonded phase separation column using F elution system to obtain 88 mg of white solid with a yield of 34.6%.
  • the first step 1-(4-(4-chlorophenyl) -2-methyl-1 11 pyrrol-3-yl)ethyl-1-unitary (I -24a)
  • the second step 4-acetyl -3- (4-chlorophenyl)-5-methyl-1//pyrrole-2-formaldehyde (
  • the preparation method is similar to the preparation of the second and third steps 1-2c of Example 2, with 2-amino--1-(4-chlorophenyl)ethan-1-one and acetylacetone as starting materials, and the dosage is 500 mg (2.43 mmol), 264 mg of white solid was finally obtained, and the two-step yield was 41 _ 6%.
  • Example 1 Step Four 1 _ 1 prepared analogously to l-24b and 4- (4-morpholin leaching 1-yl) benzene-1,2-diamine (BU 18b) as starting material,
  • the feeding amount I 23b is 150 mg (0.61 mmol)
  • a white solid of 93 mg is obtained by rapid purification and preparation of the liquid phase with an 18 C bonded phase separation column and F elution system.
  • the yield is 37.5%.
  • the preparation method is similar to the fourth step of Example 1:
  • the preparation of 1 _ 1 is similar to the preparation of 1 _ 24b and 4-(4-pipesone-1-yl)benzene-1,2-diamine (11e) as raw materials,
  • the feeding amount I 24b was 150 mg (0.61 mmol)
  • a white solid was separated and purified by an 18 C bonded phase separation column for rapid purification to prepare a liquid phase with an F elution system to obtain 85 mg of a white solid with a yield of 32.4%.
  • the first step 1-(4-(4-methoxyphenyl)-2-methyl-1//pyrrol-3-yl)ethan-1-one (l-26a)
  • the second step 4-acetyl 3-(4-methoxyphenyl)-5-methyl-1H-pyrrole-2-formaldehyde (l-26b)
  • the preparation method is similar to the preparation of the second and third steps of 1-2c in Example 2, with 2-amino-1-(4-methoxyphenyl)ethan-1-one and acetylacetone as starting materials, and the amount of charge is 500 mg (2.48 mmol), 325 mg of white solid was finally obtained, with a yield of 51.0% in two steps.
  • the preparation method is similar to the fourth step of Example 1: The preparation of 1-1, taking I-26b and 4-(4-methylpiperazin-1-yl) harmless-1,2-diamine (11e) as The raw material, the feed amount 1-226b was 150 mg (0.58 mmol), and finally 153 mg of white solid was obtained by rapid purification and preparation of the liquid phase 18 C bonded phase separation column with F elution system to obtain 153 mg of white solid. The yield was 59.3%. MS m/s (ESI): 444.3 [M+H] + .
  • the first step 1-(4-(3-methoxyphenyl)-2-methyl-1//pyrrol-3-yl)ethan-1-one (l-27a)
  • the second step 4-acetyl 3-(3-methoxyphenyl)-5-methyl-1H-pyrrole-2-formaldehyde (l-27b)
  • the preparation method is similar to the preparation of the second and third steps of 1-2c in Example 2, with 2-amino-1-(4-methoxyphenyl)ethan-1-one and acetylacetone as starting materials, and the amount of charge is 500 mg (2.48 mmol), 290 mg of white solid was finally obtained, and the two-step yield was 46.8%.
  • the preparation method is similar to the fourth step of Example 1:
  • the preparation of 1-1 is similar to that of I-27b and 4-(4-methylpiperopyr-1-yl)benzene-1,2-diamine (11e)
  • the feed amount I27b was 150 mg (0.58 mmol)
  • 153 mg of white solid was obtained by rapid purification and preparation of liquid phase by 18 G bonded phase separation column with F elution system. The yield was 56.6%.
  • the preparation method is similar to the preparation of the second and third steps of 1-2c in Example 2, with 2-amino-1-(4-methoxyphenyl)ethan-1-one and acetylacetone as starting materials, and the amount of charge is 500 mg (2.19 mmol), 280 mg of white solid was finally obtained, and the two-step yield was 45.3%.
  • the preparation method is similar to the preparation of the fourth step: 1-1 in Example 1, taking I -28b and 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine Cl-11e) as The raw material, the feed amount I 28b is 150 mg (0.56 mmol), and finally the 18 C bonded phase separation column for rapid purification to prepare the liquid phase is separated and purified by the F elution system to obtain 69 mg of white solid, with a yield of 26.4%. MS m/s (ESI): 471.3 [M+H] + .
  • the first step 1- (2 -methyl-4- (m-tolyl) -1 pyrrolidine-3 _ yl) ethyl _ 1-unitary (I _ 29a)
  • the second step 4-acetyl-5- ⁇ 3-(m-tolyl)-1 H-pyrrole-2-carboxaldehyde (l-29b)
  • the preparation method is similar to the preparation of the second and third steps of Example 2-2c.
  • 2-amino-1-(4-methoxyphenyl)ethan-1-one hydrochloride and acetylacetone are the starting materials, and the materials are charged The amount is 500 mg (2.69 mmol), and finally 349 mg of white solid is obtained, and the two-step yield is 53.8%.
  • the preparation method is the same as that of Example 1.
  • the fourth step: The preparation of I1 is similar to that of I29b and 4-(4-methylpiperno-1-yl)benzene-1, 2 -diamine (I11e) as raw materials.
  • the feeding amount I29b was 150 mg (0.62 mmol), and finally a white solid 69 mg was obtained by rapid purification and preparation of the liquid phase with an 18 C bonded phase separation column using F elution system to obtain 69 mg of white solid with a yield of 33.5%.
  • the preparation method is similar to the fourth step of Example 1:
  • the preparation of 1-1 is similar to that of BU29b and 4-(4-methan-1-yl)benzene-1,2-diamine (B11e) as raw materials.
  • the amount I 26b is 150 mg (0.62 mmol)
  • a white solid 69 mg is obtained by rapid purification and preparation of a liquid phase 18 C bonded phase separation column with F elution system to obtain 69 mg of white solid with a yield of 33.5%.
  • the first step 1-(4-(3-cyclopropoxyphenyl)-2-methyl-1H-pyrrol-3-yl)ethan-1-one (1-31 a)
  • the second step 4- Acetyl-3-(3-cyclopropoxyphenyl)-5-methyl-1H-pyrrole-2-carbaldehyde (l-31b) and its preparation method is the same as that of Example 2 in the second and third steps of l-2c
  • 2-amino-1-(4-methoxyphenyl)ethan-1-one hydrochloride and acetylacetone are starting materials, and the dosage is 500 mg (2.20 mmol), and finally 294 mg of white solid is obtained.
  • the two-step yield was 47.4%.
  • the preparation method is the same as that of Example 1.
  • the first step 1-(2-methyl-4-(3-(phenylamino)phenyl)-1 H-pyrrol-3-yl)ethan-1-one Cl-32a)
  • the second step 4- Acetyl-5-methyl-3-(3-(phenylamino)phenyl)-1 H-pyrrole-2-carboxaldehyde (l-32b)
  • Its preparation method is the same as that of Example 2 in the second and third steps l-2c
  • the preparation is similar to that of 2-amino(4-methoxyphenyl)ethan-1-one hydrochloride and acetylacetone as starting materials.
  • the dosage is 500 mg (1.90 mmol), and finally 225 mg of white solid is obtained.
  • the step yield is 37.2%.
  • the preparation method is the same as that of Example 1.
  • the fourth step The preparation of I-1 is similar to that of I-32b and 4-(4-methylpiperidone-1-yl)benzene_1,2-diamine (I-11e) as raw materials.
  • the feeding amount I 32b was 150 mg (0.47 mmol), and the silica gel column chromatography was separated and purified to obtain a white solid of 55 mg with a yield of 23.4%.
  • Step 1 1 - ⁇ 2-methyl-5-[6-(4-methylpiperazin-1-yl)-1//indi-2-yl]-4-phenyl-1//pyrrole- 3-yl) ethyl-1-one (I-33)
  • Step 1 1-[4-(4-Methoxyphenyl)-2-methyl-1//pyrrol-3-yl]ethan-1-one (1-4a)
  • the 2-helium- 1-(4-Methoxyphenyl)ethan-1-one 2.0 g (12.11 mmol)
  • acetylacetone 1.43 g (14.29 mmol) dissolved in 10 mL 50% ethanol aqueous solution .
  • the temperature was raised to 85 ° C, and the reaction was conducted under the protection of N 2 for 3 h.
  • reaction solution was cooled to room temperature, 100 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated to dryness
  • the crude product was purified by column chromatography to obtain 2.15 g of a light yellow solid with a yield of 77.5%.
  • Step 2 4-Acetyl-3-(4-methoxyphenyl)-5-methyl-1//pyrrole-2-carbaldehyde (I 34b) Under ice bath conditions, add I 34a 2.0 g (8.72 rnnol ) Dissolve in In 20 mL of dimethylformamide, control the temperature-5 ° C-0 ° C, and slowly drop 2.67 g (17.45 mmol) of phosphorus oxychloride. After dripping, react at room temperature for 2 h. After the reaction is over, under ice bath conditions, control the temperature at -5 ° C-0 ° C, and slowly add 8.7 mL (43.61 mmol) of 5 M acetic acid If aqueous solution.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated to dryness
  • the crude product was purified by column chromatography to obtain 0.32 g of a light yellow solid with a yield of 54.7%.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. Dry, the crude product was purified by column chromatography to obtain 1.35 g of a light yellow solid with a yield of 57.2%. MSm/z: 186.1 [M+H] + .
  • Step 2 2-(5-methyl-3-phenyl-1 //pyrrol-2-yl) -1 //benzo
  • benzene-1 0.2 g (1.62 mmol) of 2,4-triamine, 0.33 g (1.8 mmol) of I-35a and 0.034 g (0.18 rrniol) of sodium metabisulfite were dissolved in 10 mL of absolute ethanol. After the addition, the temperature was raised to 80 and reacted for 20 h.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. Dry, the crude product was purified by column chromatography to obtain 0.14 g of light yellow solid with a yield of 53.8%.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. Dry, the crude product was purified by column chromatography to obtain 0.16 g of a light yellow solid with a yield of 53.3%.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. Dry, the crude product was purified by column chromatography to obtain 0.2 g of light yellow solid with a yield of 55.8%.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. After drying, the crude product was purified by column chromatography to obtain 0.15 g of a pale yellow solid with a yield of 41.9% 0 ESI-MS m/z: 442.2 [M+H] + .
  • Step 1 1-[4-(4-Trifluoromethoxyphenyl)-2-methyl-1//pyrrol-3-yl]ethan-1-one (l-41a)
  • the 2- Amino-1-(4-trifluoromethoxyphenyl)ethan-1-one 2.0 g (9.13 mmol), sodium acetate 4.49 g (54.75 mmol) and acetylacetone 1.08 g (10.77 _ol) dissolved in 10 mL 50% In aqueous ethanol.
  • the temperature was raised to 85 ° C, and the reaction was conducted under the protection of N 2 for 3 h.
  • reaction solution was cooled to room temperature, 100 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. After drying, the crude product was purified by column chromatography to obtain 2.0 g of a pale yellow solid with a yield of 77.5%.
  • Step 2 4-Acetyl-3-(4-trifluoromethoxyphenyl)-5-methyl-1//pyrrole-2-formaldehyde (
  • Step 3 1- ⁇ 2 -methyl-5-[5- (4-methylpiperazin-1-yl) -1 //benzo[dimidazol-2-yl] -4- [4- (three (Fluoromethoxy)phenyl) -1 //pyrrol-3-yl) ethyl-1-one (1-41)
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. After drying, the crude product was purified by column chromatography to obtain 0.12 g of a light yellow solid with a yield of 35.8%.
  • Step 1 1-[4-(3-Trifluoromethoxyphenyl)-2-methyl-1//pyrrol-3-yl]ethan-1-one Cl-42a)
  • the 2-amino group -1-(4-trifluoromethoxyphenyl)-1-ketone 2.0 g (9.13 mmol), sodium acetate 4.49 g (54.75 mmol) and acetylacetone 1.08 g (10.77 _ol) dissolved in 10 mL 50% ethanol In aqueous solution.
  • the temperature was raised to 85 ° C, and the reaction was conducted under the protection of N 2 for 3 h.
  • reaction solution was cooled to room temperature, 100 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. Dry, the crude product is purified by column chromatography to obtain light yellow The color solid is 2.0 g, and the yield is 77_5%.
  • Step 2 4-Acetyl-3-(3-trifluoromethoxyphenyl)-5-methyl-1 pyrrole-2-formaldehyde (
  • Step 3 1- ⁇ 2 -methyl-5-[5- (4-methylpiperazin-1-yl) -1 //benzo
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. After drying, the crude product was purified by column chromatography to obtain 0.12 g of a light yellow solid with a yield of 35.8%.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. After drying, the crude product was purified by column chromatography to obtain 0.15 g of light yellow solid with a yield of 41.9%.
  • reaction solution is cooled to room temperature, 20 mL of water is added to the reaction solution, the aqueous phase is extracted with ethyl acetate (20 mL X 3), the organic phases are combined, and washed with water , Dried with anhydrous sodium sulfate, filtered with suction, evaporated to dryness, and the crude product was purified by column chromatography to obtain 0.14 g of light yellow solid with a yield of 50.4%.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. After drying, the crude product was purified by column chromatography to obtain 0.14 g of a pale yellow solid with a yield of 46.55 LES, MS m/z: 470.3 [M+H] + .
  • reaction solution is cooled to room temperature, 20 mL of water is added to the reaction solution, the aqueous phase is extracted with ethyl acetate (20 mL X 3), the organic phases are combined, washed with water, It was dried with anhydrous sodium sulfate, filtered with suction, evaporated to dryness, and the crude product was purified by column chromatography to obtain 0.14 g of a pale yellow solid with a yield of 46.5%.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. Dry, the crude product was purified by column chromatography to obtain 0.14 g of a pale yellow solid with a yield of 39.2%.
  • Step 1 1-(2-methyl-5-[5-(4-methylpiperazin-1-yl)-1// benzo[J]imidazol-2-yl] -4- ⁇ 4-[ (Tetrahydro-2//pyran-4-yl)methoxy]phenyl)-1//pyrrol-3-yl)ethan-1-one (I-49)
  • the preparation method is respectively the same as in Example 34 Step 3 is similar, 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine and 4-acetyl-5-methyl-3- ⁇ 4-[ (tetrahydro-2// Pyran-4-yl)methoxy]phenyl ⁇ -1//pyrrole-2-formaldehyde was used as the starting material, and the feed amount was 0.2 g (0.97 rrniol), and finally 0.101 g of light yellow solid was obtained, with a yield of 19.7 %.
  • Step 1 1 - ⁇ 4-(4-ethoxyphenyl)-2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo
  • Step 1 1- ⁇ 4- (4 - butoxyphenyl) -2 - methyl-5- [5- (4 - methyl-piperazin-1-yl) -1-benzo [d _ sit microphone IT 2 -base] -1 slightly -3 -base ⁇ B-1 -@ ⁇ ( I -51)
  • Step 1 1- ⁇ 4-(3,4-Dimethoxyphenyl)-2-methyl-5-[5-(4-methylpiperazin-1-yl)-1 benzo[oOimidazole -2 -yl] -1 //pyrrol-3-yl) ethyl-1-one (I-52)
  • Step 1 1 -(4-(3-fluoro-4-methoxyphenyl)-2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo [d ⁇ imidazol-2-yl] -1 //pyrrol-3-yl) ethyl-1-one (I-53)
  • Step 1 1- ⁇ 2 -methyl-5-[5- (4-methylpiperazin-1-yl) -1 //benzo IV]imidazol-2-yl] -4-(naphthalene-2- Base) -1 11 pyrrole-3 -yl) ethyl-1 -si (I -54)
  • the preparation method is similar to step 3 in Example 34, 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine and 4-acetyl-5-methyl-3-(naphthalene -2-yl)-1//pyrrole-2-formaldehyde was used as the starting material, the feed amount was 0.2 g (0.97 mmol), and 0.055 g of light yellow solid was finally obtained, with a yield of 12.2%.
  • Step 1 1- ⁇ 4- (2, 3 -Dihydrobenzo[A] [1, 4]dioxin-6 -yl)-2-methyl-5-[5- (4-methylpiper) l-yl) -l // _ benzo [0 (
  • Step 1 1- ⁇ 4-(benzo[od[1,3]dioxapentane-5-yl)-2-methyl-5-[5-(4-methylpiperazin-1-yl) ) -1 //Benzo[£/]imid-2 -yl] -1 //pyrrole-3 -yl ⁇ ethyl-1-one (I -56)
  • Step 1 1- ⁇ 2 -methyl-5-[5-(4-methylpiperazin-1-yl) -1 // harmless
  • the preparation methods are respectively similar to step 3 in Example 34, 4-(4-methylazin-1-yl)benzene-1,2-diamine and 4-acetyl-5-methyl-3-[3 -(Trifluoromethyl)phenyl] -1 //pyrrole-2-formaldehyde was used as the starting material, the feed amount was 0.2 g (0.97 mmol), and finally 0.142 g of light yellow solid was obtained, and the yield was 30.4%.
  • Step 1 1 - ⁇ 4-(3-fluorophenyl)-2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo[o!limiwa -2 -yl] -1 //pyrrole-3 -yl) ethyl-1-one (I -58)
  • Step 1 1- ⁇ 4-(2-fluorophenyl)-2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo[dimidazole
  • Step 1 1-[4-(4-chlorophenyl)-2-methyl-1//pyrrol-3-yl]ethan-1-one (Bu 60a) and step 2,
  • the preparation method is similar to step 1 and step 2 in Example 34, with 2-amino-1-(4-chlorophenyl)ethan-1-one and acetylacetone as starting materials, and the charging amount is 1.0 g (5.90 mmol). ), 0.85 g of light yellow solid was finally obtained, and the two-step yield was 55.1%.
  • Step 3 1 - ⁇ 4-(4-chlorophenyl)-2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo[o!limidazole
  • Step 1 1-[4-(3-chlorophenyl)-2-methyl-l// ⁇ pyrrol-3-yl]ethyl-1-autosame (l _ 61a) and step 2,
  • Step 3 1- ⁇ 4-(3-chlorophenyl)-2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo[oilimidazole-2- Base] -1 //pyrrole-3-yl ⁇ ethyl-1-one (Bu 61)
  • Step 1 1-[4-(3,5-Dichlorophenyl)-2-methyl-1//pyrrol-3-yl]ethan-1-one 0_62a) and step 2, 4-acetyl-3 -(3, 5 -Dichlorophenyl)-5 -methyl-1//pyrrole-2-formaldehyde (1-262b)
  • the preparation method is similar to step 1 and step 2 in Example 34, with 2-amino-1-(3,5-dichlorophenyl)ethan-1-one and acetylacetone as starting materials, and the feed amount is 1.0 g (4.90 mmol), 0.767 g of light yellow solid was finally obtained, and the two-step yield was 52.9%.
  • Step 3 1- ⁇ 4- (3, 5 -Dichlorophenyl) -2 -methyl-5- [5- (4-methylazin-1-yl) -1 //benzo[ t/] (Imidazol-2-yl] -1 //pyrrol-3-yl) ethyl-1-one 0-62)
  • the preparation method is similar to that of step 3 in Example 34, 4-(4-methylpiperazin-1-yl)benzene-1, 2-diamine and 4-acetyl-3-(3, 5-dichloro (Phenyl)-5 -methyl-1 //pyrrole-2-formaldehyde was used as the starting material, and the feed amount was 0.2 g (0.97 mmol), and finally 0.122 g of light yellow solid was obtained, and the yield was 26.1%.
  • Step 1 1- ⁇ 2-methyl-4-[4-(trifluoromethyl)phenyl] -1H-pyrrol-3-yl ⁇ ethan-1-one (I63a) and step 2, 4-acetyl 5-methyl-3-[4-(trifluoromethyl)phenyl] -1H-pyrrole-2-carboxaldehyde a_63b)
  • the preparation methods are similar to those of step 1 and step 2 in Example 34, respectively, 2-amino -1-[4-(trifluoromethyl)phenyl]ethan-1-one and acetylacetone as starting materials, the feed amount is 1.0 g (4.90 mmol), and finally 0.812 g of light yellow solid is obtained, the yield in two steps 55.6%.
  • the preparation method is similar to step 3 in Example 34, 4-(4-methylpyrazine-1-yl)benzene-1,2-diamine and 2,
  • Step 1 1-[4-(2-chlorophenyl)-2-methyl-1//pyrrol-3-yl]ethan-1-one (1-4a) and step 2,
  • the preparation method is similar to step 1 and step 2 in Example 34, with 2-amino-1-(2-chlorophenyl)ethan-1-one and acetylacetone as starting materials, and the charging amount is 1.0 g (5.90 mmol). ), 0.926 g of light yellow solid was finally obtained, with a two-step yield of 60.0%.
  • Step 3 1 - ⁇ 4- (2-chlorophenyl)-2-methyl-5-[5- (4-methylpiperazin-1-yl)-1//benzo[oilimidazole-2- Base] -1 0 pyrrole-3 -base ⁇ B-1 -S the same as (I -64)
  • Step 1 4-(4-Acetyl-5-methyl-1//pyrrol-3-yl)benzonitrile (l-65a) and Step 2, 4-(4-Acetyl-2-formyl-5) -Methyl-1 pyrrol-3-yl)benzonitrile (I -65b)
  • the preparation method is similar to step 1 and step 2 in Example 34, with 4-glycylbenzonitrile and acetylacetone as starting materials, and the dosage is 1.0 g (6.24 rnnol), and finally 0.905 g of light yellow solid is obtained.
  • the step yield is 57.5%.
  • Step 3 1 - ⁇ 4 -Acetyl-5-methyl-2-[5- (4-methylpiperazin-1-yl)-1//benzo[W]imidazol-2-yl] -1 //Pyrrol-3-yl)benzonitrile (I-65)
  • reaction solution was cooled to room temperature, and 20 mL of water was added to the reaction solution.
  • the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, evaporated to dryness, and the crude product was purified by column chromatography to obtain 1.10 g of light yellow oil. The yield was 78.6%.
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated to dryness.
  • the crude product was purified by column chromatography to obtain 0.68 g of a light yellow solid with a yield of 83.1%.
  • Step 4. 1 - ⁇ 4 -Cyclohexyl-2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo[dimidazol-2-yl] -1 0 Pyrrol-3-yl) B-1 -S with (I -66)
  • reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL X 3), the organic phases were combined, washed with water, dried with anhydrous sodium sulfate, filtered with suction, and evaporated. After drying, the crude product was purified by column chromatography to obtain 0.29 g of a light yellow solid with a yield of 71.3%.
  • the preparation method is similar to step 4 in Example 66, using 4-(4-methyltrifluoro-1-yl)benzene-1,2-diamine and 4-acetyl-3-cyclopentyl-5-methyl Base-1//pyrrole-2-formaldehyde was used as the starting material, the feed amount was 0.2 g (0.969 mnol), and finally 0.193 g of milky white solid was obtained, with a yield of 49.1%.
  • the preparation method is similar to step 4 in Example 66, using 4-(4-methylpiphon-1-yl)benzene-1, 2-diamine and 4-acetyl-3-cyclobutyl-5-methyl Base-1//pyrrole-2-formaldehyde was used as the starting material, the feed amount was 0.2 g (0.969 rrmol), and 0.181 g of milky white solid was finally obtained with a yield of 47.7%.
  • the preparation method is similar to step 4 in Example 66, with 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine and 4-acetyl-3-cyclopropyl-5- Methyl-1//pyrrole-2-formaldehyde was used as the starting material, and the feed amount was 0.2 g (0.969 irmol), and finally 0.189 g of light yellow solid was obtained, and the yield was 51.6%.
  • the preparation method is similar to step 4 in Example 66, using 4-(4-methyltriazine-1-yl)benzene-1,2-diamine and 4-acetyl-3-isopropyl-5-methyl Base-1//pyrrole-2-formaldehyde was used as the starting material, the feed amount was 0.2 g (0.969 nmol), and finally 0.167 g of light yellow solid was obtained, and the yield was 45.4%.
  • Step 1 1- ⁇ 4- (2, 4 -Dimethylthio-5-yl) -2-methyl-5-[5- (4-methylpiperazine-1-yl) -1 //benzene And [d Mijun-2 -yl] -1 //pyrrole-3 -yl ⁇ ethyl-1-one 0 -71)
  • Step 1 1- ⁇ 2 -Methyl-5-[5- (4-Methyl-1-yl) -1 //Benzo[4imidazol-2-yl] -4-(4-morpholine (Substituted phenyl) -1 //pyrrol-3-yl) ethyl-1-one (I 72)
  • Step 1 1- ⁇ 4- (1 //indino-5-yl) -2 -methyl-5-[5- (4-methylpyridox-1-yl) -1 //benzo[ d Imidazol-2-yl] -1 //pyrrol-3-yl) ethyl-1-one (I-73)
  • Step 1 1 - ⁇ 2-methyl-5-[5-(4-methylpiperazin-1-yl) -1 //benzo[oOimidazol-2-yl]-4-[4-(piper Pyridin-1-yl)phenyl] -1 //pyrrol-3-yl ⁇ ethyl-1-one (I -74)
  • the preparation method is similar to step 3 in Example 34, 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine and 4-acetyl-5-methyl-3-[4 -(Piperidone-1-yl)phenyl] -1//pyrrole-2-formaldehyde was used as the starting material, the dosage was 0.2 g (0.97 mmol), and finally 0.108 g of light yellow solid was obtained, and the yield was 22.4% 0 ESI -MS m/z: 477.7 [M+H] + .
  • Step 1 1 - ⁇ 4-[4-(2-hydroxyethoxy)phenyl] -2-methyl-5-[5- (4-methylpiperazin-1-yl)-1 // benzene And [o(l ⁇ _
  • Step 1 1- ⁇ 2 -methyl-5-[5- (4-methylpiperazin-1-yl) -1 //benzo IV]imidazol-2-yl] -4- [4- (pyrrole Alkyl-1-yl)phenyl] -1 //pyrrol-3-yl) ethyl-1-one a -76)
  • Step 1 1 - ⁇ 4- [1-(2-hydroxyethyl)-1//pyrazol-4-yl] -2 -methyl-5-[5- (4-methylpiperazine-1- Base) -1 //Benzo[o]imidin-2-yl] -1 //pyrrol-3-yl) ethyl-1-one (I -77)
  • the preparation method is similar to step 3 in Example 34, 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine and 4-acetyl-3-[1-(2-hydroxyl) Ethyl) -1 //Pyrazol-4-yl] -5 -Methyl-1 //Pyrrole-2-formaldehyde as the starting material, the dosage is 0.2g (0.97 mmol), and finally a light yellow solid 0.118 is obtained g, the yield was 27.2%.
  • Step 1 1-(4- ⁇ 1-[2-(Dimethylamino)ethyl] -1//pyrazol-4-yl ⁇ -2-methyl-5-[5- (4-methyl Pyrazin-1-yl) -1 //benzo[oOimidazol-2-yl] -1 //pyrrol-3-yl) ethyl-1-one (I78)
  • the preparation methods are respectively the same as those in Example 34 3 is similar to 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine and 4-acetyl-3- ⁇ 1-[2-(dimethylamino)ethyl] -1 //Pyrazol-4-yl ⁇ -5-methyl-1//pyrrole-2-formaldehyde as the starting material, the dosage is 0.2g (0.97rmiol), and finally 0.124g of light yellow solid is obtained, and the yield is 27_0 %.
  • Step 1 1-[2-Methyl-4-(4-phenoxyphenyl)-1//pyrrol-3-yl]ethan-1-one (I79a) and Step 2, 4-acetyl- 5-Methyl-3-(4-phenoxyphenyl)-1//pyrrole-2-formaldehyde (Bu79b)
  • the preparation method is similar to step 1 and step 2 in Example 34, with 2-amino-1-(4-phenoxyphenyl)ethan-1-one and acetylacetone as starting materials, and the feed amount is 1.0 g ( 4.40 mmol), 0.57 g of light yellow solid was finally obtained, and the two-step yield was 40.6%.
  • Step 3 1 - ⁇ 2 -Methyl-5-[5- (4-methylpiperazine-1-yl)-1//benzo
  • Step 1 1- ⁇ 2-methyl-4-[4-(phenylthio)phenyl] -1//pyrrol-3-yl ⁇ ethan-1-one (l-80a) and steps 2, 4- Acetyl-5-methyl-3-[4-(phenylthio)phenyl]-1//pyrrole-2-carboxaldehyde Cl-80b)
  • the preparation methods are similar to those of step 1 and step 2 in Example 34, respectively.
  • Step 3 1- ⁇ 2 -methyl-5-[5- (4-methylpiperazin-1-yl) -1 // really
  • Step 1 1-[2-methyl-4 -(1-methyl-1 //injun-5-yl) -1 //pyrrole-3-yl] ethyl-1-one (81a) and Step 2, 4-Acetyl-5-methyl-3-(1-methyl-1 //indazol-5-yl) -1 //pyrrole-2-formaldehyde (81b)
  • the preparation methods are respectively Similar to step 1 and step 2 in Example 34, 2-amino-1-(1-methyl-1//injun-5-yl)ethan-1-one and acetylacetone were the starting materials, and the feed amount was 1.0 g (5.28 mmol), 0.47 g of light yellow solid was finally obtained, with a yield of 31.6% in two steps.
  • Step 3 1- ⁇ 2 -methyl-4 -(1-methyl-1 //injun-5 -yl) -5-[5-(4-methylpiperidine-1-yl) -1 / /Benzo[dimijun-2 -yl] -1 //pyrrole-3 -yl ⁇ ethyl-1-one (1-81)
  • Step 1 1-(2-Methyl-4- ⁇ 4-[(tetrahydropyran-3-yl)methoxy]phenyl ⁇ -1//pyrrol-3-yl)ethan-1-one Cl -82a) and step 2, 4-acetyl-5-methyl-3- ⁇ 4-[(tetrahydrofuran-3-yl)methoxy]phenyl ⁇ -1//pyrrole-2-formaldehyde (l- 82b)
  • Step 1 1-[ 2 -Methyl- 4- (thiophen-3-yl) -1 //pyrrol-3-yl] ethyl- 1 _one (I 83a) and step 2 , 4-acetyl-5- Methyl-3-(thiophen-3 -yl) -1 //pyrrole-2-formaldehyde (I -83b)
  • the preparation method is similar to step 1 and step 2 in Example 34, with 2-amino-1-(phen-3-yl)ethan-1-one and acetylacetone as starting materials, and the charging amount is 1.0 g (7.08 mmol), 0_42 g of a light yellow solid was finally obtained, with a two-step yield of 25_4%.
  • Step 3 1 - ⁇ 2 -Methyl-5-[5- (4-methylpiperazin-1-yl)-1//benzo[t/]imidazol-2-yl]-4-(thiophene- 3-yl) -1 //pyrrol-3-yl) ethyl-1-one (I-83)
  • Step 1 1-(2-methyl-4-(pyridin-4-yl)-1//pyrrol-3-yl)ethan-1-one (1-4a) and step 2, 4-acetyl-5- Methyl-3 -(pyridine-4 -yl) -1 //pyrrole-2-formaldehyde (I -84b)
  • the preparation method is similar to step 1 and step 2 in Example 34, with 2-amino-1-(pyraze-4-yl)ethan-1-one and acetylacetone as starting materials, and the dosage is 1.0 g (7.34 mmol), 0.42 g of light yellow solid was finally obtained, with a two-step yield of 25.1%.
  • Step 3. 1 - ⁇ 2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo[oOimidazol-2-yl]-4-(pyridine-4- Base) -1 //pyrrol-3-yl ⁇ ethyl-1-one (I -84)
  • Step 1 1-(4-benzyl-2-methyl-1//pyrrol-3-yl)ethan-1-one Cl-85a) and step 2, 4-acetyl-3-benzyl-5- Methyl-1 //pyrrole-2-formaldehyde (I -85b)
  • Step 3 1 - ⁇ 4 -benzyl-2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo
  • Step 1 1-[2-Methyl-4-(tetrahydro-2//pyran-4-yl)-1 H-pyrrol-3-yl]ethan-1-one (l-86a) and step 2 , 4-Acetyl-5-methyl-3-(tetrahydro-2-//pyran-4-yl) -1 pyrrole-2-carbaldehyde (I -86b)
  • the preparation method is respectively the same as that of step 1 in Example 34
  • 2-amino-1-(tetrahydro-2//pyran-4-yl)ethan-1-one and acetylacetone are starting materials, and the dosage is 1.0 g (6.98 mmol), and the final product Pale yellow solid 0.59 g, the two-step yield is 36.1%.
  • Step 3 1- ⁇ 2-methyl-5-[5-(4-methylpiperazin-1-yl)-1//benzo[oOimidazol-2-yl]-4-(tetrahydro-2 //Pyran-4 -yl) -1 //pyrrol-3 -yl) ethyl-1-one (I -86)
  • Step 1 1-[2-Methyl-4-(phenylhelium)-1//pyrrol-3-yl]ethan-1-one (I87a) and step 2, 4-acetyl-5-methyl -3-(stupid amino) -1 //pyrrole-2-formaldehyde (I -87b)
  • the preparation method is similar to step 1 and step 2 in Example 34, with 2-amino-/V styl acetamide and acetylacetone as starting materials, and the charging amount is 2.0 g (13.32 mmol), and finally a light yellow solid 2.23 is obtained g, the two-step yield is 69.1%.
  • the preparation method is similar to step 3 in Example 34, 4-[(1-methylpyridine-4-yl)oxy]benzene-1,2-diamine and 4-acetyl-5-methyl-3 -Phenyl-1//pyrrole-2-formaldehyde was used as the starting material, the feed amount was 0.2 g (0.90 mmol), and finally 0.125 g of light yellow solid was obtained, with a yield of 34.9%.
  • the preparation method is similar to step 3 in Example 34, V-[2-(dimethylamino)ethyl] -V-methylbenzene-1,2,4-triamine and 4-acetyl-5 - ⁇ Pyro-3-phenyl-1//pyrrole-2-formaldehyde was used as the starting material, and the feed amount was 0.2 g (0.96 mmol), and finally 0.125 g of light yellow solid was obtained, and the yield was 31.3%.

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Abstract

L'invention concerne un dérivé de pyrrole, son procédé de préparation et son application; le composé a la structure représentée par la formule générale (I), ou au moins un mélange de multiples éléments choisi parmi un tautomère, un mésomère, un racémate, un énantiomère, un diastéréomère de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci, et une application d'une composition pharmaceutique utilisant le dérivé de pyrrole en tant que composant actif dans la préparation d'un produit pour la prévention et/ou le traitement de maladies associées à des protéines BRD.
PCT/CN2020/075626 2019-02-26 2020-02-18 Dérivé de pyrrole et son procédé de préparation et son application Ceased WO2020173328A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114044768A (zh) * 2021-12-08 2022-02-15 中国药科大学 吡咯类bet降解剂及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101619058A (zh) * 2009-01-08 2010-01-06 上海交通大学 一种苯并咪唑-4-酰胺型衍生物
CN107739370A (zh) * 2017-10-26 2018-02-27 中国药科大学 吡咯酮类brd4蛋白抑制剂的制备方法以及用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101619058A (zh) * 2009-01-08 2010-01-06 上海交通大学 一种苯并咪唑-4-酰胺型衍生物
CN107739370A (zh) * 2017-10-26 2018-02-27 中国药科大学 吡咯酮类brd4蛋白抑制剂的制备方法以及用途

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
""RN872103-20-3"", REGISTRY, ENTER STN, 18 January 2006 (2006-01-18), DOI: 20200403161454X *
""RN873208-91-4"", REGISTRY, ENTER STN, 1 February 2006 (2006-02-01), DOI: 20200403161407X *
""RN919949-62-5"", REGISTRY, ENTER STN, 8 February 2007 (2007-02-08), DOI: 20200403161145X *
LACK NATHAN A. ET AL.: "Targeting the Binding Function 3 (BF3) Site of the Human Androgen Receptor through Virtual Screening", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, no. 24, 2 November 2011 (2011-11-02), XP055576106, ISSN: 0022-2623, DOI: 20200403160823X *

Cited By (2)

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