WO2023284807A1 - 含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物及其制备方法与制药用途 - Google Patents
含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物及其制备方法与制药用途 Download PDFInfo
- Publication number
- WO2023284807A1 WO2023284807A1 PCT/CN2022/105579 CN2022105579W WO2023284807A1 WO 2023284807 A1 WO2023284807 A1 WO 2023284807A1 CN 2022105579 W CN2022105579 W CN 2022105579W WO 2023284807 A1 WO2023284807 A1 WO 2023284807A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- tetrahydropyrido
- benzyl
- ketone
- naphthyridin
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 542
- 238000002360 preparation method Methods 0.000 title claims abstract description 210
- DXJSIYMHOVZRCG-UHFFFAOYSA-N 3,4,4a,5-tetrahydro-1h-pyrido[3,2-d]pyrimidin-2-one Chemical group N1C=CC=C2NC(=O)NCC21 DXJSIYMHOVZRCG-UHFFFAOYSA-N 0.000 title claims abstract description 11
- MWRKXVUGPRFLTD-UHFFFAOYSA-N 3,4,4a,5-tetrahydro-1h-1,8-naphthyridin-2-one Chemical compound C1C=CN=C2NC(=O)CCC21 MWRKXVUGPRFLTD-UHFFFAOYSA-N 0.000 title abstract 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- -1 2-ethylbenzyl Chemical group 0.000 claims description 130
- 238000000034 method Methods 0.000 claims description 74
- 125000006239 protecting group Chemical group 0.000 claims description 71
- 150000001412 amines Chemical class 0.000 claims description 69
- BDTRIDKONHOQQN-UHFFFAOYSA-N 4h-pyrimidin-5-one Chemical compound O=C1CN=CN=C1 BDTRIDKONHOQQN-UHFFFAOYSA-N 0.000 claims description 31
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 17
- 150000008282 halocarbons Chemical class 0.000 claims description 14
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 14
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 13
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Chemical group 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 8
- 229940125810 compound 20 Drugs 0.000 claims description 8
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 8
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 229940126208 compound 22 Drugs 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 6
- 150000003852 triazoles Chemical group 0.000 claims description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 6
- 229940116762 ClpP agonist Drugs 0.000 claims description 5
- MTIKOXJDFCWDAD-UHFFFAOYSA-N N#CC1=CC=CC(CN(CC2)CC(C(N3CC(C=CC(F)=C4)=C4F)=O)=C2N2C3=NC=C2)=C1 Chemical compound N#CC1=CC=CC(CN(CC2)CC(C(N3CC(C=CC(F)=C4)=C4F)=O)=C2N2C3=NC=C2)=C1 MTIKOXJDFCWDAD-UHFFFAOYSA-N 0.000 claims description 5
- SHOBLJORGZCPOG-UHFFFAOYSA-N O=C(C1=C2CCN(CC3=CC=CC=C3)C1)N(CC1=CC=C(C(F)(F)F)C=C1)C1=C2SC=C1 Chemical compound O=C(C1=C2CCN(CC3=CC=CC=C3)C1)N(CC1=CC=C(C(F)(F)F)C=C1)C1=C2SC=C1 SHOBLJORGZCPOG-UHFFFAOYSA-N 0.000 claims description 5
- AWGIZCREBHRLNY-UHFFFAOYSA-N O=C(C1=C2CCN(CC3=CC=CC=C3)C1)N(CC1=CC=C(C(F)(F)F)C=C1)C1=C2SC=N1 Chemical compound O=C(C1=C2CCN(CC3=CC=CC=C3)C1)N(CC1=CC=C(C(F)(F)F)C=C1)C1=C2SC=N1 AWGIZCREBHRLNY-UHFFFAOYSA-N 0.000 claims description 5
- DCWWRDQYFWSXGX-UHFFFAOYSA-N O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C(SC=C2)=C2C2=C1CN(CC1=CC=CC=C1)CC2 Chemical compound O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C(SC=C2)=C2C2=C1CN(CC1=CC=CC=C1)CC2 DCWWRDQYFWSXGX-UHFFFAOYSA-N 0.000 claims description 5
- GRXSLPDMQGMCCJ-UHFFFAOYSA-N O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=CSC=C2C2=C1CN(CC1=CC=CC=C1)CC2 Chemical compound O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=CSC=C2C2=C1CN(CC1=CC=CC=C1)CC2 GRXSLPDMQGMCCJ-UHFFFAOYSA-N 0.000 claims description 5
- OOUIOTSGRLUYDB-UHFFFAOYSA-N O=C1N(CC2=CC=CC=C2)C2=NC=CN2C2=C1CN(CC1=CC=CC=C1)CC2 Chemical compound O=C1N(CC2=CC=CC=C2)C2=NC=CN2C2=C1CN(CC1=CC=CC=C1)CC2 OOUIOTSGRLUYDB-UHFFFAOYSA-N 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 4
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 4
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 4
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006179 2-methyl benzyl group Chemical group [H]C1=C([H])C(=C(C([H])=C1[H])C([H])([H])*)C([H])([H])[H] 0.000 claims description 4
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims description 4
- 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 claims description 4
- 125000003852 3-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Cl)=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000006180 3-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 4
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 4
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 claims description 4
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 claims description 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 4
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 claims description 4
- NDLFPEQISSBMID-UHFFFAOYSA-N CC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C#N)=CC=C4)CC2)C3=O)C=C1 Chemical compound CC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C#N)=CC=C4)CC2)C3=O)C=C1 NDLFPEQISSBMID-UHFFFAOYSA-N 0.000 claims description 4
- ZWGOEQVMCVJNFQ-UHFFFAOYSA-N CC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C)=CC=C4)CC2)C3=O)C=C1 Chemical compound CC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C)=CC=C4)CC2)C3=O)C=C1 ZWGOEQVMCVJNFQ-UHFFFAOYSA-N 0.000 claims description 4
- LPHWKOISSZTJPZ-UHFFFAOYSA-N CC1=CC=CC(CN(CC2)CC(C(N3CC(C=C4)=CC=C4OC)=O)=C2N2C3=NC=C2)=C1 Chemical compound CC1=CC=CC(CN(CC2)CC(C(N3CC(C=C4)=CC=C4OC)=O)=C2N2C3=NC=C2)=C1 LPHWKOISSZTJPZ-UHFFFAOYSA-N 0.000 claims description 4
- TVEMLJIIQTXGAT-UHFFFAOYSA-N CC1=CC=CC(CN(CC2)CC(C(N3CC(C=CC(F)=C4)=C4F)=O)=C2N2C3=NC=C2)=C1 Chemical compound CC1=CC=CC(CN(CC2)CC(C(N3CC(C=CC(F)=C4)=C4F)=O)=C2N2C3=NC=C2)=C1 TVEMLJIIQTXGAT-UHFFFAOYSA-N 0.000 claims description 4
- ZPZDIMKBTLKDFV-UHFFFAOYSA-N CC1=CC=CC(CN(CC2)CC(C(N3CC4=CC=C(C(F)(F)F)C=C4)=O)=C2N2C3=NC=C2)=C1 Chemical compound CC1=CC=CC(CN(CC2)CC(C(N3CC4=CC=C(C(F)(F)F)C=C4)=O)=C2N2C3=NC=C2)=C1 ZPZDIMKBTLKDFV-UHFFFAOYSA-N 0.000 claims description 4
- CGOQRUFDNYHBJS-UHFFFAOYSA-N CCC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C#N)=CC=C4)CC2)C3=O)C=C1 Chemical compound CCC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C#N)=CC=C4)CC2)C3=O)C=C1 CGOQRUFDNYHBJS-UHFFFAOYSA-N 0.000 claims description 4
- SNLMYCBYFIIMEF-UHFFFAOYSA-N CCC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C)=CC=C4)CC2)C3=O)C=C1 Chemical compound CCC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C)=CC=C4)CC2)C3=O)C=C1 SNLMYCBYFIIMEF-UHFFFAOYSA-N 0.000 claims description 4
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 claims description 4
- IEYUCGMEECVDQO-UHFFFAOYSA-N COC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C#N)=CC=C4)CC2)C3=O)C=C1 Chemical compound COC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(C#N)=CC=C4)CC2)C3=O)C=C1 IEYUCGMEECVDQO-UHFFFAOYSA-N 0.000 claims description 4
- JYWGXBLHLAYFHE-UHFFFAOYSA-N COC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(Cl)=CC=C4)CC2)C3=O)C=C1 Chemical compound COC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(Cl)=CC=C4)CC2)C3=O)C=C1 JYWGXBLHLAYFHE-UHFFFAOYSA-N 0.000 claims description 4
- YWHLKMMCIQYJHQ-UHFFFAOYSA-N COC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(F)=CC=C4)CC2)C3=O)C=C1 Chemical compound COC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(F)=CC=C4)CC2)C3=O)C=C1 YWHLKMMCIQYJHQ-UHFFFAOYSA-N 0.000 claims description 4
- 229940126657 Compound 17 Drugs 0.000 claims description 4
- 229940126639 Compound 33 Drugs 0.000 claims description 4
- BWGSHUPCLNNWAY-UHFFFAOYSA-N N#CC1=CC=CC(CN(CC2)CC(C(N3CC4=CC=C(C(F)(F)F)C=C4)=O)=C2N2C3=CN=C2)=C1 Chemical compound N#CC1=CC=CC(CN(CC2)CC(C(N3CC4=CC=C(C(F)(F)F)C=C4)=O)=C2N2C3=CN=C2)=C1 BWGSHUPCLNNWAY-UHFFFAOYSA-N 0.000 claims description 4
- QAQSCUGHROIHLZ-UHFFFAOYSA-N N#CC1=CC=CC(CN(CC2)CC(C(N3CC4=CC=C(C(F)(F)F)C=C4)=O)=C2N2C3=NC=C2)=C1 Chemical compound N#CC1=CC=CC(CN(CC2)CC(C(N3CC4=CC=C(C(F)(F)F)C=C4)=O)=C2N2C3=NC=C2)=C1 QAQSCUGHROIHLZ-UHFFFAOYSA-N 0.000 claims description 4
- BNBYCIFMSWKWBD-UHFFFAOYSA-N N#CC1=CC=CC(CN(CC2)CC3=C2N2N=CC=C2N(CC(C=C2)=CC=C2Cl)C3=O)=C1 Chemical compound N#CC1=CC=CC(CN(CC2)CC3=C2N2N=CC=C2N(CC(C=C2)=CC=C2Cl)C3=O)=C1 BNBYCIFMSWKWBD-UHFFFAOYSA-N 0.000 claims description 4
- QAMJXDFCTRJOCI-UHFFFAOYSA-N N#CC1=CC=CC(CN(CC2)CC3=C2N2N=CC=C2N(CC2=CC=C(C(F)(F)F)C=C2)C3=O)=C1 Chemical compound N#CC1=CC=CC(CN(CC2)CC3=C2N2N=CC=C2N(CC2=CC=C(C(F)(F)F)C=C2)C3=O)=C1 QAMJXDFCTRJOCI-UHFFFAOYSA-N 0.000 claims description 4
- ILOUDRYTVCDGNE-UHFFFAOYSA-N N#CC1=CC=CC(CN(CC2)CC3=C2N2N=CN=C2N(CC(C=C2)=CC=C2Cl)C3=O)=C1 Chemical compound N#CC1=CC=CC(CN(CC2)CC3=C2N2N=CN=C2N(CC(C=C2)=CC=C2Cl)C3=O)=C1 ILOUDRYTVCDGNE-UHFFFAOYSA-N 0.000 claims description 4
- RYBYUMKAADVPOD-UHFFFAOYSA-N N#CC1=CC=CC(CN(CC2)CC3=C2N2N=CN=C2N(CC2=CC=C(C(F)(F)F)C=C2)C3=O)=C1 Chemical compound N#CC1=CC=CC(CN(CC2)CC3=C2N2N=CN=C2N(CC2=CC=C(C(F)(F)F)C=C2)C3=O)=C1 RYBYUMKAADVPOD-UHFFFAOYSA-N 0.000 claims description 4
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 4
- XWTGQKUWTXSCML-UHFFFAOYSA-N O=C1N(CC(C=C2)=CC=C2Cl)C2=NC=NN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 Chemical compound O=C1N(CC(C=C2)=CC=C2Cl)C2=NC=NN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 XWTGQKUWTXSCML-UHFFFAOYSA-N 0.000 claims description 4
- HCTCFBRJCBRDTN-UHFFFAOYSA-N O=C1N(CC(C=C2)=CC=C2Cl)C2=NC=NN2C2=C1CN(CC1=CC(F)=CC=C1)CC2 Chemical compound O=C1N(CC(C=C2)=CC=C2Cl)C2=NC=NN2C2=C1CN(CC1=CC(F)=CC=C1)CC2 HCTCFBRJCBRDTN-UHFFFAOYSA-N 0.000 claims description 4
- HRBGNEWDZKEODW-UHFFFAOYSA-N O=C1N(CC(C=C2)=CC=C2Cl)C2=NC=NN2C2=C1CN(CC1=CC=CC=C1)CC2 Chemical compound O=C1N(CC(C=C2)=CC=C2Cl)C2=NC=NN2C2=C1CN(CC1=CC=CC=C1)CC2 HRBGNEWDZKEODW-UHFFFAOYSA-N 0.000 claims description 4
- IKLUUBSUIYHRFI-UHFFFAOYSA-N O=C1N(CC(C=CC(F)=C2)=C2F)C2=NC=CN2C2=C1CN(CC1=CC(F)=CC=C1)CC2 Chemical compound O=C1N(CC(C=CC(F)=C2)=C2F)C2=NC=CN2C2=C1CN(CC1=CC(F)=CC=C1)CC2 IKLUUBSUIYHRFI-UHFFFAOYSA-N 0.000 claims description 4
- YLOGPPCKNRATOS-UHFFFAOYSA-N O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=CN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 Chemical compound O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=CN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 YLOGPPCKNRATOS-UHFFFAOYSA-N 0.000 claims description 4
- UBJGKBXYDAQBLW-UHFFFAOYSA-N O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=CN2C2=C1CN(CC1=CC(F)=CC=C1)CC2 Chemical compound O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=CN2C2=C1CN(CC1=CC(F)=CC=C1)CC2 UBJGKBXYDAQBLW-UHFFFAOYSA-N 0.000 claims description 4
- CEFNUXZXTRLIIH-UHFFFAOYSA-N O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=NN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 Chemical compound O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=NN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 CEFNUXZXTRLIIH-UHFFFAOYSA-N 0.000 claims description 4
- QAEYKJJTXHJSSK-UHFFFAOYSA-N O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=NN2C2=C1CN(CC1=CC=CC=C1)CC2 Chemical compound O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=NN2C2=C1CN(CC1=CC=CC=C1)CC2 QAEYKJJTXHJSSK-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 claims description 4
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 4
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940125773 compound 10 Drugs 0.000 claims description 4
- 229940125797 compound 12 Drugs 0.000 claims description 4
- 229940126543 compound 14 Drugs 0.000 claims description 4
- 229940125758 compound 15 Drugs 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- 229940126086 compound 21 Drugs 0.000 claims description 4
- 229940125833 compound 23 Drugs 0.000 claims description 4
- 229940125961 compound 24 Drugs 0.000 claims description 4
- 229940125846 compound 25 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 4
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 239000011630 iodine Substances 0.000 claims description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 4
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- OAMOLDSSQFKREG-UHFFFAOYSA-N CC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(Cl)=CC=C4)CC2)C3=O)C=C1 Chemical compound CC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(Cl)=CC=C4)CC2)C3=O)C=C1 OAMOLDSSQFKREG-UHFFFAOYSA-N 0.000 claims description 3
- YYTXCVLEVXTAPA-UHFFFAOYSA-N CC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(F)=CC=C4)CC2)C3=O)C=C1 Chemical compound CC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(F)=CC=C4)CC2)C3=O)C=C1 YYTXCVLEVXTAPA-UHFFFAOYSA-N 0.000 claims description 3
- BJHMFUBZBNJVTK-UHFFFAOYSA-N CC1=CC=CC(CN(CC2)CC(C(N3CC(C=C4)=CC=C4Cl)=O)=C2N2C3=NC=C2)=C1 Chemical compound CC1=CC=CC(CN(CC2)CC(C(N3CC(C=C4)=CC=C4Cl)=O)=C2N2C3=NC=C2)=C1 BJHMFUBZBNJVTK-UHFFFAOYSA-N 0.000 claims description 3
- KQAKTXULVYMBNH-UHFFFAOYSA-N CC1=CC=CC(CN(CC2)CC(C(N3CC(C=C4)=CC=C4F)=O)=C2N2C3=NC=C2)=C1 Chemical compound CC1=CC=CC(CN(CC2)CC(C(N3CC(C=C4)=CC=C4F)=O)=C2N2C3=NC=C2)=C1 KQAKTXULVYMBNH-UHFFFAOYSA-N 0.000 claims description 3
- UQYLVEUXYOTIMY-UHFFFAOYSA-N CCC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(Cl)=CC=C4)CC2)C3=O)C=C1 Chemical compound CCC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(Cl)=CC=C4)CC2)C3=O)C=C1 UQYLVEUXYOTIMY-UHFFFAOYSA-N 0.000 claims description 3
- WLKGIKFKYITLPH-UHFFFAOYSA-N CCC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(F)=CC=C4)CC2)C3=O)C=C1 Chemical compound CCC1=CC=C(CN(C2=NC=CN2C2=C3CN(CC4=CC(F)=CC=C4)CC2)C3=O)C=C1 WLKGIKFKYITLPH-UHFFFAOYSA-N 0.000 claims description 3
- GFULIOMYYCNNNJ-UHFFFAOYSA-N O=C1N(CC(C=C2)=CC=C2Cl)C2=CC=NN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 Chemical compound O=C1N(CC(C=C2)=CC=C2Cl)C2=CC=NN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 GFULIOMYYCNNNJ-UHFFFAOYSA-N 0.000 claims description 3
- YOOJKTJIOCBHRJ-UHFFFAOYSA-N O=C1N(CC(C=CC(F)=C2)=C2F)C2=NC=CN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 Chemical compound O=C1N(CC(C=CC(F)=C2)=C2F)C2=NC=CN2C2=C1CN(CC1=CC(Cl)=CC=C1)CC2 YOOJKTJIOCBHRJ-UHFFFAOYSA-N 0.000 claims description 3
- WXRFTWJRWZYUOT-UHFFFAOYSA-N O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=COC=C2C2=C1CN(CC1=CC=CC=C1)CC2 Chemical compound O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=COC=C2C2=C1CN(CC1=CC=CC=C1)CC2 WXRFTWJRWZYUOT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 3
- 125000005605 benzo group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims description 2
- LWTIGYSPAXKMDG-UHFFFAOYSA-N 2,3-dihydro-1h-imidazole Chemical compound C1NC=CN1 LWTIGYSPAXKMDG-UHFFFAOYSA-N 0.000 claims description 2
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 2
- 206010057644 Testis cancer Diseases 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 229940127204 compound 29 Drugs 0.000 claims description 2
- 229940125877 compound 31 Drugs 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 125000003564 m-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(C#N)=C1[H])C([H])([H])* 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 201000003120 testicular cancer Diseases 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 206010046766 uterine cancer Diseases 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims 4
- MXZNUGFCDVAXLG-CHWSQXEVSA-N [(2S)-1-[(2R)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@@H](NC(=O)c1ccncc1)C(=O)N1CCC[C@@H]1B(O)O MXZNUGFCDVAXLG-CHWSQXEVSA-N 0.000 claims 3
- 125000000547 substituted alkyl group Chemical group 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims 1
- 239000005018 casein Substances 0.000 abstract description 12
- 102000004317 Lyases Human genes 0.000 abstract description 5
- 108090000856 Lyases Proteins 0.000 abstract description 5
- 235000021240 caseins Nutrition 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000001270 agonistic effect Effects 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 description 176
- 239000002994 raw material Substances 0.000 description 66
- 238000005481 NMR spectroscopy Methods 0.000 description 62
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 53
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 46
- 150000002576 ketones Chemical class 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- CVKOOKPNCVYHNY-UHFFFAOYSA-N 3-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC(C#N)=C1 CVKOOKPNCVYHNY-UHFFFAOYSA-N 0.000 description 18
- LZIYAIRGDHSVED-UHFFFAOYSA-N 1-(bromomethyl)-3-chlorobenzene Chemical compound ClC1=CC=CC(CBr)=C1 LZIYAIRGDHSVED-UHFFFAOYSA-N 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- SCBZBMXPJYMXRC-UHFFFAOYSA-N 1-(bromomethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(CBr)=C1 SCBZBMXPJYMXRC-UHFFFAOYSA-N 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000002390 rotary evaporation Methods 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 10
- FWLWTILKTABGKQ-UHFFFAOYSA-N 1-(bromomethyl)-3-methylbenzene Chemical compound CC1=CC=CC(CBr)=C1 FWLWTILKTABGKQ-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 9
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- IKSNDOVDVVPSMA-UHFFFAOYSA-N 1-(bromomethyl)-4-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=C(CBr)C=C1 IKSNDOVDVVPSMA-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- MLOYGHJCLXLZTL-UHFFFAOYSA-N 1-(bromomethyl)-2-ethylbenzene Chemical compound CCC1=CC=CC=C1CBr MLOYGHJCLXLZTL-UHFFFAOYSA-N 0.000 description 7
- OFVMSTLCDWCSBZ-UHFFFAOYSA-N O=C1N(CC2=CC=CC=C2)C2=NC=CN2C2=C1CNCC2 Chemical compound O=C1N(CC2=CC=CC=C2)C2=NC=CN2C2=C1CNCC2 OFVMSTLCDWCSBZ-UHFFFAOYSA-N 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- LJJRWKBHAGMMSV-UHFFFAOYSA-N O=C1NC2=CN=CN2C2=C1CNCC2 Chemical compound O=C1NC2=CN=CN2C2=C1CNCC2 LJJRWKBHAGMMSV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- FFWQLZFIMNTUCZ-UHFFFAOYSA-N 1-(bromomethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CBr FFWQLZFIMNTUCZ-UHFFFAOYSA-N 0.000 description 5
- WLZRPMPHIFFXCQ-UHFFFAOYSA-N O=C1NC2=CC=NN2C2=C1CNCC2 Chemical compound O=C1NC2=CC=NN2C2=C1CNCC2 WLZRPMPHIFFXCQ-UHFFFAOYSA-N 0.000 description 5
- IUEMQYBFYPYDLH-UHFFFAOYSA-N O=C1NC2=NC=NN2C2=C1CNCC2 Chemical compound O=C1NC2=NC=NN2C2=C1CNCC2 IUEMQYBFYPYDLH-UHFFFAOYSA-N 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PURSZYWBIQIANP-UHFFFAOYSA-N 1-(bromomethyl)-2-chlorobenzene Chemical compound ClC1=CC=CC=C1CBr PURSZYWBIQIANP-UHFFFAOYSA-N 0.000 description 4
- WGVYCXYGPNNUQA-UHFFFAOYSA-N 1-(bromomethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CBr WGVYCXYGPNNUQA-UHFFFAOYSA-N 0.000 description 4
- LZSYGJNFCREHMD-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)benzene Chemical compound BrCC1=CC=CC=C1Br LZSYGJNFCREHMD-UHFFFAOYSA-N 0.000 description 4
- ZPCJPJQUVRIILS-UHFFFAOYSA-N 1-bromo-3-(bromomethyl)benzene Chemical compound BrCC1=CC=CC(Br)=C1 ZPCJPJQUVRIILS-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KDLODFPTKCGQQU-UHFFFAOYSA-N O=C1NC2=CC=CN2C2=C1CNCC2 Chemical compound O=C1NC2=CC=CN2C2=C1CNCC2 KDLODFPTKCGQQU-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000011894 semi-preparative HPLC Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- VLULRUCCHYVXOH-UHFFFAOYSA-N 11-benzyl-7-[(2-methylphenyl)methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one Chemical compound CC1=CC=CC=C1CN1C(=O)C(CN(CC=2C=CC=CC=2)CC2)=C2N2CCN=C21 VLULRUCCHYVXOH-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229940126682 ONC201 Drugs 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- DFULPGUTXZTYKA-UHFFFAOYSA-N 11-benzyl-7-[[4-(trifluoromethyl)phenyl]methyl]-2,5,7,11-tetrazatricyclo[7.4.0.02,6]trideca-1(9),5-dien-8-one Chemical compound C(C1=CC=CC=C1)N1CC=2C(N(C=3N(C=2CC1)CCN=3)CC1=CC=C(C=C1)C(F)(F)F)=O DFULPGUTXZTYKA-UHFFFAOYSA-N 0.000 description 2
- VYEGAEUUQMJXTM-UHFFFAOYSA-N 2-(chloromethyl)-1-methylimidazole Chemical compound CN1C=CN=C1CCl VYEGAEUUQMJXTM-UHFFFAOYSA-N 0.000 description 2
- NJWIMFZLESWFIM-UHFFFAOYSA-N 2-(chloromethyl)pyridine Chemical compound ClCC1=CC=CC=N1 NJWIMFZLESWFIM-UHFFFAOYSA-N 0.000 description 2
- CNQCWYFDIQSALX-UHFFFAOYSA-N 3-(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1 CNQCWYFDIQSALX-UHFFFAOYSA-N 0.000 description 2
- QVAQFEBMXMVWJD-UHFFFAOYSA-N 4-(chloromethyl)-1-methylimidazole Chemical compound CN1C=NC(CCl)=C1 QVAQFEBMXMVWJD-UHFFFAOYSA-N 0.000 description 2
- NIFAUKBQIAURIM-UHFFFAOYSA-N 4-(chloromethyl)-3,5-dimethyl-1,2-oxazole Chemical compound CC1=NOC(C)=C1CCl NIFAUKBQIAURIM-UHFFFAOYSA-N 0.000 description 2
- WZIYCIBURCPKAR-UHFFFAOYSA-N 4-(chloromethyl)pyridine Chemical compound ClCC1=CC=NC=C1 WZIYCIBURCPKAR-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- LMYLEZYGXCVCEY-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)pyridine Chemical compound ClCC1=CC(Cl)=CC=N1 LMYLEZYGXCVCEY-UHFFFAOYSA-N 0.000 description 2
- PECUDCBUFUGTTE-UHFFFAOYSA-N 5-(chloromethyl)-1-methylimidazole Chemical compound CN1C=NC=C1CCl PECUDCBUFUGTTE-UHFFFAOYSA-N 0.000 description 2
- NHRPDSWALNDCIN-UHFFFAOYSA-N 5-(chloromethyl)-2-methyl-1,3-thiazole Chemical compound CC1=NC=C(CCl)S1 NHRPDSWALNDCIN-UHFFFAOYSA-N 0.000 description 2
- KWGLPTTZWGWPID-UHFFFAOYSA-N C1C2=C(C=CC=C2OCO1)CBr Chemical compound C1C2=C(C=CC=C2OCO1)CBr KWGLPTTZWGWPID-UHFFFAOYSA-N 0.000 description 2
- FGMQFFZQFRUHAP-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(N2CC3=CC=CC=C3)=O)=C1C1=C2N=CC=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(N2CC3=CC=CC=C3)=O)=C1C1=C2N=CC=C1)=O FGMQFFZQFRUHAP-UHFFFAOYSA-N 0.000 description 2
- CGVMIHOTPXSBOI-UHFFFAOYSA-N COC1=CC=C(CN(C2=NC=CN2C2=C3CNCC2)C3=O)C=C1 Chemical compound COC1=CC=C(CN(C2=NC=CN2C2=C3CNCC2)C3=O)C=C1 CGVMIHOTPXSBOI-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- DREFGZJCCRFORN-UHFFFAOYSA-N O=C1NC2=NC=CN2C2=C1CNCC2 Chemical compound O=C1NC2=NC=CN2C2=C1CNCC2 DREFGZJCCRFORN-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229940124350 antibacterial drug Drugs 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- FLHFTXCMKFVKRP-UHFFFAOYSA-N bromomethylcyclobutane Chemical compound BrCC1CCC1 FLHFTXCMKFVKRP-UHFFFAOYSA-N 0.000 description 2
- UUWSLBWDFJMSFP-UHFFFAOYSA-N bromomethylcyclohexane Chemical compound BrCC1CCCCC1 UUWSLBWDFJMSFP-UHFFFAOYSA-N 0.000 description 2
- XYZUWOHEILWUID-UHFFFAOYSA-N bromomethylcyclopentane Chemical compound BrCC1CCCC1 XYZUWOHEILWUID-UHFFFAOYSA-N 0.000 description 2
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical compound BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- QDZZDVQGBKTLHV-UHFFFAOYSA-N (2,4-difluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1F QDZZDVQGBKTLHV-UHFFFAOYSA-N 0.000 description 1
- QOWBXWFYRXSBAS-UHFFFAOYSA-N (2,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C(OC)=C1 QOWBXWFYRXSBAS-UHFFFAOYSA-N 0.000 description 1
- CJAAPVQEZPAQNI-UHFFFAOYSA-N (2-methylphenyl)methanamine Chemical compound CC1=CC=CC=C1CN CJAAPVQEZPAQNI-UHFFFAOYSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 1
- DGAGEFUEKIORSQ-UHFFFAOYSA-N (4-ethylphenyl)methanamine Chemical compound CCC1=CC=C(CN)C=C1 DGAGEFUEKIORSQ-UHFFFAOYSA-N 0.000 description 1
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- UKGJZDSUJSPAJL-YPUOHESYSA-N (e)-n-[(1r)-1-[3,5-difluoro-4-(methanesulfonamido)phenyl]ethyl]-3-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]prop-2-enamide Chemical compound CCCC1=NC(C(F)(F)F)=CC=C1\C=C\C(=O)N[C@H](C)C1=CC(F)=C(NS(C)(=O)=O)C(F)=C1 UKGJZDSUJSPAJL-YPUOHESYSA-N 0.000 description 1
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- WAUNFWSVXRPCDQ-UHFFFAOYSA-N 1-(bromomethyl)-2-methoxybenzene Chemical compound COC1=CC=CC=C1CBr WAUNFWSVXRPCDQ-UHFFFAOYSA-N 0.000 description 1
- HNUZAFPGSNEQDM-UHFFFAOYSA-N 1-(bromomethyl)-3-ethylbenzene Chemical compound CCC1=CC=CC(CBr)=C1 HNUZAFPGSNEQDM-UHFFFAOYSA-N 0.000 description 1
- ZKSOJQDNSNJIQW-UHFFFAOYSA-N 1-(bromomethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(CBr)=C1 ZKSOJQDNSNJIQW-UHFFFAOYSA-N 0.000 description 1
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 description 1
- YYPPFEKHXPADAV-UHFFFAOYSA-N 1-(bromomethyl)-4-ethylbenzene Chemical compound CCC1=CC=C(CBr)C=C1 YYPPFEKHXPADAV-UHFFFAOYSA-N 0.000 description 1
- NVNPLEPBDPJYRZ-UHFFFAOYSA-N 1-(bromomethyl)-4-fluorobenzene Chemical compound FC1=CC=C(CBr)C=C1 NVNPLEPBDPJYRZ-UHFFFAOYSA-N 0.000 description 1
- GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 description 1
- WZRKSPFYXUXINF-UHFFFAOYSA-N 1-(bromomethyl)-4-methylbenzene Chemical compound CC1=CC=C(CBr)C=C1 WZRKSPFYXUXINF-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- YLRBJYMANQKEAW-UHFFFAOYSA-N 1-bromo-4-(bromomethyl)benzene Chemical compound BrCC1=CC=C(Br)C=C1 YLRBJYMANQKEAW-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical group C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 description 1
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 description 1
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 1
- FUOFGGBHERKNOF-UHFFFAOYSA-N 2-iodothiophen-3-amine Chemical compound NC=1C=CSC=1I FUOFGGBHERKNOF-UHFFFAOYSA-N 0.000 description 1
- PZZRSEUDGCFXIH-UHFFFAOYSA-N 2-methylsulfanyl-4,5-dihydro-1h-imidazol-1-ium;iodide Chemical compound I.CSC1=NCCN1 PZZRSEUDGCFXIH-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- MYHUFJLABUEBLV-UHFFFAOYSA-N 3-(bromomethyl)-1-methylpyrazole Chemical compound CN1C=CC(CBr)=N1 MYHUFJLABUEBLV-UHFFFAOYSA-N 0.000 description 1
- YGYGASJNJTYNOL-CQSZACIVSA-N 3-[(4r)-2,2-dimethyl-1,1-dioxothian-4-yl]-5-(4-fluorophenyl)-1h-indole-7-carboxamide Chemical compound C1CS(=O)(=O)C(C)(C)C[C@@H]1C1=CNC2=C(C(N)=O)C=C(C=3C=CC(F)=CC=3)C=C12 YGYGASJNJTYNOL-CQSZACIVSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- SRVXSISGYBMIHR-UHFFFAOYSA-N 3-[3-[3-(2-amino-2-oxoethyl)phenyl]-5-chlorophenyl]-3-(5-methyl-1,3-thiazol-2-yl)propanoic acid Chemical compound S1C(C)=CN=C1C(CC(O)=O)C1=CC(Cl)=CC(C=2C=C(CC(N)=O)C=CC=2)=C1 SRVXSISGYBMIHR-UHFFFAOYSA-N 0.000 description 1
- UETNOXJRYZSQRA-UHFFFAOYSA-N 3-chloro-1,4-dimethylpyrazole Chemical compound CC1=CN(C)N=C1Cl UETNOXJRYZSQRA-UHFFFAOYSA-N 0.000 description 1
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 description 1
- UUDNBWSHTUFGDQ-UHFFFAOYSA-N 3-iodopyridin-2-amine Chemical compound NC1=NC=CC=C1I UUDNBWSHTUFGDQ-UHFFFAOYSA-N 0.000 description 1
- CJSOAJZXXHGUAJ-UHFFFAOYSA-N 3-iodothiophen-2-amine Chemical compound NC1=C(I)C=CS1 CJSOAJZXXHGUAJ-UHFFFAOYSA-N 0.000 description 1
- VJPPLCNBDLZIFG-ZDUSSCGKSA-N 4-[(3S)-3-(but-2-ynoylamino)piperidin-1-yl]-5-fluoro-2,3-dimethyl-1H-indole-7-carboxamide Chemical compound C(C#CC)(=O)N[C@@H]1CN(CCC1)C1=C2C(=C(NC2=C(C=C1F)C(=O)N)C)C VJPPLCNBDLZIFG-ZDUSSCGKSA-N 0.000 description 1
- YFCIFWOJYYFDQP-PTWZRHHISA-N 4-[3-amino-6-[(1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl]pyrazin-2-yl]-N-[(1S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl]-2-fluorobenzamide Chemical compound CNC[C@@H](NC(=O)c1ccc(cc1F)-c1nc(cnc1N)[C@H]1CC[C@H](O)[C@@H](F)C1)c1cc(F)cc(Br)c1 YFCIFWOJYYFDQP-PTWZRHHISA-N 0.000 description 1
- XYWIPYBIIRTJMM-IBGZPJMESA-N 4-[[(2S)-2-[4-[5-chloro-2-[4-(trifluoromethyl)triazol-1-yl]phenyl]-5-methoxy-2-oxopyridin-1-yl]butanoyl]amino]-2-fluorobenzamide Chemical compound CC[C@H](N1C=C(OC)C(=CC1=O)C1=C(C=CC(Cl)=C1)N1C=C(N=N1)C(F)(F)F)C(=O)NC1=CC(F)=C(C=C1)C(N)=O XYWIPYBIIRTJMM-IBGZPJMESA-N 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- BMUILTGPMHTSJE-UHFFFAOYSA-N 4-iodothiophen-3-amine Chemical compound Nc1cscc1I BMUILTGPMHTSJE-UHFFFAOYSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- RTMUJHJFHWWSOE-UHFFFAOYSA-N 5-(bromomethyl)-1,3-dimethylpyrazole Chemical compound CC=1C=C(CBr)N(C)N=1 RTMUJHJFHWWSOE-UHFFFAOYSA-N 0.000 description 1
- BTLMVZUBDGLVNM-UHFFFAOYSA-N 5-(bromomethyl)-1-methylpyrazole Chemical compound CN1N=CC=C1CBr BTLMVZUBDGLVNM-UHFFFAOYSA-N 0.000 description 1
- SGEZKPNUNBVVLB-UHFFFAOYSA-N 5-(chloromethyl)-1,3-dimethylpyrazole Chemical compound CC=1C=C(CCl)N(C)N=1 SGEZKPNUNBVVLB-UHFFFAOYSA-N 0.000 description 1
- DMALVWVARIVUJD-UHFFFAOYSA-N 5-(chloromethyl)-1-methylpyrazole Chemical compound CN1N=CC=C1CCl DMALVWVARIVUJD-UHFFFAOYSA-N 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- HTBFTDHEWCRQPJ-UHFFFAOYSA-N 5-iodopyrimidin-4-amine Chemical compound NC1=NC=NC=C1I HTBFTDHEWCRQPJ-UHFFFAOYSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- DQYOHFCVPNOXQQ-UHFFFAOYSA-N 6-(bromomethyl)-2,3-dihydro-1,4-benzodioxine Chemical compound O1CCOC2=CC(CBr)=CC=C21 DQYOHFCVPNOXQQ-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- ZRPZPNYZFSJUPA-UHFFFAOYSA-N ARS-1620 Chemical compound Oc1cccc(F)c1-c1c(Cl)cc2c(ncnc2c1F)N1CCN(CC1)C(=O)C=C ZRPZPNYZFSJUPA-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- IDQXINOTWVRMGF-UHFFFAOYSA-N C=1(C(=COC=1)I)N Chemical compound C=1(C(=COC=1)I)N IDQXINOTWVRMGF-UHFFFAOYSA-N 0.000 description 1
- BYPDSJHPDJJQFP-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(N2CC3CC3)=O)=C1C1=C2N=CC=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(N2CC3CC3)=O)=C1C1=C2N=CC=C1)=O BYPDSJHPDJJQFP-UHFFFAOYSA-N 0.000 description 1
- MUSQJPRRYWHRHZ-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(N2CC3CCC3)=O)=C1C1=C2N=CC=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(N2CC3CCC3)=O)=C1C1=C2N=CC=C1)=O MUSQJPRRYWHRHZ-UHFFFAOYSA-N 0.000 description 1
- VBVFKYCTIDEEJR-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(N2CC3CCCC3)=O)=C1C1=C2N=CC=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(N2CC3CCCC3)=O)=C1C1=C2N=CC=C1)=O VBVFKYCTIDEEJR-UHFFFAOYSA-N 0.000 description 1
- NATUCBBVJWVMAR-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CC(C(N2CC3CCCCC3)=O)=C1C1=C2N=CC=C1)=O Chemical compound CC(C)(C)OC(N(CC1)CC(C(N2CC3CCCCC3)=O)=C1C1=C2N=CC=C1)=O NATUCBBVJWVMAR-UHFFFAOYSA-N 0.000 description 1
- NCJPDYUZNSOYCJ-UHFFFAOYSA-N CC1=C(CN(C2=NC=CN2C2=C3CNCC2)C3=O)C=CC=C1 Chemical compound CC1=C(CN(C2=NC=CN2C2=C3CNCC2)C3=O)C=CC=C1 NCJPDYUZNSOYCJ-UHFFFAOYSA-N 0.000 description 1
- HMHYEUOQNCCGJZ-UHFFFAOYSA-N CC1=CC=C(CN(C2=NC=CN2C2=C3CNCC2)C3=O)C=C1 Chemical compound CC1=CC=C(CN(C2=NC=CN2C2=C3CNCC2)C3=O)C=C1 HMHYEUOQNCCGJZ-UHFFFAOYSA-N 0.000 description 1
- VTWWGGSMCKBNKG-UHFFFAOYSA-N CCC1=CC=C(CN(C2=NC=CN2C2=C3CNCC2)C3=O)C=C1 Chemical compound CCC1=CC=C(CN(C2=NC=CN2C2=C3CNCC2)C3=O)C=C1 VTWWGGSMCKBNKG-UHFFFAOYSA-N 0.000 description 1
- GISRWBROCYNDME-PELMWDNLSA-N F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C Chemical compound F[C@H]1[C@H]([C@H](NC1=O)COC1=NC=CC2=CC(=C(C=C12)OC)C(=O)N)C GISRWBROCYNDME-PELMWDNLSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000006404 Mitochondrial Proteins Human genes 0.000 description 1
- 108010058682 Mitochondrial Proteins Proteins 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- BLRCWPPRYILWOC-UHFFFAOYSA-N N1C(=O)C=CN2N=NC=C21 Chemical compound N1C(=O)C=CN2N=NC=C21 BLRCWPPRYILWOC-UHFFFAOYSA-N 0.000 description 1
- QVGFLDUQBZWNOV-UHFFFAOYSA-N NC(N=CS1)=C1I Chemical compound NC(N=CS1)=C1I QVGFLDUQBZWNOV-UHFFFAOYSA-N 0.000 description 1
- YXHDLDPHYWGNST-UHFFFAOYSA-N O=C1N(CC(C=C2)=CC=C2Cl)C2=NC=CN2C2=C1CNCC2 Chemical compound O=C1N(CC(C=C2)=CC=C2Cl)C2=NC=CN2C2=C1CNCC2 YXHDLDPHYWGNST-UHFFFAOYSA-N 0.000 description 1
- GNGKHCCDQRXEFK-UHFFFAOYSA-N O=C1N(CC(C=C2)=CC=C2F)C2=NC=CN2C2=C1CNCC2 Chemical compound O=C1N(CC(C=C2)=CC=C2F)C2=NC=CN2C2=C1CNCC2 GNGKHCCDQRXEFK-UHFFFAOYSA-N 0.000 description 1
- NCPDAAZHNFMIQV-UHFFFAOYSA-N O=C1N(CC(C=CC(F)=C2)=C2F)C2=NC=CN2C2=C1CNCC2 Chemical compound O=C1N(CC(C=CC(F)=C2)=C2F)C2=NC=CN2C2=C1CNCC2 NCPDAAZHNFMIQV-UHFFFAOYSA-N 0.000 description 1
- YAIRFQXBVZONIT-UHFFFAOYSA-N O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=CN2C2=C1CNCC2 Chemical compound O=C1N(CC2=CC=C(C(F)(F)F)C=C2)C2=NC=CN2C2=C1CNCC2 YAIRFQXBVZONIT-UHFFFAOYSA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- LZMJNVRJMFMYQS-UHFFFAOYSA-N poseltinib Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC(OC=2C=C(NC(=O)C=C)C=CC=2)=C(OC=C2)C2=N1 LZMJNVRJMFMYQS-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000007111 proteostasis Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000035806 respiratory chain Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000008684 selective degradation Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Definitions
- the invention belongs to medicinal chemistry technology, in particular to a class of compounds containing a tetrahydronalidone or tetrahydropyridopyrimidone skeleton, a preparation method and a pharmaceutical use thereof.
- Casein lyase P is an oligomeric serine protease widely present in eukaryotic and prokaryotic cells.
- ClpP is a major protease in bacteria. About 80% of the protein in bacteria is degraded by ClpP, and its function has a key impact on the infection ability of bacteria. Therefore, the early research on ClpP mainly focused on antibacterial drug research, ClpP It is an important target for the development of antibacterial drugs against drug-resistant bacterial infections.
- ClpP mainly exists in the mitochondrial matrix, which can participate in the degradation of damaged or misfolded proteins in the mitochondrial matrix, and plays a key role in the maintenance of mitochondrial protein homeostasis.
- ClpP is a unique target of anti-tumor drugs. Activating ClpP can promote the selective degradation of ClpP substrates including a variety of respiratory chain proteins, thereby affecting the intracellular oxidative phosphorylation process and leading to Malignant tumor cell death. ClpP has been reported to be overexpressed in a variety of cancers, including acute myeloid leukemia, breast cancer, lung cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, uterine cancer, gastric cancer, testicular cancer, and thyroid cancer (Nat.Rev.
- ADEP41 can effectively induce the apoptosis of various cancer cell lines such as HeLa cervical cancer cells, U2OS osteosarcoma cells and SH-SY5Y undifferentiated neuroblastoma cells (Cell Chem. Biol. 2018, 25, 1017-1030.).
- ClpP agonist ONC201 can cause tumor regression in multiple xenograft solid tumor models such as colon cancer, breast cancer, and brain tumors (Oncotarget 2016, 7, 74380-74392.).
- the purpose of the present invention is to provide a new ClpP agonist, which is a compound containing tetralone or tetrahydropyridopyrimidinone skeleton, which has significant agonism to casein lyase P (ClpP) effect.
- X is a carbon atom or a nitrogen atom
- ring A is a substituted or unsubstituted aromatic ring, a substituted or unsubstituted aromatic heterocyclic ring;
- R is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, 2 -fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2 -Methylbenzyl, 2-ethylbenzyl, 2-methoxybenzyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3-methylbenzyl, 3-ethyl Benzyl, 3-methoxybenzyl, 3-cyanobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-methylbenzyl, 4-ethylbenzyl, 4-methoxybenzyl, 4-trifluoromethylbenzyl, (1-methyl-1H-pyrazol-3-yl)methyl, (1-methyl-1H-pyrazol-5-yl) Methyl, (1,3-dimethyl-1
- R is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, 2 -fluorobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 2 -Methylbenzyl, 2-ethylbenzyl, 2-methoxybenzyl, 3-fluorobenzyl, 3-chlorobenzyl, 3-bromobenzyl, 3-methylbenzyl, 3-ethyl Benzyl, 3-methoxybenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-methylbenzyl, 4-ethylbenzyl, 4-methoxybenzyl , 4-nitrobenzyl, 4-methylaminobenzyl, 4-dimethylaminobenzyl, 4-trifluoromethylbenzyl, 2,4-difluorobenzyl, 2-fluoro-4-chlorobenzyl, 2-
- X is a carbon atom or a nitrogen atom
- Ring A is a benzene ring, pyridine ring, pyrimidine ring, imidazole ring, thiophene ring, furan ring, thiazole ring, triazole ring, pyrazole ring or pyrrole ring;
- L and M are methylene and substituted methylene respectively, and one or two hydrogens in methylene can be replaced by C1 ⁇ C6 alkyl or cycloalkyl;
- X and Y are C1-C10 alkyl or branched chain alkyl, C3-C10 cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, aromatic heterocycle or substituted aromatic heterocycle;
- the substituents in the group are halogen, alkoxy, trifluoromethyl, C1-C6 alkyl or cycloalkyl.
- Step a is to react compound 1 with di-tert-butyl dicarbonate to obtain compound 2 after hydrogenation of compound 1 to debenzyl group;
- Step b is to prepare compound 3 by reacting compound 2 with trifluoromethanesulfonic anhydride
- Step c is to prepare compound 4 by reacting compound 3 with biboronic acid pinacol ester;
- Step d is compound 5 obtained from compound 4 and iodine and amino disubstituted pyridine, benzene or pyrimidine;
- Step e is to prepare compound 6 by reacting compound 5 with different halogenated hydrocarbons
- Step f is to remove the protection of tert-butoxycarbonyl from compound 6 with trifluoroacetic acid to obtain compound 7;
- Step g is to react compound 7 with different halogenated hydrocarbons to prepare compounds (I-1 to I-100) represented by general formula II;
- Compound 4 reacts with other heterocyclic arylamines substituted by o-iodine or o-bromine according to the above-mentioned method to synthesize compounds whose ring A in general formula I is other aromatic heterocycles, including furan, thiophene, thiazole, etc. (I-101 to I-105 ).
- Step a is to prepare compound 9 by reacting compound 8 with different amines
- Step b is to prepare compound 10 by reacting compound 2 and compound 9;
- Step c is to epoxidize the dihydroimidazole in compound 10 to an imidazole ring to obtain compound 11;
- step d compound 12 is obtained by removing the tert-butoxycarbonyl protection of compound 11 with trifluoroacetic acid;
- Step e is to prepare compounds I-106 to I-141 represented by general formula III by reacting compound 12 with different halogenated hydrocarbons.
- Ring A in the general formula I is an imidazole ring, a triazole ring, a pyrazole ring or a pyrrole ring in the general formula IV, and X, Y, and Z are respectively nitrogen atoms or methine groups
- Step a is the condensation of compound 13 and compound 14 to synthesize compound 15; when the five-membered ring of compound 14 contains multiple nitrogen atoms, the Boc protecting group can be on different nitrogen atoms;
- Step b is to remove the Boc protecting group of compound 15 and carry out intramolecular aryl nucleophilic substitution reaction cyclization under basic conditions to obtain compound 16;
- Step c is to hydrogenate and reduce the pyridine ring in compound 16 to obtain compound 17;
- Step d is the reductive amination of the amino group in compound 17 and different aromatic aldehydes to synthesize compound 18;
- Step e is to synthesize compounds I-106 to I-162 represented by general formula IV through nucleophilic substitution reaction between compound 18 and different halogenated hydrocarbons.
- Ring A in the general formula I is an imidazole ring, a triazole ring or a pyrazole ring in the general formula IV, and X, Y, and Z are respectively nitrogen atoms or methine groups
- the synthetic route can also be:
- Step a is the condensation of compound 13 and compound 19 to prepare compound 20;
- Step b is to synthesize compound 22 by nucleophilic substitution reaction of aromatic ring between compound 20 and compound 21 under basic conditions;
- Step c is to synthesize compound 23 by intramolecular coupling and cyclization of compound 22 under the catalysis of cuprous salt;
- Step d is the reduction of pyridine in compound 23 to synthesize compound 24 under catalytic hydrogenation
- Step e is to synthesize compound 25 through a nucleophilic substitution reaction between compound 24 and a halogenated hydrocarbon;
- Step f is to remove 2,4-dimethoxybenzyl from compound 25 under acidic conditions to obtain compound 26;
- Step g is to carry out nucleophilic substitution reaction between compound 26 and halogenated hydrocarbon to synthesize a compound represented by general formula IV.
- R in the general formula IV does not contain a group that can be reduced by hydrogenation
- the synthetic route can also be:
- Step a is the condensation of compound 13 and compound 29 to prepare compound 30;
- Step b is to synthesize compound 31 by nucleophilic substitution reaction of aromatic ring between compound 30 and compound 21 under basic conditions;
- Step c is to synthesize compound 32 by intramolecular coupling and cyclization of compound 22 under the catalysis of cuprous salt;
- Step d is the reduction of pyridine in compound 32 to synthesize compound 33 under catalytic hydrogenation
- Step e is to synthesize the compound represented by general formula IV by nucleophilic substitution reaction between compound 33 and halogenated hydrocarbon.
- a pharmaceutical composition of the present invention comprises the above compound or a pharmaceutically acceptable salt thereof.
- 6-benzyl-5-oxo-1,4,5,6-tetrahydropyrido[3,4-C][1,8]naphthyridine-3(2H)-carboxylic acid tert Butyl ester (6-A-1) (500mg, 1.28mmol) was dissolved in 3mL of dichloromethane, added 6mL of trifluoroacetic acid, stirred at room temperature for 1h, TLC monitoring showed that the reaction was complete, and the solvent was removed by rotary evaporation under reduced pressure.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-2, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- 7.41–7.28 m, 5H
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-3, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-5, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- 7.41–7.23 m, 5H
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-6, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-7, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-8, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-9, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- 7.41–7.25 m, 5H
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-10, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-11, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-12, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-13, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-14, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-15, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-16, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-17, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-18, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-19, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-20, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-21, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-22, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-23, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-25, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-26, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-27, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-28, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-29, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-30, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-31, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-32, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-33, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-34, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-35, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-36, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-24, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-18, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-fluorobenzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- 7.52–7.45 m, 2H
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-18, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-chlorobenzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- 7.52–7.46 m, 2H
- 7.39 s,1H
- 7.19(dd,J 7.9,4.7Hz,1H)
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-18, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-bromobenzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-19, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-fluorobenzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- 7.44–7.39 m, 2H
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-19, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-chlorobenzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- 7.44–7.38 m, 3H
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-19, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-bromobenzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- 7.54 s, 1H
- 7.43–7.36 m,3H
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-20, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-chlorobenzyl bromide.
- 1 H NMR 300MHz, Chloroform-d
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-20, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-bromobenzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-B-1, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-C-1, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58, remove the Boc protecting group in compound 6-A-24, then refer to the synthesis method of compound I-1 in Example 59, and prepare by reacting the obtained amine with 3-cyanobenzyl bromide .
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-18, then refer to the synthesis method of compound I-1 in Example 59, and prepare by reacting the obtained amine with 3-cyanobenzyl bromide .
- Example 58 First refer to the method in Example 58, remove the Boc protecting group in compound 6-A-19, then refer to the synthesis method of compound I-1 in Example 59, and prepare by reacting the obtained amine with 3-cyanobenzyl bromide .
- Example 58 First refer to the method in Example 58, remove the Boc protecting group in compound 6-A-20, then refer to the synthesis method of compound I-1 in Example 59, and prepare by reacting the obtained amine with 3-cyanobenzyl bromide .
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-23, then refer to the synthesis method of compound I-1 in Example 59, and prepare by reacting the obtained amine with 3-cyanobenzyl bromide .
- Example 58 First refer to the method in Example 58, remove the Boc protecting group in compound 6-A-37, then refer to the synthesis method of compound I-1 in Example 59, and prepare by reacting the obtained amine with 3-cyanobenzyl bromide .
- Example 58 remove the Boc protecting group in compound 6-A-21, then refer to the synthesis method of compound I-1 in Example 59, and prepare by reacting the obtained amine with 3-cyanobenzyl bromide .
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-21, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-chlorobenzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-21, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-fluorobenzyl bromide.
- Example 58 First refer to the method in Example 58, remove the Boc protecting group in compound 6-A-22, then refer to the synthesis method of compound I-1 in Example 59, and prepare by reacting the obtained amine with 3-cyanobenzyl bromide .
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-22, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-fluorobenzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-22, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-chlorobenzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-38, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-chlorobenzyl bromide.
- Example 58 First refer to the method in Example 58, remove the Boc protecting group in compound 6-A-39, then refer to the synthesis method of compound I-1 in Example 59, and prepare by reacting the obtained amine with 3-cyanobenzyl bromide .
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-23, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-fluorobenzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-A-23, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with 3-chlorobenzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-D, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-E, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-F, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-G, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- Example 58 First refer to the method in Example 58 to remove the Boc protecting group in compound 6-H, and then refer to the synthesis method of compound I-1 in Example 59 to prepare by reacting the obtained amine with benzyl bromide.
- the compound 9-1 obtained in the previous step reaction was dissolved in 10 mL of methanol, and 0.54 g of ethyl 1-N-tert-butoxycarbonyl-4-piperidone-3-carboxylate (compound 2, 2 mmol) was added to the above solution and 0.16 g of sodium methylate (3 mmol), the reaction solution was heated to reflux for 2 hours, and the solvent was evaporated after TLC detected that the reaction was complete, 10 mL of water was added to the residue, the pH value was adjusted to 7 with 1N hydrochloric acid, and extracted with ethyl acetate (15mL*3), the organic phases were combined and dried with anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography to obtain 0.44 grams of compound 10-1. The yield of the two-step reaction was 56% in total, MS (ESI) m/ z:397.2[M+H] + .
- Compound I-126 was prepared by reacting compound 12-4 with 3-cyanobenzyl bromide in the same manner as compound I-106 in Example 172, MS (ESI) m/z: 432.2[M+H] + .
Abstract
一类式(I)所示含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物及其制备方法,通过实验验证,所述含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物对酪蛋白裂解酶P(ClpP)有显著的激动作用,可应用于多种癌症的治疗。
Description
本发明属于药物化学技术,特别是涉及一类含有四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物及其制备方法与制药用途。
酪蛋白裂解酶P(ClpP)是一种广泛存在于真核细胞和原核细胞中的寡聚丝氨酸蛋白酶。ClpP是细菌中一种主要的蛋白酶,在细菌中大约80%的蛋白质是由ClpP降解,而且其功能对细菌的感染能力具有关键影响,因此,早期关于ClpP的研究主要集中于抗菌药物研究,ClpP是开发针对耐药性细菌感染的抗菌药物的重要靶点。人体细胞中,ClpP主要存在于线粒体基质,能够参与降解线粒体基质中受损或错误折叠的蛋白质,对线粒体蛋白质稳态的维持起着关键的作用。近年来的研究发现,ClpP是一个独特的抗肿瘤药物的作用靶点,激活ClpP可以促使包括多种呼吸链蛋白质在内的ClpP底物选择性降解,从而影响细胞内的氧化磷酸化过程并导致恶性肿瘤细胞死亡。ClpP已被报道在多种癌症,包括急性髓系白血病、乳腺癌、肺癌、肝癌、卵巢癌、膀胱癌、***癌、子宫癌、胃癌、睾丸癌、甲状腺癌等中过度表达(Nat.Rev.Mol.Cell Biol.2018,19,109-120.;Biochem.Biophys.Res.Commun.2017,491,85-90.;PeerJ 2020,8,e8754.),而且ClpP激动剂已被报道对其中多种肿瘤细胞的生长有抑制作用并诱导肿瘤细胞凋亡,如ADEP41能够有效诱导多种癌细胞系如HeLa***细胞、U2OS骨肉瘤细胞和SH-SY5Y未分化神经母细胞瘤细胞等的凋亡(Cell Chem.Biol.2018,25,1017-1030.)。另外ClpP激动剂ONC201在结肠癌、乳腺癌和脑瘤等多个异种移植实体瘤模型中可以引起肿瘤的消退(Oncotarget 2016,7,74380-74392.)。
发明内容
发明目的:本发明目的旨在提供一种新的ClpP激动剂,为含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物,该化合物对酪蛋白裂解酶P(ClpP)有显著的激动作用。
技术方案:本发明所述的一种式I所示的化合物或其药学上可接受的盐,
优选的,X为碳原子或氮原子;环A为取代或非取代的芳环、取代或非取代的芳杂环;
优选的,R
1选自环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、苄基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-乙基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-乙基苄基、3-甲氧基苄基、3-腈基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-乙基苄基、4-甲氧基苄基、4-三氟甲基苄基、(1-甲基-1H-吡唑-3-基)甲基、(1-甲基-1H-吡唑-5-基)甲基、(1,3-二甲基-1H-吡唑-5-基)甲基、吡啶-2-基甲基、吡啶-3-基甲基、吡啶-4-基甲基、(4-氯吡啶-2-基)甲基、(1-甲基-1H-咪唑-2-基)甲基、(1-甲基-1H-咪唑-4-基)甲基、(1-甲基-1H-咪唑-5-基)甲基、(3,5-二甲基异噁唑-4-基)甲基、(2-甲基噻唑-5-基)甲基、苯并[1,3]二氧五环-4基甲基等。
优选的,R
2选自环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、苄基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-乙基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-乙基苄基、3-甲氧基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-乙基苄基、4-甲氧基苄基、4-硝基苄基、4-甲氨基苄基、4-二甲氨基苄基、4-三氟甲基苄基、2,4-二氟苄基、2-氟-4-氯苄基、2-氟-4-甲基苄基2-氟-4-甲氧基苄基、2-氟-4-三氟甲基苄基、2-氟-4-溴苄基、(1-甲基-1H-吡唑-3-基)甲基、(1-甲基-1H-吡唑-5-基)甲基、(1,3-二甲基-1H-吡唑-5-基)甲基、吡啶-2-基甲基、吡啶-3-基甲基、吡啶-4-基甲基、(4-氯吡啶-2-基)甲基、(1-甲基-1H-咪唑-2-基)甲基、(1-甲基-1H-咪唑-4-基)甲基、(1-甲基-1H-咪唑-5-基)甲基、(3,5-二甲基异噁唑-4-基)甲基、(2-甲基噻唑-5-基)甲基、苯并[1,3]二氧五环-4基甲基、苯并[1,3]二氧五环-5基甲基、苯并[1,4]二氧六环-5基甲基、苯并[1,4]二氧六环-6基甲基等。
作为一种优选的技术方案,本发明化合物如下式所示:
其中:X为碳原子或氮原子;环A为苯环、吡啶环、嘧啶环、咪唑环、噻吩环、呋喃环、噻唑环、三氮唑环、吡唑环或吡咯环;
L和M分别为亚甲基及取代的亚甲基,亚甲基中一个或两个氢可以被C1~C6烷基或环烷基取代;
X和Y分别为C1-C10的烷基或支链烷基、C3-C10的环烷基或取代的环烷基、芳基或取代的芳基、芳杂环或取代的芳杂环;上述基团中的取代基为卤素、烷氧基、三氟甲基、C1-C6的烷基或环烷基。
进一步的,本发明优选的式I化合物如下:
6-苄基-3-(环丙基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-1);
6-苄基-3-(环丁基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-2);
6-苄基-3-(环戊基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-3);
6-苄基-3-(环己基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-4);
3,6-二苄基-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-5);
6-苄基-3-(2-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-6);
6-苄基-3-(2-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-7);
6-苄基-3-(2-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-8);
6-苄基-3-(2-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-9);
6-苄基-3-(2-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-10);
6-苄基-3-(2-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-11);
6-苄基-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-12);
6-苄基-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-13);
6-苄基-3-(3-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-14);
6-苄基-3-(3-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-15);
6-苄基-3-(3-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-16);
6-苄基-3-(3-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-17);
6-苄基-3-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-18);
6-苄基-3-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-19);
6-苄基-3-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-20);
6-苄基-3-(4-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-21);
6-苄基-3-(4-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-22);
6-苄基-3-(4-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-23);
6-苄基-3-((1-甲基-1H-吡唑-3-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-24);
6-苄基-3-((1-甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-25);
6-苄基-3-((1,3-二甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-26);
6-苄基-3-(吡啶-2-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-27);
6-苄基-3-(吡啶-3-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-28);
6-苄基-3-(吡啶-4-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-29);
6-苄基-3-((4-氯吡啶-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-30);
6-苄基-3-((1-甲基-1H-咪唑-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-31);
6-苄基-3-((1-甲基-1H-咪唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-32);
6-苄基-3-((1-甲基-1H-咪唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-33);
6-苄基-3-((3,5-二甲基异噁唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-34);
6-苄基-3-((2-甲基噻唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-35);
3-苄基-6-(环丙基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-36);
3-苄基-6-(环丁基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-37);
3-苄基-6-(环戊基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-38);
3-苄基-6-(环己基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-39);
3-苄基-6-(2-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-40);
3-苄基-6-(2-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-41);
3-苄基-6-(2-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-42);
3-苄基-6-(2-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-43);
3-苄基-6-(2-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-44);
3-苄基-6-(2-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-45);
3-苄基-6-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-46);
3-苄基-6-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-47);
3-苄基-6-(3-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-48);
3-苄基-6-(3-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-49);
3-苄基-6-(3-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-50);
3-苄基-6-(3-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-51);
3-苄基-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-52);
3-苄基-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-53);
3-苄基-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-54);
3-苄基-6-(4-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-55);
3-苄基-6-(4-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-56);
3-苄基-6-(4-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-57);
3-苄基-6-((1-甲基-1H-吡唑-3-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-58);
3-苄基-6-((1-甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-59);
3-苄基-6-((1,3-二甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-60);
3-苄基-6-(吡啶-2-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-61);
3-苄基-6-(吡啶-3-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-62);
3-苄基-6-(吡啶-4-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-63);
3-苄基-6-((4-氯吡啶-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-64);
3-苄基-6-((1-甲基-1H-咪唑-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-65);
3-苄基-6-((1-甲基-1H-咪唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-66);
3-苄基-6-((1-甲基-1H-咪唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-67);
3-苄基-6-((3,5-二甲基异噁唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-68);
3-苄基-6-((2-甲基噻唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-69);
3-苄基-6-(4-(三氟甲基)苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-70);
3-(3-氟苄基)-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-71);
3-(3-氯苄基)-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-72);
3-(3-溴苄基)-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-73);
3-(3-氟苄基)-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-74);
3-(3-氯苄基)-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-75);
3-(3-溴苄基)-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-76);
3-(3-氟苄基)-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-77);
3-(3-氯苄基)-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-78);
3-(3-溴苄基)-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-79);
3-苄基-6-(4-(三氟甲基)苄基)-2,3,4,6-四氢苯并[c][2,7]萘啶-5-(1H)-酮(I-80);
8-苄基-5-(4-(三氟甲基)苄基)-7,8,9,10-四氢嘧啶基[4,5-c][2,7]萘啶-6-(5H)-酮(I-81);
6-苄基-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-82);
6-(4-三氟甲基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-83);
6-(4-氟苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-84);
6-(4-氯苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-85);
6-(4-溴苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-86);
6-(4-甲氧基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-87);
6-(4-硝基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-88);
6-(4-甲胺基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-89);
6-(4-二甲胺基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-90);
6-(4-甲基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-91);
6-(4-甲基苄基)-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-92);
6-(4-甲基苄基)-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-93);
6-(4-乙基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-94);
6-(4-乙基苄基)-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-95);
6-(4-乙基苄基)-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-96);
3-(3-氯苄基)-6-((2,3-二氢[1,4]苯并二噁英-6-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5(1H)-酮(I-97);
6-([1,3]苯并二氧五环-5-基甲基基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-98);
6-(4-甲氧基苄基)-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-99);
6-(4-甲氧基苄基)-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-100);
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢呋喃并[3,4-C][2,7]萘啶5(4H)-酮(I-101);
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻吩并[3,4-C][2,7]萘啶5(4H)-酮(I-102);
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻吩并[3,2-C][2,7]萘啶5(4H)-酮(I-103);
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻吩并[2,3-C][2,7]萘啶5(4H)-酮(I-104);
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻唑并[4,5-C][2,7]萘啶5(4H)-酮(I-105);
7-苄基-4-(2-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4)-酮(I-106);
4,7-二苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-107);
7-(3-氟苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-108);
7-(3-氯苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-109);
7-(3-甲基苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-110);
7-(3-腈基苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-111);
7-苄基-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-112);
7-(3-氟苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-113);
7-(3-氯苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-114);
7-(3-甲基苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-115);
7-(3-腈基苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-116);
7-苄基-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-117);
7-(3-氟苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-118);
7-(3-氯苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-119);
7-(3-甲基苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-120);
7-(3-腈基苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-121);
7-苄基-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-122);
7-(3-氟苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-123);
7-(3-氯苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-124);
7-(3-甲基苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-125);
7-(3-腈基苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-126);
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-127);
7-(3-氟苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-128);
7-(3-氯苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-129);
7-(3-甲基苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-130);
7-(3-腈基苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-131);
7-苄基-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-132);
7-(3-氟苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-133);
7-(3-氯苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-134);
7-(3-甲基苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-135);
7-(3-腈基苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-136);
7-苄基-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-137);
7-(3-氟苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-138);
7-(3-氯苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-139);
7-(3-甲基苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-140);
7-(3-腈基苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-141);
7-苄基-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-142);
7-(3-氟苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-143);
7-(3-氯苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-144);
7-(3-甲基苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-145);
7-(3-腈基苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-146);
7-(3-氯苄基)-4-([1,3]苯并二氧五环-5-基甲基基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-147);
7-(3-氯苄基)-4-((2,3-二氢[1,4]苯并二噁英-6-基)甲基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-148);
4-(4-三氟甲基苄基)-7-苄基-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-149);
4-(4-三氟甲基苄基)-7-(3-氯苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-150);
4-(4-三氟甲基苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-151);
4-(4-氯苄基)-7-苄基-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-152);
4-(4-氯苄基)-7-(3-氟苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-153);
4-(4-氯苄基)-7-(3-氯苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-154);
4-(4-氯苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-155);
4-苄基-7-(3-氯苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-156);
4-苄基-7-(3-腈基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-157);
4-苄基-7-(3-甲基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-158);
4-(4-三氟甲基苄基)-7-苄基-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-159);
4-(4-三氟甲基苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-160);
4-(4-氯苄基)-7-苄基-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-161);
4-(4-氯苄基)-7-(3-氯苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-162);
4-(4-氯苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-163);
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-164);
7-(3-腈基苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-165);
7-(3-氯苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-166);
7-(3-腈基苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-167);
3-苄基-6-(4-三氟甲基苄基)-1,2,3,4-四氢吡啶并[3,4-e]吡咯并[1,2-a]嘧啶-5(6H)-酮(I-168);
3-(3-氯苄基)-6-(4-氯苄基)-1,2,3,4-四氢吡啶并[3,4-e]吡咯并[1,2-a]嘧啶-5(6H)-酮(I-169)。
上述如式I所示的化合物的制备方法,当环A为通式II所示的结构时,合成路线为:
包括以下步骤:
(1)步骤a为化合物1氢化脱除苄基之后与二碳酸二叔丁酯反应制得化合物2;
(2)步骤b为化合物2与三氟甲磺酸酐反应制得化合物3;
(3)步骤c为化合物3与联硼酸频那醇酯反应制得化合物4;
(4)步骤d为化合物4与碘和氨基双取代的吡啶、苯或嘧啶制得化合物5;
(5)步骤e为化合物5与不同的卤代烃反应制得化合物6;
(6)步骤f为化合物6用三氟乙酸脱除叔丁氧羰基保护制得化合物7;
(7)步骤g为化合物7与不同的卤代烃反应制得通式II代表的化合物(I-1到I-100);
化合物4与邻碘或邻溴取代的其它杂环芳胺按照上述方法进行反应可以合成通式I中环A为其它芳杂环的化合物,包括呋喃、噻吩、噻唑等(I-101至I-105)。
通式I中环A为通式III中的咪唑环时,合成路线为:
包括以下步骤:
(1)步骤a为化合物8与不同的胺反应制得化合物9;
(2)步骤b为化合物2与化合物9反应制得化合物10;
(3)步骤c为将化合物10中的二氢咪唑环氧化成咪唑环制得化合物11;
(4)步骤d为化合物11用三氟乙酸脱除叔丁氧羰基保护制得化合物12;
(5)步骤e为化合物12与不同的卤代烃反应制得通式III代表的化合物I-106至I-141。
通式I中环A为通式IV中的咪唑环、三氮唑环、吡唑环或吡咯环,X、Y、Z分别为氮原子或次甲基
时,合成路线为:
包括以下步骤:
(1)步骤a为化合物13与化合物14缩合合成化合物15;当化合物14的五元环中含多个氮原子时,Boc保护基可以在不同的氮原子上;
(2)步骤b为化合物15脱除Boc保护基后在碱性条件下进行分子内芳基亲核取代反应环化制得化合物16;
(3)步骤c为氢化还原化合物16中的吡啶环制得化合物17;
(4)步骤d为化合物17中的氨基与不同的芳香醛进行还原氨化合成化合物18;
(5)步骤e为化合物18与不同的卤代烃进行亲核取代反应合成通式IV代表的化合物I-106至I-162。通式I中环A为通式IV中的咪唑环、三氮唑环或吡唑环,X、Y、Z分别为氮原子或次甲基
时,合成路线也可以为:
包括以下步骤:
(1)步骤a为化合物13与化合物19缩合制得化合物20;
(2)步骤b为化合物20与化合物21在碱性条件下进行芳环的亲核取代反应合成化合物22;
(3)步骤c为化合物22在亚铜盐催化下进行分子内偶联环化合成化合物23;
(4)步骤d为化合物23中的吡啶在催化氢化下还原合成化合物24;
(5)步骤e为化合物24与卤代烃进行亲核取代反应合成化合物25;
(6)步骤f为化合物25在酸性条件下脱除2,4-二甲氧基苄基制得化合物26;
(7)步骤g为化合物26与卤代烃进行亲核取代反应合成通式IV代表的化合物。
通式IV中的R
2不含可以被氢化还原的基团时,合成路线也可以为:
包括以下步骤:
(1)步骤a为化合物13与化合物29缩合制得化合物30;
(2)步骤b为化合物30与化合物21在碱性条件下进行芳环的亲核取代反应合成化合物31;
(3)步骤c为化合物22在亚铜盐催化下进行分子内偶联环化合成化合物32;
(4)步骤d为化合物32中的吡啶在催化氢化下还原合成化合物33;
(5)步骤e为化合物33与卤代烃进行亲核取代反应合成通式IV代表的化合物。
本发明所述的一种药物组合物,其包括上述化合物或其药学上可接受的盐。
上述式I化合物或其药学上可接受的盐、上述药物组合物在制备ClpP激动剂的应用也在本发明的保护范围内。
上述式I化合物或其药学上可接受的盐、上述药物组合物在制备治疗癌症的药物中的用途也在本发明的保护范围内。其中,所述药物通过激动酪蛋白裂解酶P(ClpP)达到治疗癌症的目的。
有益效果:通过实验验证,本发明含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物对酪蛋白裂解酶P(ClpP)有显著的激动作用,可应用于多种癌症的治疗。
下面通过实施例具体说明本发明的内容。
实施例1
1-N-叔丁氧羰基-4-哌啶酮-3-甲酸乙酯(2)的制备
室温条件下,将1-苄基-4-哌啶酮-3-甲酸乙酯盐酸盐(1)(10g,33.6mmol)溶解于200mL乙醇中,加入钯碳(1.0g,10%w/w),将反应体系置换成氮气氛围,然后再置换成氢气氛围,在1atm条件下氢化反应12小时,TLC监测显示反应完毕,然后加入二碳酸二叔丁酯(8.1g,37.0mmol)和三乙胺(10.3mL,73.9mmol),室温下继续搅拌反应8小时,TLC监测显示反应完毕,用硅藻土滤除钯碳,减压旋蒸除去溶剂,加入200mL水,用二氯甲烷(150mL*3)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸除去溶剂,经硅胶柱层析纯化,得无色油状液体8.6g,收率94%。1H NMR(300MHz,Chloroform-d)δ4.23(q,J=6.8Hz,2H),4.08(s,2H),3.28(t,J=5.8Hz,2H),2.37(t,J=5.8Hz,2H),1.58(s,9H),1.32(t,J=6.8Hz,3H).
实施例2
1-(叔丁基)-3-乙基-4-(((三氟甲基)磺酰基)氧基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯(3)的制备
室温条件下,将1-N-叔丁氧羰基-4-哌啶酮-3-甲酸乙酯2(7.5g,27.7mmol)溶解于150mL二氯甲烷中,在氩气保护下加入N,N-二异丙基乙胺(11.7mL,82.8mmol),将反应体系降温至-78℃,缓慢滴加三氟甲磺酸酐(6.0mL,35.9mmol),搅拌1小时后将反应体系升至0℃,并在该温度下搅拌23小时,TLC监测显示反应完毕,加入100mL饱和碳酸氢钠溶液淬灭反应,水相用二氯甲烷(50mL*3)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸除去溶剂,经硅胶柱层析纯化,得无色油状液体6.5g,收率58%。
1H NMR(300MHz,Chloroform-d)δ4.38–4.24(m,4H),3.63(t,J=5.7Hz,2H),2.57–2.46(m,2H),1.49(s,9H),1.34(t,J=7.1Hz,3H).
实施例3
1-(叔丁基)-3-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯(4)的制备
室温条件下,将1-(叔丁基)-3-乙基-4-(((三氟甲基)磺酰基)氧基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯3(6.5g,16.1mmol)溶解于130mL 1,4-二氧六环中,在氩气保护下加入联硼酸频哪醇酯(4.9g,19.4mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.18g,1.61mmol),2-二环己基膦-2',6'-二甲氧基联苯(661mg,1.61mmol)和乙酸钾(3.16g,32.2mmol),搅拌回流反应过夜,TLC监测显示反应完毕,降至室温,过滤除去固体,减压旋蒸除去溶剂,经硅胶柱层析纯化,得无色油状液体3.6g,收率54%。
1H NMR(300MHz,Chloroform-d)δ4.20–3.98(m,4H),3.36(t,J=5.4Hz,2H),2.28–2.20(m,2H),1.38(s,9H),1.26(s,12H),1.24(t,J=6.5Hz,3H).
实施例4
5-氧代-1,4,5,6-四氢吡啶并[3,4-c][1,8]萘啶-3-(2H)-羧酸叔丁酯(5-A)的制备
室温条件下,将1-(叔丁基)-3-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯(4)(3g,7.87mmol)溶解于48mL 1,4-二氧六环和8mL水的混合溶剂中,加入2-氨基-3-碘吡啶(2.60g,11.8mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(578mg,0.79mmol),2-二环己基膦-2',6'-二甲氧基联苯(324mg,0.79mmol)和碳酸铯(3.84g,11.8mmol),在氩气保护下回流搅拌反应过夜,TLC监测显示反应完毕,降至室温,过滤除去固体,减压旋蒸除去溶剂,经硅胶柱层析纯化,得白色固体1.9g,收率80%。
1H NMR(300MHz,Chloroform-d)δ13.16(s,1H),8.75(d,J=3.6Hz,1H),8.00(d,J=7.7Hz,1H),7.26(dd,J=7.9,4.8Hz,1H),4.51(s,2H),3.78(t,J=5.6Hz,2H),2.93(t,J=5.7Hz,2H),1.52(s,9H).
实施例5
5-氧代-1,4,5,6-苯并[c][2,7]萘啶-3-(2H)-羧酸叔丁酯(5-B)的制备
化合物5-B的合成用1-(叔丁基)-3-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢-1,3(2H)-吡 啶二羧酸酯(4)和2-碘苯胺为原料,参照实例4中化合物5-氧代-1,4,5,6-四氢吡啶并[3,4-c][1,8]萘啶-3-(2H)-羧酸叔丁酯(5-A)的制备方法进行。白色固体,
1H NMR(300MHz,Chloroform-d)δ12.54(s,1H),8.42(d,J=3.6Hz,1H),7.62(d,J=7.7Hz,1H),7.13(dd,J=7.9,4.8Hz,1H),4.46(s,2H),3.82(t,J=5.5Hz,2H),2.91(t,J=5.6Hz,2H),1.52(s,9H).
实施例6
6-氧代-5,7,9,10-四氢嘧啶基[4,5-c][2,7]萘啶-8-(6H)-羧酸叔丁酯(5-C)的制备
化合物5-C的合成用1-(叔丁基)-3-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯(4)和4-氨基-5-碘嘧啶为原料,参照实例4中化合物5-氧代-1,4,5,6-四氢吡啶并[3,4-c][1,8]萘啶-3-(2H)-羧酸叔丁酯(5-A)的合成方法进行。白色固体,
1H NMR(300MHz,Chloroform-d)δ11.27(s,1H),9.13(s,1H),9.00(s,1H),4.52(s,2H),3.79(t,J=5.7Hz,2H),3.00(t,J=5.5Hz,2H),1.51(s,9H).
实施例7
5-氧代-4,5,8,9-四氢呋喃并[3,4-c][2,7]萘啶-7-(6H)-羧酸叔丁酯(5-D)的制备
化合物5-D的合成用1-(叔丁基)-3-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯(4)和3-氨基-4-碘呋喃为原料,参照实例4中化合物5-氧代-1,4,5,6-四氢吡啶并[3,4-c][1,8]萘啶-3-(2H)-羧酸叔丁酯(5-A)的合成方法进行。白色固体,MS(ESI)m/z:291.2[M+H]
+。
实施例8
5-氧代-4,5,8,9-四氢噻吩并[3,4-c][2,7]萘啶-7-(6H)-羧酸叔丁酯(5-E)的制备
化合物5-E的合成用1-(叔丁基)-3-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯(4)和3-氨基-4-碘噻吩为原料,参照实例4中化合物5-氧代-1,4,5,6-四氢吡啶并[3,4-c][1,8]萘啶-3-(2H)-羧酸叔丁酯(5-A)的合成方法进行。白色固体,MS(ESI)m/z:307.2[M+H]
+。
实施例9
5-氧代-4,5,8,9-四氢噻吩并[3,2-c][2,7]萘啶-7-(6H)-羧酸叔丁酯(5-F)的制备
化合物5-F的合成用1-(叔丁基)-3-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯(4)和3-氨基-2-碘噻吩为原料,参照实例4中化合物5-氧代-1,4,5,6-四氢吡啶并[3,4-c][1,8]萘啶-3-(2H)-羧酸叔丁酯(5-A)的合成方法进行。白色固体,MS(ESI)m/z:307.2[M+H]
+。
实施例10
5-氧代-4,5,8,9-四氢噻吩并[2,3-c][2,7]萘啶-7-(6H)-羧酸叔丁酯(5-G)的制备
化合物5-G的合成用1-(叔丁基)-3-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯(4)和2-氨基-3-碘噻吩为原料,参照实例4中化合物5-氧代-1,4,5,6-四氢吡啶并[3,4-c][1,8]萘啶-3-(2H)-羧酸叔丁酯(5-A)的合成方法进行。白色固体,MS(ESI)m/z:307.2[M+H]
+。
实施例11
5-氧代-4,6,8,9-四氢噻唑并[4,5-c][2,7]萘啶-7-(5H)-羧酸叔丁酯(5-H)的制备
化合物5-H的合成用1-(叔丁基)-3-乙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢-1,3(2H)-吡啶二羧酸酯(4)和4-氨基-5-碘噻唑为原料,参照实例4中化合物5-氧代-1,4,5,6-四氢吡啶并[3,4-c][1,8]萘啶-3-(2H) -羧酸叔丁酯(5-A)的合成方法进行。白色固体,MS(ESI)m/z:308.2[M+H]
+。
实施例12
6-苄基-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-1)的制备
室温条件下,将化合物5-A-1(600mg,1.99mmol)溶解于10mL N,N-二甲基甲酰胺中,加入碳酸钾(275mg,3.98mmol),然后滴加苄溴(681mg,3.98mmol),搅拌反应过夜,TLC监测显示反应完毕,加入50mL水,用乙酸乙酯(30mL*3)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸除去溶剂,经硅胶柱层析纯化,得白色固体545mg,收率70%。
1H NMR(300MHz,Chloroform-d)δ8.55(dd,J=4.6,1.7Hz,1H),7.91(dd,J=7.9,1.7Hz,1H),7.48–7.43(m,2H),7.27(d,J=4.3Hz,1H),7.24–7.13(m,3H),5.77(s,2H),3.58(s,2H),2.93(t,J=5.6Hz,2H),2.78(t,J=5.7Hz,2H),1.43(s,9H);MS(ESI)m/z:392.2[M+H]
+。
实施例13
6-环丙基甲基-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-2)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和溴甲基环丙烷为原料制备。MS(ESI)m/z:356.2[M+H]
+。
实施例14
6-环丁基甲基-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-3)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和溴甲基环丁烷为原料制备。MS(ESI)m/z:370.2[M+H]
+。
实施例15
6-环戊基甲基-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-4)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和溴甲基环戊烷为原料制备。MS(ESI)m/z:384.2[M+H]
+。
实施例16
6-环己基甲基-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-5)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和溴甲基环己烷为原料制备。MS(ESI)m/z:398.2[M+H]
+。
实施例17
6-(2-氟苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-6)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-氟苄溴为原料制备。MS(ESI)m/z:410.2[M+H]
+。
实施例18
6-(2-氯苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-7)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-氯苄溴为原料制备。MS(ESI)m/z:426.2[M+H]
+。
实施例19
6-(2-溴苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-8)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-溴苄溴为原料制备。MS(ESI)m/z:471.1[M+H]
+。
实施例20
6-(2-甲基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-9)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-甲基苄溴为原料制备。MS(ESI)m/z:406.2[M+H]
+。
实施例21
6-(2-乙基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-10)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-乙基苄溴为原料制备。MS(ESI)m/z:420.2[M+H]
+。
实施例22
6-(2-甲氧基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-11)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-乙基苄溴为原料制备。MS(ESI)m/z:422.2[M+H]
+。
实施例23
6-(3-氟苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-12)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-氟苄溴为原料制备。MS(ESI)m/z:410.2[M+H]
+。
实施例24
6-(3-氯苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-13)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-氯苄溴为原料制备。MS(ESI)m/z:426.2[M+H]
+。
实施例25
6-(3-溴苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-14)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-溴苄溴为原料制备。MS(ESI)m/z:471.1[M+H]
+。
实施例26
6-(3-甲基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-15)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-甲基苄溴为原料制备。MS(ESI)m/z:406.2[M+H]
+。
实施例27
6-(3-乙基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-16)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-乙基苄溴为原料制备。MS(ESI)m/z:420.2[M+H]
+。
实施例28
6-(3-甲氧基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-17)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-乙基苄溴为原料制备。MS(ESI)m/z:422.2[M+H]
+。
实施例29
6-(4-氟苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-18)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-氟苄溴为原料制备。MS(ESI)m/z:410.2[M+H]
+。
实施例30
6-(4-氯苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-19)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-氯苄溴为原料制备。MS(ESI)m/z:426.2[M+H]
+。
实施例31
6-(4-溴苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-20)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-溴苄溴为原料制备。MS(ESI)m/z:471.1[M+H]
+。
实施例32
6-(4-甲基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-21)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-甲基苄溴为原料制备。MS(ESI)m/z:406.2[M+H]
+。
实施例33
6-(4-乙基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-22)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-乙基苄溴为原料制备。MS(ESI)m/z:420.2[M+H]
+。
实施例34
6-(4-甲氧基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-23)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-乙基苄溴为原料制备。MS(ESI)m/z:422.2[M+H]
+。
实施例35
6-(4-三氟甲基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-24)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和4-三氟甲基苄溴为原料制备。MS(ESI)m/z:460.2[M+H]
+。
实施例36
6-((1-甲基-1H-吡唑-3-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-25)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和3-溴甲基-1-甲基-1H-吡唑为原料制备。MS(ESI)m/z:396.2[M+H]
+。
实施例37
6-((1-甲基-1H-吡唑-5-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-26)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和5-溴甲基-1-甲基-1H-吡唑为原料制备。MS(ESI)m/z:396.2[M+H]
+。
实施例38
6-((1,3-二甲基-1H-吡唑-5-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-27)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和5-溴甲基-1,3-二甲基-1H-吡唑为原料制备。MS(ESI)m/z:410.2[M+H]
+。
实施例39
6-(吡啶-2-基甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-28)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-氯甲基吡啶为原料制备。MS(ESI)m/z:393.2[M+H]
+。
实施例40
6-(吡啶-3-基甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-29)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和3-氯甲基吡啶为原料制备。MS(ESI)m/z:393.2[M+H]
+。
实施例41
6-(吡啶-4-基甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-30)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和4-氯甲基吡啶为原料制备。MS(ESI)m/z:393.2[M+H]
+。
实施例42
6-((4-氯吡啶-2-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-31)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-氯甲基-4-氯吡啶为原料制备。MS(ESI)m/z:427.2[M+H]
+。
实施例43
6-((1-甲基-1H-咪唑-2-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-32)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和2-氯甲基-1-甲基-1H-咪唑为原料制备。MS(ESI)m/z:396.2[M+H]
+。
实施例44
6-((1-甲基-1H-咪唑-4-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-33)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和4-氯甲基-1-甲基-1H-咪唑为原料制备。MS(ESI)m/z:396.2[M+H]
+。
实施例45
6-((1-甲基-1H-咪唑-5-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-34)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和5-氯甲基-1-甲基-1H-咪唑为原料制备。MS(ESI)m/z:396.2[M+H]
+。
实施例46
6-((3,5-二甲基异噁唑-4-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-35)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和4-氯甲基-3,5-二甲基异噁唑为原料制备。MS(ESI)m/z:411.2[M+H]
+。
实施例47
6-((2-甲基噻唑-5-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-36)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和5-氯甲基-2-甲基噻唑为原料制备。MS(ESI)m/z:413.2[M+H]
+。
实施例48
6-(4-硝基苄基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-37)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和4-硝基苄溴为原料制备。MS(ESI)m/z:437.4[M+H]
+。
实施例49
6-((2,3-二氢[1,4]苯并二噁英-6-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-38)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和6-溴甲基-2,3-二氢[1,4]苯并二噁英为原料制备。MS(ESI)m/z:450.4[M+H]
+。
实施例50
6-(苯并[1,3]二氧五环-5-基)甲基)-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-39)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-A和5-溴甲基-苯并[1,3]二氧五环为原料制备。MS(ESI)m/z:436.3[M+H]
+。
实施例51
6-(4-(三氟甲基)苄基)-5-氧代-1,4,5,6-四氢苯并[c][2,7]萘啶-3-(2H)-羧酸叔丁酯(6-B-1)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-B和4-(三氟甲基)苄溴为原料制备。MS(ESI)m/z:459.2[M+H]
+。
实施例52
5-(4-(三氟甲基)苄基)-6-氧代-5,7,9,10-四氢嘧啶并[4,5c][2,7]萘啶-8-(6H)-羧酸叔丁酯(6-C-1)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-C和4-(三氟甲基)苄溴为原料制备。MS(ESI)m/z:461.2[M+H]
+。
实施例53
5-氧代-4-(4-三氟甲基苄基)-4,5,8,9-四氢呋喃并[3,4-c][2,7]萘啶-7-(6H)-羧酸叔丁酯(6-D)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-D和4-(三氟甲基)苄溴为原料制备。MS(ESI)m/z:449.3[M+H]
+。
实施例54
5-氧代-4-(4-三氟甲基苄基)-4,5,8,9-四氢噻吩并[3,4-c][2,7]萘啶-7-(6H)-羧酸叔丁酯(6-E)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-E和4-(三氟甲基)苄溴为原料制备。MS(ESI)m/z:465.3[M+H]
+。
实施例55
5-氧代-4-(4-三氟甲基苄基)-4,5,8,9-四氢噻吩并[3,2-c][2,7]萘啶-7-(6H)-羧酸叔丁酯(6-F)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-F和4-(三氟甲基)苄溴为原料制备。MS(ESI)m/z:465.3[M+H]
+。
实施例56
5-氧代-4-(4-三氟甲基苄基)-4,5,8,9-四氢噻吩并[2,3-c][2,7]萘啶-7-(6H)-羧酸叔丁酯(6-G)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-G和4-(三氟甲基)苄溴为原料制备。MS(ESI)m/z:465.3[M+H]
+。
实施例57
5-氧代-4-(4-三氟甲基苄基)-4,6,8,9-四氢噻唑并[4,5-c][2,7]萘啶-7-(5H)-羧酸叔丁酯(6-H)的制备
参照实例12中化合物6-A-1的制备方法,以化合物5-H和4-(三氟甲基)苄溴为原料制备。MS(ESI)m/z:466.3[M+H]
+。
实施例58
6-苄基-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(7-1)的制备
室温条件下,将6-苄基-5-氧代-1,4,5,6-四氢吡啶并[3,4-C][1,8]萘啶-3(2H)-羧酸叔丁酯(6-A-1)(500mg,1.28mmol)溶解于3mL二氯甲烷中,加入6mL三氟乙酸,室温搅拌反应1h,TLC监测显示反应完毕,减压旋蒸除去溶剂,用碳酸氢钠溶液中和至PH值为8,用二氯甲烷萃取,无水硫酸钠干燥、浓缩,得黄色粘稠状液体335mg,产率90%;MS(ESI)m/z:292.2[M+H]
+。
实施例59
6-苄基-3-(环丙基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-1)的制备
将100mg(0.26mmol)6-苄基-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(7-1)溶解于1mL N,N-二甲基甲酰胺中,加入50μL(0.51mmol)溴甲基环丙烷和140μL(0.77mmol)N,N-二异丙基乙胺,室温搅拌反应过夜,TLC监测显示反应完毕,加入5mL水,用乙酸乙酯(5mL×3)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸除去溶剂,经硅胶柱层析纯化,得到的粗品经半制备HPLC纯化,冷冻干燥得白色固体68.8mg,收率78%。
1H NMR(300MHz,Chloroform-d)δ8.49(dd,J=4.6,1.5Hz,1H),7.81(dd,J=7.9,1.5Hz,1H),7.49–7.43(m,2H),7.24–7.05(m,4H),5.75(s,2H),3.65(s,2H),2.87(t,J=4.6Hz,2H),2.81(t,J=4.7Hz,2H),2.47(d,J=6.6Hz,2H),1.03–0.91(m,1H),0.61–0.53(m,2H),0.23–0.16(m,2H).
13C NMR(75MHz,CDCl3)δ161.41,148.72,148.07,139.34,137.88,131.66,128.48,128.19,127.70,127.02,118.03,115.79,63.36,51.40,49.26,44.01,25.55,8.66,4.10.MS(ESI)m/z:346.2[M+H]
+,368.1[M+Na]
+.
实施例60
6-苄基-3-(环丁基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-2)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与溴甲基环丁烷制备。
1H NMR(300MHz,Chloroform-d)δ8.54(dd,J=4.6,1.7Hz,1H),7.90(dd,J=7.9,1.7Hz,1H),7.47–7.40(m,2H),7.26–7.13(m,4H),5.77(s,2H),3.54(s,2H),2.92(t,J=5.5Hz,2H),2.76(t,J=5.7Hz,2H),2.71–2.60(m,3H),2.18–2.06(m,2H),1.96–1.71(m,4H).
13C NMR(75MHz,CDCl
3)δ161.50,148.78,148.19,139.26,137.87,131.66,128.47,128.23,127.81,127.03,118.03,115.92,64.84,51.53,49.49,44.05,33.77,27.74,25.52,18.86.MS(ESI)m/z:360.2[M+H]
+,382.3[M+Na]
+。
实施例61
6-苄基-3-(环戊基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-3)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与溴甲基环戊烷制备。。
1H NMR(300MHz,Chloroform-d)δ8.55(dd,J=4.6,1.7Hz,1H),7.91(dd,J=7.9,1.7Hz,1H),7.48–7.44(m,2H),7.28–7.25(m,1H),7.23–7.14(m,3H),5.77(s,2H),3.58(s,2H),2.93(t,J=5.6Hz,2H),2.78(t,J=5.7Hz,2H),2.50(d,J=7.4Hz,2H),2.29–2.17(m,1H),1.85–1.75(m,2H),1.64–1.50(m,4H),1.28–1.19(m,2H).
13C NMR(75MHz,CDCl3)δ161.57,148.73,148.20,139.38,137.91,131.67,128.57,128.22,127.96,127.05,118.02,115.97,64.32,51.79,49.65,44.05,37.31,31.38,25.61,25.22.MS(ESI)m/z:374.2[M+H]
+,396.1[M+Na]
+.
实施例62
6-苄基-3-(环己基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-4)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与溴甲基环己烷制备。
1H NMR(300MHz,Chloroform-d)δ8.55(dd,J=4.6,1.7Hz,1H),7.92(dd,J=7.9,1.7Hz,1H),7.49–7.41(m,2H),7.28–7.15(m,4H),5.77(s,2H),3.53(s,2H),2.93(t,J=5.6Hz,2H),2.74(t,J=5.7Hz,2H),2.37(d,J=7.1Hz,2H),1.84–1.59(m,7H),1.29–1.23(m,2H),1.00–0.83(m,2H).
13C NMR(75MHz,CDCl3)δ161.58,148.73,148.21,139.41,137.90,131.67,128.60,128.22,128.01,127.06,118.02,115.99,65.58,58.44,51.99,49.82,44.06,35.16,31.90,26.80,26.13,25.65,18.47.MS(ESI)m/z:388.2[M+H]
+.
实施例63
3,6-二苄基-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-5)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与苄溴制备。
1H NMR(300MHz,Chloroform-d)δ8.54(dd,J=4.6,1.7Hz,1H),7.87(dd,J=7.9,1.7Hz,1H),7.48–7.27(m,7H),7.25–7.12(m,4H),5.75(s,2H),3.75(s,2H),3.62(s,2H),2.89(t,J=5.4Hz,2H),2.77(t,J=5.6Hz,2H).
13C NMR(75MHz,CDCl
3)δ161.45,148.82,148.21,139.42,137.89,137.78,131.73,129.23,128.61,128.44,128.24,127.84,127.34,127.09,118.06,115.92,62.65,51.74,48.65,44.08,25.70.MS(ESI)m/z:382.2[M+H]
+.
实施例64
6-苄基-3-(2-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-6)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-氟苄溴制备。MS(ESI)m/z:400.2[M+H]
+.
实施例65
6-苄基-3-(2-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-7)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-氯苄溴制备。
1H NMR(300MHz,Chloroform-d)δ8.57(dd,J=4.6,1.5Hz,1H),7.89(dd,J=7.9,1.5Hz,1H),7.57–7.47(m,3H),7.39(dd,J=7.5,1.6Hz,1H),7.31–7.14(m,6H),5.79(s,2H),3.89(s,2H),3.72(s,2H),2.96–2.84(m,4H).
13C NMR(75MHz,CDCl
3)δ161.41,148.83,148.20,139.38,137.91,135.62,134.45,131.72,130.85,129.60,128.65,128.45,128.25,127.76,127.11,126.81,118.07,115.88,59.04,51.64,48.96,44.09,25.68;MS(ESI)m/z:416.2[M+H]
+.
实施例66
6-苄基-3-(2-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-8)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-溴苄溴制备。MS(ESI)m/z:460.1[M+H]
+.
实施例67
6-苄基-3-(2-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-9)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-甲基苄溴制备。MS(ESI)m/z:396.2[M+H]
+.
实施例68
6-苄基-3-(2-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-10)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-乙基苄溴制备。MS(ESI)m/z:410.2[M+H]
+.
实施例69
6-苄基-3-(2-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-11)
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-甲氧基苄溴制备。MS(ESI)m/z:412.2[M+H]
+.
实施例70
6-苄基-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-12)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-氟苄溴制备。MS(ESI)m/z:400.2[M+H]
+.
实施例71
6-苄基-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-13)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与3-氯苄溴制备。
1H NMR(300MHz,Chloroform-d)δ8.58(dd,J=4.7,1.7Hz,1H),7.90(dd,J=7.9,1.7Hz,1H),7.53–7.46(m,2H),7.42(s,1H),7.30–7.15(m,7H),5.79(s,2H),3.74(s,2H),3.63(s,2H),2.93(t,J=5.5Hz,2H),2.79(t,J=5.6Hz,2H).
13C NMR(75MHz,CDCl
3)δ161.39,148.89,148.18,140.12,139.39,137.86,134.33,131.75,129.70,129.03,128.64,128.25,127.58,127.52,127.22,127.12,118.11,115.84,62.00,51.64,48.77,44.09,25.65;MS(ESI)m/z:416.2[M+H]
+.
实施例72
6-苄基-3-(3-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-14)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与3-溴苄溴制备。MS(ESI)m/z:460.1[M+H]
+.
实施例73
6-苄基-3-(3-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-15)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与3-甲基苄溴制备。MS(ESI)m/z:396.2[M+H]
+.
实施例74
6-苄基-3-(3-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-16)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与3-乙基苄溴制备。MS(ESI)m/z:410.2[M+H]
+.
实施例75
6-苄基-3-(3-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-17)
参照实施例59中化合物I-1的合成方法,由化合物7-1与3-甲氧基苄溴制备。
1H NMR(300MHz,Chloroform-d)δ8.55(dd,J=4.6,1.7Hz,1H),7.90(dd,J=7.9,1.7Hz,1H),7.47–7.43(m,2H),7.25–7.14(m,5H),6.98–6.94(m,2H),6.83–6.79(m,1H),5.76(s,2H),3.80(s,3H),3.73(s,2H),3.63(s,2H),2.91(t,J=5.5Hz,2H),2.77(t,J=5.6Hz,2H).
13C NMR(75MHz,CDCl
3)δ161.46,159.74,148.82,148.22,139.52,139.41,137.88,131.72,129.38,128.60,128.24,127.87,127.08,121.50,118.05,115.93,114.50,112.84,62.54,55.25,51.80,48.58,44.07,25.70;MS(ESI)m/z:412.2[M+H]
+.
实施例76
6-苄基-3-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-18)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与4-氟苄溴制备。MS(ESI)m/z:400.2[M+H]
+.
实施例77
6-苄基-3-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-19)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与4-氯苄溴制备。
1H NMR(300MHz,Chloroform-d)δ8.50(dd,J=4.6,1.7Hz,1H),7.78(dd,J=7.9,1.7Hz,1H),7.49–7.41(m,2H),7.29–7.05(m,8H),5.72(s,2H),3.65(s,2H),3.55(s,2H),2.80(t,J=5.1Hz,2H),2.70(t,J=5.2Hz,2H).
13C NMR(75MHz,CDCl
3)δ161.36,148.85,148.13,139.40,137.91,136.51,132.96,131.75,130.45,128.72,128.56,128.25,127.57,127.14,118.11,115.80,61.84,51.61,48.76,44.08,25.64;MS(ESI)m/z:416.2[M+H]
+.
实施例78
6-苄基-3-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-20)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与4-溴苄溴制备。MS(ESI)m/z:460.1[M+H]
+.
实施例79
6-苄基-3-(4-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-21)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与4-甲基苄溴制备。MS(ESI)m/z:396.2[M+H]
+.
实施例80
6-苄基-3-(4-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-22)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与4-乙基苄溴制备。MS(ESI)m/z:410.2[M+H]
+.
实施例81
6-苄基-3-(4-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-23)
参照实施例59中化合物I-1的合成方法,由化合物7-1与4-甲氧基苄溴制备。MS(ESI)m/z:412.2[M+H]
+.
实施例82
6-苄基-3-((1-甲基-1H-吡唑-3-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-24)
参照实施例59中化合物I-1的合成方法,由化合物7-1与3-氯甲基-1-甲基-1H-吡唑制备。MS(ESI)m/z:385.2[M+H]
+.
实施例83
6-苄基-3-((1-甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-25)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与5-氯甲基-1-甲基-1H-吡唑制备。MS(ESI)m/z:386.2[M+H]
+。
实施例84
6-苄基-3-((1,3-二甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-26)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与5-氯甲基-1,3-二甲基-1H-吡唑制备。MS(ESI)m/z:400.2[M+H]
+。
实施例85
6-苄基-3-(吡啶-2-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-27)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-氯甲基吡啶制备。
1H NMR(300MHz,Methanol-d
4)δ8.75–8.72(m,1H),8.70(dd,J=4.7,1.7Hz,1H),8.28(dd,J=8.0,1.7Hz,1H),7.63–7.58(m,1H),7.55–7.49(m,1H),7.42(dd,J=8.0,4.7Hz,1H),7.38–7.32(m,2H),7.26–7.16(m,3H),5.78(s,2H),4.75(s,2H),4.42(s,2H),3.77(t,J=6.2Hz,2H),3.43(t,J=6.1Hz,2H).MS(ESI)m/z:383.2[M+H]
+.
实施例86
6-苄基-3-(吡啶-3-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-28)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与3-氯甲基吡啶制备。
1H NMR(300MHz,Methanol-d
4)δ8.94–8.90(m,1H),8.83–8.78(m,1H),8.68(dd,J=4.7,1.7Hz,1H),8.38(dt,J=8.0,1.8Hz,1H),8.25(dd,J=8.0,1.7Hz,1H),7.82(dd,J=7.9,5.3Hz,1H),7.40(dd,J=8.0,4.7Hz,1H),7.35–7.27(m,2H),7.25–7.14(m,3H),5.76(s,2H),4.67(s,2H),4.24(s,2H),3.70(t,J=6.1Hz,2H),3.38(t,J=6.1Hz,2H).MS(ESI)m/z:383.2[M+H]
+.
实施例87
6-苄基-3-(吡啶-4-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-29)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与4-氯甲基吡啶制备。
1H NMR(300MHz,Methanol-d
4)δ8.93–8.87(m,2H),8.66(dd,J=4.7,1.6Hz,1H),8.24(dd,J=8.0,1.7Hz,1H),8.17–8.08(m,2H),7.39(dd,J=8.0,4.7Hz,1H),7.33–7.28(m,2H),7.24–7.15(m,3H),5.76(s,2H),4.67(s,2H),4.17(s,2H),3.59(t,J=6.0Hz,2H),3.38–3.34(m,2H).MS(ESI)m/z:383.2[M+H]
+.
实施例88
6-苄基-3-((4-氯吡啶-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-30)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-氯甲基-4-氯吡啶制备。
1H NMR(300MHz,Methanol-d
4)δ8.73(dd,J=4.7,1.7Hz,1H),8.67(d,J=5.4Hz,1H),8.30(dd,J=8.0,1.7Hz,1H),7.69(d,J=1.6Hz,1H),7.60(dd,J=5.4,2.0Hz,1H),7.44(dd,J=8.0,4.7Hz,1H),7.40–7.35(m,2H),7.29–7.18(m,3H),5.80(s,2H),4.77(s,2H),4.44(s,2H),3.79(t,J=6.1Hz,2H),3.44(t,J=6.2Hz,2H)
.MS(ESI)m/z:417.2[M+H]
+.
实施例88
6-苄基-3-((1-甲基-1H-咪唑-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-31)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与2-氯甲基-1-甲基-1H-咪唑制备。MS(ESI)m/z:386.2[M+H]
+.
实施例90
6-苄基-3-((1-甲基-1H-咪唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-32)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与4-氯甲基-1-甲基-1H-咪唑制备。MS(ESI)m/z:386.2[M+H]
+.
实施例91
6-苄基-3-((1-甲基-1H-咪唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-33)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与5-氯甲基-1-甲基-1H-咪唑制备。MS(ESI)m/z:386.2[M+H]
+.
实施例92
6-苄基-3-((3,5-二甲基异噁唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-34)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与4-氯甲基-3,5-二甲基异噁唑制备。MS(ESI)m/z:401.2[M+H]
+。
实施例93
6-苄基-3-((2-甲基噻唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-35)的制备
参照实施例59中化合物I-1的合成方法,由化合物7-1与5-氯甲基-2-甲基噻唑制备。MS(ESI)m/z:403.2[M+H]
+。
实施例94
3-苄基-6-(环丙基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-36)的制备
先参照实施例58中的方法,脱除化合物6-A-2中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.54(dd,J=4.6,1.7Hz,1H),7.91(dd,J=7.9,1.7Hz,1H),7.41–7.28(m,5H),7.16(dd,J=7.9,4.7Hz,1H),4.43(d,J=7.1Hz,2H),3.77(s,2H),3.63(s,2H),2.92(t,J=5.5Hz,2H),2.79(t,J=5.7Hz,2H),1.44–1.35(m,1H),0.55–0.48(m,2H),0.46–0.38(m,2H).
13C NMR(75MHz,CDCl
3)δ161.61,148.65,148.39,139.07,137.81,131.61,129.21,128.41,127.78,127.30,117.75,115.85,62.61,51.81,48.61,45.20,25.64,10.35,3.96,3.86;MS(ESI)m/z:346.2[M+H]
+。
实施例95
3-苄基-6-(环丁基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-37)的制备
先参照实施例58中的方法,脱除化合物6-A-3中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.54(dd,J=4.6,1.7Hz,1H),7.90(dd,J=7.9,1.7Hz,1H),7.41–7.27(m,5H),7.16(dd,J=7.9,4.7Hz,1H),4.61(d,J=7.3Hz,2H),3.77(s,2H),3.63(s,2H),2.95–2.84(m,3H),2.79(t,J=5.7Hz,2H),1.96–1.80(m,6H).
13C NMR(75MHz,CDCl3)δ161.70,148.57,148.49,138.92,137.81,131.54,129.24,128.41,127.75,127.30,117.70,115.77,62.64,51.85,48.60,45.57,34.80,26.34,25.65,18.42;MS(ESI)m/z:360.2[M+H]
+。
实施例96
3-苄基-6-(环戊基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-38)的制备
先参照实施例58中的方法,脱除化合物6-A-4中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.54(dd,J=4.6,1.7Hz,1H),7.89(dd,J=7.9,1.8Hz,1H),7.41–7.23(m,5H),7.15(dd,J=7.9,4.6Hz,1H),4.52(d,J=7.5Hz,2H),3.77(s,2H),3.63(s,2H),2.92(t,J=5.5Hz,2H),2.79(t,J=5.7Hz,2H),2.53(p,J=7.4Hz,1H),1.72–1.56(m,4H),1.53–1.34(m,4H).
13C NMR(75MHz,CDCl
3)δ161.75,148.55,138.93,137.75,131.53,129.25,128.41,127.69,127.31,117.68,115.77,62.64,51.81,48.62,45.21,39.04,30.31,25.62,24.93;MS(ESI)m/z:374.2[M+H]
+。
实施例97
3-苄基-6-(环己基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-39)
先参照实施例58中的方法,脱除化合物6-A-5中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.53(dd,J=4.6,1.7Hz,1H),7.88(dd,J=7.9,1.7Hz,1H),7.41–7.23(m,5H),7.14(dd,J=7.9,4.6Hz,1H),4.41(d,J=7.3Hz,2H),3.76(s,2H),3.62(s,2H),2.90(t,J=5.3Hz,2H),2.78(t,J=5.6Hz,2H),2.06–1.85(m,1H),1.69–1.54(m,4H),1.28–0.99(m,6H).
13C NMR(75MHz,CDCl
3)δ161.75,148.63,148.56,138.97,137.78,131.52,129.24,128.40,127.63,127.29,117.67,115.69,62.68,51.79,48.65,46.75,36.71,30.87,26.47,25.98,25.64;MS(ESI)m/z:388.2[M+H]
+。
实施例98
3-苄基-6-(2-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-40)
先参照实施例58中的方法,脱除化合物6-A-6中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:400.2[M+H]
+。
实施例99
3-苄基-6-(2-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-41)
先参照实施例58中的方法,脱除化合物6-A-7中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:416.2[M+H]
+。
实施例100
3-苄基-6-(2-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-42)
先参照实施例58中的方法,脱除化合物6-A-8中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:460.1[M+H]
+。
实施例101
3-苄基-6-(2-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-43)
先参照实施例58中的方法,脱除化合物6-A-9中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.48(dd,J=4.6,1.7Hz,1H),7.94(dd,J=7.9,1.7Hz,1H),7.41–7.25(m,5H),7.20–7.13(m,2H),7.07(t,J=6.9Hz,1H),6.95(t,J=7.5Hz,1H),6.64(d,J=7.6Hz,1H),5.72(s,2H),3.77(s,2H),3.65(s,2H),2.97(t,J=5.6Hz,2H),2.82(t,J=5.7Hz,2H),2.50(s,3H).
13C NMR(75MHz,CDCl
3)δ161.48,149.07,148.34,139.56,137.68,135.57,135.47,131.75,130.10,129.28,128.44,127.80,127.36,126.57,125.87,125.12,118.10,115.85,62.67,51.75,48.63,41.99,25.75,19.45;MS(ESI)m/z:396.2[M+H]
+。
实施例102
3-苄基-6-(2-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-44)
先参照实施例58中的方法,脱除化合物6-A-10中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:410.2[M+H]
+。
实施例103
3-苄基-6-(2-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-45)
先参照实施例58中的方法,脱除化合物6-A-11中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:412.2[M+H]
+。
实施例104
3-苄基-6-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-46)
先参照实施例58中的方法,脱除化合物6-A-12中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:400.2[M+H]
+。
实施例105
3-苄基-6-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-47)
先参照实施例58中的方法,脱除化合物6-A-13中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:416.2[M+H]
+。
实施例106
3-苄基-6-(3-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-48)
先参照实施例58中的方法,脱除化合物6-A-14中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:460.1[M+H]
+。
实施例107
3-苄基-6-(3-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-49)
先参照实施例58中的方法,脱除化合物6-A-15中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:396.2[M+H]
+。
实施例108
3-苄基-6-(3-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-50)
先参照实施例58中的方法,脱除化合物6-A-16中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:410.2[M+H]
+。
实施例109
3-苄基-6-(3-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-51)
先参照实施例58中的方法,脱除化合物6-A-17中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:412.2[M+H]
+。
实施例110
3-苄基-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-52)
先参照实施例58中的方法,脱除化合物6-A-18中的Boc保护基,再参照实施例59中化合物I-1的合成方法, 用得到的胺与苄溴反应制备。MS(ESI)m/z:400.2[M+H]
+。
实施例111
3-苄基-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-53)
先参照实施例58中的方法,脱除化合物6-A-19中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:416.2[M+H]
+。
实施例112
3-苄基-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-54)
先参照实施例58中的方法,脱除化合物6-A-20中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:460.1[M+H]
+。
实施例113
3-苄基-6-(4-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-55)
先参照实施例58中的方法,脱除化合物6-A-21中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:396.2[M+H]
+。
实施例114
3-苄基-6-(4-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-56)
先参照实施例58中的方法,脱除化合物6-A-22中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:410.2[M+H]
+。
实施例115
3-苄基-6-(4-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-57)
先参照实施例58中的方法,脱除化合物6-A-23中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:412.2[M+H]
+。
实施例116
3-苄基-6-((1-甲基-1H-吡唑-3-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-58)
先参照实施例58中的方法,脱除化合物6-A-25中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:386.2[M+H]
+。
实施例117
3-苄基-6-((1-甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-59)
先参照实施例58中的方法,脱除化合物6-A-26中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:386.2[M+H]
+。
实施例118
3-苄基-6-((1,3-二甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-60)
先参照实施例58中的方法,脱除化合物6-A-27中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:400.1[M+H]
+。
实施例119
3-苄基-6-(吡啶-2-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-61)
先参照实施例58中的方法,脱除化合物6-A-28中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Methanol-d
4)δ8.71–8.66(m,1H),8.60(dd,J=4.7,1.6Hz,1H),8.37–8.26(m,2H),7.85–7.74(m,2H),7.65–7.58(m,2H),7.56–7.48(m,3H),7.42(dd,J=8.0,4.7Hz,1H),6.03(s,2H),4.61(s,2H),4.27(s,2H),3.75(s,2H),3.41(t,J=5.7Hz,2H);MS(ESI)m/z:383.2[M+H]
+。
实施例120
3-苄基-6-(吡啶-3-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-62)
先参照实施例58中的方法,脱除化合物6-A-29中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Methanol-d
4)δ9.01(s,1H),8.75(d,J=5.6Hz,1H),8.72–8.64(m,2H),8.27(dd,J=8.0,1.5Hz,1H),8.00(dd,J=8.0,5.8Hz,1H),7.66–7.57(m,2H),7.53–7.47(m,3H),7.42(dd,J=8.0,4.7Hz,1H),5.92(s,2H),4.62(s,2H),4.29(s,2H),3.75(s,2H),3.41(t,J=5.2Hz,2H);MS(ESI)m/z:383.2[M+H]
+。
实施例121
3-苄基-6-(吡啶-4-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-63)
先参照实施例58中的方法,脱除化合物6-A-30中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Methanol-d
4)δ8.74(d,J=6.7Hz,2H),8.58(dd,J=4.7,1.5Hz,1H),8.30(dd,J=8.0,1.6Hz,1H),7.96(d,J=6.7Hz,2H),7.66–7.58(m,2H),7.54–7.48(m,3H),7.42(dd,J=8.0,4.7Hz,1H),6.00(s,2H),4.62(s,2H),4.30(s,2H),3.77(s,2H),3.44(t,J=5.6Hz,2H);MS(ESI)m/z:383.2[M+H]
+。
实施例122
3-苄基-6-((4-氯吡啶-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-64)
先参照实施例58中的方法,脱除化合物6-A-31中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Methanol-d
4)δ8.56(dd,J=4.7,1.6Hz,1H),8.43–8.32(m,1H),8.26(dd,J=8.0,1.6Hz,1H),7.66–7.58(m,2H),7.54–7.47(m,3H),7.45–7.41(m,2H),7.38(dd,J=8.0,4.7Hz,1H),5.88 (s,2H),4.62(s,2H),4.31(s,2H),3.77(s,2H),3.43(t,J=5.3Hz,2H);MS(ESI)m/z:417.1[M+H]
+。
实施例123
3-苄基-6-((1-甲基-1H-咪唑-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-65)
先参照实施例58中的方法,脱除化合物6-A-32中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:386.2[M+H]
+。
实施例124
3-苄基-6-((1-甲基-1H-咪唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-66)
先参照实施例58中的方法,脱除化合物6-A-33中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:386.2[M+H]
+。
实施例125
3-苄基-6-((1-甲基-1H-咪唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-67)
先参照实施例58中的方法,脱除化合物6-A-34中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:386.2[M+H]
+。
实施例126
3-苄基-6-((3,5-二甲基异噁唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-68)
先参照实施例58中的方法,脱除化合物6-A-35中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:401.2[M+H]
+。
实施例127
3-苄基-6-((2-甲基噻唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-69)
先参照实施例58中的方法,脱除化合物6-A-36中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:403.2[M+H]
+。
实施例128
3-苄基-6-(4-(三氟甲基)苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-70)
先参照实施例58中的方法,脱除化合物6-A-24中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.57(dd,J=4.7,1.7Hz,1H),7.96(dd,J=7.9,1.7Hz,1H),7.61–7.49(m,4H),7.44–7.27(m,5H),7.23(dd,J=7.9,4.7Hz,1H),5.82(s,2H),3.79(s,2H),3.66(s,2H),2.97(t,J=5.4Hz,2H),2.83(t,J=5.6Hz,2H).
13C NMR(75MHz,CDCl
3)δ161.40,148.88,148.02,141.88,139.78,137.70,131.91,129.44,129.22,129.01,128.76,128.45,127.84,127.37,125.23,118.33,115.99,62.64,51.65,48.62,43.75, 25.75;MS(ESI)m/z:450.2[M+H]
+。
实施例129
3-(3-氟苄基)-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-71)
先参照实施例58中的方法,脱除化合物6-A-18中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氟苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.56(dd,J=4.6,1.6Hz,1H),7.90(dd,J=7.9,1.6Hz,1H),7.52–7.45(m,2H),7.31–7.24(m,1H),7.20–7.09(m,3H),6.97–6.87(m,3H),5.70(s,2H),3.73(s,2H),3.60(s,2H),2.90(t,J=5.3Hz,2H),2.78(t,J=5.6Hz,2H).
13C NMR(75MHz,CDCl
3)δ164.64,163.58,161.35,148.84,148.06,140.71,139.48,133.70,131.82,130.74,129.91,127.64,124.59,118.18,115.90,115.58,115.12,114.84,114.35,114.07,62.01,51.59,48.75,43.33,25.66;MS(ESI)m/z:418.2[M+H]
+。
实施例130
3-(3-氯苄基)-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-72)
先参照实施例58中的方法,脱除化合物6-A-18中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氯苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.57(dd,J=4.6,1.6Hz,1H),7.91(dd,J=7.9,1.7Hz,1H),7.52–7.46(m,2H),7.39(s,1H),7.26–7.22(m,3H),7.19(dd,J=7.9,4.7Hz,1H),6.94–6.88(m,2H),5.70(s,2H),3.72(s,2H),3.60(s,2H),2.92(t,J=5.4Hz,2H),2.78(t,J=5.6Hz,2H).
13C NMR(75MHz,Chloroform-d)δ163.59,161.34,160.34,148.85,148.08,140.08,139.44,134.34,133.67,131.81,130.72,129.68,129.01,127.63,127.52,127.18,118.17,115.90,115.13,114.84,61.98,51.60,48.74,43.34,25.66;MS(ESI)m/z:434.1[M+H]
+。
实施例131
3-(3-溴苄基)-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-73)
先参照实施例58中的方法,脱除化合物6-A-18中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-溴苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.56(dd,J=4.6,1.6Hz,1H),7.90(dd,J=7.9,1.7Hz,1H),7.55–7.46(m,3H),7.40–7.36(m,1H),7.31–7.27(m,1H),7.21–7.15(m,2H),6.94–6.88(m,2H),5.70(s,2H),3.70(s,2H),3.59(s,2H),2.91(t,J=5.4Hz,2H),2.77(t,J=5.6Hz,2H).
13C NMR(75MHz,Chloroform-d)δ163.58,161.33,160.33,148.85,148.07,140.41,139.45,133.64,131.90,131.82,130.73,130.63,130.44,129.99,127.65,122.63,118.17,115.88,115.12,114.84,61.93,51.59,48.74,43.34,25.65;MS(ESI)m/z:478.1[M+H]
+。
实施例132
3-(3-氟苄基)-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-74)
先参照实施例58中的方法,脱除化合物6-A-19中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氟苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.55(dd,J=4.6,1.6Hz,1H),7.92(dd,J=7.9,1.6Hz,1H),7.44–7.39(m,2H),7.29–7.24(m,1H),7.21–7.09(m,5H),6.99–6.92(m,1H),5.70(s,2H),3.74(s,2H),3.60(s,2H),2.92(t,J=5.3Hz,2H),2.78(t,J=5.6Hz,2H).
13C NMR(75MHz,Chloroform-d)δ164.65,161.34,148.86,148.05,140.71,139.53,136.39,132.88,131.83,130.46,130.25,129.90,129.79,128.34,127.68,124.58,118.21,115.92,114.36,114.08,62.02,51.60,48.74,43.45,25.70;MS(ESI)m/z:434.1[M+H]
+。
实施例133
3-(3-氯苄基)-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-75)
先参照实施例58中的方法,脱除化合物6-A-19中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氯苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.56(dd,J=4.6,1.6Hz,1H),7.93(dd,J=7.9,1.7Hz,1H),7.44–7.38(m,3H),7.26–7.17(m,6H),5.70(s,2H),3.72(s,2H),3.60(s,2H),2.94(t,J=5.5Hz,2H),2.79(t,J=5.7Hz,2H).
13C NMR(75MHz,CDCl
3)δ161.34,148.87,148.06,140.09,139.51,136.37,134.35,132.89,131.83,130.23,129.68,129.01,128.35,127.66,127.52,127.17,118.21,115.91,61.98,51.60,48.73,43.46,25.69;MS(ESI)m/z:450.1[M+H]
+。
实施例134
3-(3-溴苄基)-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-76)
先参照实施例58中的方法,脱除化合物6-A-19中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-溴苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.54(dd,J=4.6,1.5Hz,1H),7.89(dd,J=7.9,1.6Hz,1H),7.54(s,1H),7.43–7.36(m,3H),7.31–7.26(m,1H),7.21–7.14(m,4H),5.69(s,2H),3.70(s,2H),3.58(s,2H),2.89(t,J=5.2Hz,2H),2.76(t,J=5.6Hz,2H).
13C NMR(75MHz,Chloroform-d)δ161.31,148.87,148.02,140.43,139.54,136.39,132.87,131.90,131.84,130.44,130.26,130.00,128.34,127.65,127.60,122.64,118.23,115.88,61.93,51.60,48.74,43.45,25.68;MS(ESI)m/z:494.1[M+H]
+。
实施例135
3-(3-氟苄基)-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-77)
先参照实施例58中的方法,脱除化合物6-A-20中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氟苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.55(dd,J=4.6,1.6Hz,1H),7.92(dd,J=7.9,1.6Hz,1H),7.35(s,4H),7.27–7.09(m,4H),6.99–6.92(m,1H),5.69(s,2H),3.74(s,2H),3.60(s,2H),2.92(t,J=5.3Hz,2H),2.79(t,J=5.6Hz,2H);
13C NMR(75MHz,Chloroform-d)δ164.65,161.34,148.86,148.05,140.69,139.53,136.89,131.83,131.30,130.59,129.90,127.69,124.57,124.54,121.06,118.22,115.92,115.58,114.37,114.09,62.00,51.60,48.73,43.51,25.70;MS(ESI)m/z:478.1[M+H]
+。
实施例136
3-(3-氯苄基)-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-78)
先参照实施例58中的方法,脱除化合物6-A-20中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氯苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.55(dd,J=4.6,1.6Hz,1H),7.92(dd,J=7.9,1.6Hz,1H),7.40–7.37(m,1H),7.35(s,4H),7.26–7.23(m,3H),7.19(dd,J=7.9,4.7Hz,1H),5.68(s,2H),3.72(s,2H),3.59(s,2H),2.92(t,J=5.3Hz,2H),2.78(t,J=5.6Hz,2H).
13C NMR(75MHz,Chloroform-d)δ161.33,148.87,148.03,140.09,139.54,136.89,134.35,131.84,131.30,130.59,129.68,129.01,127.63,127.52,127.18,121.06,118.23,115.90,61.98,51.59,48.73,43.51,25.69;MS(ESI)m/z:494.1[M+H]
+。
实施例137
3-(3-溴苄基)-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-79)
先参照实施例58中的方法,脱除化合物6-A-20中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-溴苄溴反应制备。
1H NMR(300MHz,Chloroform-d)δ8.54(dd,J=4.6,1.6Hz,1H),7.89(dd,J=7.9,1.6Hz,1H),7.54(s,1H),7.41–7.28(m,6H),7.20–7.14(m,2H),5.67(s,2H),3.70(s,2H),3.58(s,2H),2.90(t,J=5.3Hz,2H),2.76(t,J=5.5Hz,2H);
13C NMR(75MHz,Chloroform-d)δ161.30,148.89,148.00,140.39,139.57,136.90,131.90,131.86,131.30,130.60,130.45,130.01,127.67,127.56,122.64,121.06,118.26,115.87,61.92,51.58,48.74,43.52,25.67;MS(ESI)m/z:538.0[M+H]
+。
实施例138
3-苄基-6-(4-(三氟甲基)苄基)-2,3,4,6-四氢苯并[c][2,7]萘啶-5-(1H)-酮(I-80)
先参照实施例58中的方法,脱除化合物6-B-1中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:449.2[M+H]
+。
实施例139
8-苄基-5-(4-(三氟甲基)苄基)-7,8,9,10-四氢嘧啶基[4,5-c][2,7]萘啶-6-(5H)-酮(I-81)
先参照实施例58中的方法,脱除化合物6-C-1中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:451.2[M+H]
+。
实施例140
6-苄基-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-82)
参照实施例59中化合物I-1的合成方法,用化合物7-1与3-腈基苄溴反应制备。MS(ESI)m/z:407.3[M+H]
+。
实施例141
6-(4-三氟甲基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-83);
先参照实施例58中的方法,脱除化合物6-A-24中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-腈基苄溴反应制备。MS(ESI)m/z:475.3[M+H]
+。
实施例142
6-(4-氟苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-84);
先参照实施例58中的方法,脱除化合物6-A-18中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-腈基苄溴反应制备。MS(ESI)m/z:425.3[M+H]
+。
实施例143
6-(4-氯苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-85);
先参照实施例58中的方法,脱除化合物6-A-19中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-腈基苄溴反应制备。MS(ESI)m/z:441.3[M+H]
+。
实施例144
6-(4-溴苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-86);
先参照实施例58中的方法,脱除化合物6-A-20中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-腈基苄溴反应制备。MS(ESI)m/z:485.2[M+H]
+。
实施例145
6-(4-甲氧基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-87);
先参照实施例58中的方法,脱除化合物6-A-23中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-腈基苄溴反应制备。MS(ESI)m/z:437.3[M+H]
+。
实施例146
6-(4-硝基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-88);
先参照实施例58中的方法,脱除化合物6-A-37中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-腈基苄溴反应制备。MS(ESI)m/z:452.3[M+H]
+。
实施例147
6-(4-甲氨基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-89)和6-(4-二甲氨基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-90)
将100毫克I-88溶于甲醇中,加入0.1毫升甲醛水溶液,再在氮气保护下加入20毫克Pd-C(10%),混合物在氢气氛(1atm)下搅拌3小时,用硅藻土过滤除去催化剂,滤液浓缩后残留的含I-89和I-90的混合物用半制备HPLC分离得到纯的化合物I-89和I-90。I-89:MS(ESI)m/z:436.3[M+H]
+;I-90:MS(ESI)m/z:450.3[M+H]
+。
实施例148
6-(4-甲基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-91);
先参照实施例58中的方法,脱除化合物6-A-21中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-腈基苄溴反应制备。MS(ESI)m/z:421.3[M+H]
+。
实施例149
6-(4-甲基苄基)-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-92);
先参照实施例58中的方法,脱除化合物6-A-21中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氯苄溴反应制备。MS(ESI)m/z:430.3[M+H]
+。
实施例150
6-(4-甲基苄基)-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-93);
先参照实施例58中的方法,脱除化合物6-A-21中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氟苄溴反应制备。MS(ESI)m/z:414.3[M+H]
+。
实施例151
6-(4-乙基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-94);
先参照实施例58中的方法,脱除化合物6-A-22中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-腈基苄溴反应制备。MS(ESI)m/z:435.3[M+H]
+。
实施例152
6-(4-乙基苄基)-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-95);
先参照实施例58中的方法,脱除化合物6-A-22中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氟苄溴反应制备。MS(ESI)m/z:428.3[M+H]
+。
实施例153
6-(4-乙基苄基)-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-96);
先参照实施例58中的方法,脱除化合物6-A-22中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氯苄溴反应制备。MS(ESI)m/z:444.3[M+H]
+。
实施例154
3-(3-氯苄基)-6-((2,3-二氢[1,4]苯并二噁英-6-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5(1H)-酮(I-97);
先参照实施例58中的方法,脱除化合物6-A-38中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氯苄溴反应制备。MS(ESI)m/z:474.3[M+H]
+。
实施例155
6-([1,3]苯并二氧五环-5-基甲基基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-98);
先参照实施例58中的方法,脱除化合物6-A-39中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-腈基苄溴反应制备。MS(ESI)m/z:451.3[M+H]
+。
实施例156
6-(4-甲氧基苄基)-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-99);
先参照实施例58中的方法,脱除化合物6-A-23中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与3-氟苄溴反应制备。MS(ESI)m/z:430.3[M+H]
+。
实施例157
6-(4-甲氧基苄基)-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮(I-100);
先参照实施例58中的方法,脱除化合物6-A-23中的Boc保护基,再参照实施例59中化合物I-1的合成方法, 用得到的胺与3-氯苄溴反应制备。MS(ESI)m/z:446.3[M+H]
+。
实施例158
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢呋喃并[3,4-C][2,7]萘啶5(4H)-酮(I-101);
先参照实施例58中的方法,脱除化合物6-D中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:439.3[M+H]
+。
实施例159
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻吩并[3,4-C][2,7]萘啶5(4H)-酮(I-102);
先参照实施例58中的方法,脱除化合物6-E中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:455.3[M+H]
+。
实施例160
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻吩并[3,2-C][2,7]萘啶5(4H)-酮(I-103);
先参照实施例58中的方法,脱除化合物6-F中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:455.3[M+H]
+。
实施例161
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻吩并[2,3-C][2,7]萘啶5(4H)-酮(I-104);
先参照实施例58中的方法,脱除化合物6-G中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:455.3[M+H]
+。
实施例162
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻唑并[4,5-C][2,7]萘啶5(4H)-酮(I-105);
先参照实施例58中的方法,脱除化合物6-H中的Boc保护基,再参照实施例59中化合物I-1的合成方法,用得到的胺与苄溴反应制备。MS(ESI)m/z:456.3[M+H]
+。
实施例163
4-(2-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(12-1)的合成
将0.22克(2mmol)2-甲基苄胺溶于10mL的1,4-二氧六环中,在上述溶液中加入0.49克2-甲硫基-咪唑啉氢碘酸盐(化合物8,2mmol),在氩气保护下加热至70℃反应2小时,蒸干溶剂,得到的化合物9-1未经纯化直接用 于下一步反应。
将上步反应中得到的化合物9-1溶于10mL甲醇中,在上述溶液中加入0.54克1-N-叔丁氧羰基-4-哌啶酮-3-甲酸乙酯(化合物2,2mmol)和0.16克甲醇钠(3mmol),将反应液加热回流2小时,TLC检测反应完全后蒸除溶剂,向残留物中加入10mL水,用1N的盐酸将PH值调节至7,用乙酸乙酯萃取(15mL*3),有机相合并后用无水硫酸钠干燥、浓缩,残留物用柱层析纯化得到化合物10-1 0.44克,两步反应的产率总计56%,MS(ESI)m/z:397.2[M+H]
+。
将0.4克(1mmol)化合物10-1溶于3mL的DMSO中,向上述溶液中加入0.84克2-碘酰基苯甲酸(IBX,3mmol),室温下反应6小时,TLC检测反应完全。向反应液中加入20mL水,用乙酸乙酯萃取(20mL×3),有机相合并后用无水硫酸钠干燥、浓缩,残留物用柱层析纯化,得到化合物11-1 0.23克,产率58%,MS(ESI)m/z:395.2[M+H]
+,HRMS(ESI)m/z:[M+H]
+395.2004,理论值395.2005。
将0.2克化合物11-1溶于3mL的甲醇中,加入1mL饱和的HCl的甲醇溶液,室温下搅拌12小时后蒸干溶剂,向残留物中加入10mL水,用饱和NaHCO
3溶液中和至PH值为8,用二氯甲烷萃取(15mL×3),有机相合并后用无水硫酸钠干燥、浓缩,得到化合物12-1 0.15克,产率91%,MS(ESI)m/z:295.2[M+H]
+。
实施例164
4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(12-2)的合成
以苄胺为原料,参照实施例163中化合物12-1的合成方法制备,MS(ESI)m/z:281.1[M+H]
+。
实施例165
4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(12-3)的合成
以4-氟苄胺为原料,参照实施例163中化合物12-1的合成方法制备,MS(ESI)m/z:299.1[M+H]
+。
实施例166
4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(12-4)的合成
以2,4-二氟苄胺为原料,参照实施例163中化合物12-1的合成方法制备,MS(ESI)m/z:317.1[M+H]
+。
实施例167
4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(12-5)的合成
以4-氯苄胺为原料,参照实施例163中化合物12-1的合成方法制备,MS(ESI)m/z:315.1[M+H]
+。
实施例168
4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(12-6)的合成
以4-甲基苄胺为原料,参照实施例163中化合物12-1的合成方法制备,MS(ESI)m/z:295.3[M+H]
+。
实施例169
4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(12-7)的合成
以4-乙基苄胺为原料,参照实施例163中化合物12-1的合成方法制备,MS(ESI)m/z:309.3[M+H]
+。
实施例170
4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(12-8)的合成
以4-三氟甲基苄胺为原料,参照实施例163中化合物12-1的合成方法制备,MS(ESI)m/z:349.1[M+H]
+。
实施例171
4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(12-9)的合成
以4-甲氧基苄胺为原料,参照实施例163中化合物12-1的合成方法制备,MS(ESI)m/z:311.3[M+H]
+。
实施例172
7-苄基-4-(2-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-106)的制备
将100mg(0.34mmol)化合物12-1溶于3mL的DMF中,在上述溶液中分别加入60mg苄溴(0.35mmol)和70mg碳酸钾(0.5mmol),室温下反应6小时,TLC检测反应完全后在反应液中加入15mL水,用乙酸乙酯萃取(10mL×3),有机相合并,用无水硫酸钠干燥后过滤、浓缩,粗品先用柱层析分离,再用HPLC进一步纯化,洗脱液为含0.1%TFA的乙腈和水,得到目标化合物I-82的三氟醋酸盐88mg,产率52%。MS(ESI)m/z:385.2[M+H]
+。
实施例173
4,7-二苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-107)的制备
参照实施例172中化合物I-106的合成方法用化合物12-2与苄溴反应制备,MS(ESI)m/z:371.2[M+H]
+。
实施例174
7-(3-氟苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-108)的制备
参照实施例172中化合物I-106的合成方法用化合物12-2与3-氟苄溴反应制备,MS(ESI)m/z:389.2[M+H]
+。
实施例175
7-(3-氯苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-109)的制备
参照实施例172中化合物I-106的合成方法用化合物12-2与3-氯苄溴反应制备,MS(ESI)m/z:405.1[M+H]
+。
实施例176
7-(3-甲基苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-110)的制备
参照实施例172中化合物I-106的合成方法用化合物12-2与3-甲基苄溴反应制备,MS(ESI)m/z:385.2[M+H]
+。
实施例177
7-(3-腈基苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-111)的制备
参照实施例172中化合物I-106的合成方法用化合物12-2与3-腈基苄溴反应制备,MS(ESI)m/z:396.2[M+H]
+。
实施例178
7-苄基-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-112)的制备
参照实施例172中化合物I-106的合成方法用化合物12-3与苄溴反应制备,MS(ESI)m/z:389.2[M+H]
+。
实施例179
7-(3-氟苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-113)的制备
参照实施例172中化合物I-106的合成方法用化合物12-3与3-氟苄溴反应制备,MS(ESI)m/z:407.2[M+H]
+。
实施例180
7-(3-氯苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-114)的制备
参照实施例172中化合物I-106的合成方法用化合物12-3与3-氯苄溴反应制备,MS(ESI)m/z:423.1[M+H]
+。
实施例181
7-(3-甲基苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-115)的制备
参照实施例172中化合物I-106的合成方法用化合物12-3与3-甲基苄溴反应制备,MS(ESI)m/z:403.2[M+H]
+。
实施例182
7-(3-腈基苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-116)的制备
参照实施例172中化合物I-106的合成方法用化合物12-3与3-腈基苄溴反应制备,MS(ESI)m/z:414.2[M+H]
+。
实施例183
7-苄基-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-117)的制备
参照实施例172中化合物I-106的合成方法用化合物12-5与苄溴反应制备,MS(ESI)m/z:405.2[M+H]
+。
实施例184
7-(3-氟苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-118)的制备
参照实施例172中化合物I-106的合成方法用化合物12-5与3-氟苄溴反应制备,MS(ESI)m/z:423.2[M+H]
+。
实施例185
7-(3-氯苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-119)的制备
参照实施例172中化合物I-106的合成方法用化合物12-5与3-氯苄溴反应制备,MS(ESI)m/z:439.1[M+H]
+。
实施例186
7-(3-甲基苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-120)的制备
参照实施例172中化合物I-106的合成方法用化合物12-5与3-甲基苄溴反应制备,MS(ESI)m/z:419.2[M+H]
+。
实施例187
7-(3-腈基苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-121)的制备
参照实施例172中化合物I-106的合成方法用化合物12-5与3-腈基苄溴反应制备,MS(ESI)m/z:430.2[M+H]
+。
实施例188
7-苄基-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-122)的制备
参照实施例172中化合物I-106的合成方法用化合物12-4与苄溴反应制备,MS(ESI)m/z:407.2[M+H]
+。
实施例189
7-(3-氟苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-123)的制备
参照实施例172中化合物I-106的合成方法用化合物12-4与3-氟苄溴反应制备,MS(ESI)m/z:425.2[M+H]
+。
实施例190
7-(3-氯苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-124)的制备
参照实施例172中化合物I-106的合成方法用化合物12-4与3-氯苄溴反应制备,MS(ESI)m/z:441.1[M+H]
+。
实施例191
7-(3-甲基苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-125)的制备
参照实施例172中化合物I-106的合成方法用化合物12-4与3-甲基苄溴反应制备,MS(ESI)m/z:421.2[M+H]
+。
实施例192
7-(3-腈基苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-126)的制备
化合物I-126按照与实施例172中化合物I-106同样的方法用化合物12-4与3-腈基苄溴反应制备,MS(ESI)m/z:432.2[M+H]
+。
实施例193
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-127)的制备
参照实施例172中化合物I-106的合成方法用化合物12-8与苄溴反应制备,MS(ESI)m/z:439.2[M+H]
+。
实施例194
7-(3-氟苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-128)的制备
参照实施例172中化合物I-106的合成方法用化合物12-8与3-氟苄溴反应制备,MS(ESI)m/z:457.2[M+H]
+。
实施例195
7-(3-氯苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-129)的制备
参照实施例172中化合物I-106的合成方法用化合物12-8与3-氯苄溴反应制备,MS(ESI)m/z:473.2[M+H]
+。
实施例196
7-(3-甲基苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-130)的制备
参照实施例172中化合物I-106的合成方法用化合物12-8与3-甲基苄溴反应制备,MS(ESI)m/z:453.2[M+H]
+。
实施例197
7-(3-腈基苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-131)的制备
参照实施例172中化合物I-106的合成方法用化合物12-8与3-腈基苄溴反应制备,MS(ESI)m/z:464.2[M+H]
+。
实施例198
7-苄基-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-132)的制备
参照实施例172中化合物I-106的合成方法用化合物12-6与苄溴反应制备,MS(ESI)m/z:385.2[M+H]
+。
实施例199
7-(3-氟苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-133)的制备
参照实施例172中化合物I-106的合成方法用化合物12-6与3-氟苄溴反应制备,MS(ESI)m/z:403.2[M+H]
+。
实施例200
7-(3-氯苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-134)的制备
参照实施例172中化合物I-106的合成方法用化合物12-6与3-氯苄溴反应制备,MS(ESI)m/z:419.2[M+H]
+。
实施例201
7-(3-甲基苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-135)的制备
参照实施例172中化合物I-106的合成方法用化合物12-6与3-甲基苄溴反应制备,MS(ESI)m/z:399.2[M+H]
+。
实施例202
7-(3-腈基苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-136)的制备
参照实施例172中化合物I-106的合成方法用化合物12-6与3-腈基苄溴反应制备,MS(ESI)m/z:410.2[M+H]
+。
实施例203
7-苄基-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-137)的制备
参照实施例172中化合物I-106的合成方法用化合物12-7与苄溴反应制备,MS(ESI)m/z:399.2[M+H]
+。
实施例204
7-(3-氟苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-138)的制备
参照实施例172中化合物I-106的合成方法用化合物12-7与3-氟苄溴反应制备,MS(ESI)m/z:417.2[M+H]
+。
实施例205
7-(3-氯苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-139)的制备
参照实施例172中化合物I-106的合成方法用化合物12-7与3-氯苄溴反应制备,MS(ESI)m/z:433.2[M+H]
+。
实施例206
7-(3-甲基苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-140)的制备
参照实施例172中化合物I-106的合成方法用化合物12-7与3-甲基苄溴反应制备,MS(ESI)m/z:413.2[M+H]
+。
实施例207
7-(3-腈基苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-141)的制备
参照实施例172中化合物I-106的合成方法用化合物12-7与3-腈基苄溴反应制备,MS(ESI)m/z:424.2[M+H]
+。
实施例208
7-苄基-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-142)的制备
参照实施例172中化合物I-106的合成方法用化合物12-9与苄溴反应制备,MS(ESI)m/z:401.2[M+H]
+。
实施例209
7-(3-氟苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-143)的制备
参照实施例172中化合物I-106的合成方法用化合物12-9与3-氟苄溴反应制备,MS(ESI)m/z:419.2[M+H]
+。
实施例210
7-(3-氯苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-144)的制备
参照实施例172中化合物I-106的合成方法用化合物12-9与3-氯苄溴反应制备,MS(ESI)m/z:435.2[M+H]
+。
实施例210
7-(3-甲基苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-145)的制备
参照实施例172中化合物I-106的合成方法用化合物12-9与3-甲基苄溴反应制备,MS(ESI)m/z:415.2[M+H]
+。
实施例211
7-(3-腈基苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-146)的制备
参照实施例172中化合物I-106的合成方法用化合物12-9与3-腈基苄溴反应制备,MS(ESI)m/z:426.2[M+H]
+。
实施例212
6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(17-1)的合成
将0.63克化合物13(4mmol)溶于10毫升二氯甲烷中,0度搅拌下向上述溶液中滴加2毫升草酰氯和两滴DMF,反应液自然升温至室温,搅拌半小时,减压蒸除溶剂及过量的草酰氯,得到的酰氯重新溶于5毫升二氯甲烷备用。将0.73克化合物14-1溶于10毫升二氯甲烷,加入1.5毫升Et
3N后将溶液冷却至0度,在搅拌下向上述溶液中缓慢加入由化合物13制得的酰氯溶液,室温下搅拌3小时,蒸除溶剂后残留物经柱层析分离得到化合物15-1,MS(ESI)m/z:323.1[M+H]
+。
将上步反应中得到的化合物15-1溶于5毫升二氯甲烷中,在0度搅拌下加入10毫升三氟醋酸,反应液升至室温搅拌1小时,蒸除溶剂,残留物溶于15毫升1,4-二氧六环,向上述溶液中分批加入0.4克NaH(纯度60%),升温至80度,在氮气保护下搅拌过夜。向上述反应液中加入10毫升甲醇破坏过量的氢化钠,然后蒸除溶剂,残留物用柱层析纯化得到化合物16-1,MS(ESI)m/z:187.1[M+H]
+。
将上步反应中得到的化合物16-1溶于15毫升甲醇中,先加入0.5毫升浓盐酸,再在氮气保护下加入50毫克10%的Pd-C,混合物在氢气氛下搅拌过夜,用硅藻土滤除固体,得到的滤液浓缩后得到化合物17-1的盐酸盐,MS(ESI)m/z:191.1[M+H]
+。
实施例213
6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(17-2)的合成
参照实施例212中化合物17-1的合成方法以化合物13和化合物14-2为原料制备,MS(ESI)m/z:192.1[M+H]
+。
实施例214
6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(17-3)的合成
参照实施例212中化合物17-1的合成方法以化合物13和化合物14-3为原料制备,MS(ESI)m/z:191.1[M+H]
+。
实施例215
6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(17-4)的合成
参照实施例212中化合物17-1的合成方法以化合物13和化合物14-4为原料制备,MS(ESI)m/z:191.1[M+H]
+。
实施例216
1,2,3,4-四氢吡啶并[3,4-e]吡咯并[1,2-a]嘧啶-5(6H)-酮(17-5)的合成
参照实施例212中化合物17-1的合成方法以化合物13和化合物14-5为原料制备,MS(ESI)m/z:190.1[M+H]
+。
实施例217
4-(2,4-二甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(24-1)的合成
将0.63克化合物13(4mmol)溶于10毫升二氯甲烷中,0度搅拌下向上述溶液中滴加2毫升草酰氯和两滴DMF,反应液自然升温至室温,搅拌半小时,减压蒸除溶剂及过量的草酰氯,得到的酰氯重新溶于5毫升二氯甲烷中,将上述酰氯溶液缓慢加入冰浴冷却的含0.67克2,4-二甲氧基苄胺和1.5毫升三乙胺的10毫升的二氯甲烷溶液中,反应液升至室温,搅拌3小时,蒸除溶剂后残留物经柱层析分离得到化合物20,MS(ESI)m/z:307.1[M+H]
+。
将上步反应中得到的化合物20溶于15毫升DMF中,向该溶液中分别加入0.5克咪唑和0.4克NaH(纯度60%),升温至100度,在氮气保护下搅拌过夜。冷至室温后向上述反应液中加入30毫升水,用乙酸乙酯萃取(30mL×3),有机相合并后用饱和氯化钠溶液洗一次,有机相用无水硫酸钠干燥后蒸除溶剂,残留物用柱层析纯化得到化合物22-1,MS(ESI)m/z:339.2[M+H]
+。
将上步反应中得到的化合物22-1溶于15毫升DMF,向该溶液中分别加入0.1克CuI、0.5克叔丁醇钾和0.2克1,10-菲罗啉,得到的混合物在氧气氛下与120度反应过夜。反应结束后冷至室温,加入30毫升水,用乙酸乙酯萃取(30mL×3),有机相合并后用饱和氯化钠溶液洗一次,有机相用无水硫酸钠干燥后蒸除溶剂,残留物用柱层析纯化得到化合物23-1,MS(ESI)m/z:337.2[M+H]
+。
将上步反应中得到的化合物23-1溶于15毫升甲醇中,先加入0.5毫升浓盐酸,再在氮气保护下加入50毫克10%的Pd-C,混合物在氢气氛下搅拌过夜,用硅藻土滤除固体,得到的滤液浓缩后得到化合物24-1的盐酸盐,MS(ESI)m/z:341.2[M+H]
+。
实施例218
4-(2,4-二甲氧基苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(24-2)的合成
参照实施例217中化合物24-1的合成方法以化合物20和1,2,4-三氮唑为原料制备,MS(ESI)m/z:342.2[M+H]
+。
实施例219
4-(2,4-二甲氧基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(24-3)的合成
参照实施例217中化合物24-1的合成方法以化合物20和吡唑为原料制备,MS(ESI)m/z:341.2[M+H]
+。
实施例220
7-(3-氯苄基)-4-(苯并[1,3]二氧五环-5-基甲基基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-147)的合成
将190毫克化合物17-1溶于10毫升甲醇中,向该溶液中分别加入140毫克间氯苯甲醛和120毫克NaBH
3CN,再加入一滴浓硫酸,在室温下反应3小时后加入1毫升水,蒸除溶剂后向残留物中加入15毫升水,用乙酸乙酯萃取(20毫升×3),有机相合并后用饱和氯化钠溶液洗一次,再用无水硫酸钠干燥后蒸除溶剂,残留物溶于5毫升DMF 中,分别加入0.2克5-溴甲基苯并[1,3]二氧五环和0.2克碳酸钾,室温搅拌过夜后加入10mL水,用乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸除去溶剂,残留物先用硅胶柱层析纯化,再用半制备HPLC进一步纯化,得到化合物I-147。MS(ESI)m/z:449.2[M+H]
+。
实施例221
7-(3-氯苄基)-4-((2,3-二氢[1,4]苯并二噁英-6-基)甲基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-148)的合成
将170毫克化合物24-1溶于5毫升DMF中,分别向该溶液中加入120毫克3-氯苄溴和0.2毫升三乙胺,室温搅拌过夜后加入5mL水,用乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸除去溶剂,残留物用硅胶柱层析纯化,得到的产物溶于2毫升二氯甲烷中,向该溶液中加入10毫升三氟醋酸,在室温下搅拌2小时后蒸除溶剂和过量的三氟醋酸,残留物溶于5毫升DMF,向该溶液中分别加入120毫克6-溴甲基[2,3]二氢苯并[1,4]二噁英和0.2克碳酸钾,室温搅拌过夜后加入10mL水,用乙酸乙酯萃取(10mL×3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋蒸除去溶剂,残留物先用硅胶柱层析纯化,再用半制备HPLC进一步纯化,得到化合物I-148。MS(ESI)m/z:463.2[M+H]
+。
实施例222
4-(4-三氟甲基苄基)-7-苄基-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-149)的制备
参照实施例220中化合物I-147的合成方法用化合物17-2制备,MS(ESI)m/z:440.2[M+H]
+。
实施例223
4-(4-三氟甲基苄基)-7-(3-氯苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-150)的制备
参照实施例220中化合物I-147的合成方法用化合物17-2制备,MS(ESI)m/z:474.2[M+H]
+。
实施例224
4-(4-三氟甲基苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-151)的制备
参照实施例220中化合物I-147的合成方法用化合物17-2制备,MS(ESI)m/z:465.2[M+H]
+。
实施例225
4-(4-氯苄基)-7-苄基-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-152)的制备
参照实施例221中化合物I-148的合成方法用化合物24-2制备,MS(ESI)m/z:406.2[M+H]
+。
实施例226
4-(4-氯苄基)-7-(3-氟苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-153)的制备
参照实施例221中化合物I-148的合成方法用化合物24-2制备,MS(ESI)m/z:424.2[M+H]
+。
实施例227
4-(4-氯苄基)-7-(3-氯苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-154)的制备
参照实施例221中化合物I-148的合成方法用化合物24-2制备,MS(ESI)m/z:440.1[M+H]
+。
实施例228
4-(4-氯苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮(I-155)的制备
参照实施例221中化合物I-148的合成方法用化合物24-2制备,MS(ESI)m/z:431.2[M+H]
+。
实施例229
4-苄基-7-(3-氯苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-156)的制备
参照实施例220中化合物I-147的合成方法用化合物17-3制备,MS(ESI)m/z:405.2[M+H]
+。
实施例230
4-苄基-7-(3-腈基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-157)的制备
参照实施例220中化合物I-147的合成方法用化合物17-3制备,MS(ESI)m/z:396.2[M+H]
+。
实施例231
4-苄基-7-(3-甲基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-158)的制备
参照实施例220中化合物I-147的合成方法用化合物17-3制备,MS(ESI)m/z:385.2[M+H]
+。
实施例232
4-(4-三氟甲基苄基)-7-苄基-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-159)的制备
参照实施例221中化合物I-148的合成方法用化合物24-3制备,MS(ESI)m/z:439.2[M+H]
+。
实施例233
4-(4-三氟甲基苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-160)的制备
参照实施例221中化合物I-148的合成方法用化合物24-3制备,MS(ESI)m/z:464.2[M+H]
+。
实施例234
4-(4-氯苄基)-7-苄基-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-161)的制备
参照实施例221中化合物I-148的合成方法用化合物24-3制备,MS(ESI)m/z:405.2[M+H]
+。
实施例235
4-(4-氯苄基)-7-(3-氯苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-162)的制备
参照实施例221中化合物I-148的合成方法用化合物24-3制备,MS(ESI)m/z:439.1[M+H]
+。
实施例236
4-(4-氯苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-163)的制备
参照实施例221中化合物I-148的合成方法用化合物24-3制备,MS(ESI)m/z:430.2[M+H]
+。
实施例237
7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-164)的制备
参照实施例220中化合物I-147的合成方法用化合物17-4制备,MS(ESI)m/z:439.2[M+H]
+。
实施例238
7-(3-腈基苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-165)的制备
参照实施例220中化合物I-147的合成方法用化合物17-4制备,MS(ESI)m/z:464.2[M+H]
+。
实施例239
7-(3-氯苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-166)的制备
参照实施例220中化合物I-147的合成方法用化合物17-4制备,MS(ESI)m/z:439.1[M+H]
+。
实施例240
7-(3-腈基苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮(I-167)的制备
参照实施例220中化合物I-147的合成方法用化合物17-4制备,MS(ESI)m/z:430.2[M+H]
+。
实施例241
3-苄基-6-(4-三氟甲基苄基)-1,2,3,4-四氢吡啶并[3,4-e]吡咯并[1,2-a]嘧啶-5(6H)-酮(I-168)的制备
参照实施例220中化合物I-147的合成方法用化合物17-5制备,MS(ESI)m/z:438.1[M+H]
+。
实施例242
3-(3-氯苄基)-6-(4-氯苄基)-1,2,3,4-四氢吡啶并[3,4-e]吡咯并[1,2-a]嘧啶-5(6H)-酮(I-169)的制备
参照实施例220中化合物I-147的合成方法用化合物17-5制备,MS(ESI)m/z:438.2[M+H]
+。
实施例243
式Ⅰ化合物作为ClpP激动剂激活ClpP水解FITC-casein的EC
50值及抑制MV4;11细胞生长的活性参照文献方法进行测定(Cancer Cell 2019,35,721-737.)。具体操作如下:
(1)化合物准备:
将待测化合物用DMSO配制成100mM的母液储存,每个化合物取1μl,加9μl DMSO稀释成10mM待用。
(2)化合物稀释(2X,50μl/孔):
本发明式Ⅰ化合物按200μM,50μM,10μM,2μM,500nM,100nM,20nM,2nM浓度稀释,稀释液为测试缓冲液,每孔加入50μl不同浓度的化合物,2个复孔。终浓度为100μM,25μM,5μM,1μM,250nM,50nM,10nM,1nM。
(3)蛋白稀释(4X,25μl/孔):
参照文献方法(Cancer Cell 2019,35,721-737.)纯化出来的蛋白hClpP浓度为14mg/ml,折算成浓度为1000μM。将蛋白用测试缓冲液稀释到4μM,每孔加入25μl蛋白,37度,孵育30min。终浓度为1μM。
(4)FITC-Casein稀释(4X,25μl/孔)
参照文献方法(Cancer Cell 2019,35,721-737.)标记FITC-Casein母液为200mM,用测试缓冲液稀释到16μM,每孔加入25μL FITC-Casein。终浓度为4μM。立即上机检测。
(5)对照组设置
FITC-Casein和FITC-Casein+ClpP作为阴性对照。阳性药ONC201和ONC212作为阳性对照组,阳性药ONC201和ONC212参照文献方法(Angewandte Chemie International Edition 2014,53,6628-6631.)合成。
(6)荧光动力学检测
检测温度37℃。震板3s。激发光485±20nm,发射光525±20nm。动力学参数设置,每隔1min扫描一次,共15min。
式Ⅰ化合物作为ClpP激动剂激活ClpP水解FITC-casein的EC
50值及抑制MV4;11细胞生长的活性结果如下表所示。
Claims (10)
- 根据权利要求1所述的含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物,其特征在于,环A为苯环、吡啶环、嘧啶环、咪唑环、噻吩环、呋喃环、噻唑环、三氮唑环、吡唑环或吡咯环。
- 根据权利要求1所述的含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物,其特征在于,R 1选自环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、苄基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-乙基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-乙基苄基、3-甲氧基苄基、3-腈基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-乙基苄基、4-甲氧基苄基、4-三氟甲基苄基、(1-甲基-1H-吡唑-3-基)甲基、(1-甲基-1H-吡唑-5-基)甲基、(1,3-二甲基-1H-吡唑-5-基)甲基、吡啶-2-基甲基、吡啶-3-基甲基、吡啶-4-基甲基、(4-氯吡啶-2-基)甲基、(1-甲基-1H-咪唑-2-基)甲基、(1-甲基-1H-咪唑-4-基)甲基、(1-甲基-1H-咪唑-5-基)甲基、(3,5-二甲基异噁唑-4-基)甲基、(2-甲基噻唑-5-基)甲基、苯并[1,3]二氧五环-4基甲基。
- 根据权利要求1所述的含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物,其特征在于,R 2选自环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、苄基、2-氟苄基、2-氯苄基、2-溴苄基、2-甲基苄基、2-乙基苄基、2-甲氧基苄基、3-氟苄基、3-氯苄基、3-溴苄基、3-甲基苄基、3-乙基苄基、3-甲氧基苄基、4-氟苄基、4-氯苄基、4-溴苄基、4-甲基苄基、4-乙基苄基、4-甲氧基苄基、4-硝基苄基、4-甲氨基苄基、4-二甲氨基苄基、4-三氟甲基苄基、2,4-二氟苄基、2-氟-4-氯苄基、2-氟-4-甲基苄基2-氟-4-甲氧基苄基、2-氟-4-三氟甲基苄基、2-氟-4-溴苄基、(1-甲基-1H-吡唑-3-基)甲基、(1-甲基-1H-吡唑-5-基)甲基、(1,3-二甲基-1H-吡唑-5-基)甲基、吡啶-2-基甲基、吡啶-3-基甲基、吡啶-4-基甲基、(4-氯吡啶-2-基)甲基、(1-甲基-1H-咪唑-2-基)甲基、(1-甲基-1H-咪唑-4-基)甲基、(1-甲基-1H-咪唑-5-基)甲基、(3,5-二甲基异噁唑-4-基)甲基、(2-甲基噻唑-5-基)甲基、苯并[1,3]二氧五环-4基甲基、苯并[1,3]二氧五环-5基甲基、苯并[1,4]二氧六环-5基甲基、苯并[1,4]二氧六环-6基甲基。
- 根据权利要求1所述的含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物,其特征在于,所述化合物选自下列化合物:6-苄基-3-(环丙基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(环丁基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(环戊基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(环己基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3,6-二苄基-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(2-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(2-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(2-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(2-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(2-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(2-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(3-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(3-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(3-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(3-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(4-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(4-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(4-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-((1-甲基-1H-吡唑-3-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-((1-甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-((1,3-二甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(吡啶-2-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(吡啶-3-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-(吡啶-4-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-((4-氯吡啶-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-((1-甲基-1H-咪唑-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-((1-甲基-1H-咪唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-((1-甲基-1H-咪唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-((3,5-二甲基异噁唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-苄基-3-((2-甲基噻唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(环丙基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(环丁基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(环戊基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(环己基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(2-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(2-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(2-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(2-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(2-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(2-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(3-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(3-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(3-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(3-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(4-甲基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(4-乙基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(4-甲氧基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-((1-甲基-1H-吡唑-3-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-((1-甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-((1,3-二甲基-1H-吡唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(吡啶-2-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(吡啶-3-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(吡啶-4-基甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-((4-氯吡啶-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-((1-甲基-1H-咪唑-2-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-((1-甲基-1H-咪唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-((1-甲基-1H-咪唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-((3,5-二甲基异噁唑-4-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-((2-甲基噻唑-5-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(4-(三氟甲基)苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-氟苄基)-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-氯苄基)-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-溴苄基)-6-(4-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-氟苄基)-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-氯苄基)-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-溴苄基)-6-(4-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-氟苄基)-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-氯苄基)-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-溴苄基)-6-(4-溴苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-苄基-6-(4-(三氟甲基)苄基)-2,3,4,6-四氢苯并[c][2,7]萘啶-5-(1H)-酮;8-苄基-5-(4-(三氟甲基)苄基)-7,8,9,10-四氢嘧啶基[4,5-c][2,7]萘啶-6-(5H)-酮;6-苄基-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-三氟甲基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-氟苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-氯苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-溴苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-甲氧基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-硝基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-甲胺基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-二甲胺基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-甲基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-甲基苄基)-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-甲基苄基)-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-乙基苄基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-乙基苄基)-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-乙基苄基)-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;3-(3-氯苄基)-6-((2,3-二氢[1,4]苯并二噁英-6-基)甲基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5(1H)-酮;6-([1,3]苯并二氧五环-5-基甲基基)-3-(3-腈基苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-甲氧基苄基)-3-(3-氟苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;6-(4-甲氧基苄基)-3-(3-氯苄基)-2,3,4,6-四氢吡啶并[3,4-c][1,8]萘啶-5-(1H)-酮;7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢呋喃并[3,4-C][2,7]萘啶5(4H)-酮;7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻吩并[3,4-C][2,7]萘啶5(4H)-酮;7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻吩并[3,2-C][2,7]萘啶5(4H)-酮;7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻吩并[2,3-C][2,7]萘啶5(4H)-酮;7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢噻唑并[4,5-C][2,7]萘啶5(4H)-酮;7-苄基-4-(2-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4)-酮;4,7-二苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氟苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-甲基苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-苄基-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-苄基-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氟苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-甲基苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-(4-氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-苄基-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氟苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-甲基苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-苄基-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氟苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-甲基苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-(2,4-二氟苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氟苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-甲基苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-苄基-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氟苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-甲基苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-(4-甲基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-苄基-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氟苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-甲基苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-(4-乙基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-苄基-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氟苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-甲基苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-(4-甲氧基苄基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-([1,3]苯并二氧五环-5-基甲基基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-((2,3-二氢[1,4]苯并二噁英-6-基)甲基)-6,7,8,9-四氢咪唑并[1,2-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;4-(4-三氟甲基苄基)-7-苄基-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮;4-(4-三氟甲基苄基)-7-(3-氯苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮;4-(4-三氟甲基苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮;4-(4-氯苄基)-7-苄基-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮;4-(4-氯苄基)-7-(3-氟苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮;4-(4-氯苄基)-7-(3-氯苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮;4-(4-氯苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡啶并[3,4-e][1,2,4]***并[1,5-a]嘧啶-5(4H)-酮;4-苄基-7-(3-氯苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;4-苄基-7-(3-腈基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;4-苄基-7-(3-甲基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;4-(4-三氟甲基苄基)-7-苄基-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;4-(4-三氟甲基苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;4-(4-氯苄基)-7-苄基-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;4-(4-氯苄基)-7-(3-氯苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;4-(4-氯苄基)-7-(3-腈基苄基)-6,7,8,9-四氢吡唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-苄基-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-(4-三氟甲基苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-氯苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;7-(3-腈基苄基)-4-(4-氯苄基)-6,7,8,9-四氢咪唑并[1,5-a]吡啶并[3,4-e]嘧啶-5(4H)-酮;3-苄基-6-(4-三氟甲基苄基)-1,2,3,4-四氢吡啶并[3,4-e]吡咯并[1,2-a]嘧啶-5(6H)-酮;3-(3-氯苄基)-6-(4-氯苄基)-1,2,3,4-四氢吡啶并[3,4-e]吡咯并[1,2-a]嘧啶-5(6H)-酮。
- 权利要求1所述通式I中化合物的制备方法,其特征在于,当环A为通式II所示结构时合成路线为:包括以下步骤:(1)步骤a为化合物1氢化脱除苄基之后与二碳酸二叔丁酯反应制得化合物2;(2)步骤b为化合物2与三氟甲磺酸酐反应制得化合物3;(3)步骤c为化合物3与联硼酸频那醇酯反应制得化合物4;(4)步骤d为化合物4与碘和氨基双取代的吡啶、苯或嘧啶制得化合物5;(5)步骤e为化合物5与不同的卤代烃反应制得化合物6;(6)步骤f为化合物6用三氟乙酸脱除叔丁氧羰基保护制得化合物7;(7)步骤g为化合物7与不同的卤代烃反应制得通式II代表的化合物;化合物4与邻碘或邻溴取代的其它杂环芳胺按照上述方法进行反应合成通式I中环A为其它芳杂环的化合物,包括呋喃、噻吩、噻唑;或者,当通式I中环A为通式III咪唑环时,合成路线为:包括以下步骤:(1)步骤a为化合物8与不同的胺反应制得化合物9;(2)步骤b为化合物2与化合物9反应制得化合物10;(3)步骤c为将化合物10中的二氢咪唑环氧化成咪唑环制得化合物11;(4)步骤d为化合物11用三氟乙酸脱除叔丁氧羰基保护制得化合物12;(5)步骤e为化合物12与不同的卤代烃反应制得通式III代表的化合物;或者,通式I中环A为通式IV中的咪唑环、三氮唑环、吡唑环或吡咯环,X、Y、Z分别为氮原子或次甲基时,合成路线为:包括以下步骤:(1)步骤a为化合物13与化合物14缩合合成化合物15;当化合物14的五元环中含多个氮原子时,Boc保护基在不同的氮原子上;(2)步骤b为化合物15脱除Boc保护基后在碱性条件下进行分子内芳基亲核取代反应环化制得化合物16;(3)步骤c为氢化还原化合物16中的吡啶环制得化合物17;(4)步骤d为化合物17中的氨基与不同的芳香醛进行还原氨化合成化合物18;(5)步骤e为化合物18与不同的卤代烃进行亲核取代反应合成通式IV代表的化合物;或者,当通式I中环A为通式IV中的咪唑环、三氮唑环或吡唑环,X、Y、Z分别为氮原子或次甲基时,合成路线为:包括以下步骤:(1)步骤a为化合物13与化合物19缩合制得化合物20;(2)步骤b为化合物20与化合物21在碱性条件下进行芳环的亲核取代反应合成化合物22;(3)步骤c为化合物22在亚铜盐催化下进行分子内偶联环化合成化合物23;(3)步骤d为化合物23中的吡啶在催化氢化下还原合成化合物24;(4)步骤e为化合物24与卤代烃进行亲核取代反应合成化合物25;(5)步骤f为化合物25在酸性条件下脱除2,4-二甲氧基苄基制得化合物26;(6)步骤g为化合物26与卤代烃进行亲核取代反应合成通式IV代表的化合物;或者,通式IV中化合物的合成路线为:包括以下步骤:(1)步骤a为化合物13与化合物29缩合制得化合物30;(2)步骤b为化合物30与化合物21在碱性条件下进行芳环的亲核取代反应合成化合物31;(3)步骤c为化合物22在亚铜盐催化下进行分子内偶联环化合成化合物32;(4)步骤d为化合物32中的吡啶在催化氢化下还原合成化合物33;(5)步骤e为化合物33与卤代烃进行亲核取代反应合成通式IV代表的化合物。
- 一种药物组合物,其特征在于,包括权利要求1-5中任一所述化合物或其药学上可接受的盐,以及药学上可接受的载体。
- 权利要求1-5中任一所述化合物或权利要求7所述药物组合物在制备ClpP激动剂中的应用。
- 权利要求1-5中任一所述化合物或权利要求7所述药物组合物在制备治疗癌症的药物中的应用。
- 根据权利要求9所述应用,其特征在于,所述癌症包括急性髓系白血病、乳腺癌、肺癌、肝癌、卵巢癌、膀胱癌、***癌、子宫癌、胃癌、睾丸癌、甲状腺癌、***、骨肉瘤、神经母细胞瘤、结肠癌和脑瘤。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110805091.6 | 2021-07-16 | ||
CN202110805091 | 2021-07-16 | ||
CN202210814872.6 | 2022-07-12 | ||
CN202210814872.6A CN115611896A (zh) | 2021-07-16 | 2022-07-12 | 含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物及其制备方法与制药用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023284807A1 true WO2023284807A1 (zh) | 2023-01-19 |
Family
ID=84856449
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/105579 WO2023284807A1 (zh) | 2021-07-16 | 2022-07-14 | 含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物及其制备方法与制药用途 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN115611896A (zh) |
WO (1) | WO2023284807A1 (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3991064A (en) * | 1975-01-17 | 1976-11-09 | Warner-Lambert Company | Benzonaphthyridines |
US4680298A (en) * | 1983-05-31 | 1987-07-14 | Schering Corporation | Tricyclic anti-allergy and use as anti-inflammatory agents |
WO2008103357A1 (en) * | 2007-02-21 | 2008-08-28 | E. I. Du Pont De Nemours And Company | Fungicidal tricyclic 1,2,4-triazoles |
WO2010077530A1 (en) * | 2008-12-17 | 2010-07-08 | Merck Patent Gmbh | C-ring modified tricyclic benzonaphthiridinone protein kinase inhibitors and use thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9255096B1 (en) * | 2014-10-07 | 2016-02-09 | Allergan, Inc. | Substituted 1,2,3,4-tetrahydrobenzo[C][2,7] naphthyridines and derivatives thereof as kinase inhibitors |
US20220143024A1 (en) * | 2019-02-22 | 2022-05-12 | Board Of Regents, The University Of Texas System | Methods of using imipridones |
AU2020228047A1 (en) * | 2019-02-27 | 2021-09-30 | Madera Therapeutics, LLC | Use of caseinolytic protease P function as a biomarker of drug response to imipridone-like agents |
-
2022
- 2022-07-12 CN CN202210814872.6A patent/CN115611896A/zh active Pending
- 2022-07-14 WO PCT/CN2022/105579 patent/WO2023284807A1/zh unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3991064A (en) * | 1975-01-17 | 1976-11-09 | Warner-Lambert Company | Benzonaphthyridines |
US4680298A (en) * | 1983-05-31 | 1987-07-14 | Schering Corporation | Tricyclic anti-allergy and use as anti-inflammatory agents |
WO2008103357A1 (en) * | 2007-02-21 | 2008-08-28 | E. I. Du Pont De Nemours And Company | Fungicidal tricyclic 1,2,4-triazoles |
WO2010077530A1 (en) * | 2008-12-17 | 2010-07-08 | Merck Patent Gmbh | C-ring modified tricyclic benzonaphthiridinone protein kinase inhibitors and use thereof |
Non-Patent Citations (2)
Title |
---|
BOMMAGANI SHOBANBABU; LEE NA-RA; ZHANG XUAN; DWOSKIN LINDA P.; ZHENG GUANGRONG: "Synthesis ofO- andN-alkylated products of 1,2,3,4-tetrahydrobenzo[c][2,7]naphthyrin-5(6H)-one", TETRAHEDRON LETTERS, vol. 56, no. 46, 18 November 2015 (2015-11-18), Amsterdam , NL , pages 6472 - 6474, XP029321131, ISSN: 0040-4039, DOI: 10.1016/j.tetlet.2015.09.156 * |
UNANGST PAUL C., CONNOR DAVID T., CARETHERS MARY E., SCHWENDER CHARLES S., BROWN RICHARD E., PUCHALSKI CHESTER: "Preparation of benzo[c][2,7]naphthyridin-5(1 H )-ones as analogs of benzopyrano[3,4- c ]pyridin-5-one bronchodilators", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 23, no. 3, 1 May 1986 (1986-05-01), US , pages 941 - 944, XP093023548, ISSN: 0022-152X, DOI: 10.1002/jhet.5570230355 * |
Also Published As
Publication number | Publication date |
---|---|
CN115611896A (zh) | 2023-01-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8530489B2 (en) | 5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors | |
US20210363139A1 (en) | Cxcr4 inhibitors and uses thereof | |
US9637453B2 (en) | 3-spirocyclic-6-hydroxamic acid tetralins as HDAC inhibitors | |
TWI680970B (zh) | 可做為sumo活化酵素抑制劑之雜芳基化合物 | |
TWI608002B (zh) | 布魯頓氏(bruton’s)酪胺酸激酶之聯芳基抑制劑 | |
EP2247592B1 (en) | Pyrrolopyrazine kinase inhibitors | |
JP2022547504A (ja) | Rip1阻害化合物ならびにそれを作製および使用するための方法 | |
EP3412663B1 (en) | Nitrogen-containing heterocycle and carbocycle derivatives having trka inhibitory activity | |
CN102803265A (zh) | 吡咯并吡嗪激酶抑制剂 | |
JP7379641B2 (ja) | Irak阻害剤としてのピラゾールアミド化合物 | |
KR102580087B1 (ko) | 자가포식 조절인자(autophagy regulator)로서 사용된 화합물, 및 이에 대한 제조 방법 및 이의 용도 | |
JP7464920B2 (ja) | 免疫調節としての芳香環誘導体及びその製造方法と使用 | |
US11440907B1 (en) | Antiproliferation compounds and uses thereof | |
WO2016192132A1 (zh) | 作为alk抑制剂的嘧啶衍生物 | |
CN115279769A (zh) | N-(4-(1-(2,6-二氟苄基)-5-((二甲基氨基)甲基)-3-(6-甲氧基-3-哒嗪基)-2,4-二氧代-1,2,3,4-四氢噻吩并[2,3-d]嘧啶-6-基)苯基)-n’-甲氧基脲的结晶形式 | |
US20180127370A1 (en) | PHENYL AMINO PIPERIDINE mTORC INHIBITORS AND USES THEREOF | |
US20230374034A1 (en) | Novel bicyclic compounds | |
WO2023284807A1 (zh) | 含四氢萘啶酮或四氢吡啶并嘧啶酮骨架的化合物及其制备方法与制药用途 | |
US20230026466A1 (en) | Wdr5 inhibitors and modulators | |
JP4737495B2 (ja) | エリスロマイシン誘導体 | |
WO2023025109A1 (zh) | 一类Toll样受体抑制剂及其制备和应用 | |
WO2019154053A1 (zh) | Iap抑制剂及其在药物中的应用 | |
WO2024006776A1 (en) | Estrogen receptor alpha degraders and medical use thereof | |
WO2023196429A1 (en) | Modulators of cystic fibrosis transmembrane conductance regulator | |
WO2023174383A1 (zh) | 二氢异喹啉类化合物及其医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22841440 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |