CN111606888A - Pyrrole derivative and preparation method and application thereof - Google Patents
Pyrrole derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN111606888A CN111606888A CN201910140996.9A CN201910140996A CN111606888A CN 111606888 A CN111606888 A CN 111606888A CN 201910140996 A CN201910140996 A CN 201910140996A CN 111606888 A CN111606888 A CN 111606888A
- Authority
- CN
- China
- Prior art keywords
- methyl
- benzo
- imidazol
- pyrrol
- phenyl
- 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
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 64
- 150000003233 pyrroles Chemical class 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- -1 amino aryl ethanone derivative Chemical class 0.000 claims abstract description 62
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 239000000203 mixture Substances 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical class CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 9
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 120
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 106
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 52
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 150000002430 hydrocarbons Chemical group 0.000 claims description 21
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 239000007858 starting material Substances 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000005605 benzo group Chemical group 0.000 claims description 11
- 125000002837 carbocyclic group Chemical group 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 6
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 6
- 102000001805 Bromodomains Human genes 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 150000002460 imidazoles Chemical class 0.000 claims description 5
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 5
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
- 108091005575 Bromodomain-containing proteins Proteins 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 4
- 239000004305 biphenyl Chemical group 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- SJMCLWCCNYAWRQ-UHFFFAOYSA-N propane-2-sulfonamide Chemical compound CC(C)S(N)(=O)=O SJMCLWCCNYAWRQ-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 206010000830 Acute leukaemia Diseases 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 201000005569 Gout Diseases 0.000 claims description 2
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 125000004986 diarylamino group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
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- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
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- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
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- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
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- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
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- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 4
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 claims 1
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- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- XTKDAFGWCDAMPY-UHFFFAOYSA-N azaperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCN(C=2N=CC=CC=2)CC1 XTKDAFGWCDAMPY-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-N disulfurous acid Chemical compound OS(=O)S(O)(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-N 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- QPWLRODRTRANFI-UHFFFAOYSA-N ethyl 3-(1-methylpyrazol-4-yl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C=1C=NN(C)C=1 QPWLRODRTRANFI-UHFFFAOYSA-N 0.000 description 1
- KRAHENMBSVAAHD-UHFFFAOYSA-N ethyl 3-(4-methoxyphenyl)-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=C(OC)C=C1 KRAHENMBSVAAHD-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- DRINJBFRTLBHNF-UHFFFAOYSA-N propane-2-sulfonyl chloride Chemical compound CC(C)S(Cl)(=O)=O DRINJBFRTLBHNF-UHFFFAOYSA-N 0.000 description 1
- 108020001580 protein domains Proteins 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 229930185107 quinolinone Natural products 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
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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
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- 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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- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
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- 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
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- 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
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- 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
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- 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
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Abstract
The invention belongs to the field of medical chemistry, and particularly relates to a pyrrole derivative and a preparation method and application thereof. The compound has a structure shown as a general formula (I)
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to pyrrole derivatives, a preparation method and application thereof, and especially application of the pyrrole derivatives as a BET protein inhibitor.
Background
In recent years, tumors have become one of the leading causes of human death worldwide. The tumor has the characteristics of low overall cure rate, high recurrence rate and the like generally, so that the prevention, treatment and inhibition of tumor recurrence have important scientific research values, and the prevention and cure of the tumor are quite urgent and challenging.
Bromodomains (brds) are conserved protein domains that are capable of specifically recognizing acetylated lysine residues in histones. BRDs are present in different proteins and play a key regulatory role in chromatin assembly and gene transcription. The BRDs small molecule inhibitor can interfere the specific binding of the BRDs domain and the acetylated lysine, thereby blocking or partially blocking the function of the acetylated lysine in gene transcription and chromatin structure regulation. BRDs have been proven to be highly adaptable targets, and small molecule inhibitors acting on BRDs also have broad application prospects in disease treatment, which further enhances the cognition of researchers on BRDs proteins and related diseases.
In recent years, BRDs have become popular drug targets, and the biological functions and disease indications of members of the human BRDs family have been elaborated. The association of BRDs proteins with disease has prompted the development of BRDs inhibitors targeted at drug discovery. These small molecule inhibitors have two main applications: firstly, the molecules can be used as chemical probes to explore the biological functions of the BRDs protein in chromatin signal pathways and transcriptional activation and silencing processes; secondly, these molecules have the potential to treat a variety of human diseases. Transformation studies of small molecule inhibitors of BRDs are currently focused mainly on the BET family, which contains BRD2, BRD3, BRD4 and BRDT, and researchers are working on developing BET inhibitors that are highly effective and highly selective. The emergence of new BET inhibitors will advance the understanding of transcriptional regulation knowledge in the disease context and may be a potential epigenetic therapeutic for the treatment of a number of clinical conditions, such as cancer, inflammatory diseases, autoimmune diseases, and cardiovascular diseases.
At present, the small molecule inhibitors have fewer structural types, and the compounds entering clinical research are mainly triazole, quinolinone and pyridopyrrole. The inhibitors in the above classes have single structures, and the PK properties and in vitro properties of the compounds are not very ideal. The present invention therefore seeks to develop a novel class of BET inhibitors of structural mother nuclei for the prevention and treatment of diseases associated with this protein pathway. The invention provides a new BET of parent nucleus structure, and finds that the compound has good activity and shows excellent druggability.
Disclosure of Invention
According to the invention, the pyrrole derivatives, the preparation method and the application thereof are designed and synthesized by researching a crystal structure model of BET protein and summarizing the structure-activity relationship of BET, and pharmacological test results show that: the compound has good BET protein inhibition activity and good application prospect.
In order to solve the problems of the prior art, the invention adopts the technical scheme that:
having the general formula (I)
The compound shown in the formula (I), or one or more mixtures of tautomers, mesomers, racemates, enantiomers and diastereomers, or pharmaceutically acceptable salts thereof;
wherein R is1Represents hydrogen, halogen, alkyl, haloalkyl, heterocycloalkyl, cycloalkyl;
R2and R3Each independently selected from halo, cyano, aryl, Het, R5、-COR5、-CONHR5、-CONR5Het、-COR5Het、-COOR5、 -COOHet、-NHR5、-NH(CH2)1-10Het、-NH(CH2)1-10OR5、-NH(CH2)1-10NR5 2、-NHCOOR5、-NHCOOHet、 -NHCONHR5、-NHCONHHet、-OR5、-O(CH2)1-10NR5 2、-O(CH2)1-10Het or-O (CH)2)1-10OR5；
R4Represents halogen, cyano, Het, R5、-COR5、-CONR5Het、-COR5Het、-CONHHet、-COOHet、-NHR5、-NH(CH2)1-10Het、-NH(CH2)1-10OR5、-NH(CH2)1-10NR5 2、-NHCOOR5、-NHCOOHet、-NHCONHR5、 -NHCONHHet、-OR5、-O(CH2)1-10NR5 2、-O(CH2)1-10Het or-O (CH)2)1-10OR5；
Y represents S, O, NR5、CH2or-COCH ═ c;
x represents N, CNHR5、CNHCOR5CNHHet or CNHCOlet;
z represents NR5；
A represents alkenyl, alkynyl, biphenyl, cycloalkyl, cycloheteroalkyl, aryl ring or Het, which biphenyl, aryl, diarylamino or Het may be optionally substituted with: halogen, -CN, -OH, -CF3、OCF3、-OR5、-SH、-SR5、-NH2、-NHR5、-NR5 2、 -NHCOR5、-NHSO2R5、-NRSO2R5、-COR5、-COOR5、-CONHR5、-CON(R5 2)、-CONH(CH2)1-10N(R5 2)、 -CONR5 2、-CON(R5 2)O、-CONH(CH2)1-10N(R5 2)O、-CON(R5 2)NR5、-CON(R5 2)NCOOR5、 -CONH(CH2)1-10N(R5 2)NR5or-CONH (CH)2)1-10N(R5 2)NCOOR5；
B represents a single bond, O, S, NH, NR5、NHR5、OR5、SR5、R5Wherein R is5Represents a hydrogen atomAlkyl, haloalkyl, heterocycloalkyl, cycloalkyl;
the aryl is a carbocyclic ring comprising phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, and the phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl can each be optionally substituted with 1,2 or 3 substituents independently selected from hydrogen, alkyl, cyano, halo, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, a phenyl-containing carbocyclic ring, a naphthyl-containing carbocyclic ring, an acenaphthyl-containing carbocyclic ring, a tetrahydronaphthyl-containing carbocyclic ring, or Het;
het is selected from the group consisting of piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, piperazinyl, substituted piperazinyl, pyrazinyl or pyridazinyl, or from the group consisting of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [ b][1,4]Dioxane or benzo [ d ]][1,3]A bicyclic heterocycle of dioxolan, each of said monocyclic or bicyclic heterocycles being optionally substituted with 1,2 or 3 substituents each independently selected from halogen, haloalkyl, hydroxy, alkyl, alkoxy, C3-C8Aliphatic carbocycle, tetrahydropyrrolyl, morpholinyl, alkoxymorpholinyl, piperazinyl, piperidinyl or alkylaminopiperidinyl; the alkyl group is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is bonded; the alkoxy group is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is attached, wherein each carbon atom is optionally substituted with oxygen; the alkylamino is a straight-chain or branched saturated hydrocarbon group with 1-6 carbon atoms, or a cyclic saturated hydrocarbon group with 3-6 carbon atoms, or a straight-chain or branched chain connected with 1-6 carbon atomsA cyclic saturated hydrocarbon group having 3 to 6 carbon atoms of a chain saturated hydrocarbon group, wherein each carbon atom is optionally substituted with nitrogen;
the halogen is one of fluorine, chlorine or bromine.
As an improvement, the compound has the general formula (IA)
One or more mixtures of the compounds shown or tautomers, mesomers, racemates, enantiomers and diastereoisomers of the compounds, or pharmaceutically acceptable salts of the compounds; wherein Y is selected from S, O or NR5One of them.
As an improvement, the compound has the general formula (IB)
One or more mixtures of the compounds shown or tautomers, mesomers, racemates, enantiomers and diastereoisomers of the compounds, or pharmaceutically acceptable salts of the compounds; wherein Y is selected from S, O or NR5One of the above two methods; wherein X represents N, CNHR5、CNHCOR5CNHHet, CNHCOjet; y represents S, O, NR5、CH2-COCH-; z represents NR5；
As an improvement, R1Represents hydrogen, halogen, alkyl, haloalkyl, heterocycloalkyl having 3 to 7 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms.
As improvements, 2- (5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d ] imidazole (I-1), 1- (5- (benzo [ d ] oxazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-2), 1- (5- (benzo [ d ] thiazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-3), 1- (5- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-3), 1- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3 -3-yl) ethan-1-one (I-4), ethyl 5- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylate (I-5), 5- (H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (I-6), 5- (1H-benzo [ d ] imidazol-2-yl) -N- (2- (diethylamino) ethyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-7), 5- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-N- (2- (4-methylpiperazin-1-yl) ethyl) -4-phenyl-1H-pyrrole-3-carboxamide (I-8), 5- (1H-benzo [ d ] imidazol-2-yl) -N- (tert-butyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-9), 5- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-N- (1-methylpiperidin-4-yl) -4-phenyl-1H-pyrrole-3-carboxamide (I-10), 1- (2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-11), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (pyridin-3-yl) -1H-pyrrol-3-yl) ethan-1-one (I-12), 1- (4- (furan-3-yl) -2-methyl-5-yl) - (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-13), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (naphthalen-1-yl) -1H-pyrrol-3-yl) ethan-1-one (I-14), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (quinolin-7-yl) -1H-pyrrol-3-yl) ethan-1-one (I-15), 1- (4- (1H-indol-6-yl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-16), 1- (5- (5-amino-1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-17), 1- (2-methyl-5- (5-morpholinyl-1H- Benzo [ d ] imidazol-2-yl) -4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-18), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-19), N- (2- (4-acetyl-5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d ] imidazol-5-yl) propane-2-sulfonamide (I-20), 1- (5- (5- ((2- (dimethylamino) ethyl) amino) -1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-21), N- (2- (4-acetyl-5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d ] imidazol-5-yl) acetamide (I-22), 1- (4- (4-fluorophenyl) -2-methyl-5- (5-morpholinyl-1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-one 1-one (I-23), 1- (4- (4-chlorophenyl) -2-methyl-5- (5-morpholinyl-1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-24), 1- (4- (4-fluorophenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-25), 1- (4- (4-methoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1- 1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-26), 1- (4- (3-methoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-27), N- (3- (4-acetyl-5-methyl-2- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) phenyl) acetamide (I-27) -28), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (m-tolyl) -1H-pyrrol-3-yl) ethan-1-one (I-29), 1- (4- (4-methoxyphenyl) -2-methyl-5- (5-morpholinyl-1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-30), 1- (4- (3-cyclopropoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-pyrrol-3-yl) ethan-1-one (I-30), 1- (4- (3-cyclopropoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin -benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-31) or 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (3- (phenylamino) phenyl) -1H-pyrrol-3-yl) ethan-1-one (I-32).
The specific structure is shown in the table:
the improvement is that the pharmaceutically acceptable salt comprises an acid addition salt formed by one or more mixtures of a compound shown in a general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer and a diastereomer thereof and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid, or an acid salt formed by an inorganic base containing a basic metal cation, an alkaline earth metal cation or an ammonium cation salt.
A pharmaceutical composition comprises a compound having the general formula (I) or a mixture thereof or an acceptable salt thereof as an active ingredient.
The pharmaceutical composition is applied to the preparation of products for preventing or treating the BRD protein-related clinical symptoms.
The BRD protein-related clinical symptoms are rheumatoid arthritis, gouty arthritis melanoma, liver cancer, kidney cancer, acute leukemia, multiple myeloma, lymph cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, gastrointestinal cancer or mesothelioma.
Experimental studies on the binding ability of the above compounds to BRD4 protein:
BRD4 protein binding Capacity test
AlphaScreen method
1) Experimental materials and equipment: BRD4 protein; PHERAstar FS plate reader (B MG Labtech, Germany); HEPES, NaCl, BSA, CHAPS; 384 low volume whiteboards (Corning, USA); gun head (Axygen, USA); DMSO (Sigma, USA)
2) The experimental principle is as follows: the activity of BRD4 protein was detected by the Amplified luminescence reagent promoter activity assay (AlphaScreen). The donor and acceptor beads are coupled to two different antibody epitopes of the antibody against proteoglycan (aggrecan), respectively. When the substrate proteoglycan structure is intact, the paired beads are drawn closer together, and an optical signal is generated. When BRD4 protein and small molecule compound exist, it can break the whole structure of proteoglycan, and the light signal intensity is reduced. Therefore, the method can be used for detecting the binding force of the small molecules and the BRD4 protein, and has the advantages of rapidness, simplicity, high efficiency, sensitivity, reliable technical route and the like. AlphaScreen has the advantage of being able to utilize larger molecular substrates, particularly suitable assays for BRD4 inhibitor activity, as compared to conventional protease activity detection techniques (e.g., FRET-based detection methods).
3) Experimental procedures and methods: the Amplified luminescence reagent promoter homology (AlphaScreen) method specifically comprises the following steps (taking BRD4 as an example): a mixed buffer solution of 50mM HEPES, 100mM NaCl, 0.1% BSA, and 0.05% CHAPS was prepared in each well at room temperature at pH 7.4. The ligand was serially diluted from 150 μ M at a ratio of 1:2 to give 24 gradients of concentration and 4 μ l of the HIS-labeled BRD 4250 nM was added to each well; after incubation in the well plate for 30 minutes, 4. mu.l biotinylated peptide (H4K5KAc8KAc12KAc16ac) was added; after 30 minutes of further incubation, 4. mu.l of streptavidin-coated donor strain (25. mu.g/mL) and 4. mu.l of nickel chelate acceptor strain (25. mu.g/mL) were added under low light, and after incubation for 60 minutes in the absence of light, the light intensity was read using a PHERAStar FS plate reader (B MG Labtech, Germany) instrument at 680/570nm excitation/emission wavelengths, respectively.
Compound experimental results are shown in the following table:
note:athe protein activity rate under the concentration of 2 MuM,bno test was performed
In vitro anti-tumor Activity assay for Compounds of interest
The inhibitory effect on the leukemia cell line MV4-11 tumor cell line was determined by the MTT method.
The MTT method utilizes the fact that dehydrogenase related to NADP exists in mitochondria of living cells to reduce exogenous MTT into a difficultly soluble bluish purple crystal (Formazan) and deposits the bluish purple crystal in the cells, but dead cells do not have the function. Then, the purple crystal in the cells is dissolved by dimethyl sulfoxide (DMSO) or triple liquid (10% SDS-5% isobutanol-0.01 mol/L HCL), and the OD value of the purple crystal is measured by an enzyme-linked immunosorbent assay detector at the wavelength of 570nm to indirectly reflect the living cell amount.
The specific method comprises the following steps: inoculating the tumor cells to be tested in the logarithmic growth phase of the cells into a 96-well culture plate according to a certain cell amount, culturing for 24h, adding the screened sample (directly adding the suspension cells after connecting the plate), and culturing the cells at 37 ℃ with 5% CO2After further culturing for 48 hours under the condition, MTT is added for further culturing for 4 hours, and the crystals are dissolved by DMSO and detected under a microplate reader.
The results of the in vitro antitumor activity of the compounds of interest against the leukemic cells MV4-11 are as follows:
the biological activity test result shows that the compound provided by the invention has a BET protein inhibition effect. The compounds of the invention are useful in the treatment of various parenchymal 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, bone cancer, brain cancer, esophageal cancer, gastrointestinal cancer, soft tissue tumors, leukemia, lymphoma, and the like, either as cancers mediated by BET proteins and inflammation or as cancers independent of the above mechanisms. Therefore, the invention provides that the compound can be used for preparing anti-cancer drugs.
In vitro metabolic stability assay for a compound of interest
The drug concentration of different species of liver microsomes was determined by HPLC-MS.
HPLC-MS/MS method A mixture of the microsomal solution and the compound was incubated at 37 ℃ for a certain period of time, and the reaction was terminated by adding potassium phosphate buffer to NCF60 and a frozen mixture of Tolbutamide and Labetalol (1: 1) and incubating for various periods of time. The supernatant was collected by centrifugation and analyzed by LC-MS/MS. Analysis of data by first order kinetics to calculate T1/2And CL.
The specific method comprises the following steps: metabolic stability in MLM (mouse liver microsomes), RLM (rat liver microsomes), DLM (dog liver microsomes), CLM (monkey liver microsomes) and HLM (human liver microsomes) was tested by the following method according to the same procedure: no tin ApTec, Inc. to all plates (T0, T5, T10, T20, T30, T60, NCF60) 10. mu.L of compounds I-18, I-19 and I-30 or control working solution/well were added, except for the matrix blank. Then 80. mu.L/well was added to each plate by Apricot, and the mixture of microsomal solution and compound was mixedIncubate at 37 ℃ for about 10 minutes. To NCF60, 10. mu.L of 100mM potassium phosphate buffer/well was added and incubated at 37 ℃ for 1 hour. After preheating, 10. mu.L/well was added to each plate by Apricot to start the reaction. The reaction was terminated at 5,10,20,30 and 60 minutes incubation with a frozen mixture of Tolbutamide and Labetalol (1: 1). The mixture was vortexed for 5 minutes, centrifuged at 4000rpm for 20 minutes at 4 ℃, and the supernatant was analyzed by LC-MS/MS. Analysis of data by first order kinetics to calculate T1/2And CL.
The results for stability of the target compound to liver microsomes of four genera are as follows:
athe control drug, midazolam, is a fast-metabolizing sedative drug.
The biological activity test result shows that the compound provided by the invention has very good drug property. Compounds I-18, I-19 and I-30 all showed strong in vitro metabolic stability, and the metabolic half-lives in all four species were superior to the positive control Midazolam (Midazolam). Wherein the half-life of the I-19 in human and rat liver microsomes is respectively 199.3min and 66.4min, and the clearance rate is respectively as low as 7.0ul/min/mg and 20.9 ul/min/mg. Has good metabolic stability, long half-life and low clearance rate.
In-vitro BET protein activity tests show that the compound provided by the invention has remarkable BET protein binding capacity. Because BET has a key role in the growth and proliferation of tumor cells and has in vitro protein inhibition activity and liver microsome stability experimental support, the compound provided by the invention can be used in medicaments for preventing or treating diseases related to BET protein inhibitors, in particular to medicaments for tumors.
The preparation method of the compound shown in the general formula (I) or the mixture or the acceptable salt thereof takes an acetoacetic ester derivative or an amino aryl ethanone derivative as a starting material and prepares the compound through continuous reaction.
The specific steps are shown as the following reaction formula:
preparation of intermediates 1-d
Method 1
Step 1: ethyl acetoacetate derivative (1-a) is prepared by adding sodium nitrite, zinc powder and acetyl derivative (1-b) into glacial acetic acid solvent, stirring at room temperature for 8 hr, and heating to react to obtain compound (1-c).
Step 2: and (3) heating and decarboxylating the compound of the general formula (1-c) under strong alkaline conditions to obtain a compound (1-d), wherein the strong alkaline comprises: NaOH and KOH.
Method two
And step 3: the aminoarylethyl ketone derivative (1-e) and the acetyl derivative (1-b) of the general formulae are heated in anhydrous ethanol until the compound (1-d) is obtained. Preparation of the target product (1-x)
And 4, step 4: pyrrole (1-d) with the general formula is subjected to Vilsmeier-Haack reaction under the condition of phosphorus oxychloride to obtain a compound (1-e).
And 5: the compound (1-g) is obtained by nucleophilic reaction of nitrobenzene derivatives (1-f) in the general formula under alkaline condition.
Step 6: the nitrobenzene derivative (1-g) is obtained by substitution of the general formula, and the compound (1-h) is obtained by reduction reaction of iron powder, ammonium chloride or palladium on carbon and hydrogen.
And 7: the compound (1-e) of the general formula and the compound (1-h) are heated under the conditions of pyrosulfurous acid and nitrogen to obtain the target compound (1-x).
Has the advantages that:
the invention belongs to the field of medical chemistry, and particularly relates to a pyrrole derivative and a preparation method and application thereof. When the compound is prepared, an ethyl acetoacetate derivative and an amino aryl ethanone derivative are used as initial raw materials, and the pyrrole derivative (I) is obtained through continuous reaction. The pyrrole derivatives are a brand-new BET protein inhibitor and have excellent protein activity and anti-tumor cell proliferation activity.
Meanwhile, the liver microsome has very good druggability, stable liver microsome metabolism, longer half-life period and lower clearance rate. The compounds are found to have better water solubility in the preparation process and are potential to be used as anti-tumor oral medicaments.
Detailed Description
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (S) at 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-300 or Bruker AVANCE-400 nuclear magnetic spectrometer using neon dimethylsulfoxide (DMSO-d) as the solvent6) Deuterated chloroform (CDC 1)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).
The preparation of the compound with larger water solubility adopts Biotage rapid purification preparation liquid chromatography Flash Isolerone, and the column used is a bonding phase series rapid separation column of Santai corporation of Hezhou (SW-5222-.
The thin-layer chromatography silica gel plate uses a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of a child silica gel plate used by thin-layer chromatography (TLC) is 0.15-0.2 mm, and the specification of a thin-layer chromatography separation and purification product is 0.4-0.5 mm, and the column chromatography generally uses tobacco yellow sea silica gel 200-300 meshes as a carrier.
Known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from the companies ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, shao distal Chemical technology (AccelaChemBio Inc), shanghai bi medical technology limited, ann naigi chemistry, dary chemicals, etc.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC), a developing solvent used for the reaction, an eluent system for column chromatography for purifying the compound, a developing solvent system for thin layer chromatography, and preparative liquid phase for rapid purification18The C bonding phase separation column system comprises a dichloromethane/methanol system, a normal hexane/ethyl acetate system, a petroleum ether/ethyl acetate system, a ethyl acetate/dichloromethane system, an ethyl acetate/dichloromethane/normal hexane system, a methanol/water/methylamine water solution system, and an acetonitrile/water system, wherein the volume ratio of a solvent is adjusted according to different polarities of compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
The process of the present invention is described and illustrated in detail below with reference to specific examples. The content is to explain the invention and not to limit the scope of protection of the invention.
Example 1
2- (5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d ] imidazole (I-1)
Step 1, 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (I-1a)
Heating and stirring aminophenylethyl ketone (2g,14.80mmol,1equi) and ethyl acetoacetate (1.13mL,17.76mmol) in anhydrous ethanol (40mL) at 90 deg.C for 5 hr, checking by TLC that the reaction is complete, cooling to room temperature, concentrating by distillation under reduced pressure, addingAdding 100mL of water, extracting with ethyl acetate (50mL × 3), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by silica gel column chromatography using system C to obtain white solid I-1a (2.45g,10.70mmol), yield 72.3% MS M/s (ESI): 230.2[ M + H ]]+。
Step 2, 2-methyl-4-phenyl-1H-pyrrole (I-1b)
800mg of ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate (I-1a) was placed in a 50mL round-bottom flask, 15mL of trifluoroacetic acid was added and the reaction was heated to 50 ℃, TLC was performed to check completion, the mixture was cooled to room temperature, after concentration by vacuum distillation, 100mL of water was added, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by vacuum filtration, and purified by silica gel column chromatography using the system C to obtain white solid I-1a (308mg,1.96mmol), yield 56.2%. MS M/s (ESI) 186.2[ M + H ]: 186.2]+。
Step 3, 5-methyl-3-phenyl-1H-pyrrole-2-carbaldehyde (I-1c)
The compound 2-methyl-4-phenyl-1H-pyrrole (I-1b) (300mg,1.91mmol) and DMF 5mL (43.74mmol) were sequentially added to a 100mL eggplant-shaped bottle, cooled in an ice bath, added with phosphorus oxychloride 0.5mL (2.43mmol), reacted at room temperature for 2H, detected by TLC, cooled in an ice bath, added with an aqueous solution of potassium acetate 1.19g (12.15mmol) 10mL, heated at 105 ℃ for 2H, detected by TLC, cooled, the reaction mixture was slowly poured into 100mL of ice water, extracted with ethyl acetate (50mL × 3), the organic phase was collected, washed with saturated sodium chloride 100mL, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and separated by silica gel column chromatography (ethyl acetate: petroleum ether: 1:5) to give a white solid 283mg, yield 80.2%, MS M/s ESI (M + H2]+。
Step 4, 2- (5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d ] imidazole (I-1)
Adding 250mg (1.35mmol) of 5-methyl-3-phenyl-1H-pyrrole-2-formaldehyde (I-1c), 175mg (1.62mmol) of o-phenylenediamine, 24mg (0.10mmol) of sodium metabisulfite and 20mL of absolute ethyl alcohol into a 50mL two-neck bottle in sequence, heating at 90 ℃ for 5H under the protection of nitrogen, detecting the end of the reaction by TLC, cooling, pouring the reaction liquid into 100mL of water, and reacting with ethyl acetate (50mL × 3)Extraction, organic phases are combined, washed by 100mL of saturated saline solution, dried by anhydrous sodium sulfate and kept stand. Filtration was carried out, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate: petroleum ether: 1) to give 133mg of a pale yellow solid, with a yield of 36.10%. MS m/s (ESI): 247.2[ M + H]+。1H NMR(300MHz,DMSO-d6)11.95 (s,1H),10.56(s,1H),7.55(d,J＝6.8Hz,1H),7.44(d,J＝6.9Hz,3H),7.29–7.31(m,3H),7.16–7.05(m,2H), 6.36(s,1H),1.86(s,3H)。
Example 2
1- (5- (benzo [ d ] oxazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-2)
Step 1, Ethyl 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (I-2a)
Adding ethyl acetoacetate 14.40g (75.04mmol) and glacial acetic acid 20mL into 250mL eggplant-shaped bottle in turn, cooling with ice bath, adding sodium nitrite 5.59g (81.04mmol) of aqueous solution 20mL, reacting at room temperature for 8H, detecting by TLC, adding zinc powder 9.81g (150.08 mmol) and acetylacetone 7.51g (75.04mmol) into the reaction solution in turn, heating at 60 deg.C for 1H, detecting by TLC, cooling, pouring the reaction solution slowly into 200mL ice water, extracting with dichloromethane (100mL × 3), collecting organic phase, washing with 200mL saturated saline solution, drying with anhydrous sodium sulfate, standing, filtering, distilling off solvent under reduced pressure, separating and purifying by silica gel column chromatography with C system to obtain white solid 15.17g, yield 74.68%, MS/s (ESI), 272.2[ M + H ] (M + H)]+。
Step 2, 1- (2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-2b)
13g (47.79mmol) of the compound ethyl 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (I-2a), 13.41 g (238.95mmol) of potassium hydroxide and 40mL of ethylene glycol are sequentially added into a 100mL eggplant-shaped bottle, the bottle is heated at 140 ℃ for 1H, TLC detection reaction is finished, cooling is carried out, the reaction liquid is slowly poured into 200mL ice water, ethyl acetate (200mL × 2) is used for extraction, an organic phase is collected, 200mL saturated saline solution is washed, anhydrous sodium sulfate is dried, and standing is carried out.Filtering, decompressing and distilling off the solvent, separating and purifying by silica gel column chromatography with the C system to obtain 8.30g of white solid with the yield of 87.3%. MS m/s (ESI): 200.1[ M + H]+。
Step 3, 4-Ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carbaldehyde (I-2c)
Adding 2.90g (14.58mmol) of compound 1- (2-methyl-4-phenyl-1H-pyrrole-3-yl) ethyl-1-ketone (I-2b) and 20mL of DMF into a 100mL eggplant-shaped bottle in sequence, cooling in an ice bath, adding 3mL (14.58mmol) of phosphorus oxychloride, reacting for 2H at room temperature, finishing TLC detection reaction, cooling in the ice bath, adding 10mL of aqueous solution of 7.15g (72.90mmol) of potassium acetate, heating for 2H at 105 ℃, finishing TLC detection reaction, cooling, slowly pouring the reaction liquid into 100mL of ice water, extracting with ethyl acetate (50mL × 3), collecting an organic phase, washing with 100mL of saturated saline solution, drying with anhydrous sodium sulfate, standing, filtering, distilling off the solvent under reduced pressure, separating and purifying by a C system through silica gel column chromatography to obtain 2.74g of white solid, wherein the yield is 67.81%, MS/s (ESI) is 228.3[ M + H + E%]+。
Step 4, 1- (5- (benzo [ d ] oxazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-2)
Adding 200mg (0.88mmol) of 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-formaldehyde (I-2C), 115mg (1.05mmol) of o-aminophenol, 19mg (0.10mmol) of sodium pyrosulfite and 20mL of absolute ethyl alcohol into a 50mL two-neck flask in sequence, heating for 5H at 90 ℃, detecting the end of the reaction by TLC, cooling, pouring the reaction liquid into 100mL of water, extracting with ethyl acetate (50mL × 3), combining organic phases, washing with 100mL of anhydrous saturated saline, drying with sodium sulfate, standing, filtering, evaporating the solvent under reduced pressure, separating and purifying by silica gel column chromatography with a C system to obtain 122mg of white solid, wherein the yield is 44.17%. MS M/s (ESI): 317.2[ M + H + ESI ]]+。1H NMR(300MHz,DMSO-d6)11.85(s,1H), 7.55(d,J＝6.8Hz,1H),7.34(d,J＝6.5Hz,3H),7.26–7.28(m,3H),7.06–7.15(m,2H),2.51(s,3H),2.47(s, 3H)。
Example 3
1- (5- (benzo [ d ] thiazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-3)
Step 1, 1- (5- (benzo [ d ] thiazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-3)
Adding 140mg (0.5mmol) of 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-formaldehyde (I-2C), 68mg (0.55mmol) of 2-aminobenzenethiol, 15mg (0.08mmol) of sodium metabisulfite and 20mL of absolute ethyl alcohol into a 50mL two-neck flask in sequence, heating for 5H at 90 ℃ under the protection of nitrogen, detecting the reaction by TLC, cooling to room temperature, pouring the reaction liquid into 100mL of water, extracting with ethyl acetate (50mL × 3), combining organic phases, washing with 100mL of saturated saline solution, drying with anhydrous sodium sulfate, standing, filtering, evaporating the solvent under reduced pressure, separating and purifying by silica gel column chromatography with a C system to obtain 84mg of white solid, wherein the yield is 51.31 percent, MS M/s (ESI) is 333.2[ M + H ], (ESI)]+。1H NMR(300MHz,DMSO-d6)11.25 (s,1H),8.05(d,J＝6.8Hz,2H),7.44(d,J＝6.9Hz,2H),7.39–7.45(m,5H),2.51(s,3H),2.16(s,3H)。
Example 4
1- (5- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-4)
Step 1, 1- (5- (benzo [ d ] thiazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-3)
Adding 140mg (0.5mmol) of 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-formaldehyde (I-2C), 60mg (0.55mmol) of o-phenylenediamine, 15mg (0.08mmol) of sodium metabisulfite and 20mL of absolute ethyl alcohol into a 50mL two-neck bottle in sequence, heating for 5H at 90 ℃ under the protection of nitrogen, detecting the reaction by TLC, cooling, pouring the reaction solution into 100mL of water, extracting with ethyl acetate (50mL × 3), combining organic phases, washing with 100mL of saturated saline, drying with anhydrous sodium sulfate, standing, filtering, distilling off the solvent under reduced pressure, separating and purifying by silica gel column chromatography with a C system to obtain 51mg of white solid, wherein the yield is 32.75%, MS M/s (ESI) 316.1[ M + H ] M + H]+。1H NMR(300MHz,DMSO-d6)12.25(s,1H),10.86 (s,1H),7.55(d,J＝6.8Hz,1H),7.44(d,J＝6.9Hz,3H),7.39–7.45(m,3H),7.16–7.05(m,2H),2.49(s,3H), 1.76(s,3H)。
Example 5
Ethyl 5- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylate (I-5)
Step 1, 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (I-5a)
The preparation was carried out in analogy to 5-methyl-3-phenyl-1H-pyrrole-2-carbaldehyde (I-1c) from 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (I-1a) in 3g (13.10mmol) and final purification gave 2.66g of white solid in 79.33% yield in analogy to step 3 of example 1. MS m/s (ESI): 257.3[ M + H]+。
Step 2, Ethyl 5- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylate (I-5)
The preparation method and 2- (5-methyl-3-phenyl-1H-pyrrole-2-yl) -1H-benzo [ d of step 4 in the embodiment 1]Imidazole (I-1) was similarly prepared from ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate (I-1a) and o-phenylenediamine as starting materials in a charge of 150mg (0.58mmol), and was finally purified to obtain 103mg of a white solid in 51.10% yield. MS m/s (ESI): 346.2[ M + H]+。1H NMR(300MHz,Chloroform-d)11.87 (s,1H),8.28(s,1H),7.45-7.45(m,6H),7.16(dd,J＝5.9,3.1Hz,3H),4.07(q,J＝7.1Hz,2H),2.49(s,3H),
1.01(t,J＝7.1Hz,3H)。
Example 6
5- (H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (I-6)
Reacting ethyl 5- (1H-benzo [ d ]]Imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylate (I-5)500mg (1.45mmol) was dissolved in 10mL of methanol, stirred at room temperature, followed by addition of 4mL of 2mmol/mL aqueous sodium hydroxide solution. TLC detection reactionAfter completion of the reaction, the reaction mixture was neutralized or weakly acidic with dilute hydrochloric acid, poured into 100mL of water, extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with 100mL of saturated brine, dried over anhydrous sodium sulfate, left to stand, filtered, the solvent was evaporated under reduced pressure, and purified by silica gel column chromatography using System A to obtain a white solid (372 mg) in a yield of 81.46%. MS M/s (ESI): 318.2[ M + H ], (ESI)]+。1H NMR(300MHz,DMSO-d6) 12.75(s,1H),12.15(s,1H),10.96(s,1H),7.70(d,J＝7.2Hz,2H),7.39(d,J＝6.9Hz,1H),7.39–7.45(m, 3H),7.16–7.05(m,3H),1.36(s,3H)。
Example 7
5- (1H-benzo [ d ] imidazol-2-yl) -N- (2- (diethylamino) ethyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-7)
Weighing 80Mg (0.25mmol) of I-6, placing in a 100mL single-neck flask, dissolving with 15mL anhydrous DMF, stirring in ice-water bath, adding HATU 140Mg (0.375mmol) and DIPEA 60 μ L (0.375mmol) respectively, adding N, N-diethylethylenediamine 30Mg (0.25mmol) after 30mins, stirring at room temperature for 4h, detecting by TLC that the reaction is complete, slowly pouring the reaction solution into water (100mL), extracting with EA (4 × 100mL), mixing, washing the organic layer with saturated saline, and washing with Mg2SO4Drying, filtering, concentrating, and preparing liquid phase by rapid purification18The bonded phase separation column obtained 58mg of a white solid in 55.8% yield with F elution. MS m/s (ESI): 416.2[ M + H]+。1H NMR(300MHz,DMSO-d6) 12.15(s,1H),11.05(s,1H),8.96(s,1H),7.70(d,J＝7.2Hz,2H),7.39(d,J＝6.9Hz,1H),7.21–7.32(m,3H), 7.12–7.01(m,3H),3.40–3.03(m,2H),2.46(q,J＝7.2Hz,4H),2.41–2.35(m,2H),2.19(s,3H),0.99–0.89 (t,J＝7.2Hz,6H)。
Example 8
5- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-N- (2- (4-methylpiperazin-1-yl) ethyl) -4-phenyl-1H-pyrrole-3-carboxamide (I-8)
Preparation method and 5- (1H-benzo [ d ] in example 7]Imidazol-2-yl) -N- (2- (diethylamino) ethyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-7) analogous to the reaction with 5- (H-benzo [ d [)]Imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (I-6) and 4-methyl-1-piperazineethylamine as starting materials at a charge level of 80mg (0.25mmol) I-6, and finally preparing a liquid phase by rapid purification18The bound phase separation column obtained 46mg of a white solid in 42.3% yield as F-eluted system. MS m/s (ESI): 443.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.15(s,1H), 11.15(s,1H),8.76(s,1H),7.70(d,J＝7.2Hz,2H),7.39(d,J＝6.9Hz,1H),7.21–7.32(m,3H),7.12–7.01(m, 3H),3.40(s,4H),3.28(t,J＝4.1Hz 2H),2.61-2.56(m,2H),2.41(s,4H),2.17(s,3H),2.15(s,3H)。
Example 9
5- (1H-benzo [ d ] imidazol-2-yl) -N- (tert-butyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-9)
Preparation method and 5- (1H-benzo [ d ] in example 7]Imidazol-2-yl) -N- (2- (diethylamino) ethyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-7) analogous to the reaction with 5- (H-benzo [ d [)]Imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (I-6) and tert-butylamine as starting materials, a charge of 80mg (0.25mmol) I-6, and finally preparation of the liquid phase by rapid purification18The bonded phase separation column obtained 50mg of a white solid in 53.9% yield with F elution. MS m/s (ESI): 373.2[ M + H]+。1H NMR(300MHz,DMSO-d6)12.05(s,1H),11.05(s,1H), 8.56(s,1H),7.55(d,J＝7.9Hz,4H),7.21–7.28(m,2H),7.12–7.01(m,3H),2.19(s,3H),1.43(s,9H)。
Example 10
5- (1H-benzo [ d ] imidazol-2-yl) -2-methyl-N- (1-methylpiperidin-4-yl) -4-phenyl-1H-pyrrole-3-carboxamide (I-10)
Preparation method and 5- (1H-benzo [ d ] in example 7]Imidazol-2-yl) -N- (2- (diethylamino) ethyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-7) analogous to the reaction with 5- (H-benzo [ d [)]Imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (I-6) and 1-methylpiperidine-4-amine as starting materials, with a charge of 100mg (0.32mmol) I-6, and finally preparing a liquid phase by rapid purification18The bound phase separation column obtained 74mg of a white solid in 57.2% yield as F elution. MS m/s (ESI): 414.2[ M + H]+。1H NMR(300MHz,DMSO-d6)12.10(s,1H),10.84 (s,1H),8.56(s,1H),7.68(d,J＝7.6Hz,2H),7.55–7.39(m,5H),7.22–7.17(m,2H),3.34–3.27(m,1H),2.37 (s,3H),2.10(s,3H),1.90–1.82(m,2H),.1.61–1.55(m,2H)。
Example 11
1- (2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-11)
Step 1, 4-acetyl-5-methyl-3- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole-2-carboxylic acid ethyl ester (I-11a)
The preparation method comprises the following steps of 2: analogy to 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (I-2a) starting from ethyl 3- (1-methyl-1H-pyrazol-4-yl) -3-oxopropanoate and acetylacetone was charged 800mg (4.01mmol), 900 mg of white solid was finally obtained in 82.6% yield. MS m/s (ESI): 276.2[ M + H]+。
Step 2, 1- (2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrol-3-yl) ethan-1-one (I-11b)
The preparation method was similar to that of ethyl 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxylate (I-2a) in step 2 of example 2, starting from ethyl 4-acetyl-5-methyl-3- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole-2-carboxylate (I-11a) at a charge of 850mg (3.10mmol), to finally obtain 489mg of white solid in 77.8% yield. MS m/s (ESI): 204.3.
step 3, 4-acetyl-5-methyl-3- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole-2-carbaldehyde (I-11c)
The preparation method comprises the following steps of 1: analogous to 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carbaldehyde (I-2c), starting from 1- (2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrol-3-yl) ethan-1-one (I-11b) at a charge of 450mg (2.22mmol), 437mg of a white solid was finally obtained in 85.4% yield. MS m/s (ESI): 232.1.
step 4, 1- (3, 4-dinitrophenyl) -4-methylpiperazine (I-11d)
Weighing 800Mg (4.30mmol) of 3, 4-dinitrofluorobenzene, placing the weighed material in a 100mL thick-wall sealed tube, dissolving the material in 15mL of anhydrous DMF, adding 714mL (6.45mmol) of N-methylpiperazine and 1.18g (8.60mmol) of potassium carbonate, stirring and heating the mixture at 100 ℃ for 4 hours to detect the reaction completion by TLC, slowly pouring the reaction solution into water (200mL), using EA (4 × 200mL), washing an organic layer with saturated saline solution, and washing Mg on the organic layer2SO4Drying, filtration and concentration, 1.08g of crude yellow product was recrystallized from 75% with yield 94.1%. MS m/s (ESI): 267.1.
step 5, 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e)
200mg (4.30mmol) of 1- (3, 4-dinitrophenyl) -4-methylpiperazine (I-11d) is weighed into a 100mL thick-wall sealed tube, 100mg of 10% Pd/C is added, the solution is dissolved by 25mL of ethanol, a hydrogen balloon is pumped out for 3 times, the mixture is stirred for 5 hours at room temperature, the TLC detection reaction is complete, and the mixture is filtered and concentrated by diatomite to obtain 194mg of crude black oil.
Step 6, 1- (2-methyl-4- (1-methyl-1H-pyrazol-4-yl) -5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-11)
Method for the production thereof and 2- (5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d ] for carrying out step 1, step 4]Imidazole (I-1) analogously starting from 4-acetyl-5-methyl-3- (1-methyl-1H-pyrazol-4-yl) -1H-pyrrole-2-carbaldehyde (I-11c) and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e) in a charge of 100mg (0.43mmol) and finally preparing a liquid phase by rapid purification18The C bonded phase separation column was separated and purified by an F elution system to obtain 110mg of a white solid in a yield of 61.7%. MS m/s (ES)I)：418.3。1H NMR(300MHz,DMSO-d6)12.16(s, 1H),10.43(s,1H),7.93(d,J＝7.0Hz,2H),7.35(dd,J＝7.4,2.0Hz,2H),6.91(s,1H),3.45(s,3H),3.09(t,J＝4.8Hz,4H),2.59(s,4H),2.42(s,6H),1.75(s,3H)。
Example 12
1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (pyridin-3-yl) -1H-pyrrol-3-yl) ethan-1-one (I-12)
Step 1, 1- (2-methyl-4- (pyridin-3-yl) -1H-pyrrol-3-yl) ethan-1-one (I-12a)
Amino-3-pyridylethyl ketone (1g,5.79mmol) and ethyl acetoacetate (0.713mL,6.95mmol) were heated and stirred at 90 ℃ for 5 hours under the condition of absolute ethanol (40mL), TLC checked for completion of the reaction, cooled to room temperature, concentrated by distillation under reduced pressure, added with 100mL of water, extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated by reduced pressure, and purified by silica gel column chromatography as system C to obtain white solid I-1a (852mg,4.26mmol), yield 73.5%. MS M/s (ESI): 201.2[ M + H ] M/s]+。
Step 2, 1- (2-methyl-4- (pyridin-3-yl) -1H-pyrrol-3-yl) ethan-1-one (I-12b)
The preparation method is similar to that of the 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carbaldehyde (I-2c) in the step 3 in the example 2, and the I-12a is used as a raw material, the feeding amount is 800mg (4.00mmol), 769mg of white solid is finally obtained, and the yield is 84.33%. MS m/s (ESI): 228.3[ M + H]+。
Step 3, 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (pyridin-3-yl) -1H-pyrrol-3-yl) ethan-1-one (I-12)
The preparation was carried out analogously to step 4I-1 of example 1, starting from I-12b and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge of 200mg (0.87mmol) of I-12b, and finally using a rapid purification to prepare the liquid phase18Separating and purifying the C bonded phase separation column by using an F elution system to obtain 89mg of white solid,the yield thereof was found to be 24.7%. MS m/s (ESI): 415.3[ M + H]+。1H NMR(300MHz,DMSO-d6) 12.16(s,1H),10.43(s,1H),7.45(d,J＝7.0Hz,3H),7.37(dd,J＝7.2,3.0Hz,2H),6.84–6.76(m,2H),3.19(t, J＝7.1Hz,4H),2.51(s,3H),2.47(t,J＝7.1Hz,4H),1.97(s,3H),1.84(s,3H)。
Example 13
1- (4- (furan-3-yl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-13)
Step 1, 1- (2-methyl-4- (pyridin-3-yl) -1H-pyrrol-3-yl) ethan-1-one (I-13a)
The preparation was carried out analogously to example 12, step 1I-12a, starting from 2-amino-1- (furan-2-yl) ethan-1-one and acetylacetone, starting from a charge of 2-amino-1- (furan-2-yl) ethan-1-one hydrochloride of 500mg (3.09mmol), giving 293 mg of white solid in 50.2% yield. MS m/s (ESI): 190.3[ M + H]+。
Step 2, 4-acetyl-3- (furan-2-yl) -5-methyl-1H-pyrrolecarboxaldehyde (I-13b)
The preparation was carried out in analogy to 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carbaldehyde (I-2c) from step 3 of example 2, starting from I-12a in a charge of 250mg (1.32mmol), giving 240mg of white solid in 83.8% yield. MSm/s (ESI): 228.3[ M + H]+。
Step 3, 1- (4- (furan-3-yl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-13)
The preparation was carried out analogously to step 4I-1 of example 1, starting from I-13b and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge of 200mg (0.90mmol) of I-13b, and finally using a rapid purification to prepare the liquid phase18The C bonded phase separation column is separated and purified by an F elution system to obtain 110mg of white solid with the yield of 30.1 percent. MS m/s (ESI): 404.3[ M + H]+。1H NMR(300MHz,DMSO-d6) 12.16(s,1H),10.43(s,1H),7.45(d,J＝7.0Hz,3H),7.37(dd,J＝7.2,3.0Hz,1H),6.84–6.76(m,2H),3.09 -3.01(m,4H),2.49(s,3H),2.48-2.40(m,4H),1.90(s,3H),1.82(s,3H)。
Example 14
1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (naphthalen-1-yl) -1H-pyrrol-3-yl) ethan-1-one (I-14)
Step 1, 1- (2-methyl-4- (naphthalen-1-yl) -1H-pyrrol-3-yl) ethan-1-one (I-14a)
The preparation was carried out analogously to example 12, step 1I-12a, starting from 2-amino-1- (furan-2-yl) ethan-1-one and acetylacetone, starting from a charge of 2-amino-1- (furan-2-yl) ethan-1-one hydrochloride of 500mg (2.26mmol), giving 408 mg of white solid in a yield of 72.7%. MS m/s (ESI): 250.3[ M + H]+。
Step 2, 4-acetyl-5-methyl-3- (naphthalen-1-yl) -1H-pyrrole-2-carbaldehyde (I-14b)
The preparation process is similar to that of 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carbaldehyde (I-2c) in step 3 of example 2, with I-14a as the starting material and a charge of 350mg (1.40mmol), yielding 260mg of a white solid in 66.9% yield. MS m/s (ESI): 278.3[ M + H]+。
Step 3, 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (naphthalen-1-yl) -1H-pyrrol-3-yl) ethan-1-one (I-14)
The preparation was carried out analogously to step 4I-1 of example 1, starting from I-14b and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge of 200mg (0.72mmol) of I-13b, and finally using a rapid purification to prepare the liquid phase18The C bonded phase separation column was separated and purified by an F elution system to obtain 61mg of a white solid in a yield of 18.5%. MS m/s (ESI): 464.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.14 (s,1H),10.43(s,1H),8.84–8.66(m,2H),8.14–8.06(m,4H),7.45(d,J＝7.0Hz,3H),7.37(dd,J＝7.2,3.0Hz, 1H),3.17–3.09(m,4H),2.49(s,3H),2.37-2.31(m,4H),1.90(s,3H),1.79(s,3H)。
Example 15
1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (quinolin-7-yl) -1H-pyrrol-3-yl) ethan-1-one (I-15)
Step 1, 1- (2-methyl-4- (quinolin-7-yl) -1H-pyrrol-3-yl) ethan-1-one (I-15a)
The preparation was carried out analogously to example 12, step 1I-12a, starting from 2-amino-1- (furan-2-yl) ethan-1-one and acetylacetone, starting from a charge of 2-amino-1- (furan-2-yl) ethan-1-one hydrochloride of 500mg (2.25mmol), giving 366mg of white solid in 65.2% yield. MS m/s (ESI): 251.3[ M + H]+。
Step 2, 4-acetyl-5-methyl-3- (quinolin-7-yl) -1H-pyrrole-2-carbaldehyde (I-15b)
The preparation was carried out analogously to 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carbaldehyde (I-2c) from step 3 of example 2, starting from I-15a in a charge of 350mg (1.40mmol), giving 210mg of white solid in 54.2% yield. MS m/s (ESI): 279.3[ M + H]+。
Step 3, 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (quinolin-7-yl) -1H-pyrrol-3-yl) ethan-1-one (I-15)
The preparation was carried out analogously to step 4I-1 of example 1, starting from I-15b and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge of 200mg (0.71mmol) of I-15b, and finally using a rapid purification to prepare the liquid phase18The C bonded phase separation column was separated and purified by an F elution system to obtain 72mg of a white solid with a yield of 21.6%. MS m/s (ESI): 464.3[ M + H]+。1H NMR(300MHz,DMSO-d6) 12.14(s,1H),10.43(s,1H),8.84–8.66(m,2H),8.14–8.06(m,3H),7.45(d,J＝7.0Hz,3H),7.35(dd,J＝7.7, 5.4Hz,1H),3.17(s,4H),2.49(s,3H),2.37(s,4H),1.90(s,3H),1.79(s,3H)。
Example 16
1- (4- (1H-indol-6-yl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-16)
Step 1, 1- (4- (1H-indol-3-yl) -2-methyl-1H-pyrrol-3-yl) ethan-1-one (I-16a)
The preparation was carried out analogously to example 12, step 1I-12a, starting from 2-amino-1- (1H-indol-3-yl) eth-1-one hydrochloride and acetylacetone, starting from a charge of 2-amino-1- (furan-2-yl) eth-1-one hydrochloride of 800mg (2.55mmol), giving 366mg of white solid in 63.1% yield. MS m/s (ESI): 239.3[ M + H]+。
Step 2, 4-acetyl-3- (1H-indol-3-yl) -5-methyl-1H-pyrrole-2-carbaldehyde (I-16b)
The preparation was carried out analogously to 4-ethyl-5-methyl-3-phenyl-1H-pyrrole-2-carbaldehyde (I-2c) from step 3 of example 2, starting from I-16a in a charge of 350mg (1.47mmol), giving 194mg of white solid in 49.8% yield. MS m/s (ESI): 267.3[ M + H]+。
Step 3, 1- (4- (1H-indol-3-yl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-pyridin-3-yl) ethan-1-one (I-16)
The preparation was carried out analogously to step 4I-1 of example 1, starting from I-16b and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge of 150mg (0.56mmol) of I-16b, and finally using a rapid purification to prepare the liquid phase18The C bonded phase separation column was separated and purified by using an F elution system to obtain 84mg of a white solid in a yield of 33.2%. MS m/s (ESI): 453.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.14(s, 1H),11.43(s,1H),10.03(s,1H),8.34–8.16(m,2H),7.74–7.66(m,2H),7.45(d,J＝7.0Hz,3H),7.35(dd,J＝ 7.7,5.4Hz,1H),3.17(s,4H),2.49(s,3H),2.37(s,4H),1.90(s,3H),1.79(s,3H)。
Example 17
1- (5- (5-amino-1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-17)
The preparation was carried out analogously to step 4I-1 of example 1, starting from I-3c and 1,2, 4-triphenylamine (I-3c), with a charge of I-3c of 200mg (1.10mmol), and the liquid phase was finally prepared by rapid purification18The C bonded phase separation column was separated and purified by an F elution system to obtain 129 mg of a white solid in a yield of 35.7%. MS m/s (ESI): 331.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.04(s,1H),10.29(s,1H), 7.50–7.26(m,6H),6.45(d,J＝7.9Hz,2H),4.82(s,2H),3.32(s,3H),1.76(s,3H)。
Example 18
1- (2-methyl-5- (5-morpholinyl-1H-benzo [ d ] imidazol-2-yl) -4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-18)
Step 1, 1- (3, 4-dinitrophenyl) -4-morpholine (I-18a)
Weighing 800Mg (4.30mmol) of 3, 4-dinitrofluorobenzene, placing in a 100mL thick-wall sealed tube, dissolving with 15mL of anhydrous DMF, adding 0.428mL (5.16mmol) of morpholine and 1.18g (8.60mmol) of potassium carbonate, stirring, heating at 100 ℃ for 4h, detecting the reaction completion by TLC, slowly pouring the reaction solution into water (100mL), washing with EA (4 × 100mL), washing the organic layer with saturated saline, and washing with Mg2SO4Drying, filtration and concentration, 0.95g of crude yellow product was recrystallized from 75% with 91.6% yield. MS m/s (ESI): 254.1[ M + H]+。
Step 2,4- (4-Morpholin-1-yl) benzene-1, 2-diamine (I-18b)
Weighing 800mg (3.16mmol) of 4- (4-morpholin-1-yl) benzene-1, 2-diamine (I-18b) and placing in a 100mL thick-wall sealed tube, adding 100mg of 10% Pd/C, dissolving with 25mL of ethanol, exhausting for 3 times by a hydrogen balloon, stirring for 5 hours at room temperature, detecting the reaction by TLC, filtering and concentrating by using kieselguhr to obtain a crude black oil body. MS m/s (ESI): 193.1[ M + H]+。
Step 3, 1- (2-methyl-5- (5-morpholinyl-1H-benzo [ d ] imidazol-2-yl) -4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-18)
Preparation and example 1 step 42- (5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d]Analogous to imidazole (I-1), starting from I-3c and 4- (4-morpholin-1-yl) benzene-1, 2-diamine (I-11e), with a charge of 150mg (0.65mmol) of I-3c, and finally preparing the liquid phase by rapid purification18The C bonded phase separation column was separated and purified by an F elution system to obtain 100mg of a white solid with a yield of 37.8%. MS m/s (ESI): 401.3 [ M + H]+。1H NMR(300MHz,DMSO-d6)12.15(s,1H),10.88–10.40(m,1H),7.44(s,1H),7.42(s,2H),7.39– 7.27(m,3H),6.89(d,J＝6.7Hz,2H),3.74(t,J＝4.6Hz,4H),3.03(t,J＝4.6Hz,4H),2.50(s,3H),1.75(s, 3H)。
Example 19
1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-19)
Preparation and example 1 step 42- (5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d]Analogous to imidazole (I-1), starting from I-3c and 4- (4-N-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), with a charge of I-3c of 150mg (0.65mmol), a liquid phase was finally prepared by rapid purification18The C bonded phase separation column was separated and purified by an F elution system to obtain 138mg of a white solid with a yield of 50.8%. MS m/s (ESI): 414.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.16(s,1H),10.43(s,1H),7.43(d,J＝7.0Hz,4H),7.35(dd, J＝7.4,2.0Hz,2H),6.91–6.79(m,2H),3.09(t,J＝4.8Hz,4H),2.59(s,4H),2.31(s,3H),1.75(s,3H),1.24(s, 3H)。
Example 20
N- (2- (4-acetyl-5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d ] imidazol-5-yl) propane-2-sulfonamide (I-20)
I-17(100mg, 0.30mmol) and isopropylsulfonyl chloride (47mg, 33mmol) were placed in a 100mL round bottom flask, dissolved in 20mL dichloromethane, and 0.5mL pyridine was added and stirred at room temperature overnight. The reaction was checked by TLC, and after concentration by distillation under reduced pressure, purification was performed by silica gel column chromatography in system C to obtain 105mg of a white solid, yield: 79.8 percent. MS m/s (ESI): 437.2[ M + H]+。1H NMR(300MHz, DMSO-d6)12.18(s,1H),10.78(s,1H),9.60(s,1H),7.44(d,J＝6.6Hz,4H),7.38–7.30(m,3H),7.03(dd,J＝ 8.6,2.1Hz,1H),3.10(q,J＝6.8Hz,1H),2.49(s,3H),1.74(s,3H),1.21(d,J＝6.8Hz,6H)。
Example 21
1- (5- (5- ((2- (dimethylamino) ethyl) amino) -1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-21)
Step 1, N1- (3, 4-dinitrophenyl) -N2,N2Dimethyl-1, 2-diamine (I-21a)
Weighing 800mg (4.30mmol) of 3, 4-dinitrofluorobenzene, placing in a 100mL thick-wall sealed tube, dissolving with 15mL of anhydrous DMF, adding N1,N1Dimethyl ethyl 1,2 diamine hydrochloride (800Mg, 6.45mmol) and potassium carbonate 1.18g (8.60mmol) were heated to 100 ℃ for 4h with stirring, TLC checked for completion of the reaction, the reaction solution was slowly poured into water (100mL), EA (4 × 100mL) was added, the organic layer was washed with saturated brine, Mg was added to the reaction solution, and the mixture was washed with brine, dried over anhydrous sodium sulfate, dried over magnesium sulfate2SO4Drying, filtration and concentration, 0.95g of crude yellow product was recrystallized from 75% and yield 93.4%. MSm/s (ESI): 255.1[ M + H]+。
Step 2, N4- (2- (dimethylamino) ethyl) phenyl-1, 2, 4-triamine (I-21b)
Weighing N1- (3, 4-dinitrophenyl) -N2,N2800mg (3.15mmol) of-dimethylethyl-1, 2-diamine (I-21a) is placed in a 100mL thick-walled sealed tube, 100mg of 10% Pd/C is added, the solution is dissolved in 25mL of ethanol, a hydrogen balloon is pumped out for 3 times, the solution is stirred for 5 hours at room temperature, the TLC detection reaction is complete, the solution is filtered and concentrated by diatomite,the crude dark oil was obtained as a solid. MS m/s (ESI): 193.1[ M + H]+。
Step 3, 1- (5- (5- ((2- (dimethylamino) ethyl) amino) -1H-benzo [ d ] imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-21)
Preparation and example 1 step 42- (5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d]Analogous to imidazole (I-1), starting from I-3c and I-21b, with a charge of 150mg (0.66mmol) of I-3c, and finally preparing the liquid phase by rapid purification18The C bonded phase separation column was separated and purified by an F elution system to obtain 65mg of a white solid in a yield of 24.9%. MS m/s (ESI): 402.3[ M + H]+。1H NMR(300MHz, DMSO-d6)12.16(s,1H),10.53(s,1H),7.43(d,J＝7.0Hz,4H),7.35(dd,J＝7.4,2.0Hz,2H),6.91–6.79(m, 2H),6.08(s,1H),3.39(t,J＝4.8Hz,2H),2.61–2.57(m,5H),2.49(s,3H),2.31(s,6H)。
Example 22
N- (2- (4-acetyl-5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ d ] imidazol-5-yl) acetamide (I-22)
Preparation method and 5- (1H-benzo [ d ] in example 7]Analogous of imidazol-2-yl) -N- (2- (diethylamino) ethyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-7), starting with I-17 and acetic acid in a charge of 100mg (0.30mmol) of I-17, and finally preparing the liquid phase by rapid purification18The bound phase separation column obtained 88mg of a white solid in 78.5% yield as F-eluting system. MS m/s (ESI): 373.3[ M + H]+。1H NMR (300MHz,DMSO-d6)12.04(s,1H),10.52(s,1H),9.92(s,1H),7.43(d,J＝7.0Hz,4H),7.35(dd,J＝7.4,2.0 Hz,2H),6.91–6.79(m,2H),2.49(s,3H),2.31(s,3H),2.06(s,3H).。
Example 23
1- (4- (4-fluorophenyl) -2-methyl-5- (5-morpholinyl-1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-23)
Step 1, 4-acetyl-3- (4-fluorophenyl) -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (I-23a) to step 3, 4-acetyl-3- (1H-indol-3-yl) -5-methyl-1H-pyrrole-2-carbaldehyde (I-23c)
The preparation was analogous to that of example 2, steps 1 to 3I-2c, respectively, starting with ethyl 3- (4-fluorophenyl) -3-oxopropanoate and acetylacetone in a charge of 550mg (2.64mmol) to yield 200mg of a white solid in 31.3% yield over two steps. MS m/s (ESI): 246.3[ M + H]+。
Step 4, 1- (4- (1H-indol-3-yl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-pyridin-3-yl) ethan-1-one (I-23)
The preparation was carried out analogously to step 4I-1 of example 1, starting from I-23c and 4- (4-morpholin-1-yl) benzene-1, 2-diamine (I-18b), with a charge of 150mg (0.61mmol) of I-23c, and finally by rapid purification to prepare the liquid phase18The C bonded phase separation column was separated and purified by an F elution system to obtain 88mg of a white solid with a yield of 34.6%. MS m/s (ESI): 419.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.17(s, 1H),10.53(s,1H),7.48–7.18(m,5H),7.04–6.80(m,2H),3.74(q,J＝4.2Hz,4H),3.18–2.92(m,4H),2.49(s, 3H),1.80(s,3H)。
Example 24
1- (4- (4-chlorophenyl) -2-methyl-5- (5-morpholinyl-1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-24)
Step 1, 4-acetyl-3- (4-chlorophenyl) -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (I-24a) to step 3, 4-acetyl-3- (4-chlorophenyl) -5-methyl-1H-pyrrole-2-carbaldehyde (I-24c)
The preparation was analogous to that of example 2, steps 1 to 3I-2c, respectively, with ethyl 3- (4-fluorophenyl) -3-oxopropanoate and acetylacetone as starting materials in a charge of 550mg (2.43mmol) to yield 264mg of white solid in 41.6% yield over two steps。MS m/s(ESI)： 262.3[M+H]+。
Step 4, 1- (4- (4-chlorophenyl) -2-methyl-5- (5-morpholinyl-1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-24)
The preparation was carried out analogously to example 1, step 4I-1, starting from I-24c and 4- (4-morpholin-1-yl) benzene-1, 2-diamine (I-18b), with a charge of 150mg (0.61mmol) of I-23c, and finally by rapid purification to prepare the liquid phase18The C bonded phase separation column was separated and purified by using an F elution system to obtain 93mg of a white solid in a yield of 37.5%. MS m/s (ESI): 435.3[ M + H]+。1HNMR(300MHz,DMSO-d6)12.24(s,1H), 11.30(s,1H),7.56–7.42(m,2H),7.43–7.23(m,3H),6.92(d,J＝8.6Hz,2H),3.75(dd,J＝6.0,3.4Hz,4H), 3.06(q,J＝5.3,4.8Hz,4H),2.51(d,J＝1.9Hz,3H),1.85(s,3H)。
Example 25
1- (4- (4-fluorophenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-25)
The preparation was carried out analogously to example 1, step 4I-1, starting from I-24b and 4- (4-N-piperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge I-24b of 150mg (0.61mmol), and finally by rapid purification to prepare a liquid phase18The C bonded phase separation column was separated and purified by an F elution system to obtain 85mg of a white solid with a yield of 32.4%. MS m/s (ESI): 432.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.25 (s,1H),10.67(s,1H),7.46–7.16(m,5H),7.04–6.77(m,2H),3.13(s,4H),2.68(s,4H),2.49(s,3H),2.37(s, 3H),1.80(s,3H)。
Example 26
1- (4- (4-methoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-26)
Step 1, 4-acetyl-3- (4-methoxyphenyl) -5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (I-26a) to step 3, 4-acetyl-3- (4-methoxyphenyl) -5-methyl-1H-pyrrole-2-carbaldehyde (I-26c)
The preparation was carried out analogously to Steps 1 to 3I-2c, respectively, of example 2, starting from ethyl 3- (4-methoxyphenyl) -3-oxopropanoate and acetylacetone in a charge of 550mg (2.48mmol), giving 325mg of a white solid in 51.0% yield in two steps. MS m/s (ESI): 258.3[ M + H]+。
Step 4, 1- (4- (4-methoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-26)
The preparation was carried out analogously to example 1, step 4I-1, starting from I-26c and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge of 150mg (0.58mmol) of I-26c, and finally by rapid purification to prepare a liquid phase18The C bonded phase separation column was separated and purified by using an F elution system to obtain 153mg of a white solid in a yield of 59.3%. MS m/s (ESI): 444.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.10(s, 1H),10.28(s,1H),7.27(d,J＝8.2Hz,3H),7.01(d,J＝8.2Hz,2H),6.86(d,J＝8.5Hz,2H),3.82(s,3H),3.05 (d,J＝5.8Hz,4H),2.51(d,J＝1.9Hz,4H),2.47(s,3H),2.25(s,3H),1.75(s,3H)。
Example 27
1- (4- (3-methoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-27)
Step 1, 1- (4- (3-methoxyphenyl) -2-methyl-1H-pyrrol-3-yl) ethan-1-one (I-27a) and step 2, 4-acetyl-3- (3-methoxyphenyl) -5-methyl-1H-pyrrole-2-carbaldehyde (I-27b)
The preparation method is similar to that of step 1 and step 3 in example 1, respectively, and 2-amino-1- (4-methoxyphenyl) ethan-1-one hydrochloride and acetylacetone are used as starting materials, the charging amount is 500mg (2.48mmol), and finally 290mg of white solid is obtained, and the yield in two steps is two46.8％。MS m/s(ESI)： 258.3[M+H]+。
The third step: 1- (4- (3-methoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-27)
The preparation was carried out analogously to example 1, step 4I-1, starting from I-27b and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge of 150mg (0.58mmol) of I-27b, and finally by rapid purification to prepare a liquid phase18The C bonded phase separation column was separated and purified by using an F elution system to obtain 153mg of a white solid with a yield of 56.6%. MS m/s (ESI): 444.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.11(s, 1H),10.29(s,1H),7.24(d,J＝8.2Hz,3H),7.04(d,J＝8.0Hz,2H),6.86(d,J＝8.4Hz,2H),3.82(s,3H),3.05 (d,J＝4.8Hz,4H),2.51(d,J＝4.8Hz,4H),2.48(s,3H),2.27(s,3H),1.80(s,3H)。
Example 28
N- (3- (4-acetyl-5-methyl-2- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) phenyl) acetamide (I-28)
Step 1, N- (3- (4-acetyl-5-methyl-1H-pyrrol-3-yl) phenyl) acetamide (I-28a) and step 2, N, N- (3- (4-acetyl-2-formyl-5-methyl-1H-pyrrol-3-yl) phenyl) acetamide (I-28b)
The preparation method is similar to that of step 1 and step 3 of example 1, and 2-amino-1- (4-methoxyphenyl) ethan-1-one hydrochloric acid and acetylacetone are used as starting materials, the feeding amount is 550mg (2.19mmol), 280mg of white solid is finally obtained, and the yield of the two steps is 45.3%. MS m/s (ESI): 285.3[ M + H]+。
Step 3, N- (3- (4-acetyl-5-methyl-2- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) phenyl) acetamide (I-28)
The preparation was carried out analogously to example 1, step 4I-1, starting from I-28b and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge of 150mg (0.56mmol) of I-28b, and finally in the form of a fast-acting tabletFor preparing liquid phase by rapid purification18The C bonded phase separation column was separated and purified by an F elution system to obtain 69mg of a white solid in a yield of 26.4%. MS m/s (ESI): 471.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.16(s, 1H),10.43(s,1H),10.16(s,1H),7.43(d,J＝7.0Hz,3H),7.35(dd,J＝7.4,2.0Hz,2H),6.91–6.79(m,2H), 3.09(t,J＝4.8Hz,4H),2.59(s,J＝4.8,4H),2.01(s,3H),2.31(s,3H),1.75(s,3H),1.24(s,3H)。
Example 29
1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (m-tolyl) -1H-pyrrol-3-yl) ethan-1-one (I-29)
Step 1, 1- (2-methyl-4- (m-tolyl) -1H-pyrrol-3-yl) ethan-1-one (I-29a) and step 2, 4-acetyl-5-methyl-3- (m-tolyl) -1H-pyrrole-2-carbaldehyde (I-29b)
The preparation method is similar to that of step 1 and step 3 in example 1, and 2-amino-1- (4-methoxyphenyl) ethan-1-one hydrochloride and acetylacetone are used as starting materials, the charging amount is 500mg (2.69mmol), 349mg of white solid is finally obtained, and the yield of the two steps is 53.8%. MS m/s (ESI): 242.3[ M + H]+。
Step 3, 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (m-tolyl) -1H-pyrrol-3-yl) ethan-1-one (I-29)
The preparation was carried out analogously to step 4I-1 of example 1, starting from I-29b and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), in a charge of 150mg (0.62mmol) of I-29b, and finally using a rapid purification to prepare the liquid phase18The C bonded phase separation column was separated and purified by using an F elution system to obtain 69mg of a white solid in a yield of 33.5%. MS m/s (ESI): 428.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.10 (s,1H),10.28(s,1H),7.27(d,J＝8.2Hz,3H),7.05(d,J＝8.1Hz,2H),6.84(d,J＝8.5Hz,2H),3.09(t,J＝4.3 Hz,4H),2.54(t,J＝4.3Hz,4H),2.49(s,3H),2.46(s,3H),2.25(s,3H),1.73(s,3H)。
Example 30
1- (4- (4-methoxyphenyl) -2-methyl-5- (5-morpholinyl-1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-30)
The preparation was carried out analogously to step 4I-1 of example 1, starting from I-29b and 4- (4-morpholin-1-yl) benzene-1, 2-diamine (I-11e), with a charge of I-26b of 150mg (0.62mmol), and finally by rapid purification to prepare the liquid phase18The C bonded phase separation column was separated and purified by using an F elution system to obtain 69mg of a white solid in a yield of 33.5%.1H NMR(300MHz,DMSO-d6)12.12(s,1H),10.33(s,1H),7.40(d,J＝ 8.5Hz,1H),7.32–7.21(m,2H),7.06–6.97(m,2H),6.87(dt,J＝10.4,2.8Hz,2H),3.81(d,J＝2.4Hz,3H), 3.74(q,J＝4.6Hz,4H),3.03(q,J＝4.7Hz,4H),2.47(s,3H),1.75(d,J＝2.4Hz,3H)。
Example 31
1- (4- (3-Cyclopropoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-31)
Step 1, 1- (4- (3-Cyclopropoxyphenyl) -2-methyl-1H-pyrrol-3-yl) ethan-1-one (I-31a) and step 2, 4-acetyl-3- (3-Cyclopropoxyphenyl) -5-methyl-1H-pyrrole-2-carbaldehyde (I-31b)
The preparation method is similar to that of step 1 and step 3 in example 1, respectively, and 2-amino-1- (4-methoxyphenyl) ethan-1-one hydrochloride and acetylacetone are used as starting materials, the charging amount is 500mg (2.20mmol), 294mg of white solid is finally obtained, and the yield in two steps is 47.4%. MS m/s (ESI): 284.3[ M + H]+。
Step 3, 1- (4- (3-Cyclopropoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-31)
The preparation was carried out in analogy to example 1, step 4I-1, starting from I-29b and 4- (4-methylpiperazin-1-yl) benzene-1,2-diamine (I-11e) as starting material in a charge of 150mg (0.53mmol) of I-31b, and finally preparation of the liquid phase by rapid purification18The C bonded phase separation column was separated and purified by an F elution system to obtain 54mg of a white solid with a yield of 21.9%. MS m/s (ESI): 470.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.11 (s,1H),10.29(s,1H),7.24(d,J＝8.2Hz,3H),7.04(d,J＝8.0Hz,2H),6.86(d,J＝8.4Hz,2H),3.25–3.12(m, J＝5.8Hz,5H),2.51(d,J＝2.1Hz,4H),2.47(s,3H),2.25(s,3H),1.75(s,3H),0.65–0.59(m,J＝2.8Hz,2H), 0.41–0.37(m,J＝2.1Hz,2H)。
Example 32
Step 1, 1- (2-methyl-4- (3- (phenylamino) phenyl) -1H-pyrrol-3-yl) ethan-1-one (I-32a) and step 2, 4-acetyl-5-methyl-3- (3- (phenylamino) phenyl) -1H-pyrrole-2-carbaldehyde (I-32b)
The preparation method is similar to that of step 1 and step 3 in example 1, and 2-amino-1- (4-methoxyphenyl) ethan-1-one hydrochloride and acetylacetone are used as starting materials, the charging amount is 500mg (1.90mmol), and finally 225mg of white solid is obtained, and the yield of the two steps is 37.2%. MS m/s (ESI): 319.3[ M + H]+。
Step 3, 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ d ] imidazol-2-yl) -4- (3- (phenylamino) phenyl) -1H-pyrrol-3-yl) ethan-1-one (I-32)
The preparation method is similar to that of step 4I-1 in example 1, and the raw materials are I-32b and 4- (4-methylpiperazin-1-yl) benzene-1, 2-diamine (I-11e), the charging amount of I-32b is 150mg (0.47mmol), and the white solid is obtained by silica gel column chromatography separation and purification, and the yield is 23.4%. MS m/s (ESI): 505.3[ M + H]+。1H NMR(300MHz,DMSO-d6)12.10(s,1H),10.28(s,1H),8.38(s,1H),7.57– 7.41(m,4H),7.21–7.09(m,5H),6.86–6.59(m,3H),3.15(t,J＝4.6Hz,4H),2.53(t,J＝4.6Hz,4H),2.48(s, 3H),2.24(s,3H),1.72(s,3H)。
The above-mentioned embodiments, objects, technical solutions and advantages of the present invention are further described in detail, it should be understood that the above-mentioned embodiments are only illustrative of the present invention and are not intended to limit the present invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A compound having the general formula (I)
wherein:
R1represents hydrogen, halogen, alkyl, haloalkyl, heterocycloalkyl, cycloalkyl;
R2and R3Each independently selected from halo, cyano, aryl, Het, R5、-COR5、-CONHR5、-CONR5Het、-COR5Het、-COOR5、-COOHet、-NHR5、-NH(CH2)1-10Het、-NH(CH2)1-10OR5、-NH(CH2)1-10NR5 2、-NHCOOR5、-NHCOOHet、-NHCONHR5、-NHCONHHet、-OR5、-O(CH2)1-10NR5 2、-O(CH2)1-10Het or-O (CH)2)1-10OR5；
R4Represents halogen, cyano, Het, R5、-COR5、-CONR5Het、-COR5Het、-CONHHet、-COOHet、-NHR5、-NH(CH2)1-10Het、-NH(CH2)1-10OR5、-NH(CH2)1-10NR5 2、-NHCOOR5、-NHCOOHet、-NHCONHR5、-NHCONHHet、-OR5、-O(CH2)1-10NR5 2、-O(CH2)1-10Het or-O (CH)2)1-10OR5；
X represents N, CNHR5、CNHCOR5CNHHet or CNHCOlet;
y represents S, O, NR5、CH2or-COCH =;
z represents NR5；
A represents alkenyl, alkynyl, biphenyl, cycloalkyl, cycloheteroalkyl, aryl ring or Het, which biphenyl, aryl, diarylamino or Het may be optionally substituted with: halogen, -CN, -OH, -CF3、OCF3、-OR5、-SH、-SR5、-NH2、-NHR5、-NR5 2、-NHCOR5、-NHSO2R5、-NRSO2R5、-COR5、-COOR5、-CONHR5、-CON(R5 2)、-CONH(CH2)1-10N(R5 2)、-CONR5 2、-CON(R5 2)O、-CONH(CH2)1-10N(R5 2)O、-CON(R5 2)NR5、-CON(R5 2)NCOOR5、-CONH(CH2)1-10N(R5 2)NR5or-CONH (CH)2)1-10N(R5 2)NCOOR5；
B represents a single bond, O, S, NH, NR5、NHR5、OR5、SR5、R5Wherein R is5Represents a hydrogen atom, an alkyl group, a haloalkyl group, a heterocycloalkyl group, a cycloalkyl group;
the aryl is a carbocyclic ring comprising phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, and the phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl can each be optionally substituted with 1,2 or 3 substituents independently selected from hydrogen, alkyl, cyano, halo, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, a phenyl-containing carbocyclic ring, a naphthyl-containing carbocyclic ring, an acenaphthyl-containing carbocyclic ring, a tetrahydronaphthyl-containing carbocyclic ring, or Het;
each Het is selected from the group consisting of a monocyclic heterocycle of piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, morpholinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, piperazinyl, substituted piperazinyl, pyrazinyl or pyridazinyl, or from the group consisting of quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [ 2 ]b][1,4]Dioxane group or benzo [ alpha ], [ beta ], [ alpha ], [ beta ], [ alpha ], [ beta ] -ad][1,3]A bicyclic heterocycle of dioxolan, each of said monocyclic or bicyclic heterocycles being optionally substituted with 1,2 or 3 substituents each independently selected from halogen, haloalkyl, hydroxy, alkyl, alkoxy, C3-C8Aliphatic carbocycle, tetrahydropyrrolyl, morpholinyl, alkoxymorpholinyl, piperazinyl, piperidinyl or alkylaminopiperidinyl; the alkyl group is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms; or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is bonded; the alkoxy group is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is attached, wherein each carbon atom is optionally substituted with oxygen; the alkylamino group is a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, or a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms to which a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms is attached, wherein each carbon atom is optionally substituted by nitrogen;
the halogen is one of fluorine, chlorine or bromine.
2. A compound according to claim 1, or a mixture or acceptable salt thereof, of formula (IA)
A compound shown in the formula (I):
or one or more mixtures of tautomers, mesomers, racemates, enantiomers, diastereomers thereof, or a pharmaceutically acceptable salt thereof,
wherein:
y is selected from S, O or NR5One of them.
3. A compound or mixture of compounds or acceptable salts thereof as claimed in claim 1 of formula (IB)
The compound shown in the formula (I) is shown in the specification,
or one or more mixtures of tautomers, mesomers, racemates, enantiomers, diastereomers thereof, or a pharmaceutically acceptable salt thereof,
wherein:
y is selected from S, O or NR5One of the above two methods; wherein X represents N, CNHR5、CNHCOR5CNHHet, CNHCOjet; y represents S, O, NR5、CH2-COCH =; z represents NR5。
4. A compound or mixture of compounds or acceptable salt thereof according to any one of claims 1-3, characterized in that R1Represents hydrogen, halogen, alkyl, haloalkyl, heterocycloalkyl having 3 to 7 carbon atoms, or cycloalkyl having 3 to 7 carbon atoms.
5. A compound according to any one of claims 1 to 4 or mixtures or acceptable salts thereof, characterized in that 2- (5-methyl-3-phenyl-1)H-pyrrol-2-yl) -1H-benzo [ 2 ]d]Imidazole (I-1), 1- (5- (benzo [ 2 ])d]Oxazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-2), 1- (5- (benzo [ 2 ])d]Thiazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-3), 1- (5- (1)H-benzo [ 2 ]d]Imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-4), ethyl 5- (1)H-benzo [ 2 ]d]Imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylate (I-5), 5- (5-) (H-benzo [ 2 ]d]Imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (I-6), 5- (1)H-benzo [ 2 ]d]Imidazol-2-yl) -N- (2- (diethylamino) ethyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-7), 5- (1)H-benzo [ 2 ]d]Imidazol-2-yl) -2-methyl-N- (2- (4-methylpiperazin-1-yl) ethyl) -4-phenyl-1H-pyrrole-3-carboxamide (I-8), 5- (1)H-benzo [ 2 ]d]Imidazol-2-yl) -N- (tert-butyl) -2-methyl-4-phenyl-1H-pyrrole-3-carboxamide (I-9), 5- (1)H-benzo [ 2 ]d]Imidazol-2-yl) -2-methyl-N- (1-methylpiperidin-4-yl) -4-phenyl-1H-pyrrole-3-carboxamide (I-10), 1- (2-methyl-4- (1-methyl-1)H-pyrazol-4-yl) -5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-11), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -4- (pyridin-3-yl) -1H-pyrrol-3-yl) ethan-1-one (I-12), 1- (4- (furan-3-yl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-13), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -4- (naphthalen-1-yl) -1H-pyrrol-3-yl) ethan-1-one (I-14), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -4- (quinolin-7-yl) -1H-pyrrol-3-yl) ethan-1-one (I-15), 1- (4- (1)H-indol-6-yl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-16), 1- (5- (5-amino-1)H-benzo [ 2 ]d]Imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-17), 1- (2-methyl-5- (5-morpholinyl-1)H-benzo [ 2 ]d]Imidazol-2-yl) -4-phenyl-1H-pyrrol-3-yl) ethan-1-one (I-18), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -4-phenyl-1H-pyrrol-3-yl) eth-1-one (I-19),N- (2- (4-ethyl)Acyl-5-methyl-3-phenyl-1H-pyrrol-2-yl) -1H-benzo [ 2 ]d]Imidazol-5-yl) propane-2-sulfonamide (I-20), 1- (5- (5- ((2- (dimethylamino) ethyl) amino) -1H-benzo [ 2 ]d]Imidazol-2-yl) -2-methyl-4-phenyl-1H-pyrrol-3-yl) eth-1-one (I-21),N- (2- (4-acetyl-5-methyl-3-phenyl-1)H-pyrrol-2-yl) -1H-benzo [ 2 ]d]Imidazol-5-yl) acetamide (I-22), 1- (4- (4-fluorophenyl) -2-methyl-5- (5-morpholinyl-1)H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-23), 1- (4- (4-chlorophenyl) -2-methyl-5- (5-morpholinyl-1)H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-24), 1- (4- (4-fluorophenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-25), 1- (4- (4-methoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-26), 1- (4- (3-methoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) eth-1-one (I-27),N- (3- (4-acetyl-5-methyl-2- (5- (4-methylpiperazin-1-yl) -1)H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) phenyl) acetamide (I-28), 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -4- (m-tolyl) -1H-pyrrol-3-yl) ethan-1-one (I-29), 1- (4- (4-methoxyphenyl) -2-methyl-5- (5-morpholinyl-1)H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-30), 1- (4- (3-cyclopropoxyphenyl) -2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -1H-pyrrol-3-yl) ethan-1-one (I-31) or 1- (2-methyl-5- (5- (4-methylpiperazin-1-yl) -1H-benzo [ 2 ]d]Imidazol-2-yl) -4- (3- (phenylamino) phenyl) -1H-pyrrol-3-yl) ethan-1-one (I-32).
6. A compound according to any one of claims 1 to 5 or a mixture thereof or an acceptable salt thereof, wherein the pharmaceutically acceptable salt comprises an acid addition salt of a compound of formula (I) or one or more of its tautomers, mesomers, racemates, enantiomers, diastereomers and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic or succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid, or an acid salt with an inorganic base containing a basic metal cation, an alkaline earth metal cation or an ammonium cation salt.
7. A process for the preparation of a compound according to any one of claims 1 to 6 or a mixture or acceptable salt thereof, characterized in that: the compound is prepared by taking an ethyl acetoacetate derivative or an amino aryl ethanone derivative as a starting material through continuous reaction.
8. A pharmaceutical composition characterized in that the active ingredient is a compound of formula (I) as claimed in claim 1 or a mixture or an acceptable salt thereof.
9. Use of a pharmaceutical composition according to claim 1 for the preparation of a product for the prevention or treatment of a clinical condition associated with BRD protein.
10. The use according to claim 9, wherein the clinical condition associated with BRD protein is rheumatoid arthritis, gouty arthritis melanoma, liver cancer, kidney cancer, acute leukemia, multiple myeloma, lymphoid cancer, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, gastrointestinal cancer or mesothelioma.
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