CN110177785A - 一种二氢异喹啉类化合物 - Google Patents
一种二氢异喹啉类化合物 Download PDFInfo
- Publication number
- CN110177785A CN110177785A CN201880006642.9A CN201880006642A CN110177785A CN 110177785 A CN110177785 A CN 110177785A CN 201880006642 A CN201880006642 A CN 201880006642A CN 110177785 A CN110177785 A CN 110177785A
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- CN
- China
- Prior art keywords
- butyl
- base
- alkyl
- methyl
- ethyl
- 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
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 93
- -1 C1‐6Alkyl Chemical group 0.000 claims abstract description 1121
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 248
- 229910052805 deuterium Inorganic materials 0.000 claims abstract description 248
- 239000011737 fluorine Substances 0.000 claims abstract description 163
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 156
- 239000001257 hydrogen Substances 0.000 claims abstract description 156
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 141
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims abstract description 136
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 70
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 60
- 150000002367 halogens Chemical class 0.000 claims abstract description 60
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims abstract description 58
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 37
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 27
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 27
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 27
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 22
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims abstract description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 13
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims abstract description 9
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims abstract description 9
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000001786 isothiazolyl group Chemical group 0.000 claims abstract description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims abstract description 9
- 150000004866 oxadiazoles Chemical class 0.000 claims abstract description 9
- 125000002971 oxazolyl group Chemical group 0.000 claims abstract description 9
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 9
- 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 9
- 150000003536 tetrazoles Chemical class 0.000 claims abstract description 9
- 125000001113 thiadiazolyl group Chemical group 0.000 claims abstract description 9
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 9
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims abstract description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 5
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims abstract description 5
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 5
- 125000005956 isoquinolyl group Chemical group 0.000 claims abstract description 5
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims abstract description 5
- 125000005493 quinolyl group Chemical group 0.000 claims abstract description 5
- 239000002585 base Substances 0.000 claims description 712
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 582
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 181
- 229910052731 fluorine Inorganic materials 0.000 claims description 161
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 152
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 149
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 134
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 103
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 103
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 103
- 229910052794 bromium Inorganic materials 0.000 claims description 103
- 239000000460 chlorine Substances 0.000 claims description 103
- 229910052801 chlorine Inorganic materials 0.000 claims description 103
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 99
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 85
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 85
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 85
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 81
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 79
- 125000005936 piperidyl group Chemical group 0.000 claims description 61
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 60
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- 125000002757 morpholinyl group Chemical group 0.000 claims description 52
- 239000000203 mixture Substances 0.000 claims description 49
- 125000004193 piperazinyl group Chemical group 0.000 claims description 49
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 48
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 48
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 41
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 37
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 36
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 31
- 125000003118 aryl group Chemical group 0.000 claims description 30
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 25
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 24
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 24
- 125000002393 azetidinyl group Chemical group 0.000 claims description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 20
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 20
- WKGHUAZJNBXABN-UHFFFAOYSA-N 3-bromo-2-chloro-6-methyl-5-nitropyridine Chemical compound CC1=NC(Cl)=C(Br)C=C1[N+]([O-])=O WKGHUAZJNBXABN-UHFFFAOYSA-N 0.000 claims description 19
- IFSCYCNNAIADLI-UHFFFAOYSA-N ethyl isoquinoline-3-carboxylate Chemical compound C1=CC=C2C=NC(C(=O)OCC)=CC2=C1 IFSCYCNNAIADLI-UHFFFAOYSA-N 0.000 claims description 18
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 18
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 16
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims description 14
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 14
- GRRPTTNYXRTGKW-UHFFFAOYSA-N 1-(methylamino)piperidin-4-ol Chemical compound CNN1CCC(O)CC1 GRRPTTNYXRTGKW-UHFFFAOYSA-N 0.000 claims description 12
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 12
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 12
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 12
- 125000003566 oxetanyl group Chemical group 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- GYUFLTOWUVCCNO-UHFFFAOYSA-N 1-(difluoromethyl)pyrazole Chemical class FC(F)N1C=CC=N1 GYUFLTOWUVCCNO-UHFFFAOYSA-N 0.000 claims description 9
- ANMVTDVBEDVFRB-UHFFFAOYSA-N 1-propan-2-ylpyrazole Chemical class CC(C)N1C=CC=N1 ANMVTDVBEDVFRB-UHFFFAOYSA-N 0.000 claims description 9
- ZBFAXMKJADVOGH-UHFFFAOYSA-N 2-fluoro-4-methylpyridine Chemical compound CC1=CC=NC(F)=C1 ZBFAXMKJADVOGH-UHFFFAOYSA-N 0.000 claims description 9
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical class CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 claims description 8
- BDMFEFZOOOYCKN-UHFFFAOYSA-N 1-propylpyrazole Chemical class CCCN1C=CC=N1 BDMFEFZOOOYCKN-UHFFFAOYSA-N 0.000 claims description 8
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 8
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 8
- VZWOXDYRBDIHMA-UHFFFAOYSA-N 2-methyl-1,3-thiazole Chemical compound CC1=NC=CS1 VZWOXDYRBDIHMA-UHFFFAOYSA-N 0.000 claims description 8
- PCXCZMYBFGWKKH-UHFFFAOYSA-N 2-pyrrolidin-1-ylpyrimidine Chemical compound C1CCCN1C1=NC=CC=N1 PCXCZMYBFGWKKH-UHFFFAOYSA-N 0.000 claims description 8
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 8
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 8
- OUMGIYIBWRLOAF-UHFFFAOYSA-N n,n-dimethylpyrimidin-2-amine Chemical compound CN(C)C1=NC=CC=N1 OUMGIYIBWRLOAF-UHFFFAOYSA-N 0.000 claims description 8
- BQNXHDSGGRTFNX-UHFFFAOYSA-N n-methylpyrimidin-2-amine Chemical compound CNC1=NC=CC=N1 BQNXHDSGGRTFNX-UHFFFAOYSA-N 0.000 claims description 8
- 150000002921 oxetanes Chemical class 0.000 claims description 8
- NODLZCJDRXTSJO-UHFFFAOYSA-N 1,3-dimethylpyrazole Chemical class CC=1C=CN(C)N=1 NODLZCJDRXTSJO-UHFFFAOYSA-N 0.000 claims description 7
- 125000006311 cyclobutyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 229960005486 vaccine Drugs 0.000 claims description 7
- PSFQZUIYYGSLQU-UHFFFAOYSA-N 3-(1,2,4-triazol-4-yl)propan-1-ol Chemical compound OCCCN1C=NN=C1 PSFQZUIYYGSLQU-UHFFFAOYSA-N 0.000 claims description 6
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical class CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 6
- 150000003230 pyrimidines Chemical class 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- ILROLYQPRYHHFG-UHFFFAOYSA-N 1-$l^{1}-oxidanylprop-2-en-1-one Chemical group [O]C(=O)C=C ILROLYQPRYHHFG-UHFFFAOYSA-N 0.000 claims description 5
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims description 5
- LNJMHEJAYSYZKK-UHFFFAOYSA-N 2-methylpyrimidine Chemical compound CC1=NC=CC=N1 LNJMHEJAYSYZKK-UHFFFAOYSA-N 0.000 claims description 5
- LOSKNFQZTWYZHI-UHFFFAOYSA-N 2-pyrazol-1-ylacetic acid Chemical class OC(=O)CN1C=CC=N1 LOSKNFQZTWYZHI-UHFFFAOYSA-N 0.000 claims description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- 229940002612 prodrug Drugs 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 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 3
- 108010079944 Interferon-alpha2b Proteins 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 239000003513 alkali Substances 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 229940071870 hydroiodic acid Drugs 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 1
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- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
Abstract
本发明提供一种通式I的化合物：，其中：R是氢、C1‑6烷基中的任一种；R1是氢、氘、卤素、C1‑6烷基、C1‑6烷基氨基、C1‑6烷氧基中的任一种；R2是氢、氘、卤素、C1‑6烷基、被最少一个氟所取代的C1‑6烷基、C3‑7环烷基、C1‑6烷基氨基，C1‑6烷氧基、杂环烷基中的任一种；Ar是苯基、噻吩基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡啶‑2(1H)‑酮基、吡啶‑4(1H)‑酮基、吡咯基、吡唑基、噻唑基、1，2，3‑***基、1，2，4‑***基、咪唑基、四氮唑基、异噻唑基、噁唑基、异噁唑基、噻二唑基、噁二唑基、萘基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并呋喃基、喹啉基、异喹啉基、喹唑啉基中的任一种；R3是氢、氘、卤素、氰基、C1‑6烷基、C3‑7环烷基、C1‑6烷基氨基、C1‑6烷氧基、杂环烷基中的任一种；R4是氢、氘、C1‑6烷基中的任一种；R5是氢、氘、C1‑6烷基、被最少一个氟所取代的C1‑6烷基、C3‑7环烷基中的任一种。本发明提供的化合物可以用于治疗和预防乙肝病毒感染。
Description
PCT国内申请，说明书已公开。
Claims (38)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2017100274433 | 2017-01-13 | ||
| CN201710027443.3A CN106810548B (zh) | 2017-01-13 | 2017-01-13 | 一种二氢异喹啉类化合物 |
| PCT/CN2018/072057 WO2018130152A1 (zh) | 2017-01-13 | 2018-01-10 | 一种二氢异喹啉类化合物 |
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| Publication Number | Publication Date |
|---|---|
| CN110177785A true CN110177785A (zh) | 2019-08-27 |
| CN110177785B CN110177785B (zh) | 2022-02-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910001831.3A Active CN109369640B (zh) | 2017-01-13 | 2017-01-13 | 一种二氢异喹啉类化合物的制备方法 |
| CN201710027443.3A Active CN106810548B (zh) | 2017-01-13 | 2017-01-13 | 一种二氢异喹啉类化合物 |
| CN201880006642.9A Active CN110177785B (zh) | 2017-01-13 | 2018-01-10 | 一种二氢异喹啉类化合物 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201910001831.3A Active CN109369640B (zh) | 2017-01-13 | 2017-01-13 | 一种二氢异喹啉类化合物的制备方法 |
| CN201710027443.3A Active CN106810548B (zh) | 2017-01-13 | 2017-01-13 | 一种二氢异喹啉类化合物 |
Country Status (3)
| Country | Link |
|---|---|
| US (2) | US10647712B2 (zh) |
| CN (3) | CN109369640B (zh) |
| WO (1) | WO2018130152A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110066278A (zh) * | 2017-06-01 | 2019-07-30 | 广东东阳光药业有限公司 | 稠合三环类化合物及其在药物中的应用 |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10738035B2 (en) | 2015-05-13 | 2020-08-11 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| WO2017011552A1 (en) | 2015-07-13 | 2017-01-19 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| WO2017155844A1 (en) | 2016-03-07 | 2017-09-14 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| CN109843296A (zh) | 2016-06-10 | 2019-06-04 | 英安塔制药有限公司 | 乙型肝炎抗病毒药剂 |
| WO2018019297A1 (zh) * | 2016-07-29 | 2018-02-01 | 银杏树药业(苏州)有限公司 | 异喹啉酮类化合物及其制备抗病毒药物的应用 |
| CN107759585A (zh) * | 2016-07-29 | 2018-03-06 | 银杏树药业(苏州)有限公司 | 一种异喹啉类化合物及其药用组合物和作为抗病毒药物的应用 |
| KR102522060B1 (ko) | 2016-11-07 | 2023-04-14 | 아뷰터스 바이오파마 코포레이션 | 치환된 피리디논 함유 트리시클릭 화합물, 및 그의 사용 방법 |
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| US10647712B2 (en) | 2020-05-12 |
| CN109369640B (zh) | 2020-03-27 |
| CN106810548B (zh) | 2019-02-15 |
| US10717730B1 (en) | 2020-07-21 |
| WO2018130152A1 (zh) | 2018-07-19 |
| CN106810548A (zh) | 2017-06-09 |
| US20200207755A1 (en) | 2020-07-02 |
| CN110177785B (zh) | 2022-02-08 |
| CN109369640A (zh) | 2019-02-22 |
| US20190389855A1 (en) | 2019-12-26 |
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