CN107556318B - Pyrrolopyrimidine compound containing piperidine as well as preparation method and application thereof - Google Patents
Pyrrolopyrimidine compound containing piperidine as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN107556318B CN107556318B CN201710726360.3A CN201710726360A CN107556318B CN 107556318 B CN107556318 B CN 107556318B CN 201710726360 A CN201710726360 A CN 201710726360A CN 107556318 B CN107556318 B CN 107556318B
- Authority
- CN
- China
- Prior art keywords
- pyrrolo
- piperidin
- pyrimidin
- amino
- ethanone
- 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.)
- Expired - Fee Related
Links
- -1 Pyrrolopyrimidine compound Chemical class 0.000 title claims abstract description 122
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 102
- 239000007787 solid Substances 0.000 claims description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 13
- 238000001704 evaporation Methods 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 150000003053 piperidines Chemical class 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 claims description 9
- BPTCCCTWWAUJRK-UHFFFAOYSA-N 4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C=CN2 BPTCCCTWWAUJRK-UHFFFAOYSA-N 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 5
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 3
- 150000004944 pyrrolopyrimidines Chemical class 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000008685 targeting Effects 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims 2
- NULJZZQMTQVLPG-UHFFFAOYSA-N n,n-dimethylmorpholin-4-amine Chemical compound CN(C)N1CCOCC1 NULJZZQMTQVLPG-UHFFFAOYSA-N 0.000 claims 2
- 101100322915 Caenorhabditis elegans akt-1 gene Proteins 0.000 claims 1
- XWPMLYYOTNUFGN-UHFFFAOYSA-N NC1N(CCCC1)N(C)C Chemical compound NC1N(CCCC1)N(C)C XWPMLYYOTNUFGN-UHFFFAOYSA-N 0.000 claims 1
- 230000000690 anti-lymphoma Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical compound NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 claims 1
- 238000007348 radical reaction Methods 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 14
- 101000779417 Mus musculus RAC-alpha serine/threonine-protein kinase Proteins 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 3
- 230000035755 proliferation Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 249
- 238000005160 1H NMR spectroscopy Methods 0.000 description 83
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 32
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 15
- 108091008611 Protein Kinase B Proteins 0.000 description 11
- 210000004881 tumor cell Anatomy 0.000 description 10
- 230000012010 growth Effects 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 5
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 230000001028 anti-proliverative effect Effects 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000012156 elution solvent Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 201000001475 prostate lymphoma Diseases 0.000 description 3
- 239000003197 protein kinase B inhibitor Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- VFTPONHUNNOSKG-UHFFFAOYSA-N 4,5-dichloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound C1=NC(Cl)=C2C(Cl)=CNC2=N1 VFTPONHUNNOSKG-UHFFFAOYSA-N 0.000 description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 2
- HUYFCWFTAOFDQD-UHFFFAOYSA-N 5-bromo-4-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=NC(Cl)=C2C(Br)=C1 HUYFCWFTAOFDQD-UHFFFAOYSA-N 0.000 description 2
- OXLMTRZWMHIZBY-UHFFFAOYSA-N 5-bromo-4-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=NC2=C1C(Br)=CN2 OXLMTRZWMHIZBY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 101000798015 Homo sapiens RAC-beta serine/threonine-protein kinase Proteins 0.000 description 2
- 101000798007 Homo sapiens RAC-gamma serine/threonine-protein kinase Proteins 0.000 description 2
- FMTWKNMNGCKWTD-UHFFFAOYSA-N NC1N(CCOC1)N(C)C Chemical compound NC1N(CCOC1)N(C)C FMTWKNMNGCKWTD-UHFFFAOYSA-N 0.000 description 2
- 102100032315 RAC-beta serine/threonine-protein kinase Human genes 0.000 description 2
- 102100032314 RAC-gamma serine/threonine-protein kinase Human genes 0.000 description 2
- DSBHGWITGSLZTD-UHFFFAOYSA-N S(=O)(=O)(C1=CC=C(C)C=C1)N1C=CC2=C1N=CN=C2NC1CCN(CC1)C(=O)OC(C)(C)C Chemical compound S(=O)(=O)(C1=CC=C(C)C=C1)N1C=CC2=C1N=CN=C2NC1CCN(CC1)C(=O)OC(C)(C)C DSBHGWITGSLZTD-UHFFFAOYSA-N 0.000 description 2
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- 150000002500 ions Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 2
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- GRZXWCHAXNAUHY-NSISKUIASA-N (2S)-2-(4-chlorophenyl)-1-[4-[(5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-1-piperazinyl]-3-(propan-2-ylamino)-1-propanone Chemical compound C1([C@H](C(=O)N2CCN(CC2)C=2C=3[C@H](C)C[C@@H](O)C=3N=CN=2)CNC(C)C)=CC=C(Cl)C=C1 GRZXWCHAXNAUHY-NSISKUIASA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- JBGYKRAZYDNCNV-UHFFFAOYSA-N 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxamide Chemical compound N12N=C(C(=O)N)C=CC2=NC(C=2C=CC(=CC=2)C2(N)CCC2)=C1C1=CC=CC=C1 JBGYKRAZYDNCNV-UHFFFAOYSA-N 0.000 description 1
- HNFMVVHMKGFCMB-UHFFFAOYSA-N 3-[3-[4-(1-aminocyclobutyl)phenyl]-5-phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine Chemical compound NC1=NC=CC=C1C1=NC2=CC=C(C=3C=CC=CC=3)N=C2N1C1=CC=C(C2(N)CCC2)C=C1 HNFMVVHMKGFCMB-UHFFFAOYSA-N 0.000 description 1
- JDUBGYFRJFOXQC-KRWDZBQOSA-N 4-amino-n-[(1s)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide Chemical compound C1([C@H](CCO)NC(=O)C2(CCN(CC2)C=2C=3C=CNC=3N=CN=2)N)=CC=C(Cl)C=C1 JDUBGYFRJFOXQC-KRWDZBQOSA-N 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- 101100356020 Haemophilus influenzae (strain ATCC 51907 / DSM 11121 / KW20 / Rd) recA gene Proteins 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- ULDXWLCXEDXJGE-UHFFFAOYSA-N MK-2206 Chemical compound C=1C=C(C=2C(=CC=3C=4N(C(NN=4)=O)C=CC=3N=2)C=2C=CC=CC=2)C=CC=1C1(N)CCC1 ULDXWLCXEDXJGE-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 101100042680 Mus musculus Slc7a1 gene Proteins 0.000 description 1
- AFJRDFWMXUECEW-LBPRGKRZSA-N N-[(2S)-1-amino-3-(3-fluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-2-methyl-3-pyrazolyl)-2-thiophenecarboxamide Chemical compound CN1N=CC(Cl)=C1C1=C(Cl)SC(C(=O)N[C@H](CN)CC=2C=C(F)C=CC=2)=C1 AFJRDFWMXUECEW-LBPRGKRZSA-N 0.000 description 1
- 102000038030 PI3Ks Human genes 0.000 description 1
- 108091007960 PI3Ks Proteins 0.000 description 1
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
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- 239000012634 fragment Substances 0.000 description 1
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- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
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- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000011242 molecular targeted therapy Methods 0.000 description 1
- AXTAPYRUEKNRBA-JTQLQIEISA-N n-[(2s)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-2-methylpyrazol-3-yl)furan-2-carboxamide Chemical compound CN1N=CC(Cl)=C1C1=C(Cl)OC(C(=O)N[C@H](CN)CC=2C=C(F)C(F)=CC=2)=C1 AXTAPYRUEKNRBA-JTQLQIEISA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 1
- 229950010632 perifosine Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
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- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a pyrrolopyrimidine compound containing piperidine and a preparation method and application thereof. The compounds have a structure shown as a general formula (I) or (II). The invention also provides a preparation method and application of the compound. The compound has certain activity of inhibiting AKT1 kinase and anti-cell proliferation activity, and is used for preparing antitumor drugs.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis and medicine, and particularly relates to a pyrrolopyrimidine compound containing piperidine as well as a preparation method and application thereof.
Background
Protein kinase B (also known as AKT) is a serine/threonine kinase and belongs to the AGC kinase family. AKT possesses three subtypes, i.e., AKT1, AKT2, AKT3, which are encoded by different genes, but they have about 80% homology in the entire gene sequence. The three subtypes of AKT have mutually overlapped and different functions, and the activities of inhibiting the three subtypes of AKT1, AKT2 and AKT3 are closely related to the induction of cancer cell apoptosis and the reduction of tumor growth and the reversal of tumor resistance. Studies have shown that abnormally activated AKT is present in a number of solid tumors (prostate, colon, breast, melanoma) and hematological malignancies (lymphoma). (see Yang D, Wang P, Liu J, et al. DesIgn, syntheses and devaluate ion of novel index derivative as AKT In vivo-based assays, 2014,22(1): 366-73; LIU T, Zhan W, Wang Y, et al. Structure-based assays, synthsis and IoblogIcal ion of phosphatidylmethylium derivative as Akt1InhIbItors [ J, European Journal of MedInrather Chem, IsId, 73: 167) T Is phosphatIdylInosItol 3-kInase (phospho-kInase) survival signal (see III) 3523. the growth of tumour cells Is significantly inhibited by the growth of kInase I/mTOR 3. the growth of tumour cells Is significantly inhibited by the growth of tumour cells as AKT/III In vitro kInase (see III) 3. the growth of tumour cells as well as the growth inhibition of growth of tumour cells as well as the growth of tumour growth inhibition of tumour cells as well as the growth of tumour cells as the growth of tumour cells as well as the growth inhibition of tumour growth of tumour cell growth of tumour cells as I/survival signal of III, see Pi 3. Purpork, III .). Therefore, AKT would be a very promising target for tumor therapy, and inhibition of AKT would be a new strategy for molecular targeted therapy. Although various AKT InhIbItors have been introduced into clinical or preclinical studies such as GDC0068, AZD5363, GSK2110183, GSK2141795, MK2206, ARQ-092, BAY1125976, PerifosIne, etc. (see B.R. Huck, I.Mochalkin, Recent progress devices cl Icalcall relevant ATP-completIve Akt InhbItors, [ J ] BIoorganic & MedIcInal ChemIstry letters, 2017,27: 2838-. Therefore, the development of novel high-efficiency, low-toxicity and high-selectivity AKT inhibitors is repeated and far away, and the related reports of the compounds are not found in the prior art.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a piperidine-containing pyrrolopyrimidine compound which has certain PC-3 cell growth inhibitory activity and AKT1 kinase inhibitory activity, and also aims to provide a preparation method and application of the compound.
The technical scheme of the invention is as follows:
piperidine-containing pyrrolopyrimidine compounds
A pyrrolopyrimidine compound containing substituted piperidine or a pharmaceutically acceptable salt thereof has a structure represented by the following general formula (I) or (II):
wherein R is1Hydrogen, mono-halogen substitution, di-halogen substitution, methoxy, alkane;R2hydrogen, chlorine, bromine; r3Hydrogen, amino, substituted piperidine, pyrrole, morpholine, substituted piperazine; n is 0 or 1.
Preferred according to the invention are those R of the general formula (I) or (II)1Is hydrogen, 4-chloro, 4-bromo, 4-fluoro, 4-methoxy, 4-tert-butyl, 3-bromo, 3, 4-dichloro or 2, 4-dichloro; r2Is hydrogen, chlorine or bromine; r3Is hydrogen, amino, dimethylamino, morpholine, piperazine, N-methylpiperazine, 4-hydroxypiperidine, acetylpiperazine, phenylpiperazine, isopropylaminomethylene, piperidine, pyrrole or 4-piperidinyl.
Further preferred, formula (I) or (II) is one of the following compounds:
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2-phenylethanone (I-a1),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a2),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a3),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a4),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a5),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 6-dichlorophenyl) ethanone (I-a6),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (3, 4-dichlorophenyl) ethanone (I-a7),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (3-bromophenyl) ethanone (I-a8),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methoxyphenyl) ethanone (I-a9),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-tert-butylphenyl) ethanone (I-a10),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylphenyl) ethanone (I-a11),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-phenylpropan-1-one (I-a12),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3- (4-fluorophenyl) propan-1-one (I-a13),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3- (4-bromophenyl) propan-1-one (I-a14),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a15),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a16),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a17),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a18),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a19),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a20),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a21),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a22),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2-thiomorpholinone (I-a23),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) ethanone (I-a24),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) ethanone (I-a25),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) ethanone (I-a26),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (dimethylamino) ethanone (I-a27),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-ylamino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) ethanone (I-a28),
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) ethanone (I-a29),
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-4-yl) ethanone (I-a30),
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propan-1-one (I-a31),
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propan-1-one (I-a32),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) acetamide (II-a1),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a2),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2-amino-2- (4-chlorophenyl) acetamide (II-a3), N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a4),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -3- (isopropylamino) propionamide (II-a5),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-bromophenyl) -3- (isopropylamino) propionamide (II-a6),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2-thiomorpholinoacetamide (II-a7),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2-morpholineacetamide (II-a8),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperazin-1-yl) acetamide (II-a9),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-hydroxypiperidin-1-yl) acetamide (II-a10),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) acetamide (II-a11),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a12),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a13),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a14),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -4- (4-chlorophenyl) piperidine-4-carboxamide (II-a15),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) acetamide (II-a16),
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (pyrrol-1-yl) acetamide (II-a17),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a18),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2-amino-2- (4-chlorophenyl) acetamide (II-a19),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a20),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -3- (isopropylamino) propionamide (II-a21),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propanamide (II-a22),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a23),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperazin-1-yl) acetamide (II-a24),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a25),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-hydroxypiperidin-1-yl) acetamide (II-a26),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a27),
N- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -4- (4-chlorophenyl) piperidine-4-carboxamide (II-a28),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a29),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a30),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propanamide (II-a31),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a32),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a33),
N- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a 34).
Preparation method of pyrrolopyrimidine compound containing piperidine
The preparation method of the pyrrolopyrimidine compound containing piperidine comprises the following steps: 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine is used as a starting material, bromination or chlorination is carried out through free radicals to obtain an intermediate 2, the intermediate 1 or 2 reacts with p-toluenesulfonyl chloride to obtain an intermediate 3, the intermediate 3 and 1-tert-butyloxycarbonyl-4-aminopiperidine or 4-tert-butyloxycarbonyl-aminopiperidine undergo nucleophilic substitution, Boc protecting groups are removed to obtain an intermediate 5 or 8, the intermediate 5 or 8 and substituted acid undergo amide condensation, and Ts protecting groups are removed to obtain a target product I or II.
The synthetic route is as follows:
wherein R is1、R2、R3As described in general formula (I) or (II).
The reagents and reaction conditions used were as follows:
a) n-bromosuccinimide or N-chlorosuccinimide, N-Dimethylformamide (DMF), room temperature; b) p-toluenesulfonyl chloride (TsCl), sodium hydroxide solution, acetone, room temperature; c) 1-tert-butoxycarbonyl-4-aminopiperidine or 4-tert-butoxycarbonylaminopiperidine, N-Diisopropylethylamine (DIEA), microwave, 150 ℃, d) trifluoroacetic acid (TFA), Dichloromethane (DCM), room temperature, e) (1) a substituted acid, O-benzotriazol-tetramethyluronium Hexafluorophosphate (HBTU), DIEA, DMF, room temperature; (2) TFA, DCM, cesium carbonate at room temperature (3), tetrahydrofuran/methanol in a volume ratio of 3:1 at room temperature; or (1) substituted acid, HBTU, DIEA, DMF, room temperature; (2) cesium carbonate, tetrahydrofuran/methanol, volume ratio 3:1, room temperature.
According to the invention, the preparation method comprises the following steps:
1) dissolving 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine in N, N-Dimethylformamide (DMF), adding N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS) in batches, reacting at room temperature for 10-12H, pouring the reaction solution into 8-10 times of DMF ice water, separating out a large amount of off-white precipitate, filtering, washing a filter cake with purified water, and drying to obtain an intermediate 2 which is directly used in the next step without purification, wherein the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine: the mol ratio of the N-bromosuccinimide or the N-chlorosuccinimide is 1: 1.1.
2) the intermediate 2 or 4-chloro-7H-pyrrolo [2,3-d]Dissolving pyrimidine in acetone, adding sodium hydroxide solution, stirring in ice bath for 10-15mIn, and adding in batchesAdding p-toluenesulfonyl chloride, naturally heating to room temperature, reacting for 10-12h, precipitating a large amount of white solid, filtering, and filtering a filter cake by using a volume ratio of 1: 1, washing with acetone/water, and drying to obtain a middle part 3; in intermediate 3, R1Hydrogen, chlorine, bromine; in this reaction, the intermediate 2 or 4-chloro-7H-pyrrolo [2,3-d]The molar ratio of pyrimidine to tosyl chloride to sodium hydroxide is 1: 1.1: 1.2;
3) adding the intermediate 3 into N-methylpyrrolidone (NMP), sequentially adding DIEA, 1-tert-butoxycarbonyl-4-aminopiperidine or 4-tert-butoxycarbonyl aminopiperidine, heating the reaction liquid to 150 ℃ by microwave, reacting for 30-40mIn, quenching the reaction liquid by using 10 times of ice water, extracting by using ethyl acetate, washing an organic phase by using saturated amine chloride and saturated salt water, drying by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and performing vacuum distillation by using a solvent in a volume ratio of 1: 2 to obtain an intermediate 4 or an intermediate 7, wherein in the reaction, the molar ratio of the intermediate 2, DIEA, 1-tert-butyloxycarbonyl-4-aminopiperidine or 4-tert-butyloxycarbonyl-aminopiperidine is 1: 1.5: 1.2;
4) and (2) adding the intermediate 4 or the intermediate 7 solvent into dichloromethane, adding trifluoroacetic acid, reacting at room temperature for 4-5h, evaporating the reaction solution to dryness, adjusting the pH to 9 with saturated sodium carbonate aqueous solution, extracting with ethyl acetate, washing the organic phase with saturated salt water, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and performing reaction on the product by using a solvent with a volume ratio of 1: 25 to obtain intermediate 5 or intermediate 8, wherein the volume ratio of trifluoroacetic acid to dichloromethane is 1: 3;
5) dissolving substituted acid in dichloromethane, sequentially adding HBTU and DIEA, stirring at room temperature for 15-20mIn, adding an intermediate 5 or an intermediate 8, reacting at room temperature for 10-12h, washing the reaction solution with saturated ammonium chloride and saturated salt water, and evaporating to obtain an oily substance, wherein in the reaction, the molar ratio of the substituted acid to the HBTU to the DIEA to the intermediate 5 or the intermediate 8 is 1: 1.05: 1.5: dissolving the oily matter in dichloromethane, adding trifluoroacetic acid, reacting at room temperature for 3-4h, evaporating the reaction solution to dryness, adjusting pH to 9 with saturated sodium carbonate, extracting with dichloromethane, washing the organic phase with saturated salt water, evaporating to dryness under reduced pressure to obtain solid, wherein the volume ratio of trifluoroacetic acid to dichloromethane is 1:3, and dissolving the solid in dichloromethane, and dissolving the solid in water to obtain the final productDissolving the mixture by using methanol/tetrahydrofuran in a volume ratio of 1:3, adding cesium carbonate, reacting at room temperature overnight, and directly adding dichloromethane in a volume ratio of 50:1 into a reaction solution: and (3) performing column chromatography purification on methanol to obtain a target product I or II, wherein in the step of reaction, the molar ratio of cesium carbonate to a solid obtained by the reaction is 4: 1; in this step, R in the target product I or II is substituted for acid, intermediate 5 or intermediate 81Is hydrogen, 4-chloro, 4-bromo, 4-fluoro, 4-methoxy, 4-tert-butyl, 3-bromo, 3, 4-dichloro, 2, 4-dichloro; r2Hydrogen, chlorine, bromine; r3Is hydrogen, amino, dimethylamino, morpholine, piperazine, N-methylpiperazine, 4-hydroxypiperidine, acetylpiperazine, phenylpiperazine, isopropylaminomethyl, substituted piperidine, pyrrole or 4-piperidinyl.
The room temperature of the invention is 15-25 ℃.
The substituted acid used in the above preparation method has a structure represented by the following general formula (iii):
wherein R is1、R3N is as described in general formula (I) or (II).
Preferably, according to the invention, the substituted acid of formula (iii) is one of the following:
application of pyrrolopyrimidine compound containing piperidine
The invention designs and synthesizes a series of pyrrolopyrimidine compounds containing piperidine with novel structures, which are shown in general formulas I and II, wherein the introduction of an R3 group (amino or hydroxyl side chain) is a remarkable characteristic of the series of compounds, the introduction of the amino or hydroxyl side chain is based on the summary analysis of the reported structure-activity relationship of AKT1inhibitors, and the amino or hydroxyl side chain structure is most likely to be an active necessary fragment. Through the design and modification mode, the compound with AKT1 kinase inhibitory activity is obtained, and the compound shows inhibitory activity on prostate cancer and lymphoma cell strains.
Therefore, the invention also provides the application of the piperidine-containing pyrrolopyrimidine compound or the medicinal salt thereof in preparing antitumor drugs. Preferably, the anti-tumor drug is an AKT 1-targeted anti-prostate cancer and lymphoma drug.
The invention also provides a pharmaceutical composition suitable for oral or parenteral administration, comprising the piperidine-containing pyrrolopyrimidine compounds of the invention and one or more pharmaceutically acceptable carriers or excipients.
Detailed Description
The present invention will be further described with reference to examples, but the following description is only for the purpose of explaining the present invention and does not limit the contents thereof. The conditions used in the examples can be further adjusted according to the existing equipment conditions, and the implementation conditions not specified are generally the conditions in routine experiments.
Example 1: preparation of Compound I and Compound II
Preparation of intermediate 2:
dissolving 4-chloro-pyrrolo [2,3-d ] pyrimidine (20mmol) in DMF (6mL), adding NBS or NCS (21mmol) in batches in ice bath, reacting at room temperature for 12h, pouring the reaction liquid into 80mL ice water, separating out a large amount of off-white solid, filtering, washing a filter cake with 15mL water, and drying to obtain an intermediate 2.
4, 5-dichloro-pyrrolo [2,3-d ] pyrimidine (2a)
Grey solid, yield 95%,1H NMR(400MHz,DMSO d6):＝12.87(s,1H),8.63(s,1H),7.91(s,1H).MS(ESI)m/z:188[M+H]+.
4-chloro-5-bromo-pyrrolo [2,3-d ] pyrimidine (2b)
Off-white solid, yield 95%,1H NMR(400MHz,DMSO):＝13.00(s,1H),8.64(s,1H),7.97(s,1H).MS(ESI)m/z:232[M+H]+.
preparation of intermediate 3:
4-chloro-pyrrolo [2,3-d ] pyrimidine or intermediate 2(10mmol) was dissolved in acetone (35mL), p-toluenesulfonyl chloride (11mmol) was added while cooling on ice, and 2.0mol/L NaOH solution (12.5mmol,6.25mL) was added, followed by stirring at room temperature overnight. After the reaction is finished, a large amount of white solid is separated out, filtered, and the filter cake is washed by 20mL of acetone/water (1: 1) and dried to obtain an intermediate 3.
4-chloro-7-p-toluenesulfonyl 7H-pyrrolo [2,3-d ] pyrimidine (3a)
Off-white solid, yield 95%,1H-NMR(400MHz,DMSO d6):＝8.83(s,1H),8.13(d,J＝4.0Hz,1H),8.05(d,J＝8Hz 2H),7.48(d,J＝8.0Hz,2H),6.96((d,J＝4.0Hz,1H),3.31(s，3H).MS(ESI)：m/z 308[M+H]+.
4, 5-dichloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidine (3b)
White solid, yield 94%, mp:201-,1H NMR(400MHz,DMSO)8.85(s,1H),8.43(s,1H),8.07(d,J＝8.3Hz,2H),7.49(d,J＝8.2Hz,2H),2.38(s,3H).
4-chloro-5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidine (3c)
Off-white solid, yield 94%, mp:205-,1H NMR(400MHz,DMSO)8.85(d,J＝2.8Hz,1H),8.43(d,J＝2.5Hz,1H),8.07(t,J＝6.1Hz,2H),7.50(t,J＝6.3Hz,2H),2.38(d,J＝3.4Hz,3H).
preparation of intermediate 4 or 7:
dissolving intermediate 3(10mmol) completely with NMP (15mL), sequentially adding DIEA (15mmol,2.6mL), 1-tert-butoxycarbonyl-4-aminopiperidine or 4-tert-butoxycarbonyl-aminopiperidine (10.5mmol), reacting at 150 deg.C for 30 min with microwave, quenching the reaction solution with ice water (150mL), extracting with ethyl acetate (3X 30mL), washing the organic phase with saturated amine chloride (3X 20mL), saturated saline (3X 20mL), drying over anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate: 9: 1) to obtain intermediate 4 or 7
4- ((7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (4a)
Off-white solid, yield 95%, mp:138- & 141 ℃,1H NMR(400MHz,DMSO)8.23(s,1H),7.96(d,J＝8.3Hz,2H),7.67(d,J＝7.6Hz,1H),7.56(d,J＝3.9Hz,1H),7.43(d,J＝8.2Hz,2H),6.89(d,J＝4.0Hz,1H),4.26–4.14(m,1H),3.94(d,J＝9.8Hz,2H),2.78(d,J＝61.2Hz,2H),2.35(s,3H),1.87(d,J＝10.4Hz,2H),1.40(s,9H),1.37-1.32(m,2H).
4- ((5-chloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (4b)
White solid, yield 94%, mp:145-147 ℃,1H NMR(400MHz,DMSO)8.64(s,1H),8.30(s,1H),7.99(d,J＝8.3Hz,2H),7.46(d,J＝8.2Hz,2H),6.50(d,J＝8.0Hz,1H),4.27(dt,J＝11.3,9.4Hz,1H),3.97(d,J＝41.8Hz,2H),2.79(s,2H),1.82(d,J＝9.9Hz,2H),1.53(dd,J＝10.6,7.1Hz,2H),1.40(s,9H).
4- ((5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (4c)
White solid, yield 93%, mp:170-,1H NMR(400MHz,DMSO)8.31(s,1H),8.00(d,J＝8.3Hz,2H),7.88(s,1H),7.46(d,J＝8.2Hz,2H),6.38(d,J＝7.8Hz,1H),4.23(br,1H),3.89(d,J＝11.4Hz,2H),2.91(br,2H),2.37(s,3H),1.91-1.84(m,2H),1.59-1.45(m,2H),1.40(s,9H).
(1- (7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) carboxylic acid tert-butyl ester (7a)
White solid, yield 89%,1H NMR(400MHz,DMSO)8.30–8.19(m,1H),7.98(d,J＝8.4Hz,2H),7.64(d,J＝4.1Hz,1H),7.43(d,J＝8.2Hz,2H),6.95(d,J＝4.2Hz,1H),4.47(d,J＝13.4Hz,2H),3.57(br,1H),3.19(t,J＝11.5Hz,2H),2.36(s,3H),1.82(d,J＝10.3Hz,2H),1.38(s,9H),1.36–1.28(m,2H).
(1- (5-chloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) carboxylic acid tert-butyl ester (7b)
White solid, yield 83%,1H NMR(400MHz,DMSO)8.36(s,1H),8.01(d,J＝8.0Hz,2H),7.97(s,1H),7.44(d,J＝8.0Hz,2H),4.14–4.00(m,2H),3.48(d,J＝31.7Hz,1H),3.10(t,J＝11.4Hz,2H),2.38(d,J＝5.7Hz,3H),1.82(d,J＝10.7Hz,2H),1.55–1.44(m,2H),1.37(s,9H).
(1- (5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) carboxylic acid tert-butyl ester (7c)
White solid, yield 91%,1H NMR(400MHz,DMSO)8.37(s,1H),8.04(d,J＝8.0Hz,2H),8.02(s,1H),7.44(d,J＝8.4Hz,2H),4.11–3.97(m,2H),3.60–3.41(m,1H),3.08(t,J＝11.5Hz,2H),2.37(s,3H),1.83(d,J＝10.6Hz,2H),1.57-1.47(m,2H),1.37(s,9H).
synthesis of intermediate 5 and intermediate 8:
intermediate 4 or intermediate 7(4.0g) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (3.5mL) was added to react at room temperature for 4 h. After the reaction, the solvent was evaporated to dryness under reduced pressure, the pH was adjusted to 9 with saturated sodium carbonate, and the mixture was extracted with dichloromethane (3 × 20mL), the organic layers were combined, the organic layer was washed with saturated brine (3 × 20mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give an oil, and intermediate 5 or intermediate 8 was isolated and purified by column chromatography, and the elution solvent was dichloromethane/methanol ═ 30: 1.
n- (piperidin-4-yl) -7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (5a)
Off-white solid, yield 93%, mp:214-216 ℃,1H NMR(400MHz,DMSO)9.02(br,2H),8.25(s,1H),7.98(dd,J＝12.7,7.9Hz,3H),7.57(d,J＝3.9Hz,1H),7.43(d,J＝8.2Hz,2H),7.03(d,J＝4.0Hz,1H),4.28(s,1H),3.31(d,J＝12.9Hz,2H),3.00(t,J＝11.2Hz,2H),2.36(s,3H),2.03(d,J＝13.3Hz,2H),1.78(d,J＝11.8Hz,2H).
5-chloro-N- (piperidin-4-yl) -7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (5b)
Off-white solid, yield 89%, mp:235-,1H NMR(400MHz,DMSO)8.76(br 2H),8.33(s,1H),8.27(s,1H),8.00(d,J＝8.4Hz,2H),7.46(d,J＝8.3Hz,2H),6.58(t,J＝10.1Hz,1H),4.38(dd,J＝11.2,7.4Hz,1H),4.21(d,J＝13.0Hz,2H),3.13(dd,J＝23.7,11.9Hz,2H),2.37(s,3H),2.06–1.93(m,2H),1.94–1.78(m,2H).
5-bromo-N- (piperidin-4-yl) -7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (5c)
Brown solid, yield 88%, mp:188-,1H NMR(400MHz,DMSO)8.71(br,2H),8.33(s,1H),8.00(d,J＝8.4Hz,2H),7.91(s,1H),7.46(d,J＝8.2Hz,2H),6.40(d,J＝7.4Hz,1H),4.27(br,1H),3.35(br,2H),2.99(t,J＝13.8Hz,2H),2.39(s,3H),2.11-2.05(m,2H),1.73-1.65(m,2H).
1- (7-p-toluenesulfonyl-7H-pyrrolo [2,3-b ] pyrimidin-4-yl) piperidin-4-amine (8a)
Off-white solid, yield 90%,1H NMR(400MHz,DMSO)8.23(s,1H),7.98(d,J＝8.3Hz,2H),7.63(d,J＝4.1Hz,1H),7.43(d,J＝8.2Hz,2H),6.94(d,J＝4.1Hz,1H),4.41(t,J＝16.0Hz,2H),3.19(t,J＝16.0Hz,2H),2.85(td,J＝9.6,4.8Hz,1H),2.35(s,3H),1.78(d,J＝9.5Hz,2H),1.30-1.13(m,2H).
1- (5-chloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-amine (8b)
Off-white solid, yield 92%,1H NMR(400MHz,DMSO)8.36(s,1H),8.01(d,J＝8.0Hz,2H),7.97(s,1H),7.44(d,J＝8.0Hz,2H),4.14–4.00(m,2H),3.48(d,J＝31.7Hz,1H),3.10(t,J＝11.4Hz,2H),2.38(d,J＝5.7Hz,3H),1.82(d,J＝10.7Hz,2H),1.55–1.44(m,2H).
1- (5-bromo-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-amine (8c)
Off-white solid, yield 91%,1H NMR(400MHz,DMSO)8.37(s,1H),8.04(d,J＝8.0Hz,2H),8.02(s,1H),7.44(d,J＝8.4Hz,2H),4.11–3.97(m,2H),3.60–3.41(m,1H),3.08(t,J＝11.5Hz,2H),2.37(s,3H),1.83(d,J＝10.6Hz,2H),1.57-1.47(m,2H).
preparation of target compounds I and II:
the preparation route of the target compounds I and II will follow two schemes a and B:
A) the substituted acid (1mmol) was dissolved in dichloromethane (6mL) in a25 mL eggplant-shaped bottle, HBTU (1.05mmol) and DIEA (1.5mmol) were added in this order, and the mixture was stirred at room temperature for 15 minutes, and then intermediate 5 or intermediate 8(1mmol) was added and reacted at room temperature overnight. After the reaction, the reaction mixture was washed with saturated ammonium chloride (3 × 20mL) and saturated brine (3 × 20mL), dichloromethane was evaporated under reduced pressure to obtain an oil, the oil was dissolved with dichloromethane (4), trifluoroacetic acid (1.3mL) was added to the solution, the reaction was carried out at room temperature for 4 hours, the solvent was evaporated under reduced pressure, the pH was adjusted to 9 with saturated sodium carbonate solution, dichloromethane (3 × 20mL) was used for extraction, the organic phases were combined, washed with saturated brine (3 × 20mL), dichloromethane was evaporated under reduced pressure to obtain a solid, and the solid was dissolved in methanol/tetrahydrofuran (1: and (3), (6) dissolving, adding cesium carbonate (4mmol), reacting at room temperature overnight, and separating and purifying the reaction liquid by direct column chromatography to obtain a target product I or II, wherein an elution solvent is dichloromethane/methanol (50): 1.
B) the substituted acid (1mmol) was dissolved in dichloromethane (6mL) in a25 mL eggplant-shaped bottle, HBTU (1.05mmol) and DIEA (1.5mmol) were added in this order, and the mixture was stirred at room temperature for 15 minutes, and then intermediate 5 or intermediate 8(1mmol) was added and reacted at room temperature overnight. After completion of the reaction, the reaction mixture was washed with saturated ammonium chloride (3 × 20mL) and saturated brine (3 × 20mL), and dichloromethane was distilled off under reduced pressure to obtain an oil, which was purified by methanol/tetrahydrofuran (1: 3(6mL), adding cesium carbonate (4mmol), reacting at room temperature overnight, and separating and purifying the reaction liquid by direct column chromatography to obtain a target product I or II, wherein an elution solvent is dichloromethane/methanol (50: 1.
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2-phenylethanone (I-a1)
White solid, yield 69%, mp: 197 ℃ and 200 ℃,1H NMR(400MHz,DMSO)11.51(s,1H),8.09(s,1H),7.27-7.23(m,6H),7.06(s,1H),6.57(s,1H),4.40(d,J＝13.1Hz,1H),4.29-4.26(m,1H),4.07–3.94(m,1H),3.74(d,J＝5.7Hz,2H),3.16(t,J＝12.0Hz,1H),2.76(t,J＝11.8Hz,1H),1.92(t,J＝11.6Hz,2H),1.39–1.24(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a2)
White solid, yield 64%, mp: 197 at the temperature of 201 ℃,1H NMR(400MHz,DMSO)11.47(s,1H),8.08(s,1H),7.29(dd,J＝8.2,5.8Hz,2H),7.15(dd,J＝15.6,6.7Hz,3H),7.09–7.02(m,1H),6.55(s,1H),4.38(d,J＝12.7Hz,1H),4.29(br,1H),4.02(d,J＝13.4Hz,1H),3.74(q,J＝15.1Hz,2H),3.17(dd,J＝14.5,9.5Hz,1H),2.75(t,J＝11.6Hz,1H),1.92(br,2H),1.29(dd,J＝22.2,12.2Hz,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a3)
White solid, yield 75%, mp: at the temperature of 270 ℃ and 273 ℃,1H NMR(400MHz,DMSO)11.49(s,1H),8.08(s,1H),7.38(d,J＝8.0Hz,2H),7.22(t,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),7.05(dd,J＝4.0Hz,1H),6.55(t,J＝4.0Hz,1H),4.38(t,J＝11.4Hz,1H),4.27(m,1H),3.75(dd,J＝8.0Hz 1H),3.16(t,J＝12.8Hz,1H),2.75(t,J＝12.8Hz,1H),1.94(m,2H),1.37(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a4)
White solid, yield 74%, mp: 267-271 ℃,1H NMR(400MHz,DMSO)11.47(s,1H),8.09(s,1H),7.51(d,J＝7.6Hz,2H),7.22(d,J＝7.7Hz,3H),7.05(s,1H),6.55(s,1H),4.38(d,J＝12.4Hz,1H),4.28(br,1H),4.00(d,J＝13.6Hz,1H),3.73(q,J＝15.5Hz,2H),3.17(t,J＝12.4Hz,1H),2.76(t,J＝11.5Hz,1H),2.02–1.87(m,2H),1.31-1.25(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a5)
White solid, yield 77%, mp: 202-205 deg.c,1H NMR(400MHz,DMSO)11.50(s,1H),8.11(s,1H),7.58(s,1H),7.37(dd,J＝20.3,5.1Hz,2H),7.26(d,J＝7.7Hz,1H),7.06(s,1H),6.59(s,1H),4.36(m,2H),4.05(m,1H),3.85(q,J＝16.3Hz,2H),3.24(t,J＝12.0Hz,1H),2.82(t,J＝11.7Hz,1H),2.03-1.99(m,2H),1.61–1.29(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 6-dichlorophenyl) ethanone (I-a6)
White solid, yield 75%, mp: 271, 273 ℃ of the temperature control agent,1H NMR(400MHz,DMSO)11.49(s,1H),8.11(s,1H),7.46(d,J＝8.0Hz,2H),7.35–7.23(m,2H),7.08(s,1H),6.57(s,1H),4.37(m,2H),4.15(d,J＝13.7Hz,1H),4.03(q,J＝16.6Hz,2H),2.80(t,J＝11.6Hz,1H),2.65(b.r.,1H),2.06(d,J＝11.2Hz,1H),1.96(d,J＝10.8Hz,1H),1.63–1.49(m,1H),1.47-1.39(m,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (3, 4-dichlorophenyl) ethanone (I-a7)
White solid, yield 68%, mp: 222-224 deg.c,1H NMR(400MHz,DMSO)11.49(s,1H),8.09(s,1H),7.63–7.44(m,2H),7.23(dd,J＝12.5,8.0Hz,2H),7.06(s,1H),6.53(s,1H),4.39-4.28(m,2H),4.03(d,J＝13.4Hz,1H),3.79(q,J＝15.6Hz,2H),3.19(t,J＝12.6Hz,1H),2.77(t,J＝12.6Hz,1H),1.96(b.r.,2H),1.37(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (3-bromophenyl) ethanone (I-a8)
White solid, yield 79%, mp: 211-213 deg.c of water for the first time,1H NMR(400MHz,DMSO)11.49(s,1H),8.09(s,1H),7.58(d,J＝8.2Hz,1H),7.53(s,1H),7.23(dd,J＝12.5,8.0Hz,2H),7.06(s,1H),6.56(s,1H),4.39-4.31(m,2H),4.02(d,J＝10.8Hz,1H),3.90–3.71(m,2H),3.28–3.13(m,1H),2.77(t,J＝13.2Hz,1H),1.94(s,2H),1.41-1.36(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methoxyphenyl) ethanone (I-a9)
White solid, yield 68%, mp: 210-212 deg.c,1H NMR(400MHz,DMSO)11.48(s,1H),8.10(s,1H),7.21(s,1H),7.18(d,J＝8.6Hz,2H),7.05(s,1H),6.88(d,J＝8.6Hz,2H),6.56(s,1H),4.40(d,J＝13.2Hz,1H),4.35–4.22(m,1H),4.01(d,J＝13.7Hz,1H),3.73(s,3H),3.72–3.60(m,2H),3.14(t,J＝13.1Hz,1H),2.74(t,J＝11.7Hz,1H),1.95-1.85(m,2H),1.41–1.22(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-tert-butylphenyl) ethanone (I-a10)
White solid, yield 65%, mp: 213-215 ℃ of the mixed gas,1H NMR(400MHz,DMSO)11.49(s,1H),8.10(s,1H),7.33(d,J＝8.2Hz,2H),7.22(d,J＝7.7Hz,1H),7.17(d,J＝8.2Hz,2H),7.09–7.03(m,1H),6.57(s,1H),4.39(d,J＝13.2Hz,1H),4.34–4.24(m,1H),4.02(d,J＝13.2Hz,1H),3.69(s,2H),3.16(t,J＝12.1Hz,1H),2.76(t,J＝11.8Hz,1H),1.94(d,J＝10.3Hz,2H),1.37(ddd,J＝15.3,12.7,4.2Hz,2H),1.27(s,9H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methylphenyl) ethanone (I-a11)
White solid, yield 67%, mp: 236-238 ℃,1H NMR(400MHz,DMSO)11.50(s,1H),8.09(s,1H),7.23(d,J＝7.6Hz,1H),7.18–7.09(m,4H),7.05(s,1H),6.56(s,1H),4.40(d,J＝13.2Hz,1H),4.29-4.26(m,1H),3.99(d,J＝13.3Hz,1H),3.79–3.60(m,2H),3.14(t,J＝12.1Hz,1H),2.74(t,J＝11.7Hz,1H),2.27(s,3H),1.91(t,J＝12.7Hz,2H),1.39–1.23(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3-phenylpropan-1-one (I-a12)
White solid, yield 84%, mp:167-,1H NMR(400MHz,DMSO)11.47(s,1H),8.09(s,1H),7.36–7.12(m,6H),7.05(s,1H),6.55(s,1H),4.39(d,J＝13.0Hz,1H),4.35–4.21(m,1H),3.91(d,J＝14.1Hz,1H),3.12(t,J＝12.0Hz,1H),2.83(t,J＝7.7Hz,2H),2.73(t,J＝11.6Hz,1H),2.68–2.61(m,2H),1.94(s,2H),1.47–1.28(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3- (4-fluorophenyl) propan-1-one (I-a13)
White solid, yield 67%, mp: 210-214 deg.c,1H NMR(400MHz,DMSO)11.48(s,1H),8.10(s,1H),7.35–7.24(m,2H),7.19(d,J＝7.6Hz,1H),7.08(dd,J＝15.7,6.5Hz,3H),6.56(s,1H),4.39(d,J＝12.8Hz,1H),4.28(s,1H),3.92(d,J＝16.3Hz,1H),3.12(t,J＝12.0Hz,1H),2.82(t,J＝7.5Hz,2H),2.73(t,J＝12.1Hz,1H),2.64(t,J＝7.5Hz,2H),1.94(s,2H),1.38(dd,J＝21.7,10.6Hz,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -3- (4-bromophenyl) propan-1-one (I-a14)
White solid, yield 64%, mp: 271, 274 ℃,1H NMR(400MHz,DMSO)12.10(s,1H),8.23(s,1H),7.56(s,1H),7.27(br,4H),7.18(s,1H),6.79(s,1H),4.43(br,1H),4.21(br,1H),3.94(br,1H),3.18–3.07(m,1H),2.95–2.77(m,2H),2.82–2.55(m,3H),2.08–1.82(m,2H),1.53-1.35(m,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a15)
White solid, yield: 58%, mp: 185-187 ℃ in sequence,1H NMR(400MHz,DMSO)11.99(s,1H),8.16(s,1H),7.31(s,1H),7.30–7.24(m,2H),7.13(t,J＝8.8Hz,2H),6.16(d,J＝6.8Hz,1H),4.36(d,J＝11.5Hz,2H),3.99(d,J＝13.5Hz,1H),3.82–3.65(m,2H),3.18(t,J＝12.3Hz,1H),2.77(t,J＝12.0Hz,1H),1.95-1.85(m,2H),1.54-.145(m,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a16)
White solid, yield 54%, mp: 191-193 ℃ of the temperature of the reaction kettle,1H NMR(400MHz,DMSO)11.91(s,1H),8.15(s,1H),7.37(d,J＝8.4Hz,2H),7.30(d,J＝2.4Hz,1H),7.27(d,J＝8.4Hz,2H),6.09(d,J＝7.9Hz,1H),4.35(d,J＝13.7Hz,2H),3.98(d,J＝13.9Hz,1H),3.84–3.60(m,2H),3.18(t,J＝12.6Hz,1H),2.77(t,J＝11.5Hz,1H),1.95-1.92(m,2H),1.55–1.42(m,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a17)
Off-white solid, yield 64%, mp: 182-184 ℃, the temperature of the reaction kettle is changed,1H NMR(400MHz,DMSO)11.98(s,1H),8.19(d,J＝28.2Hz,1H),7.50(d,J＝8.2Hz,2H),7.36–7.24(m,1H),7.21(d,J＝8.1Hz,2H),6.09(d,J＝7.8Hz,1H),4.35(d,J＝11.3Hz,2H),3.98(d,J＝13.1Hz,1H),3.81–3.63(m,2H),3.18(t,J＝12.1Hz,1H),2.77(t,J＝11.9Hz,1H),1.95-1.92(m,2H),1.57-1.44(m,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a18)
White solid, yield 57%, mp: 217-219 deg.c,1H NMR(400MHz,DMSO)11.94(s,1H),8.16(s,1H),7.59(d,J＝1.9Hz,1H),7.39(dd,J＝8.2,2.0Hz,1H),7.35(s,1H),7.34–7.29(m,1H),6.14(d,J＝7.9Hz,1H),4.40-4.33(m,2H),4.02(d,J＝14.2Hz,1H),3.85(s,2H),3.26(t,J＝12.0Hz,1H),2.81(t,J＝11.7Hz,1H),2.07–1.87(m,2H),1.69-1.47(m,2H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (I-a19)
Light yellow solid, yield: 56%, mp: 155 ℃ at 157 ℃ in addition to the temperature,1H NMR(400MHz,DMSO)12.02(s,1H),8.17(s,1H),7.36(s,1H),7.28(q,J＝8.0Hz,5H),6.03(d,J＝7.8Hz,1H),4.32-4.29(m,2H),3.99-3.94(m,1H),3.79–3.64(m,2H),3.21(t,J＝13.9Hz,1H),2.84(t,J＝11.1Hz,1H),1.98-1.96(m,2H),1.48-1.40(m,2H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone (I-a20)
Light yellow solid, yieldRate 56%, mp: 202-205 deg.c,1H NMR(400MHz,DMSO)12.03(s,1H),8.16(s,1H),7.37(t,J＝5.4Hz,2H),7.27(d,J＝8.4Hz,2H),6.04(d,J＝7.7Hz,1H),4.35-4.29(m,2H),3.97-3.94(m,1H),3.81–3.67(m,2H),3.22(t,J＝11.7Hz,1H),2.84(t,J＝11.3Hz,1H),1.99-1.91(m,2H),1.54–1.33(m,2H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone (I-a21)
Brown solid, yield 52%, mp: 192 deg.c and 195 deg.c,1H NMR(400MHz,DMSO)12.04(s,1H),8.16(s,1H),7.51(d,J＝8.4Hz,2H),7.36(s,1H),7.21(d,J＝8.4Hz,2H),6.03(d,J＝7.7Hz,1H),4.38–4.25(m,2H),3.97-3.94(m,1H),3.78(s,2H),3.22(t,J＝11.6Hz,1H),2.85(t,J＝11.3Hz,1H),2.05–1.93(m,2H),1.57–1.34(m,2H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone (I-a22)
White solid, yield 58%, mp:170 ℃ and 173 ℃ below zero,1H NMR(400MHz,DMSO)12.05(s,1H),8.18(s,1H),7.58(d,J＝2.0Hz,1H),7.37-7.34(m,3H),6.08(d,J＝7.7Hz,1H),4.47–4.22(m,2H),4.01-3.97(m,1H),3.85(s,2H),3.29(d,J＝11.5Hz,1H),2.88(t,J＝11.3Hz,1H),2.07-1.99(,2H),1.70–1.42(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2-thiomorpholinone (I-a23)
White solid, yield 74%, mp: the temperature of the mixture is 98-102 ℃,1H NMR(400MHz,DMSO)11.46(s,1H),8.08(s,1H),7.43(d,J＝7.3Hz,4H),7.18(d,7.7Hz,1H),7.05(d,J＝13.8Hz,1H),6.54(d,J＝13.2Hz,1H),4.80(s,1H),4.43(d,J＝11.6Hz,1H),4.22(m,2H),3.01(t,J＝12.0Hz,1H),2.87–2.62(m,5H),2.60-2.55(m,4H),2.03-1.78(m,2H),1.56–1.13(m,2H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) ethanone (I-a24)
Light yellow solid, yield 67%, mp: 132-135 deg.c,1H NMR(400MHz,DMSO)11.47(s,1H),8.07(s,1H),7.44(dt,J＝22.4,7.5Hz,4H),7.11(d,J＝7.8Hz,1H),7.04(d,J＝11.6Hz,1H),6.53(d,J＝20.6Hz,1H),4.56(d,J＝11.8Hz,1H),4.44–4.18(m,3H),3.25–3.15(m,1H),3.04(t,J＝12.2Hz,1H),2.67(br,4H),2.39(br,4H),2.14(s,3H),1.99–1.79(m,2H),1.48–1.29(m,1H),1.23–1.10(m,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) ethanone (I-a25)
White solid, yield 74%,1H NMR(400MHz,DMSO)11.53(br,1H),8.09(d,J＝4.9Hz,1H),7.53(s,4H),7.21(t,J＝7.8Hz,2H),7.07(d,J＝12.4Hz,1H),6.91(d,J＝7.9Hz,2H),6.79(t,J＝7.0Hz,1H),6.55(d,J＝25.3Hz,1H),4.78(s,1H),4.42(d,J＝11.3Hz,1H),4.27(br,2H),3.32–2.97(m,5H),2.92–2.55(m,4H),2.06–1.74(m,2H),1.51-1.38(m,1H),1.34–1.05(m,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) ethanone (I-a26)
White solid, yield 75%,1H NMR(400MHz,DMSO)11.48(d,J＝10.0Hz,1H),8.08(d,J＝4.9Hz,1H),7.46(p,J＝8.6Hz,4H),7.24(d,J＝7.7Hz,0.5H),7.13(d,J＝7.6Hz,0.5H),7.09–7.02(m,1H),6.54(d,J＝19.6Hz,1H),4.71(d,J＝10.9Hz,1H),4.41(d,J＝12.7Hz,1H),4.21(dd,J＝26.8,16.4Hz,2H),3.39(br,4H),3.21(t,J＝12.1Hz,0.5H),3.02(t,J＝12.1Hz,0.5H),2.82–2.65(m,1H),2.42(br,4H),2.03–1.73(m,5H),1.55–1.27(m,1H),1.25-1.14(m,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (dimethylamino) ethanone (I-a27)
Off-white solid, yield 61%, mp: 134 deg.c, 137 deg.c,1H NMR(400MHz,DMSO)11.47(d,J＝8.0Hz,1H),8.09(t,J＝8.8Hz,1H),7.46(dq,J＝16.8,8.3Hz,4H),7.12(d,J＝7.8Hz,1H),7.04(d,J＝11.4Hz,1H),6.53(d,J＝16.8Hz,1H),4.52(s,1H),4.41(d,J＝10.2Hz,1H),4.28-4.16(m,2H),3.01(t,J＝12.3Hz,1H),2.84–2.60(m,1H),2.27–2.07(m,6H),1.99–1.74(m,2H),1.49–1.27(m,1H),1.29-1.11(d,J＝9.3Hz,1H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-ylamino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) ethanone (I-a28)
White solid, yield 69%, mp: 121-124 deg.c,1H NMR(400MHz,DMSO)11.48(d,J＝8.6Hz,1H),8.08(d,J＝3.9Hz,1H),7.47(dt,J＝15.2,8.4Hz,4H),7.19(7.7Hz,1H),7.05(d,J＝12.5Hz,1H),6.54(d,J＝23.8Hz,1H),4.69(d,J＝13.5Hz,1H),4.40(d,J＝12.8Hz,1H),4.24(dd,J＝20.2,13.5Hz,2H),3.46(d,J＝13.3Hz,1H),3.21(d,J＝9.5Hz,2H),3.05(t,J＝12.3Hz,1H),2.80-2.65(m,1H),2.19(s,3H),2.01-1.81(m,2H),1.55-1.33(m,1H),1.18-1.10(m,1H).HRMS(ESI):m/z for C23H27BrCl2N6O[M+H]+,calculated 553.0807,found553.0884
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) ethanone (I-a29)
White solid, yield 59%, mp: 142-146 deg.C,1H NMR(400MHz,DMSO)11.49(s,1H),8.08(d,J＝4.5Hz,1H),7.43(dd,J＝18.5,7.1Hz,4H),7.19(7.7Hz,1H),7.05(d,J＝10.2Hz,1H),6.54(d,J＝17.5Hz,1H),4.57(s,1H),4.42-4.25(m,3H),3.22-3.03(m,1H),2.84–2.61(m,1H),2.37(br,4H),2.01-1.84(m,2H),1.56-1.27(m,7H).
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-4-yl) ethanone (I-a30)
White solid, yield 64%, mp: the temperature of the mixture is 96-99 ℃,1H NMR(400MHz,DMSO)11.94(br,1H),8.11(s,1H),7.50(d,J＝8.4Hz,2H),7.29(d,J＝6.5Hz,3H),5.99(d,J＝7.6Hz,1H),4.19(br,1H),3.28(d,J＝12.4Hz,2H),3.05(t,J＝12.1Hz,2H),2.98–2.93(m,2H),2.76(t,J＝12.0Hz,2H),2.33(d,J＝13.4Hz,2H),2.13(s,2H),1.74(br,2H),1.30(br,2H).
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propan-1-one (I-a31)
White solid, yield 51%, mp: at the temperature of between 88 and 92 ℃,1H NMR(400MHz,DMSO)11.94(br,1H),8.13(d,J＝4.3Hz,1H),7.66(d,J＝3.5Hz,1H),7.49–7.39(m,1H),7.40–7.27(m,2H),6.03(d,J＝7.7Hz,1H),4.42-4.31(m,4H),3.78(t,J＝13.0Hz,1H),3.03(dt,J＝24.4,11.8Hz,2H),2.83–2.63(m,3H),2.02-1.83(m,2H),1.71–1.32(m,2H),0.96(br,6H).
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propan-1-one (I-a32)
White solid, yield 52%, mp:106-,1H NMR(400MHz,DMSO)11.99(s,1H),8.14(d,J＝5.1Hz,1H),7.66(d,J＝6.9Hz,1H),7.50–7.41(m,1H),7.40–7.32(m,2H),5.84(d,J＝7.5Hz,1H),4.46–4.21(m,3H),3.74(dd,J＝29.6,13.9Hz,1H),3.30–3.15(m,1H),3.17–2.97(m,2H),2.87(dd,J＝24.4,14.8Hz,1H),2.79–2.61(m,2H),2.05–1.95(m,1H),1.87(dd,J＝12.7,4.5Hz,1H),1.71–1.59(m,1H),1.49(dd,J＝20.9,9.3Hz,1H),0.97(s,6H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) acetamide (II-a1)
White solid, yield 85%,1H NMR(400MHz,DMSO)11.70(s,1H),8.14(s,1H),8.10(d,J＝7.6Hz,1H),7.35(d,J＝8.4Hz,2H),7.27(d,J＝8.4Hz,2H),7.18(s,1H),6.58(s,1H),4.55(d,J＝13.4Hz,2H),3.87(s,1H),3.39(s,2H),3.23(t,J＝11.4Hz,2H),1.84(d,J＝12.4Hz,2H),1.43-1.34(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a2)
White solid, yield 74%, mp: 209 at 212 c,1H NMR(400MHz,DMSO)11.69(s,1H),8.12(d,J＝14.9Hz,2H),7.41(d,J＝8.4Hz,4H),7.18(s,1H),6.57(s,1H),4.59(br,2H),3.89(s,1H),3.15(br,2H),2.10(s,6H),1.76(br,2H),1.45(br,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2-amino-2- (4-chlorophenyl) acetamide (II-a3)
White solid, yield 56%, mp: at 229-,1H NMR(400MHz,DMSO)11.68(s,1H),8.13(s,1H),8.06(s,1H),7.38(d,J＝10.1Hz,4H),7.18(s,1H),6.58(s,1H),4.55(t,J＝13.9Hz,2H),4.32(s,1H),3.88(s,1H),3.20(br,2H),1.86-1.74(m,2H),1.45-1.34(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a4)
White solid, yield 59%,1H NMR(400MHz,DMSO)11.68(s,1H),8.13(s,1H),8.00(d,J＝7.7Hz,1H),7.32–7.25(m,4H),7.21(ddd,J＝6.3,4.3,2.2Hz,1H),7.18–7.15(m,1H),6.57(dd,J＝3.5,1.6Hz,1H),4.79(s,1H),4.53(dd,J＝28.7,13.6Hz,2H),4.00–3.83(m,2H),3.61–3.45(m,2H),3.20(dd,J＝25.8,12.3Hz,2H),1.88(d,J＝10.0Hz,1H),1.73(d,J＝10.0Hz,1H),1.48–1.36(m,1H),1.31–1.24(m,1H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -3- (isopropylamino) propionamide (II-a5)
White solid, yield 63%, mp: 162-165 deg.c,1H NMR(400MHz,DMSO)11.69(s,1H),8.22–8.05(m,2H),7.35(q,J＝8.5Hz,4H),7.17(s,1H),6.56(s,1H),4.53(dd,J＝29.1,13.5Hz,2H),3.89(s,1H),3.64(s,1H),3.26–3.12(m,3H),2.79(dd,J＝20.8,9.0Hz,2H),1.89(d,J＝13.2Hz,1H),1.73(d,J＝10.6Hz,1H),1.43(dd,J＝21.7,12.1Hz,1H),1.32–1.20(m,1H),0.99(d,J＝6.1Hz,6H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-bromophenyl) -3- (isopropylamino) propionamide (II-a6)
White solid, yield 58%, mp: 193 deg.c, 196 deg.c,1H NMR(400MHz,DMSO)11.70(s,1H),8.23–8.14(m,1H),8.13(s,1H),7.49(d,J＝8.3Hz,2H),7.27(d,J＝8.3Hz,2H),7.22–7.12(m,1H),6.56(d,J＝2.1Hz,1H),4.52(dd,J＝25.2,13.5Hz,2H),3.88(s,1H),3.65–3.50(m,1H),3.22(dd,J＝26.2,12.0Hz,2H),3.13–3.00(m,1H),2.71(dd,J＝10.6,5.1Hz,2H),1.88(d,J＝10.7Hz,1H),1.72(d,J＝10.6Hz,1H),1.49–1.29(m,2H),0.94(d,J＝6.1Hz,6H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2-thiomorpholinoacetamide (II-a7)
White solid, yield 74%, mp: 254-256 deg.c,1H NMR(400MHz,DMSO)11.69(s,1H),8.14(s,1H),8.10(d,J＝8.0Hz,1H),7.44–7.33(m,4H),7.21–7.15(m,1H),6.59(s,1H),4.58(br,2H),3.99(s,1H),3.92(s,1H),3.18(dd,J＝19.0,11.5Hz,2H),2.60(s,8H),1.85-1.71(m,2H),1.54–1.35(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2-morpholinoacetamide (II-a8)
Light yellow solid, yieldRate 65%, mp: 118 at a temperature of 121 c,1H NMR(400MHz,DMSO)11.68(s,1H),8.17–8.07(m,2H),7.42(q,J＝8.5Hz,4H),7.18(s,1H),6.57(s,1H),4.57(t,J＝12.3Hz,2H),3.97–3.82(m,1H),3.77(s,1H),3.57(s,4H),3.17(dd,J＝21.6,10.4Hz,2H),2.31-2.25(m,4H),1.82(d,J＝10.5Hz,1H),1.72(d,J＝10.5Hz,1H),1.55–1.31(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperazin-1-yl) acetamide (II-a9)
Light yellow solid, yield 64%, mp: 125 ℃ and 129 ℃,1H NMR (400MHz, DMSO)11.69(s,1H),8.18(d, J ═ 8.0Hz,1H),8.14(s,1H),7.41(s,4H),7.18(s,1H),6.57(s,1H),4.57(t, J ═ 11.1Hz,2H),3.92(br,2H),3.18(br,2H),3.00(br,4H),2.47(br,4H),1.79-1.68(m,2H), 1.53-1.34 (m,2H).
N- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-hydroxypiperidin-1-yl) acetamide (II-a10)
Off-white solid, yield 73%, mp: 116-119 deg.c,1H NMR(400MHz,DMSO)11.69(s,1H),8.13(d,J＝9.4Hz,1H),8.07(dd,J＝22.5,8.1Hz,1H),7.43–7.33(m,4H),7.21–7.15(m,1H),6.62–6.53(m,1H),4.66–4.50(m,3H),3.96–3.88(m,1H),3.84(d,J＝18.0Hz,1H),3.39–3.26(m,2H),3.20(br,2H),2.63–2.53(m,2H),1.98-1.89(m,1H),1.81–1.55(m,4H),1.54–1.34(m,3H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) acetamide (II-a11)
White solid, yield 71%, mp: 226-,1H NMR(400MHz,DMSO)11.69(s,1H),8.15(d,J＝7.2Hz,2H),7.51–7.34(m,4H),7.25–7.02(m,1H),6.57(s,1H),4.58(t,J＝12.5Hz,2H),3.90(br,1H),3.84(s,1H),3.39(dd,J＝14.3,9.0Hz,4H),3.18(dd,J＝21.5,10.3Hz,2H),2.39–2.16(m,4H),1.95(s,3H),1.85-1.71(m,2H),1.53–1.33(m,2H).13C NMR(101MHz,DMSO)169.20,168.51,156.66,152.42,151.10,136.71,132.76(2C),130.84(2C),128.67,121.89,102.64,101.36,73.39,51.28,50.79,46.43,45.98,44.80(2C),41.17,31.79,31.46,21.59.
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a12)
White solid, yield 54%, mp:>270℃，1H NMR(400MHz,DMSO)11.68(s,1H),8.14(s,2H),7.49-7.40(m,3H),7.15(d,J＝18.1Hz,2H),6.57(s,1H),4.56(br,2H),4.00–3.63(m,2H),3.19(br,2H),2.23(br,8H),2.17(s,3H),1.93–1.71(m,2H),1.47(br,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a13)
White solid, yield 71%, mp: at 229-,1H NMR(400MHz,DMSO)11.77(s,1H),8.36(br,1H),8.15(s,1H),7.48(dd,J＝18.1,7.7Hz,4H),7.20(t,J＝7.7Hz,3H),6.90(d,J＝8.1Hz,2H),6.78(t,J＝7.1Hz,1H),6.60(s,1H),4.56(t,J＝15.7Hz,2H),4.11(br,1H),3.93(s,1H),3.29–3.05(m,6H),2.65(br,4H),1.87(d,J＝11.6Hz,1H),1.73(d,J＝11.2Hz,1H),1.55–1.35(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a14)
White solid, yield 61%, mp: 216-128 deg.c,1H NMR(400MHz,DMSO)11.62(s,1H),8.13(d,J＝7.9Hz,1H),8.07(s,1H),7.40(d,J＝8.5Hz,2H),7.33(d,J＝8.5Hz,2H),7.13–7.08(m,1H),6.50(dd,J＝3.3,1.5Hz,1H),4.49(t,J＝14.5Hz,2H),3.87(s,1H),3.79(s,1H),3.28(s,2H),3.13(d,J＝2.1Hz,1H),3.09(d,J＝10.7Hz,2H),2.13(s,3H),1.74(d,J＝10.4Hz,1H),1.61(d,J＝10.5Hz,1H),1.46–1.24(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -4- (4-chlorophenyl) piperidine-4-carboxamide (II-a15)
White solid, yield 46%, mp: 142-145 deg.c of the raw materials,1H NMR(400MHz,DMSO)11.69(s,1H),8.13(s,1H),7.35(q,J＝8.9Hz,5H),7.17(d,J＝3.6Hz,1H),6.56(d,J＝3.6Hz,1H),4.63(d,J＝13.3Hz,2H),3.98(s,1H),3.07(t,J＝12.0Hz,2H),2.80(d,J＝12.1Hz,2H),2.59(t,J＝11.3Hz,2H),2.40(dt,J＝16.6,10.2Hz,4H),1.71-1.58(m,4H),1.46–1.32(m,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) acetamide (II-a16)
White solid, yield 56%, mp: 240-,1H NMR(400MHz,DMSO)11.69(s,1H),8.15(s,1H),8.04(d,J＝8.0Hz,1H),7.43–7.30(m,4H),7.26–7.05(m,1H),6.59(ddd,J＝11.8,3.5,1.7Hz,1H),4.58(s,2H),3.91(s,1H),3.74(s,1H),3.18(dd,J＝20.4,9.8Hz,2H),2.26(s,4H),1.78(dd,J＝34.6,12.2Hz,2H),1.58-1.41(m,6H),1.33(t,J＝13.3Hz,2H).
n- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (pyrrol-1-yl) acetamide (II-a17)
White solid, yield 54%, mp: 195 deg.c, 198 deg.c,1H NMR(400MHz,DMSO)11.68(s,1H),8.14(s,1H),8.02(d,J＝8.1Hz,1H),7.46(d,J＝8.4Hz,2H),7.37(d,J＝8.5Hz,2H),7.20–7.14(m,1H),6.57(d,J＝2.0Hz,1H),4.59(d,J＝13.2Hz,2H),3.87(s,1H),3.69(s,1H),3.14(t,J＝13.2Hz,2H),2.41(s,2H),2.30(s,2H),1.81–1.70(m,2H),1.69(br,4H),1.55–1.35(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a18)
Light yellow solid, yield 60%, mp: 198-201 ℃ of the raw materials,1H NMR(400MHz,DMSO)12.17(s,1H),8.26(s,1H),8.18(d,J＝7.9Hz,1H),7.49(s,1H),7.42(dd,J＝20.0,8.6Hz,4H),4.11(br,2H),3.83(br,1H),3.67(s,1H),3.03(br,2H),2.44(dd,J＝14.1,7.0Hz,2H),2.11(s,6H),1.84-1.73(m,2H),1.71–1.55(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2-amino-2- (4-chlorophenyl) acetamide (II-a19)
White solid, yield 55%, mp: 197 ℃ and 199 ℃ are adopted,1H NMR(400MHz,DMSO)12.14(s,1H),8.26(s,1H),8.11(d,J＝7.8Hz,1H),7.48(s,1H),7.43(d,J＝8.5Hz,2H),7.37(d,J＝8.5Hz,2H),4.34(s,1H),4.10(t,J＝13.2Hz,2H),3.82(br,1H),3.09(q,J＝12.4Hz,2H),1.88(d,J＝10.1Hz,1H),1.79(d,J＝10.9Hz,1H),1.71–1.49(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a20)
White solid, yield 53%, mp:205 at a temperature of 208 deg.c,1H NMR(400MHz,DMSO)12.15(s,1H),8.25(s,1H),8.06(s,1H),7.47(s,1H),7.30(d,J＝7.1Hz,4H),7.22(s,1H),4.79(s,1H),4.08(dd,J＝26.5,12.6Hz,2H),3.89(d,J＝48.1Hz,2H),3.55(d,J＝30.6Hz,2H),3.08(dd,J＝28.2,12.4Hz,2H),1.91(d,J＝10.5Hz,1H),1.75(d,J＝10.8Hz,1H),1.60(d,J＝9.9Hz,1H),1.47(d,J＝9.8Hz,1H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -3- (isopropylamino) propionamide (II-a21)
White solid, yield 57%, mp: 198-202 deg.c,1H NMR(400MHz,DMSO)12.14(s,1H),8.25(s,1H),8.22(d,J＝7.7Hz,1H),7.48(s,1H),7.36(q,J＝8.7Hz,4H),4.07(br,2H),3.83(s,1H),3.69–3.58(m,1H),3.11(t,J＝14.2Hz,3H),2.77(td,J＝12.0,5.9Hz,2H),1.91(d,J＝10.0Hz,1H),1.76(d,J＝13.7Hz,1H),1.68–1.53(m,1H),1.46(dd,J＝21.7,12.8Hz,1H),0.97(d,J＝6.2Hz,6H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propanamide (II-a22)
Yellow solid, yield 57%, mp: 179-182 deg.C,1H NMR(400MHz,DMSO)12.17(br,1H),8.39(d,J＝7.7Hz,1H),8.26(s,1H),7.60(d,J＝2.0Hz,1H),7.49(d,J＝10.3Hz,2H),7.41(dd,J＝8.5,2.1Hz,1H),4.08(br,3H),3.90(s,1H),3.12(br,3H),2.87(br,2H),1.92-1.81(m,2H),1.47-1.66(m,2H),1.02(s,6H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a23)
White solid, yield 66%,1H NMR(400MHz,DMSO)12.15(s,1H),8.25(d,J＝6.0Hz,1H),8.24(d,J＝7.5Hz,1H),7.54–7.45(m,3H),7.42(d,J＝8.5Hz,2H),7.19(t,J＝7.9Hz,2H),6.90(d,J＝8.1Hz,2H),6.76(t,J＝7.2Hz,1H),4.11(t,J＝12.3Hz,2H),3.93–3.77(m,2H),3.13(s,4H),3.11–3.01(m,2H),2.48-2.41(m,4H),1.88(d,J＝10.4Hz,1H),1.76(d,J＝10.3Hz,1H),1.62-1.51(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (piperazin-1-yl) acetamide (II-a24)
A pale yellow solid, yield 67%,1H NMR(400MHz,DMSO)12.16(s,1H),8.33–8.18(m,2H),7.53–7.33(m,5H),4.11(t,J＝12.6Hz,2H),3.99(s,1H),3.87(br,1H),3.20–2.82(m,6H),2.51–2.39(m,4H),1.89-1.75(m,2H),1.71–1.51(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a25)
White solid, yield 56%,1H NMR(400MHz,DMSO)12.16(s,1H),8.26(s,1H),8.17(d,J＝7.8Hz,1H),7.48(s,1H),7.42(dd,J＝18.4,8.3Hz,4H),4.10(t,J＝12.5Hz,2H),3.81(br,2H),3.06(dd,J＝22.2,10.9Hz,2H),2.33(br,8H),2.17(s,3H),1.86(d,J＝10.7Hz,1H),1.74(d,J＝11.8Hz,1H),1.60(dd,J＝24.9,12.1Hz,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-hydroxypiperidin-1-yl) acetamide (II-a26)
White solid, yield 64%,1H NMR(400MHz,DMSO)12.16(s,1H),8.26(s,1H),8.15(dd,J＝22.4,8.1Hz,1H),7.49(s,1H),7.40(d,J＝6.1Hz,4H),4.12(br,2H),3.87(d,J＝16.0Hz,2H),3.36(br,2H),3.08(br,2H),2.46(q,J＝7.1Hz,4H),2.03–1.76(m,4H),1.73–1.57(m,4H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a27)
Light cyan solid, yield 61%, mp: at the temperature of between 87 and 91 ℃,1H NMR(400MHz,DMSO)12.15(s,1H),8.28(s,1H),8.25(s,1H),7.49(s,1H),7.48(d,J＝8.0Hz,2H),7.41(d,J＝8.5Hz,2H),4.09(t,J＝14.4Hz,2H),3.97(s,1H),3.80(s,1H),3.21(br,1H),3.13(d,J＝15.1Hz,1H),3.09-2.99(m,2H),2.22(s,3H),1.84(d,J＝10.2Hz,1H),1.69(d,J＝12.1Hz,1H),1.61–1.45(m,2H).
n- (1- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -4- (4-chlorophenyl) piperidine-4-carboxamide (II-a28)
Light yellow solid, yield: 53%, mp: the temperature of the mixture is 96-99 ℃,1H NMR(400MHz,MeOD)8.19(s,1H),7.48–7.30(m,5H),7.23(s,1H),4.28(d,J＝13.1Hz,2H),3.99(br,1H),3.23(d,J＝13.8Hz,2H),3.08(br,4H),2.63(d,J＝14.0Hz,2H),2.06(d,J＝11.1Hz,2H),1.86(d,J＝13.4Hz,2H),1.69–1.58(m,2H).HRMS(ESI):m/z for C23H26ClN6O[M+H]+,calculated 473.1545,found473.1620.
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (dimethylamino) acetamide (II-a29)
Yellow solid, yield 62%, mp: 124-127 deg.C,1H NMR(400MHz,DMSO)12.26(s,1H),8.27(s,1H),8.19(d,J＝8.0Hz,1H),7.55(s,1H),7.42(dd,J＝19.7,8.6Hz,4H),4.13–3.99(m,2H),3.81(s,1H),3.67(s,1H),3.02(dd,J＝18.9,10.7Hz,2H),2.09(s,6H),1.88–1.57(m,4H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -3-hydroxy-2-phenylpropanamide (II-a30)
Off-white solid, yield 58%, mp: 185-188 ℃ of the reaction kettle,1H NMR(400MHz,DMSO)12.24(s,1H),8.26(s,1H),8.07(d,J＝7.0Hz,1H),7.53(s,1H),7.39–7.14(m,5H),4.78(s,1H),4.11–3.89(m,3H),3.83(s,1H),3.55(d,J＝32.3Hz,2H),3.05(d,J＝10.2Hz,2H),1.90(br,1H),1.74(br,1H),1.63-1.50(m,2H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (2, 4-dichlorophenyl) -3- (isopropylamino) propanamide (II-a31)
Yellow solid, yield 58%, mp: 136 deg.c and 139 deg.c,1H NMR(400MHz,DMSO)12.25(s,1H),8.42(d,J＝7.7Hz,1H),8.27(s,1H),7.58(d,J＝2.0Hz,1H),7.54(s,1H),7.51(d,J＝8.5Hz,1H),7.40(dd,J＝8.5,2.2Hz,1H),4.07–3.98(m,3H),3.93–3.83(m,1H),3.14–2.98(m,3H),2.79–2.70(m,2H),1.90(d,J＝10.4Hz,1H),1.82(d,J＝10.2Hz,1H),1.65(dd,J＝18.3,9.2Hz,1H),1.60–1.53(m,1H),0.96(d,J＝2.5Hz,6H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) acetamide (II-a32)
Yellow solid, yield 57%, mp: 181-184 deg.c,1H NMR(400MHz,DMSO)12.25(s,1H),8.27(s,1H),8.18(d,J＝7.8Hz,1H),7.54(s,1H),7.41(dd,J＝18.5,8.6Hz,4H),4.05(t,J＝12.4Hz,2H),3.79(br,2H),3.03(dd,J＝22.2,10.9Hz,2H),2.79(br,4H),2.31(br,4H),2.15(s,3H),1.85(d,J＝12.1Hz,1H),1.74-1.55(m,3H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) acetamide (II-a33)
White solid, yield 64%, mp: 135-138 deg.c,1H NMR(400MHz,DMSO)12.25(s,1H),8.28(s,1H),8.25(d,J＝8.0Hz,1H),7.54(d,J＝2.3Hz,1H),7.46(dd,J＝27.8,8.5Hz,4H),7.19(t,J＝7.9Hz,2H),6.90(d,J＝8.1Hz,2H),6.76(t,J＝7.2Hz,1H),4.06(t,J＝12.2Hz,2H),3.92–3.82(m,2H),3.14-3.01(m,6H),2.49-2.39(m,4H),1.88(d,J＝10.0Hz,1H),1.81–1.54(m,3H).
n- (1- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) piperidin-4-yl) -2- (4-chlorophenyl) -2- (methyl- (prop-2-ynyl) amino) acetamide (II-a34)
Light yellow solid, yield 63%, mp: 188-191 ℃,1H NMR(400MHz,DMSO)12.20(s,1H),8.31–8.23(m,2H),7.53(dd,J＝7.1,2.4Hz,1H),7.49(d,J＝8.5Hz,2H),7.41(d,J＝8.4Hz,2H),4.11–3.92(m,3H),3.77(dd,J＝15.5,11.8Hz,1H),3.21(s,1H),3.18–2.92(m,3H),2.22(s,3H),1.84(d,J＝10.3Hz,1H),1.74–1.50(m,3H).
EXAMPLE 2 determination of AKT1 kinase inhibitory Activity, anti-proliferative Activity of the Compounds on prostate cancer PC-3 cells and mantle lymphoma (Rec-1, Jeko-R, Maver, Z138, Mino) cells
The compounds I-a1 to I-a32 and II-a1 to II-a34 of example 1 were tested for biological activity as follows, and the results are shown in tables 1 and 2.
The AKT1 kinase inhibitory activity and the anti-proliferative activity of PC-3 and lymphoma cells of the compounds are performed by the methods reported in the literature, and the specific references are as follows: LIu Y, YIN Y, Zhang J, NomIe K, Zhang L, Yang D, Wang ML, ZhaoG.2016.DIscovery of 4- (PIPerazm-1-yl) -7H-pyrrolo [2,3-D ] pyrImIdeDerivatives as Akt InhIbItors. Arch Pharm (WeInheim)349:356-362.LIU Y, YIN Y, Zhang Z, LIC.J, Zhang H, Zhang D, JIang C, NomIe K, Zhang L, Wang M.L, ZhaoG.2017. Structrul OptIzatIon antibodies sheets pot terminal InhIhIhItors Ak J543: 138 EuvJ.
TABLE 1 inhibitory Activity of Compounds on AKT1 kinase and antiproliferative Activity of PC-3 cells
aMedian Inhibitory Concentration (IC) of compounds on AKT1 kinase50)
bND＝not detected
TABLE 2 antiproliferative activity of the compounds on lymphoma cells
aND＝not detected
The experimental result shows that most compounds have weak inhibiting activity on AKT1 kinase under the concentration of 1 mu M, wherein the inhibiting activity of the compounds I-a32, II-a21, II-a22, II-a28 and II-a31 on AKT1 is 69%, 88%, 78%, 79% and 68%, respectively, and the half inhibiting concentrations of the compounds on AKT1 kinase are 0.60 mu M, 0.29 mu M, 0.69 mu M, 0.23 mu M and 0.36 mu M. The inhibitory activity of the compounds I-a20, I-a32 and II-a28 on lymphoma cells is equivalent to that of the marketed drug of Imatinib (IBN), so that the compounds of the invention can be used as drugs for targeting AKT1 to prostate cancer and lymphoma.
Claims (9)
1. A substituted piperidine-containing pyrrolopyrimidine compound or a pharmaceutically acceptable salt thereof, characterized by having a structure represented by the following general formula (I):
wherein R is1Is single halogen substituted, multiple halogen substituted, methoxy; r2Hydrogen, chlorine, bromine; r3Is amino, dimethylamino, piperidine, pyrrole, morpholine, piperazine, N-methylpiperazine, acetyl piperazine, phenyl piperazine; n is 0 or 1.
2. The substituted piperidine-containing pyrrolopyrimidine compound according to claim 1, wherein R in the general formula (I)1Is 4-chloro, 4-bromo, 4-fluoro, 4-methoxy or 2, 4-dichloro; r2Is hydrogen, chlorine or bromine; r3Is dimethylamino, morpholine, N-methylpiperazine, acetylpiperazine, phenylpiperazine or 4-piperidyl.
3. A substituted piperidine-containing pyrrolopyrimidine compound, which is one of the following compounds:
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-methoxyphenyl) ethanone,
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone,
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone,
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone,
1- (4- (5-chloro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone,
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-fluorophenyl) ethanone,
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) ethanone,
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-bromophenyl) ethanone,
1- (4- (5-bromo-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (2, 4-dichlorophenyl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2-thiomorpholinone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-methylpiperazin-1-yl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-phenylpiperazin-1-yl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (4-acetylpiperazin-1-yl) ethanone,
1- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (dimethylamino) ethanone,
1- (4- ((7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) piperidin-1-yl) -2- (4-chlorophenyl) -2- (piperidin-1-yl) ethanone.
4. The preparation method of the substituted piperidine-containing pyrrolopyrimidine compound according to claim 1, wherein 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine is used as a starting material, bromination or chlorination is carried out through a free radical reaction to obtain an intermediate 2, the intermediate 2 reacts with p-toluenesulfonyl chloride to obtain an intermediate 3, the intermediate 3 and 1-tert-butoxycarbonyl-4-aminopiperidine undergo nucleophilic substitution, then a protecting group is removed to obtain an intermediate 5, the intermediate 5 and a substituted acid undergo amide condensation, and then the protecting group is removed to obtain a target product I;
the synthetic route is as follows:
wherein R is1、R2、R3As described in general formula (I);
the substituted acid has a structure shown in the following general formula (III):
wherein R is1、R3N is as described in formula (I);
the reagents and reaction conditions used were as follows:
a) n-bromosuccinimide or N-chlorosuccinimide, N-Dimethylformamide (DMF), room temperature; b) p-toluenesulfonyl chloride, sodium hydroxide solution, acetone, room temperature; c) 1-tert-butoxycarbonyl-4-aminopiperidine, N-Diisopropylethylamine (DIEA), microwave, 150 ℃, d) trifluoroacetic acid (TFA), Dichloromethane (DCM), room temperature, e) (1) substituted acid, HBTU, DIEA, DMF, room temperature; (2) TFA, DCM, cesium carbonate at room temperature (3), tetrahydrofuran/methanol in a volume ratio of 3:1 at room temperature; or (1) substituted acid, HBTU, DIEA, DMF, room temperature; (2) cesium carbonate, tetrahydrofuran/methanol, volume ratio 3:1, room temperature.
5. The process for producing a substituted piperidine-containing pyrrolopyrimidine compound according to claim 4, which comprises the steps of:
1) dissolving 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine in N, N-Dimethylformamide (DMF), adding N-bromosuccinimide or N-chlorosuccinimide in batches, reacting at room temperature for 10-12H, pouring the reaction solution into 8-10 times of DMF ice water, separating out a large amount of off-white precipitate, filtering, washing a filter cake with purified water, and drying to obtain an intermediate 2, wherein the intermediate 2 is not purified and is directly used in the next step, and the 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine: the mol ratio of the N-bromosuccinimide or the N-chlorosuccinimide is 1: 1.1;
2) reacting the intermediate 2 or 4-chloro-7H-pyrrolo [2,3-d]Dissolving pyrimidine in acetone, adding a sodium hydroxide solution, stirring for 10-15mIn in an ice bath, adding p-toluenesulfonyl chloride in batches, naturally heating to room temperature, reacting for 10-12h, separating out a large amount of white solid, filtering, and filtering a filter cake by using a filter mass in a volume ratio of 1: 1, washing with acetone/water, and drying to obtain a middle part 3; in intermediate 3, R1Hydrogen, chlorine, bromine; in this reaction, the intermediate 2 or 4-chloro-7H-pyrrolo [2,3-d]The molar ratio of pyrimidine to tosyl chloride to sodium hydroxide is 1: 1.1: 1.2;
3) adding the intermediate 3 into NMP, sequentially adding DIEA, 1-tert-butyloxycarbonyl-4-aminopiperidine, heating the reaction liquid to 150 ℃ by microwave, reacting for 30-40mIn, quenching the reaction liquid by using 10 times of ice water, extracting by using ethyl acetate, washing an organic phase by using saturated amine chloride and saturated salt water, drying by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and reacting by using a solvent prepared by the volume ratio of 1: 2 to obtain an intermediate 4, wherein in the reaction, the molar ratio of the intermediate 2, DIEA and 1-tert-butyloxycarbonyl-4-aminopiperidine is 1: 1.5: 1.2;
4) and (2) adding the intermediate 4 solvent into dichloromethane, adding trifluoroacetic acid, reacting at room temperature for 4-5h, evaporating the reaction solution to dryness, adjusting the pH to 9 by using saturated sodium carbonate aqueous solution, extracting by using ethyl acetate, washing an organic phase by using saturated salt, drying by using anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and reacting the solvent with a solvent prepared by a volume ratio of 1: 25 to give intermediate 5, which was purified by column chromatography using dichloromethane/methanol in which the ratio by volume of trifluoroacetic acid to dichloromethane was 1: 3;
5) dissolving substituted acid in dichloromethane, sequentially adding HBTU and DIEA, stirring at room temperature for 15-20mIn, adding an intermediate 5, reacting at room temperature for 10-12h, washing the reaction solution with saturated ammonium chloride and saturated salt water, and evaporating to obtain an oily substance, wherein in the reaction, the molar ratio of the substituted acid to the HBTU to the DIEA to the intermediate 5 is 1: 1.05: 1.5: dissolving the oily matter in dichloromethane, adding trifluoroacetic acid, reacting at room temperature for 3-4h, evaporating the reaction solution to dryness, adjusting pH to 9 with saturated sodium carbonate, extracting with dichloromethane, washing the organic phase with saturated saline, evaporating to dryness under reduced pressure to obtain a solid, wherein the volume ratio of trifluoroacetic acid to dichloromethane is 1:3, dissolving the solid with methanol/tetrahydrofuran at the volume ratio of 1:3, adding cesium carbonate, reacting at room temperatureOvernight, the reaction was run with 50:1 dichloromethane: and (3) carrying out column chromatography purification on methanol to obtain a target product I, wherein in the step of reaction, the molar ratio of cesium carbonate to a solid obtained by the reaction is 4: 1; in this step, the substituted acid, intermediate 5, in the target product I, R1Is 4-chloro, 4-bromo, 4-fluoro, 4-methoxy, 2, 4-dichloro; r2Hydrogen, chlorine, bromine; r3Is dimethylamino, morpholine, N-methylpiperazine, acetylpiperazine, phenylpiperazine or 4-piperidyl.
6. The process for preparing a substituted piperidine-containing pyrrolopyrimidine compound according to claim 4, wherein the substituted acid is one of:
7. use of the substituted piperidine-containing pyrrolopyrimidine compounds or pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 3 for the preparation of antitumor agents.
8. The use according to claim 7, characterized in that the antineoplastic drug is an anti-prostate cancer and anti-lymphoma drug targeting AKT 1.
9. A pharmaceutical composition suitable for oral or parenteral administration comprising a compound according to any one of claims 1 to 3 and one or more pharmaceutically acceptable carriers or excipients.
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