WO2023165263A1 - 吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用 - Google Patents
吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用 Download PDFInfo
- Publication number
- WO2023165263A1 WO2023165263A1 PCT/CN2023/071042 CN2023071042W WO2023165263A1 WO 2023165263 A1 WO2023165263 A1 WO 2023165263A1 CN 2023071042 W CN2023071042 W CN 2023071042W WO 2023165263 A1 WO2023165263 A1 WO 2023165263A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- independently
- substituted
- halogen
- compound
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 111
- -1 Pyrrolotriazinone compound Chemical class 0.000 title claims abstract description 58
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 101000996780 Homo sapiens Probable G-protein coupled receptor 139 Proteins 0.000 claims abstract description 18
- 102100033836 Probable G-protein coupled receptor 139 Human genes 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims description 124
- 125000000217 alkyl group Chemical group 0.000 claims description 114
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 36
- 125000005842 heteroatom Chemical group 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 23
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 22
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 21
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 18
- 201000000980 schizophrenia Diseases 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 208000010877 cognitive disease Diseases 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 208000011117 substance-related disease Diseases 0.000 claims description 7
- 208000028698 Cognitive impairment Diseases 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 4
- 208000020925 Bipolar disease Diseases 0.000 claims description 4
- 208000030814 Eating disease Diseases 0.000 claims description 4
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 4
- 208000001640 Fibromyalgia Diseases 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 4
- 208000029560 autism spectrum disease Diseases 0.000 claims description 4
- 235000014632 disordered eating Nutrition 0.000 claims description 4
- 208000030459 obsessive-compulsive personality disease Diseases 0.000 claims description 4
- 208000007656 osteochondritis dissecans Diseases 0.000 claims description 4
- 230000036407 pain Effects 0.000 claims description 4
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 4
- BEBRHYJBTAMGRW-UHFFFAOYSA-N pyrrolo[3,2-d]triazin-4-one Chemical class O=C1N=NN=C2C=CN=C12 BEBRHYJBTAMGRW-UHFFFAOYSA-N 0.000 claims description 4
- 208000019116 sleep disease Diseases 0.000 claims description 4
- 201000009032 substance abuse Diseases 0.000 claims description 4
- 231100000736 substance abuse Toxicity 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 206010013663 drug dependence Diseases 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- 208000020685 sleep-wake disease Diseases 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- 208000022925 sleep disturbance Diseases 0.000 claims 1
- 230000001270 agonistic effect Effects 0.000 abstract description 6
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 138
- 238000005481 NMR spectroscopy Methods 0.000 description 98
- 239000007787 solid Substances 0.000 description 66
- 239000003153 chemical reaction reagent Substances 0.000 description 41
- 239000002994 raw material Substances 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 241000699670 Mus sp. Species 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- QGCLEUGNYRXBMZ-LURJTMIESA-N (1s)-1-(4-fluorophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(F)C=C1 QGCLEUGNYRXBMZ-LURJTMIESA-N 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- UZDDXUMOXKDXNE-QMMMGPOBSA-N (1s)-1-(4-methylphenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(C)C=C1 UZDDXUMOXKDXNE-QMMMGPOBSA-N 0.000 description 13
- 239000007832 Na2SO4 Substances 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000012267 brine Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- 235000011152 sodium sulphate Nutrition 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000004698 Polyethylene Substances 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- CDQPLIAKRDYOCB-LURJTMIESA-N 4-[(1s)-1-aminoethyl]phenol Chemical compound C[C@H](N)C1=CC=C(O)C=C1 CDQPLIAKRDYOCB-LURJTMIESA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- RTCUCQWIICFPOD-VIFPVBQESA-N (1s)-1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C([C@@H](N)C)=CC=CC2=C1 RTCUCQWIICFPOD-VIFPVBQESA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- 239000007821 HATU Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 210000001753 habenula Anatomy 0.000 description 7
- JZGLECLGVQRPPI-NSHDSACASA-N 2-(4-oxo-1,2,3-benzotriazin-3-yl)-N-[(1S)-1-[4-(trifluoromethoxy)phenyl]ethyl]acetamide Chemical compound O=C1C2=C(N=NN1CC(=O)N[C@@H](C)C1=CC=C(C=C1)OC(F)(F)F)C=CC=C2 JZGLECLGVQRPPI-NSHDSACASA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940126092 TAK-041 Drugs 0.000 description 6
- 230000006399 behavior Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 230000003542 behavioural effect Effects 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- HJCNJFKANUPALG-UHFFFAOYSA-N 3-(4-fluorophenyl)butanamide Chemical compound NC(=O)CC(C)C1=CC=C(F)C=C1 HJCNJFKANUPALG-UHFFFAOYSA-N 0.000 description 4
- LFWLUDLUCDRDAF-UHFFFAOYSA-N 5-methyl-1h-pyrrole-2-carbaldehyde Chemical compound CC1=CC=C(C=O)N1 LFWLUDLUCDRDAF-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000164 antipsychotic agent Substances 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
- 239000006143 cell culture medium Substances 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 4
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 3
- GFLUEYAXNOWLIN-PPHPATTJSA-N (1s)-1-(4-fluorophenyl)-2-methylpropan-1-amine;hydrochloride Chemical compound Cl.CC(C)[C@H](N)C1=CC=C(F)C=C1 GFLUEYAXNOWLIN-PPHPATTJSA-N 0.000 description 3
- JTDGKQNNPKXKII-ZETCQYMHSA-N (1s)-1-(4-methoxyphenyl)ethanamine Chemical compound COC1=CC=C([C@H](C)N)C=C1 JTDGKQNNPKXKII-ZETCQYMHSA-N 0.000 description 3
- BADVPOKOZMYLPI-UHFFFAOYSA-N 1-(4-chlorophenyl)ethanamine;hydrochloride Chemical group Cl.CC(N)C1=CC=C(Cl)C=C1 BADVPOKOZMYLPI-UHFFFAOYSA-N 0.000 description 3
- NEJBNENMSPOJDE-UHFFFAOYSA-N 3-(4-methoxyphenyl)butanamide Chemical compound COC1=CC=C(C(C)CC(N)=O)C=C1 NEJBNENMSPOJDE-UHFFFAOYSA-N 0.000 description 3
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 3
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940005529 antipsychotics Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 3
- VYSYZMNJHYOXGN-UHFFFAOYSA-N ethyl n-aminocarbamate Chemical compound CCOC(=O)NN VYSYZMNJHYOXGN-UHFFFAOYSA-N 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- QGCLEUGNYRXBMZ-ZCFIWIBFSA-N (1r)-1-(4-fluorophenyl)ethanamine Chemical compound C[C@@H](N)C1=CC=C(F)C=C1 QGCLEUGNYRXBMZ-ZCFIWIBFSA-N 0.000 description 2
- JRZGPXSSNPTNMA-JTQLQIEISA-N (1s)-1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=CC=C2[C@@H](N)CCCC2=C1 JRZGPXSSNPTNMA-JTQLQIEISA-N 0.000 description 2
- SOZMSEPDYJGBEK-LURJTMIESA-N (1s)-1-(4-bromophenyl)ethanamine Chemical compound C[C@H](N)C1=CC=C(Br)C=C1 SOZMSEPDYJGBEK-LURJTMIESA-N 0.000 description 2
- JVLWNYKROJNLAS-RGMNGODLSA-N (1s)-1-[4-(trifluoromethyl)phenyl]ethanamine;hydrochloride Chemical compound Cl.C[C@H](N)C1=CC=C(C(F)(F)F)C=C1 JVLWNYKROJNLAS-RGMNGODLSA-N 0.000 description 2
- AQFLVLHRZFLDDV-VIFPVBQESA-N (1s)-1-phenylpropan-1-amine Chemical compound CC[C@H](N)C1=CC=CC=C1 AQFLVLHRZFLDDV-VIFPVBQESA-N 0.000 description 2
- IQVQNBXPYJGNEA-LURJTMIESA-N (1s)-1-pyridin-3-ylethanamine Chemical compound C[C@H](N)C1=CC=CN=C1 IQVQNBXPYJGNEA-LURJTMIESA-N 0.000 description 2
- ZIGRFQVTVOTIOG-JTQLQIEISA-N (1s)-2-methyl-1-[4-(trifluoromethyl)phenyl]propan-1-amine Chemical compound CC(C)[C@H](N)C1=CC=C(C(F)(F)F)C=C1 ZIGRFQVTVOTIOG-JTQLQIEISA-N 0.000 description 2
- PDNHLCRMUIGNBV-UHFFFAOYSA-N 1-pyridin-2-ylethanamine Chemical compound CC(N)C1=CC=CC=N1 PDNHLCRMUIGNBV-UHFFFAOYSA-N 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- UXNGEVJNOQJIJW-UHFFFAOYSA-N 2-(4-methylpiperazin-1-yl)-1-phenylethanamine Chemical compound C1CN(C)CCN1CC(N)C1=CC=CC=C1 UXNGEVJNOQJIJW-UHFFFAOYSA-N 0.000 description 2
- CLAGARRWBBUZDR-UHFFFAOYSA-N 2-morpholin-4-yl-1-phenylethanamine Chemical compound C=1C=CC=CC=1C(N)CN1CCOCC1 CLAGARRWBBUZDR-UHFFFAOYSA-N 0.000 description 2
- OQRPWJFDQXSBRH-UHFFFAOYSA-N 3h-pyrrolo[1,2-d][1,2,4]triazin-4-one Chemical compound OC1=NN=CC2=CC=CN12 OQRPWJFDQXSBRH-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000011725 BALB/c mouse Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 229940126093 GPR139 agonist Drugs 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 239000012124 Opti-MEM Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960003878 haloperidol Drugs 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- NPGAXSHDDOESHB-UHFFFAOYSA-N n',n'-dimethyl-1-phenylethane-1,2-diamine Chemical compound CN(C)CC(N)C1=CC=CC=C1 NPGAXSHDDOESHB-UHFFFAOYSA-N 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- ZSKGQVFRTSEPJT-UHFFFAOYSA-N pyrrole-2-carboxaldehyde Chemical compound O=CC1=CC=CN1 ZSKGQVFRTSEPJT-UHFFFAOYSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 230000003997 social interaction Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- XBWOPGDJMAJJDG-ZETCQYMHSA-N (1s)-1-cyclohexylethanamine Chemical compound C[C@H](N)C1CCCCC1 XBWOPGDJMAJJDG-ZETCQYMHSA-N 0.000 description 1
- LZDSYIZUCSUNKJ-PPHPATTJSA-N (1s)-2-methyl-1-phenylpropan-1-amine;hydrochloride Chemical compound Cl.CC(C)[C@H](N)C1=CC=CC=C1 LZDSYIZUCSUNKJ-PPHPATTJSA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- 229940114069 12-hydroxystearate Drugs 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- DMSSTTLDFWKBSX-UHFFFAOYSA-N 1h-1,2,3-benzotriazin-4-one Chemical group C1=CC=C2C(=O)N=NNC2=C1 DMSSTTLDFWKBSX-UHFFFAOYSA-N 0.000 description 1
- TVCXVUHHCUYLGX-UHFFFAOYSA-N 2-Methylpyrrole Chemical compound CC1=CC=CN1 TVCXVUHHCUYLGX-UHFFFAOYSA-N 0.000 description 1
- KTOQRRDVVIDEAA-UHFFFAOYSA-N 2-methylpropane Chemical compound [CH2]C(C)C KTOQRRDVVIDEAA-UHFFFAOYSA-N 0.000 description 1
- RDFZYUOHJBXMJA-UHFFFAOYSA-N 3,5-dimethyl-1h-pyrrole-2-carbaldehyde Chemical compound CC1=CC(C)=C(C=O)N1 RDFZYUOHJBXMJA-UHFFFAOYSA-N 0.000 description 1
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 1
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 229940123603 Dopamine D2 receptor antagonist Drugs 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102000038630 GPCRs class A Human genes 0.000 description 1
- 108091007907 GPCRs class A Proteins 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- RGCVKNLCSQQDEP-UHFFFAOYSA-N Perphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(Cl)=CC=C2SC2=CC=CC=C21 RGCVKNLCSQQDEP-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000013200 Stress disease Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- ZEEBGORNQSEQBE-UHFFFAOYSA-N [2-(3-phenylphenoxy)-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound C1(=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F)C1=CC=CC=C1 ZEEBGORNQSEQBE-UHFFFAOYSA-N 0.000 description 1
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 1
- SAHIZENKTPRYSN-UHFFFAOYSA-N [2-[3-(phenoxymethyl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound O(C1=CC=CC=C1)CC=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 SAHIZENKTPRYSN-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 238000003766 bioinformatics method Methods 0.000 description 1
- 150000001621 bismuth Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 229960001210 brexpiprazole Drugs 0.000 description 1
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 230000003185 calcium uptake Effects 0.000 description 1
- 229960005123 cariprazine Drugs 0.000 description 1
- KPWSJANDNDDRMB-QAQDUYKDSA-N cariprazine Chemical compound C1C[C@@H](NC(=O)N(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 KPWSJANDNDDRMB-QAQDUYKDSA-N 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 231100000868 delusion Toxicity 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000000442 dopamine 2 receptor blocking agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000006397 emotional response Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000002599 functional magnetic resonance imaging Methods 0.000 description 1
- 230000003370 grooming effect Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000007758 minimum essential medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000008450 motivation Effects 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229960001057 paliperidone Drugs 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 229960000762 perphenazine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 208000016254 weariness Diseases 0.000 description 1
Images
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
- A61K31/495—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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention relates to a pyrrolotriazinone compound, a pharmaceutical composition containing it, a preparation method and application thereof.
- Schizophrenia affects more than 20 million people worldwide. Its symptoms can be roughly divided into three categories according to their clinical features: positive symptoms, negative symptoms, and cognitive dysfunction. Positive symptoms refer to exaggeration or distortion of normal functional behavior, including hallucinations, delusions, and confusion. Negative symptoms refer to some defects in normal emotional responses or other thinking processes, including depression-like features such as apathy, aphasia, loss of motivation and pleasure, and negative world-weariness. Cognitive dysfunction is mainly manifested in the decline of attention, memory, and learning ability.
- First-generation antipsychotics also known as classic antipsychotics, are potent antagonists of dopamine D2 receptors.
- drugs include haloperidol, chlorpromazine, perphenazine, etc., which can effectively suppress the positive symptoms of schizophrenia, but long-term use of these drugs can induce extrapyramidal reactions similar to Parkinson's disease.
- the second-generation antipsychotic drugs include clozapine, risperidone, paliperidone, etc., which exert their effects by doubly blocking dopamine D2 receptors and serotonin 2A (5-HT 2A ) receptors.
- the third-generation antischizophrenia drugs include aripiprazole, brexpiprazole and cariprazine, which are partial agonists of dopamine D2 receptors.
- a "stabilizer" of dopamine the third-generation drug stabilizes the activity of the brain dopamine loop in a moderate range, greatly reduces extrapyramidal side effects, and significantly improves safety.
- the second and third generation are also collectively referred to as atypical antischizophrenia drugs.
- all drugs for the treatment of schizophrenia can effectively relieve positive symptoms, but most drugs have limited or no effect on improving negative symptoms and cognitive function. Therefore, there is an urgent need to develop drugs with a new mechanism of action for the negative symptoms and cognitive impairment of schizophrenia.
- the orphan receptor GPR139 was identified from bioinformatics analysis of the human genome and belongs to the class A G protein-coupled receptors (GPCRs). In mammals, GPR139 is mainly expressed in the central nervous system. GPR139 is highly expressed in the medial habenula of animals and humans. Multiple studies have shown a link between the habenula and schizophrenia. Damage to the overall structure of the habenula in rodents can lead to schizophrenia-related symptoms such as reduced social activities, impaired cognitive function, and hyperresponse to stressful stimuli (Wang et al., Neuroreport 2013, 24:276-280).
- GPCRs G protein-coupled receptors
- Calcification of the habenula occurs more frequently in patients with chronic schizophrenia than in normal individuals, and the volume of the habenula is also altered (Sandyk et al., Int J Neurosci 1992, 67:19-30).
- Functional magnetic resonance (fMRI) studies have shown that when normal people do matching tasks, the habenula is activated when errors occur, but in patients with chronic schizophrenia, the habenula is not activated significantly after matching errors occur ( Shepard et al., Schizophr Bull 2006, 32:417-421).
- the GPR139 knockout mouse model exhibits behavioral characteristics associated with schizophrenia, such as decreased spontaneous movement, sensorimotor gating defects, and cognitive impairment, and its symptoms can be improved by administering the dopamine D2 receptor antagonist haloperidol (Dao et al., Neuropsychopharmacology 2021). Based on these results, targeting GPR139 has the potential to enable the development of novel antischizophrenia drugs, especially for negative symptoms.
- the technical problem to be solved by the present invention is the defect of single structure of the existing GPR139 receptor agonists.
- the present invention provides a pyrrolotriazinone compound, a pharmaceutical composition containing it, a preparation method and application thereof.
- the pyrrolotriazinone compound of the invention has a novel structure and strong agonistic activity on the GPR139 receptor.
- the present invention solves the above-mentioned technical problems through the following technical solutions.
- the present invention provides a pyrrolotriazinone compound represented by formula I or a pharmaceutically acceptable salt thereof;
- R 1 , R 2 , R 3 and R 4 are independently H, halogen , C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl , 1 , 2 or 3 C 1-6 alkyl substituted by R 1-1 , C 3-6 cycloalkyl substituted by 1, 2 or 3 R 1-2 or substituted by 1, 2 or 3 R 1-3 -OC 1-6 alkyl ;
- R 1-1 , R 1-2 and R 1-3 are independently halogen
- R 5 is H or C 1-6 alkyl
- R 6 and R 7 are independently H, C 1-6 alkyl , C 3-6 cycloalkyl , C 1-6 alkyl substituted by 1, 2 or 3 R 6-1 or substituted by 1 , 2 or 3 R 6-2 substituted C 3 - 6 cycloalkyl groups;
- R 6-1 is independently halogen, -OC 1 - 6 alkyl or -NR a R b ;
- R 6-2 is independently halogen, -OC 1 - 6 alkyl or -NR a R b ;
- R a and R b are independently C 1 - 6 alkyl
- R a and R b together form a 5-6 membered heterocycloalkyl group or a 5-6 membered heterocycloalkyl group substituted by 1, 2 or 3 R a-1 with the nitrogen atoms connected to them;
- the 5 -6-membered heterocycloalkyl is independently 1, 2 or 3 heteroatoms independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 5-6 membered heterocycloalkyl;
- R a-1 is independently C 1 - 6 alkyl
- Q is a C 6-10 aromatic ring, a 5-10 membered heteroaryl ring, a C 3-6 cycloalkyl group or a 5-6 membered heterocycloalkyl group;
- the 5-10 membered heteroaryl ring is a heteroatom independently selected from 1, 2 or 3 of N, O and S, 5-10 membered heteroaromatic rings with 1, 2 or 3 heteroatoms;
- n 0, 1, 2, 3, 4 or 5;
- R 8 is independently halogen, -OH, -CN, -NH 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 1 - substituted by 1, 2 or 3 R 8-1 6 alkyl or -OC 1 - 6 alkyl substituted by 1, 2 or 3 R 8-2 ;
- R 8-1 and R 8-2 are independently halogen
- R 8 and R 7 together form -(CH 2 ) m -, m is 2 or 3;
- the carbon atoms with "*" and “#” are achiral carbon atoms or chiral carbon atoms, and when they are chiral carbon atoms, they are independently in S configuration and/or R configuration.
- R 1 , R 2 , R 3 and R 4 are independently H, halogen , C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl , 1 , 2 or 3 C 1-6 alkyl substituted by R 1-1 , C 3-6 cycloalkyl substituted by 1, 2 or 3 R 1-2 or substituted by 1, 2 or 3 R 1-3 -OC 1-6 alkyl ;
- R 1-1 , R 1-2 and R 1-3 are independently halogen
- R 5 is H or C 1-6 alkyl
- R 6 and R 7 are independently H, C 1-6 alkyl , C 3-6 cycloalkyl, C 1-6 alkyl substituted by 1, 2 or 3 R 6-1 or substituted by 1 , 2 or 3 R 6-2 substituted C 3 - 6 cycloalkyl groups;
- R 6-1 is independently halogen, -OC 1 - 6 alkyl or -NR a R b ;
- R 6-2 is independently halogen, -OC 1 - 6 alkyl or -NR a R b ;
- R a and R b are independently C 1 - 6 alkyl
- R a and R b together form a 5-6 membered heterocycloalkyl group or a 5-6 membered heterocycloalkyl group substituted by 1, 2 or 3 R a-1 with the nitrogen atoms connected to them;
- the 5 -6-membered heterocycloalkyl is independently 1, 2 or 3 heteroatoms independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 5-6 membered heterocycloalkyl;
- R a-1 is independently C 1 - 6 alkyl
- Q is a C6-10 aromatic ring or a 5-10 membered heteroaromatic ring; the 5-10 membered heteroaromatic ring is one, two or three heteroatoms independently selected from N, O and S, and the heteroatoms are independently selected from N, O and S. 5-10 membered heteroaromatic rings with 1, 2 or 3 atoms;
- n 0, 1, 2, 3, 4 or 5;
- R 8 is independently halogen, -OH, -CN, -NH 2 , C 1-6 alkyl, -OC 1-6 alkyl, C 1 - substituted by 1, 2 or 3 R 8-1 6 alkyl or -OC 1 - 6 alkyl substituted by 1, 2 or 3 R 8-2 ;
- R 8-1 and R 8-2 are independently halogen
- R 8 and R 7 together form -(CH 2 ) m -, m is 2 or 3;
- the carbon atoms with "*" and “#” are achiral carbon atoms or chiral carbon atoms, and when they are chiral carbon atoms, they are independently in S configuration and/or R configuration.
- R 1 , R 2 and R 3 are independently H or C 1-6 alkyl.
- R4 is independently H.
- R 5 is H.
- R 6 is H.
- R 7 is C 1-6 alkyl or C 1-6 alkyl substituted by 1 , 2 or 3 R 6-1 .
- R 6-1 is independently -NR a R b .
- R a and R b are independently C 1-6 alkyl. In a certain aspect, n is 0 or 1.
- R 8 is halogen, -OH, -CN, C 1 - 6 alkyl, -OC 1 - 6 alkyl, C 1 - substituted by 1, 2 or 3 R 8-1 6 alkyl or -OC 1 - 6 alkyl substituted by 1, 2 or 3 R 8-2 ;
- R 8 and R 7 together form -(CH 2 ) m -, m is 2 or 3; for example, R 8 is halogen, -OH, C 1 - 6 alkyl, -OC 1 - 6 alkyl or replaced by 1 -OC 1-6 alkyl substituted by one, two or three R 8-2 ; or, R 8 and R 7 together form -(CH 2 ) m -, m is 2 or 3.
- the C 1-6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl radical or tert-butyl, for example methyl.
- the halogen is F, Cl, Br or I.
- the C 1-6 alkyl in the C 1-6 alkyl and the C 1-6 alkyl substituted by 1, 2 or 3 R 6-1 are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, for example methyl or ethyl.
- the C 1-6 alkyl group is independently methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl or tert-butyl, For example methyl.
- R a and R b together form a 5-6 membered heterocycloalkyl group or a 5-6 membered heterocycloalkane substituted by 1, 2 or 3 R a- 1
- the 5-6 membered heterocycloalkyl group or the 5-6 membered heterocycloalkyl group in the 5-6 membered heterocycloalkyl group substituted by 1, 2 or 3 R a-1 is independently
- the heteroatoms are independently selected from N and O, and the number of heteroatoms is 1 or 2 5-6 membered heterocycloalkyl groups; for example,
- the C 1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl, for example For methyl.
- the C 6 -10 aromatic ring is a benzene ring or a naphthalene ring, for example, a benzene ring.
- the 5-10 membered heteroaromatic ring is a 5-6 membered heteroaromatic ring, such as a pyridine ring, and another example is
- the C 3-6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclohexyl.
- the halogen is independently F, Cl, Br or I, such as F, Cl or Br.
- the C 1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert -butyl, such as methyl base.
- R 8 the -OC 1 - 6 alkyl in the -OC 1 - 6 alkyl and the -OC 1 - 6 alkyl in the -OC 1 - 6 alkyl substituted by 1, 2 or 3 R 8-2
- the radicals are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, for example methoxy.
- the halogen is independently F, Cl, Br or I, such as F.
- R 8-a , R 8-b , R 8-c and R 8-d are independently H, halogen, -OH, -CN, -NH 2 , C 1 - 6 alkyl, -OC 1 - 6 alkyl , C 1-6 alkyl substituted by 1, 2 or 3 R 8-1 or -OC 1-6 alkyl substituted by 1, 2 or 3 R 8-2 ;
- R 8-e is H, halogen, -OH, -CN, -NH 2 , C 1-6 alkyl, -OC 1-6 alkyl, C substituted by 1, 2 or 3 R 8-1 1 - 6 alkyl or -OC 1 - 6 alkyl substituted by 1, 2 or 3 R 8-2 ;
- R 8-e forms -(CH 2 ) m - together with R 7 , m is 2 or 3.
- R 6 is H.
- R 7 is -CH 3 , -CH 2 CH 3 ,
- R 7 is -CH 3 , -CH 2 CH 3 ,
- R 8 is independently F, Cl, Br, -OH, -CH 3 , -OCH 3 , -OCF 3 , -CF 3 or CN, such as F, Cl, Br, -OH, - CH 3 , —OCH 3 , or —OCF 3 .
- the pyrrolotriazinone compound shown in formula I is selected from any of the following compounds:
- the present invention also provides a pharmaceutical composition, which comprises the pyrrolotriazinone compound represented by formula I or a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.
- the present invention also provides a preparation method for the pyrrolotriazinone compound represented by formula I and a pharmaceutically acceptable salt thereof: it comprises the following steps: a condensation reaction occurs between compound II and compound III;
- the present invention also provides the application of the pyrrolotriazinone compound shown in formula I and its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of medicines, the medicines are used for the treatment of and/or Prevent GPR139 receptor-related diseases;
- the GPR139 receptor-related diseases can be schizophrenia, bipolar disorder, depression, cognitive impairment, autism spectrum disorder, sleep disorder, attention deficit hyperactivity disorder, trauma Post-stress disorder, substance abuse, drug addiction, eating disorders, OCD, anxiety, pain, or fibromyalgia.
- the present invention also provides the application of the pyrrolotriazinone compound shown in formula I and its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of medicines, the medicines are used for the treatment of and/or Prevention of Schizophrenia, Bipolar Disorder, Depression, Cognitive Impairment, Autism Spectrum Disorder, Sleep Disorder, ADHD, PTSD, Substance Abuse, Addiction, Eating Disorders, OCD , anxiety, pain, or fibromyalgia.
- halogen refers to fluorine, chlorine, bromine or iodine.
- alkyl refers to a straight-chain or branched-chain alkyl group having the specified number of carbon atoms (eg, C 1-6 ).
- Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
- cycloalkyl refers to a cyclic group consisting only of carbon atoms having a specified number of carbon atoms (eg, C 3 to 6 ). Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
- heterocycloalkyl refers to a group having a specified number of ring atoms (such as 5-6 members), a specified number of heteroatoms (such as 1, 2 or 3), a specified type of heteroatom (N, O, and S One or more of the cyclic groups.
- Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
- aromatic ring refers to a cyclic group consisting only of carbon atoms with a specified number of carbon atoms (such as C 6-10 ), which is monocyclic or polycyclic, and at least one ring is aromatic (according to Huckell rule).
- Aromatic rings include, but are not limited to, benzene rings, naphthalene rings, and the like.
- heteromatic ring refers to a specified number of ring atoms (such as 5-10 members), a specified number of heteroatoms (such as 1, 2 or 3), and a specified heteroatom type (in N, O and S One or more of ), which is monocyclic or polycyclic, and at least one ring is aromatic (according to Huckel's rule). Heteroaromatic rings are connected to other segments in the molecule through aromatic rings or non-aromatic rings.
- Heteroaromatic rings include, but are not limited to, furan rings, pyrrole rings, thiophene rings, pyrazole rings, imidazole rings, oxazole rings, thiazole rings, pyridine rings, pyrimidine rings, indole rings, and the like.
- a "-" at the end of a group means that the group is attached to other fragments in the molecule through this site.
- -OCH3 is methoxy.
- any variable (such as the group R a-1 ) appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other.
- a 5-6 membered heterocycloalkyl group substituted by 3 R a-1 means that the 5-6 membered heterocycloalkyl group will be substituted by 3 R a-1 , and the definitions of the 3 R a-1 are independent of each other , do not affect each other.
- pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base.
- base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like.
- acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
- Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, and the like. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.
- therapeutically effective amount refers to the amount of a compound administered to a patient sufficient to effectively treat the disease.
- the therapeutically effective amount will vary according to the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.
- pharmaceutical excipients refers to the excipients and additives used in the production of drugs and the preparation of prescriptions, and refers to all substances contained in pharmaceutical preparations except for active ingredients. For details, see Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).
- treating refers to any of the following: (1) amelioration of one or more biological manifestations of disease; (2) interference with one or more points in the biological cascade leading to disease; (3) slowing of disease The development of one or more biological manifestations.
- prevention refers to reducing the risk of developing a disease.
- patient refers to any animal, preferably a mammal, most preferably a human, who has been or is about to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.
- the reagents and raw materials used in the present invention are all commercially available.
- the positive and progressive effect of the present invention lies in that the pyrrolotriazinone compound of the present invention has novel structure and strong agonistic activity on GPR139 receptor.
- FIG. 1 is a graph showing the results of biological test Example 3.
- Step 2 Preparation of ethyl 2-(4-oxopyrrolo[1,2-d][1,2,4]triazin-3(4H)yl)acetate
- Step 4 (S)-N-(1-(4-fluorophenyl)ethyl-2-(4-oxopyrrolo[1,2-d][1,2,4]triazine-3( 4H) base) the preparation of acetamide (compound I-1)
- Example 2 Replace (S)-1-(4-methylphenyl)ethylamine in Example 2 with (S)-1-(4-methoxyphenyl)ethylamine, the rest of the required raw materials, reagents and preparation The method was the same as in Example 2 to obtain white solid compound (I-3) (0.060 g, yield 23%).
- Example 2 (S)-1-(4-methylphenyl)ethylamine in Example 2 is replaced by (S)-1-phenylethylamine, and all the other required raw materials, reagents and preparation methods are the same as in Example 2 to obtain white Solid compound (I-4) (0.070 g, yield 30%).
- Example 2 (S)-1-(4-methylphenyl)ethylamine in Example 2 is replaced by (S)-1-4-(trifluoromethoxy)phenethylamine, all the other required raw materials, reagents and The preparation method was the same as in Example 2 to obtain white solid compound (I-5) (0.120 g, yield 40%).
- Example 2 (S)-1-(4-methylphenyl)ethylamine in Example 2 is replaced with (S)-1-(4-chlorophenyl)ethylamine hydrochloride, the rest of the required raw materials, reagents and The preparation method was the same as in Example 2 to obtain white solid compound (I-6) (0.112 g, yield 51%).
- Example 2 (S)-1-(4-methylphenyl)ethylamine in Example 2 is replaced by (S)-4-(1-aminoethyl)phenol, and the rest of the required raw materials, reagents and preparation methods are implemented with Example 2.
- Example 2 (S)-1-(4-methylphenyl)ethylamine in Example 2 is replaced by (S)-1-phenylpropylamine, and all the other required raw materials, reagents and preparation methods are the same as in Example 2 to obtain white Solid compound (I-8) (0.095 g, yield 59%).
- Example 7 Replace (S)-4-(1-aminoethyl)phenol in Example 7 with N1,N1-dimethyl-2-phenylethane-1,2-diamine, the rest of the required raw materials, reagents And the preparation method was the same as in Example 7 to obtain brown foamy solid compound (I-10) (0.050 g, yield 28%).
- Step 3 Preparation of ethyl 2-(6-methyl-4-oxopyrrolo[1,2-d][1,2,4]triazin-3(4H)yl)acetate
- Step 2 Preparation of ethyl 2-(6,8-dimethyl-4-oxopyrrolo[1,2-d][1,2,4]triazin-3(4H)yl)acetate
- Step 4 (S)-2-(6,8-Dimethyl-4-oxopyrrolo[1,2-d][1,2,4]triazin-3(4H)yl)-N- Preparation of (1-(4-fluorophenyl)ethyl)acetamide (I-17)
- Example 2 (S)-1-(4-methylphenyl)ethylamine in Example 2 is replaced by (S)-1-(1-naphthyl)ethylamine, and the rest of the required raw materials, reagents and preparation methods are implemented in the same way Example 2, white solid compound (I-23) (0.130 g, yield 72%) was obtained.
- Example 2 (S)-1-(4-methylphenyl)ethylamine in Example 2 is replaced by (S)-1-(4-bromophenyl)ethylamine, and the rest of the required raw materials, reagents and preparation methods are implemented in the same way Example 2, white solid compound (I-24) (0.130 g, yield 66%) was obtained.
- Example 2 (S)-1-(4-methylphenyl)ethylamine in Example 2 is replaced by (S)-1-(pyridin-2-yl)ethylamine, and the rest of the required raw materials, reagents and preparation methods are the same Example 2, white solid compound (I-25) (0.110 g, yield 71%) was obtained.
- 11 step 3 is replaced by (S)-1-(pyridin-2-yl)ethylamine, and all the other required raw materials, reagents and preparation methods are the same as embodiment 11 step 3, to obtain white solid compound (I -28) (0.080 g, yield 53%).
- Example 7 The (S)-4-(1-aminoethyl)phenol in Example 7 is replaced by (S)-1-(pyridin-3-yl)ethylamine, and the rest of the required raw materials, reagents and preparation methods are the same as the examples 7. Obtained white solid compound (I-29) (0.064 g, yield 41%).
- Example 7 Replace (S)-4-(1-aminoethyl)phenol in Example 7 with (R)-1-(4-fluorophenyl)ethylamine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 7. Obtain white solid compound I-31 (0.130 g, yield 79%).
- Example 7 (S)-4-(1-aminoethyl)phenol in Example 7 is replaced by (S)-1-[4-(trifluoromethyl)phenyl]ethylamine hydrochloride, and all the other required raw materials , the reagents and preparation method were the same as in Example 7 to obtain white solid compound I-32 (0.105 g, yield 79%).
- Example 7 Replace (S)-4-(1-aminoethyl)phenol in Example 7 with (S)-4-(1-aminoethyl)benzocyanide hydrochloride, the rest of the required raw materials, reagents and preparation The method was the same as in Example 7 to obtain white solid compound I-33 (0.060 g, yield 72%).
- Example 7 (S)-4-(1-aminoethyl)phenol in Example 7 is replaced by (S)-2-methyl-1-phenylpropan-1-amine hydrochloride, the rest of the required raw materials, reagents And the preparation method was the same as in Example 7 to obtain white solid compound I-34 (0.035 g, yield 41%).
- Example 7 (S)-4-(1-aminoethyl)phenol in Example 7 is replaced by (S)-1-cyclohexylethylamine, and all the other required raw materials, reagents and preparation methods are the same as in Example 7 to obtain light yellow Solid compound I-36 (0.090 g, yield 57%).
- Example 7 (S)-4-(1-aminoethyl)phenol in Example 7 is replaced by (S)-1-(4-fluorophenyl)-2-methylpropan-1-amine hydrochloride, and the rest The required raw materials, reagents and preparation methods were the same as in Example 7 to obtain white solid compound I-37 (0.100 g, yield 80%).
- Example 7 (S)-4-(1-aminoethyl)phenol in Example 7 was replaced by (S)-2-methyl-1-(4-(trifluoromethyl)phenyl)propan-1-amine , the rest of the required raw materials, reagents and preparation methods were the same as in Example 7 to obtain white solid compound I-38 (0.110 g, yield 77%).
- Example I-39 (S)-1-(4-fluorophenyl)-2-methylpropan-1-amine hydrochloride in Example I-39 was replaced by (S)-2-methyl-1-(4- (Trifluoromethyl)phenyl)propan-1-amine, the rest of the required raw materials, reagents and preparation methods were the same as in Example 26 to obtain white solid compound I-40 (0.120 g, yield 76%).
- Example 26 (S)-1-(1-naphthyl)ethylamine was replaced by (S)-1-phenylpropylamine, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 26 to obtain white solid compound I -41 (0.05 g, yield 31%).
- Example 26 Replace (S)-1-(1-naphthyl)ethylamine with (S)-1,2,3,4-tetrahydro-1-naphthylamine in Example 26, and the remaining required raw materials, reagents and preparation methods Similar to Example 26, white solid compound I-42 (0.085 g, yield 63%) was obtained.
- Example 26 Replace (S)-1-(1-naphthyl)ethylamine with (S)-1-(pyridin-3-yl)ethylamine in Example 26, and the remaining required raw materials, reagents and preparation methods are the same as in Example 26 , to obtain white solid compound I-43 (0.065 g, yield 52%).
- Example 26 Replace (S)-1-(1-naphthyl)ethylamine in Example 26 with N 1 ,N 1 -dimethyl-2-phenylethane-1,2-diamine, and the rest of the required raw materials, The reagents and preparation method were the same as in Example 26 to obtain brown foamy solid compound I-44 (0.055 g, yield 40%).
- Example 26 Replace (S)-1-(1-naphthyl)ethylamine with (R)-1-(4-fluorophenyl)ethylamine in Example 26, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 26 , to obtain white solid compound I-45 (0.040 g, yield 18%).
- Example 26 (S)-1-(1-naphthyl)ethylamine in Example 26 was replaced with (S)-1-[4-(trifluoromethyl)phenyl]ethylamine hydrochloride, and the rest of the required raw materials, The reagents and preparation method were the same as in Example 26 to obtain white solid compound I-46 (0.092 g, yield 71%).
- the agonistic activity of the compound of the present invention on GPR139 is determined by calcium flux assay (Molecular Devices).
- the specific operation method is as follows:
- Cell culture (CHO-K1 cell line, cell culture medium: Ham's F12+10%FBS+1%PS (Penicillin-Streptomycin).
- the cells were resuspended with 17 mL of cell culture medium, spread into a black-bottomed 384-well plate (Greiner, Cat#781091), and 40 ⁇ L of cell fluid was added to each well, and the number of cells was 15,000 to 20,000 per well. ; Incubate at 37°C, 5% CO 2 for 16 hours.
- the compound to be tested was prepared into a stock solution with a concentration of 10 mM with DMSO, then diluted to 30 ⁇ M with 0.1% BSA (bovine serum albumin) solution, and then diluted 3 times, 16 concentration points; agonist positive Both the control TAK-041 and the blank control DMSO started at 30 ⁇ M, with 16 concentration points.
- BSA bovine serum albumin
- Table 1 shows the agonistic activity of the compounds of the present invention on GPR139.
- E max maximum effect of the compound of the present application/maximum effect of TAK-041; NT, not tested.
- mice After a single intraperitoneal injection of the compound in male mice, blood samples and brain tissue were collected at different time points. Pharmacokinetic characteristics and brain distribution in mice.
- mice Thirty-six male C57 mice were randomly divided into 4 groups according to body weight, with 9 mice in each group. One day before the administration, fasting without water for 12-14 hours, and giving food 4 hours after the administration.
- Compound vehicle 10% DMSO + 10% solutol (polyethylene glycol-12 hydroxystearate) + 80% physiological saline.
- 0.1 mL of blood was collected through the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube and placed on an ice bath. Centrifuge at 5000 rpm for 10 min at 4°C to collect plasma. IP plasma and brain tissue collection time points: 0.5h, 2h and 4h. Before analysis and detection, all plasma samples were stored at -80°C. Brain tissue was collected at 0.5h, 2h, and 4h. After the mice were euthanized by bloodletting, the brain tissue was taken out and cleaned. After accurate weighing, it was homogenized with 50% methanol water at a ratio of 1:4. The homogenate samples were stored at -80°C for analysis.
- the peak integration method of the spectrum sample is automatic integration; the ratio of the peak area of the sample to the peak area of the internal standard is used as the index, and the concentration of the sample is used for regression. Regression method: linear regression, the weight coefficient is 1/X 2 .
- Pharmacokinetic parameters were analyzed with WinNonlin Professional v6.3 (Pharsight, USA) using non-compartmental models.
- C max is the measured maximum blood drug concentration
- the area under the blood drug concentration-time curve AUC (0 ⁇ t) is calculated by the trapezoidal method
- t max is the peak time of blood drug concentration after administration.
- mice were intraperitoneally injected with different doses of I-5, and the therapeutic effect of the developed compound on the negative symptoms of schizophrenia was verified by social interaction experiments
- the experimental subjects were 6-week-old male BALB/c wild-type mice weighing about 22 grams, which were purchased from Shanghai Lingchang Biotechnology Co., Ltd. Raised in SPF-grade breeding facilities, 2 per cage, 12-hour light-dark cycle, free access to food and water. All behavioral experiments in this project were done during the light cycle. This experiment complied with the relevant laws and regulations on experimental animal welfare ethics throughout the whole process, and accepted the supervision and inspection of the ethics committee and laboratory animal managers.
- the behavior box used in this experiment is 40 centimeters in length, width and height. During the experiment, 4 mice were tested in 4 behavior boxes at the same time. This experiment uses EthoVision XT for experimental setup and video recording.
- mice were randomly divided into 6 groups, respectively negative control group; positive control group: TAK-041 (3mg/kg), TAK-041 (1mg/kg); experimental group: I-5 (3mg/kg), I-5 -5 (1mg/kg), I-5 (0.3mg/kg), ⁇ 12 rats in each group.
- mice were 5 weeks old when they were purchased. After one week of observation, the experiment was started when they were 6 weeks old and their body weight reached about 22 grams. Before each experiment, the experimental mice were restricted in food 18 hours in advance. On the day of the experiment, the mice were transferred to the behavioral laboratory to familiarize themselves with the environment 1 hour in advance. Next, administration was administered by intraperitoneal injection, and each mouse was returned to the original mouse cage after administration. After 20 minutes, the experimental mice were put into the behavior box to adapt for 10 minutes, and then the stimulus mice (the same batch of BALB/c) were put into the corner of the behavior box away from the experimental mice, and the two mice were allowed to explore freely for 10 minutes. The camera monitors and records mouse activity and archives it.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Addiction (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种式(I)所示的吡咯并三嗪酮类化合物或其药学上可接受的盐、含其的药物组合物、其制备方法及其应用。该吡咯并三嗪酮类化合物对GPR139受体具有激动活性。
Description
本申请要求申请日为2022年3月1日的中国专利申请202210195902X的优先权。本申请引用上述中国专利申请的全文。
本发明涉及一种吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用。
精神分裂症在全世界影响着超过2000万人。其症状根据其临床特征可大致划分为三类：阳性症状、阴性症状和认知功能障碍。阳性症状是指正常功能行为的夸大或歪曲，包括幻觉、妄想、思维混乱等。阴性症状是指正常情绪反应或其他思维过程中所存有的一些缺陷，包括情感淡然、贫语症、动机与快感丧失、消极厌世等抑郁样特征。认知功能障碍主要表现为注意力、记忆力、学习能力等下降。
以药物研发的历史脉络和药理学特性划分，当前的抗精神分裂症药物可以分为三代。第一代抗精神病药物也被称为典型抗精神病药物，是多巴胺D2受体的强效拮抗剂。目前常用的包括氟哌啶醇、氯丙嗪、奋乃静等，可以有效抑制精神分裂症阳性症状，但长期服用这类药物会诱发类似帕金森病的锥体外系反应。第二代抗精神病药物包括氯氮平、利培酮、帕利哌酮等，通过双重阻断多巴胺D2受体和血清素2A(5-HT
2A)受体而产生作用。由于抑制5-HT
2A受体可以间接促进多巴胺神经元释放多巴胺，因此第二代药物诱发的锥体外系副作用明显降低。但是，二代药物的代谢综合征(过度肥胖、胰岛素抵抗、血脂异常和高血压)的风险高于传统抗精神病药物。第三代抗精神分裂症药物包括阿立哌唑(aripiprazole)、依匹哌唑(brexpiprazole)和卡利拉嗪(cariprazine)三种，是多巴胺D2受体的部分激动剂。作为多巴胺的“稳定剂”，第三代药物稳定大脑多巴胺环路活性在适中范围，大大降低了锥体外系副作用，安全性也得到明显提升。第二代与第三代也合称为非典型抗精神分裂症药物。目前，所有针对精神分裂症治疗的药物都能有效缓解阳性症状，然而绝大部分药物在改善阴性症状和认知功能方面药效有限或无效。因此，亟需研发针对精神分裂症阴性症状和认知障碍的全新作用机制药物。
孤儿受体GPR139是从人类基因组的生物信息学分析中鉴定到的，属于A类G蛋白偶联受体(GPCR)。在哺乳动物中，GPR139主要在中枢神经系统中表达，最高表达部位为纹状体、垂体、缰核、丘脑和下丘脑(Matsuo等,Biochem Biophys Res Commun 2005,331:363-369)，在啮齿动物和人类缰核的内侧GPR139高度表达。多项研究表明缰核与精神分裂症具有一定联系。啮齿类动物缰核的整体结构损伤会导致其社交活动减少、认知功能损伤、对压力刺激的过度反应等精神分裂症相关的症状(Wang等,Neuroreport 2013,24:276-280)。慢性精神分裂症患者与正常人对比其缰核发生钙化的频率更高，而且缰核的体积也发生改变(Sandyk等,Int J Neurosci 1992,67:19-30)。功能核磁共振(fMRI)研究显示，正常人在做匹配任务时，当发生错误时其缰核会被激活，而在慢性精神分裂症患者中，发 生匹配错误后，其缰核并没有明显激活(Shepard等,Schizophr Bull 2006,32:417-421)。在GPR139敲除的小鼠模型上表现出自发运动下降、感觉运动门控缺陷、认知障碍等与精神分裂症相关的行为特征，通过给予多巴胺D2受体拮抗剂氟哌啶醇可以改善其症状(Dao等,Neuropsychopharmacology 2021)。基于这些结果，靶向GPR139有潜力能够开发新型抗精神分裂症药物，尤其是针对阴性症状的药物。
2018年被报道的选择性GPR139激动剂JNJ-63533054(EC
50＝16nM)可以减少酒精依赖性大鼠的自我饮酒和痛觉过敏(Kononoff等,eNeuro 2018,5)，但在体内研究中并没有表现出明显的行为调节。2021年日本Takeda公司公布了一种具有苯并三嗪酮结构的选择性GPR139激动剂TAK-041(EC
50＝22nM)，已被证实在小鼠模型上可用于治疗与精神分裂症相关的阴性症状(Reichard等,J Med Chem 2021,64:11527-11542)，目前已成功进入临床Ⅱ期试验。
发明内容
本发明要解决的技术问题是现有的GPR139受体激动剂的结构单一的缺陷，本发明提供了一种吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用。本发明的吡咯并三嗪酮类化合物结构新颖，对GPR139受体有较强的激动活性。
本发明通过下述技术方案解决上述技术问题。
本发明提供了一种如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐；
其中，
R
1、R
2、R
3和R
4独立地为H、卤素、C
1-
6烷基、C
3-
6环烷基、-O-C
1-
6烷基、被1个、2个或3个R
1-1取代的C
1-
6烷基、被1个、2个或3个R
1-2取代的C
3-
6环烷基或被1个、2个或3个R
1-3取代的-O-C
1-
6烷基；
R
1-1、R
1-2和R
1-3独立地为卤素；
R
5为H或C
1-
6烷基；
R
6和R
7独立地为H、C
1-
6烷基、C
3-
6环烷基、被1个、2个或3个R
6-1取代的C
1-
6烷基或被1个、2个或3个R
6-2取代的C
3-
6环烷基；
R
6-1独立地为卤素、-O-C
1-
6烷基或-NR
aR
b；
R
6-2独立地为卤素、-O-C
1-
6烷基或-NR
aR
b；
R
a和R
b独立地为C
1-
6烷基；
或，R
a和R
b与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个R
a-1取代的5-6元杂环烷基；所述5-6元杂环烷基独立地为杂原子独立地选自N、O和S中的1种、2种或3种，杂原子的个数为1个、2个或3个的5-6元杂环烷基；
R
a-1独立地为C
1-
6烷基；
Q为C
6-
10芳环、5-10元杂芳环、C
3-6环烷基或5-6元杂环烷基；所述5-10元杂芳环为杂原子独立地选自N、O和S中的1种、2种或3种，杂原子的个数为1个、2个或3个的5-10元杂芳环；
n为0、1、2、3、4或5；
R
8独立地为卤素、-OH、-CN、-NH
2、C
1-
6烷基、-O-C
1-
6烷基、被1个、2个或3个R
8-1取代的C
1-
6烷基或被1个、2个或3个R
8-2取代的-O-C
1-
6烷基；
R
8-1和R
8-2独立地为卤素；
或，R
8与R
7一起形成-(CH
2)
m-，m为2或3；
带“*”、“#”的碳原子为非手性碳原子或手性碳原子，当为手性碳原子时，独立地为S构型和/或R构型。
在某一方案中，如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐中，某些基团的定义可如下所述，其他基团的定义可如本发明任一方案所述(以下简称“在某一方案中”)：
其中，
R
1、R
2、R
3和R
4独立地为H、卤素、C
1-
6烷基、C
3-
6环烷基、-O-C
1-
6烷基、被1个、2个或3个R
1-1取代的C
1-
6烷基、被1个、2个或3个R
1-2取代的C
3-
6环烷基或被1个、2个或3个R
1-3取代的-O-C
1-
6烷基；
R
1-1、R
1-2和R
1-3独立地为卤素；
R
5为H或C
1-
6烷基；
R
6和R
7独立地为H、C
1-
6烷基、C
3-
6环烷基、被1个、2个或3个R
6-1取代的C
1-
6烷基或被1个、2个或3个R
6-2取代的C
3-
6环烷基；
R
6-1独立地为卤素、-O-C
1-
6烷基或-NR
aR
b；
R
6-2独立地为卤素、-O-C
1-
6烷基或-NR
aR
b；
R
a和R
b独立地为C
1-
6烷基；
或，R
a和R
b与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个R
a-1取代的5-6元杂环烷基；所述5-6元杂环烷基独立地为杂原子独立地选自N、O和S中的1种、2种或3种，杂原子的个数为1个、2个或3个的5-6元杂环烷基；
R
a-1独立地为C
1-
6烷基；
Q为C
6-
10芳环或5-10元杂芳环；所述5-10元杂芳环为杂原子独立地选自N、O和S中的1种、2种或3种，杂原子的个数为1个、2个或3个的5-10元杂芳环；
n为0、1、2、3、4或5；
R
8独立地为卤素、-OH、-CN、-NH
2、C
1-
6烷基、-O-C
1-
6烷基、被1个、2个或3个R
8-1取代的C
1-
6烷基或被1个、2个或3个R
8-2取代的-O-C
1-
6烷基；
R
8-1和R
8-2独立地为卤素；
或，R
8与R
7一起形成-(CH
2)
m-，m为2或3；
带“*”、“#”的碳原子为非手性碳原子或手性碳原子，当为手性碳原子时，独立地为S构型和/或R构型。
在某一方案中，
其中，*、#、R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、Q和n的定义如前所述。
在某一方案中，R
1、R
2和R
3独立地为H或C
1-
6烷基。
在某一方案中，R
4独立地为H。
在某一方案中，R
5为H。
在某一方案中，R
6为H。
在某一方案中，R
7为C
1-
6烷基或被1个、2个或3个R
6-1取代的C
1-
6烷基。
在某一方案中，R
6-1独立地为-NR
aR
b。
在某一方案中，R
a和R
b独立地为C
1-6烷基。在某一方案中，n为0或1。
在某一方案中，R
8为卤素、-OH、-CN、C
1-
6烷基、-O-C
1-
6烷基、被1个、2个或3个R
8-1取代的C
1-
6烷基或被1个、2个或3个R
8-2取代的-O-C
1-
6烷基；
或，R
8与R
7一起形成-(CH
2)
m-，m为2或3；例如，R
8为卤素、-OH、C
1-
6烷基、-O-C
1-
6烷基或被1个、2个或3个R
8-2取代的-O-C
1-
6烷基；或，R
8与R
7一起形成-(CH
2)
m-，m为2或3。
在某一方案中，R
1、R
2、R
3和R
4中，所述C
1-
6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，例如为甲基。
在某一方案中，R
1-1、R
1-2和R
1-3中，所述卤素为F、Cl、Br或I。
在某一方案中，R
6和R
7中，所述C
1-
6烷基和被1个、2个或3个R
6-1取代的C
1-
6烷基中的C
1-
6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，例如为甲基或乙基。
在某一方案中，R
a和R
b中，所述C
1-
6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，例如为甲基。
在某一方案中，当R
a和R
b与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个R
a-
1取代的5-6元杂环烷基，所述的5-6元杂环烷基或被1个、2个或3个R
a-1取代的5-6元杂环烷基中的5-6元杂环烷基独立地为杂原子独立地选自N和O，杂原子的个数为1个或2个的5-6元杂环烷基；例如为
在某一方案中，R
a-1中，所述C
1-
6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，例如为甲基。
在某一方案中，Q中，所述C
6-
10芳环为苯环或萘环，例如为苯环。
在某一方案中，Q中，所述5-10元杂芳环为5-6元杂芳环，例如为吡啶环，再例如为
在某一方案中，Q中，所述C
3-6环烷基为环丙基、环丁基、环戊基或环已基，例如为环己基。
在某一方案中，R
8中，所述卤素独立地为F、Cl、Br或I，例如为F、Cl或Br。
在某一方案中，R
8中，所述C
1-
6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，例如为甲基。
在某一方案中，R
8中，所述-O-C
1-
6烷基和被1个、2个或3个R
8-2取代的-O-C
1-
6烷基中的-O-C
1-
6烷基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基，例如为甲氧基。
在某一方案中，R
8-1和R
8-2中，所述卤素独立地为F、Cl、Br或I，例如为F。
在某一方案中，当R
8与R
7一起形成-(CH
2)
m-，m为3。
在某一方案中，当Q为苯环时，
为
R
8-a、R
8-b、R
8-c和R
8-d独立地为H、卤素、-OH、-CN、-NH
2、C
1-
6烷基、-O-C
1-
6烷基、被1个、2个或3个R
8-1取代的C
1-
6烷基或被1个、2个或3个R
8-2取代的-O-C
1-
6烷基；
R
8-e为H、卤素、-OH、-CN、-NH
2、C
1-
6烷基、-O-C
1-
6烷基、被1个、2个或3个R
8-1取代的C
1-
6烷基或被1个、2个或3个R
8-2取代的-O-C
1-
6烷基；
或者，R
8-e与R
7一起形成-(CH
2)
m-，m为2或3。
在某一方案中，
为
在某一方案中，R
6为H。
在某一方案中，R
7为-CH
3、-CH
2CH
3、
例如为-CH
3、-CH
2CH
3或
在某一方案中，R
8独立地为F、Cl、Br、-OH、-CH
3、-OCH
3、-OCF
3、-CF
3或CN，例如为F、Cl、Br、-OH、-CH
3、-OCH
3或-OCF
3。
在某一方案中，
为
例如为
在某一方案中，
为
例如为
在某一方案中，所述如式I所示的吡咯并三嗪酮类化合物选自以下任一化合物：
本发明还提供了一种药物组合物，所述药物组合物包含如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐，以及药用辅料。
本发明还提供了所述如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐的制备方法：其包括以下步骤：化合物II和化合物III发生缩合反应；
其中，*、#、R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、Q和n的定义如前任一方案所述。
本发明还提供了所述如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐或所述药物组合物在制备药物中的应用，所述药物用于治疗和/或预防GPR139受体相关的疾病；所述GPR139受体相关的疾病可为精神分裂症、双相情感障碍、抑郁症、认知障碍、自闭症谱系障碍、睡眠障碍、注意缺陷多动障碍、创伤后应激障碍、物质滥用、吸毒成瘾、饮食失调、强迫症、焦虑症、疼痛或纤维肌痛。
本发明还提供了所述如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐或所述药物组合物在制备药物中的应用，所述药物用于治疗和/或预防精神分裂症、双相情感障碍、抑郁症、认知障碍、自闭症谱系障碍、睡眠障碍、注意缺陷多动障碍、创伤后应激障碍、物质滥用、吸毒成瘾、饮食失调、强迫症、焦虑症、疼痛或纤维肌痛。
如无特别说明，本发明所用术语具有如下含义：
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数(例如C
1～6)的直链或支链烷基。烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基和正己基等。
术语“环烷基”是指具有指定的碳原子数(例如C
3～
6)的、仅由碳原子组成的环状基团。环烷基包括但不限于环丙基、环丁基、环戊基和环己基等。
术语“杂环烷基”是指具有指定环原子数(例如5-6元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团。杂环烷基包括但不限于氮杂环丁烷基、四氢吡咯基、四氢呋喃基、吗啉基和哌啶基等。
术语“芳环”是指具有指定的碳原子数(例如C
6-10)的、仅由碳原子组成的环状基团，其为单环或多环，且至少一个环具有芳香性(符合休克尔规则)。芳环包括但不限于苯环和萘环等。
术语“杂芳环”是指具有指定环原子数(例如5-10元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的一种或多种)的环状基团，其为单环或多环，且至少一个环具有芳香性(符合休克尔规则)。杂芳环通过具有芳香性的环或不具有芳香性的环与分子中的其他片段连接。杂芳环包括但不限于呋喃环、吡咯环、噻吩环、吡唑环、咪唑环、噁唑环、噻唑环、吡啶环、嘧啶环、吲哚环等。
基团末端的“-”是指该基团通过该位点与分子中的其他片段连接。例如，-OCH
3是指甲氧基。
当任意变量(例如基团R
a-1)在化合物的定义中多次出现时，它们的定义互相独立、互不影响。例如，被3个R
a-1取代的5-6元杂环烷基是指5-6元杂环烷基会被3个R
a-1取代，3个R
a-1的定义互相独立的、互不影响。
术语“药学上可接受的盐”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱反应得到的盐。当化合物中含有相对酸性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物的游离形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于钠盐、钾盐、钙盐、铝盐、镁盐、铋盐、铵盐等。当化合物中含有相对碱性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物的游离形式接触的方式获得酸加成盐。药学上可接受的酸加成盐包括但不限于盐酸盐、硫酸盐、甲磺酸盐等。具体参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl,2002)。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物、疾病种类、疾病的严重度、患者的年龄等变化，但可由本领域技术人员视情况调整。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。具体参见中华人民共和国药典(2020年版)或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009)。
术语“治疗”是指下述任一情形：(1)缓解疾病的一种或多种生物学表现；(2)干扰引发疾病的生物级联中的一个或多个点；(3)减缓疾病的一种或多种生物学表现发展。
术语“预防”是指降低发生疾病的风险。
术语“患者”是指已经或即将接受治疗的任何动物，优选哺乳动物，最优选人类。哺乳动物包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人类等。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的吡咯并三嗪酮类化合物结构新颖，对GPR139受体有较强的激动活性。
图1为生物测试实施例3中的结果图。
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1：(S)-N-(1-(4-氟苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-1)的制备
步骤1：吡咯并[1,2-d][1,2,4]三嗪-4(3H)-酮的制备
将2-吡咯甲醛(1.00g，10.52mmol)和肼基甲酸乙酯(1.20g,11.57mmol)溶于DMF(10mL)中，90℃搅拌24小时。冷却至室温之后在0℃条件下加入NaH(60％在矿物油中,0.235g，5.26mmol)，90℃搅拌12小时。反应液加水稀释，乙酸乙酯萃取三次，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至20％EA/PE)，得黄色固状的标题化合物(0.90g，收率63％)。
1H NMR(800MHz,DMSO-d
6)δ12.24(s,1H),8.24(s,1H),7.77–7.75(m,1H),6.84–6.82(m,2H).
13C NMR(201MHz,DMSO-d
6)δ144.72,132.44,125.60,116.23,115.43,109.10.HRMS(ESI)C
6H
6N
3O
3
+[M+H]
+计算值:136.0505；实测值:136.0508。
步骤2：2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯的制备
将碳酸钾(1.17g，8.44mmol)溶解在丙酮(8mL)溶液中，然后将吡咯并[1,2-d][1,2,4]三嗪-4(3H)-酮 (0.38g，2.81mmol)加入其中。在搅拌状态下加入溴乙酸乙酯(0.939g，5.62mmol)，55℃搅拌3小时。反应液加水稀释，乙酸乙酯萃取，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5％EA/PE)，得淡黄色油状的标题化合物(0.49g，收率78％)。
1H NMR(600MHz,DMSO-d
6)δ8.32(s,1H),7.81(d,J＝2.5Hz,1H),6.90(dd,J＝3.7,1.4Hz,1H),6.88–6.85(m,1H),4.85(s,2H),4.17(q,J＝7.0Hz,2H),1.21(t,J＝7.2Hz,3H).HRMS(ESI)C
10H
12N
3O
3
+[M+H]
+计算值:222.0873；实测值:222.0875。
步骤3：2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯(0.40g，1.81mmol)溶解在THF:H
2O(1:1，8mL)溶液中，在0℃条件下加入氢氧化锂(0.227g，5.42mmol)，室温搅拌2小时。然后使用1M盐酸调节PH至2左右，减压蒸干溶剂，得相应固体标题化合物(0.35g,粗品)，其不经进一步纯化使用。HRMS(ESI)C
8H
8N
3O
3
+[M+H]
+计算值:194.0560；实测值:194.0561。
步骤4：(S)-N-(1-(4-氟苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-1)的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.100g，0.51mmol)溶解于DMF(6mL)溶液中，然后加入HATU(0.393g，1.03mmol)室温搅拌30分钟。依次加入DIPEA(0.201g，1.55mmol)和(S)-1-(4-氟苯基)乙胺(0.108g，0.77mmol)，室温搅拌过夜。反应液加水稀释，乙酸乙酯萃取两次，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至50％EA/PE)，得白色固体化合物(I-1)(0.100g，收率61％)。
1H NMR(800MHz,DMSO-d
6)δ8.62(d,J＝7.9Hz,1H),8.27(s,1H),7.78(d,J＝2.2Hz,1H),7.37–7.34(m,2H),7.17–7.13(m,2H),6.86(dd,J＝3.6,1.4Hz,1H),6.85–6.83(m,1H),4.96-4.92(m,1H),4.68and 4.66(ABq,J＝16.7Hz,2H),1.36(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.81,161.02(d,J＝242.5Hz),144.59,140.46(d,J＝3.3Hz),132.32,127.88(2C,d,J＝8.1Hz),125.61,117.02,115.88,114.91(2C,d,J＝20.9Hz),109.60,52.91,47.49,22.36.HRMS(ESI)C
16H
16FN
4O
2
+[M+H]
+计算值:315.1252；实测值:315.1251。
实施例2：(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(对甲苯基)乙基)乙酰胺(化合物I-2)的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.15g，0.77mmol)溶解于DMF(6mL)溶液中，然后加入HATU(0.59g，1.55mmol)室温搅拌30分钟。依次加入DIPEA(0.301g，2.33mmol)和(S)-1-(4-甲基苯基)乙胺(0.126g，0.93mmol)，室温搅拌过夜。反应液加水稀释，乙酸乙酯萃取两次，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至50％EA/PE)，得白色固体化合物(I-2)(0.092g，收率38％)。
1H NMR(800MHz,DMSO-d
6)δ8.56(d,J＝8.0Hz,1H),8.27(s,1H),7.78(d,J＝2.9Hz,1H),7.20(d,J＝8.0Hz,2H),7.13(d,J＝7.9Hz,2H),6.86(dd,J＝3.7,1.4Hz,1H),6.84(dd,J＝3.7,2.8Hz,1H),4.91-4.88(m,1H),4.67and 4.65(ABq,J＝16.4Hz,2H),2.27(s,3H),1.35(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.66,144.59,141.23,135.70,132.28,128.76(2C),125.88(2C),125.61,117.00,115.86,109.56,52.88,47.78,22.36,20.60.HRMS(ESI)C
17H
19N
4O
2
+[M+H]
+计算值:311.1503；实测值:311.1504。
实施例3：(S)-N-(1-(4-甲氧基苯基)乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-3)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(4-甲氧基苯基)乙胺，其余所需原料，试剂及制备方法同实施例2，得白色固体化合物(I-3)(0.060g，收率23％)。
1H NMR(800MHz,DMSO-d
6)δ8.53(d,J＝8.0Hz,1H),8.27(s,1H),7.78(d,J＝2.2Hz,1H),7.26–7.21(m,2H),6.91–6.87(m,2H),6.86(dd,J＝3.7,1.4Hz,1H),6.85–6.83(m,1H),4.91-4.87(m,1H),4.67and 4.64(ABq,J＝16.3Hz,2H),3.73(s,3H),1.35(d,J＝6.9Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.61,158.07,144.59,136.17,132.28,127.12(2C),125.61,117.01(2C),115.87,113.61,109.57,55.05,52.88,47.44,22.35.HRMS(ESI)C
17H
19N
4O
3
+[M+H]
+计算值:327.1452；实测值:327.1452。
实施例4：(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯乙基)乙酰胺(化合物I-4)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-苯乙胺，其余所需原料，试剂及制备方法同实施例2，得白色固体化合物(I-4)(0.070g，收率30％)。
1H NMR(800MHz,DMSO-d
6)δ8.62(d,J＝8.0Hz,1H),8.27(s,1H),7.78(d,J＝3.5Hz,1H),7.34–7.30(m,4H),7.25–7.21(m,1H),6.86(dd,J＝3.6,1.4Hz,1H),6.84(dd,J＝3.7,2.8Hz,1H),4.96-4.92(m,1H),4.69and 4.67(ABq,J＝16.3Hz,2H),1.37(d,J＝6.9Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.76,144.59,144.25,132.30,128.24(2C),126.67,125.94(2C),125.61,117.02,115.87,109.58,52.90,48.06,22.38.HRMS(ESI)C
16H
17N
4O
2
+[M+H]
+计算值:297.1346；实测值:297.1347。
实施例5：(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲氧基)苯基)乙基)乙酰胺(化合物I-5)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-4-(三氟甲氧基)苯乙胺，其余所需原料，试剂及制备方法同实施例2，得白色固体化合物(I-5)(0.120g，收率40％)。
1H NMR(800MHz,DMSO-d
6)δ8.67(d,J＝7.8Hz,1H),8.28(s,1H),7.78(d,J＝2.3Hz,1H),7.45(d,J＝8.7Hz,2H),7.32(d,J＝8.3Hz,2H),6.86(dd,J＝3.7,1.4Hz,1H),6.84(t,J＝3.3Hz,1H),5.00–4.94(m,1H),4.69(s,2H),1.38(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.96,147.04,144.60,143.81,132.34,127.82(2C),125.61,120.89(2C),120.09(q,J＝256.3Hz),117.03,115.88,109.62,52.92,47.60,22.23.HRMS(ESI)C
17H
16F
3N
4O
3
+[M+H]
+计算值:381.1169；实测值:381.1170。
实施例6：(S)-N-1-(4-氯苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-6)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(4-氯苯基)乙胺盐酸盐，其余所需原料，试剂及制备方法同实施例2，得白色固体化合物(I-6)(0.112g，收率51％)。
1H NMR(800MHz,DMSO- d
6)δ8.65(d,J＝7.8Hz,1H),8.27(s,1H),7.78(d,J＝1.8Hz,1H),7.38(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),6.86(d,J＝2.2Hz,1H),6.84(t,J＝3.3Hz,1H),4.95–4.90(m,1H),4.69and 4.67(ABq,J＝16.6Hz,2H),1.36(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.90,144.58,143.36,132.32,131.20,128.17(2C),127.86(2C),125.60,117.02,115.88,109.60,52.91,47.60,22.19.HRMS(ESI)C
16H
16ClN
4O
2
+[M+H]
+计算值:331.0956,实测值:331.0955。
实施例7：(S)-N-(1-(4-羟基苯基)乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-7)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-4-(1-氨基乙基)苯酚，其余所需原料，试剂及制备方法同实施例2。
得白色固体化合物(I-7)(0.074g，收率45％)。
1H NMR(800MHz,DMSO-d
6)δ9.26(s,1H),8.48(d,J＝8.0Hz,1H),8.27(s,1H),7.78(d,J＝1.5Hz,1H),7.13–7.10(m,2H),6.86(dd,J＝3.7,1.4Hz,1H),6.84(dd,J＝3.7,2.9Hz,1H),6.72–6.69(m,2H),4.88–4.83(m,1H),4.65and 4.63(ABq,J＝16.4Hz,2H),1.33(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.55,156.14,144.61,134.33,132.29,127.14(2C),125.63,117.03,115.89,114.92(2C),109.58,52.89,47.46,22.33.HRMS(ESI)C
16H
17N
4O
3
+[M+H]
+计算值:313.1295,实测值:313.1298。
实施例8：(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯丙基)乙酰胺(化合物I-8)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-苯基丙胺，其余所需原料，试剂及制备方法同实施例2，得白色固体化合物(I-8)(0.095g，收率59％)。
1H NMR(800MHz,DMSO-d
6)δ8.55(d,J＝8.5Hz,1H),8.27(s,1H),7.78(d,J＝2.2Hz,1H),7.34–7.29(m,4H),7.25–7.22(m,1H),6.86(dd,J＝3.6,1.4Hz,1H),6.84(dd,J＝3.7,2.9Hz,1H),4.74–4.69(m,2H),4.67(d,J＝16.3Hz,1H),1.74–1.66(m,2H),0.86(t,J＝7.4Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.11,144.59,143.32,132.28,128.21(2C),126.71,126.42(2C),125.62,117.02,115.88,109.58,54.29,52.91,29.22,10.98.HRMS(ESI)C
17H
19N
4O
2
+[M+H]
+计算值:311.1503,实测值:311.1501。
实施例9：(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1,2,3,4-四氢萘-1-基)乙酰胺(化合物I-9)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1,2,3,4-四氢-1-萘胺，其余所需原料，试剂及制备方法同实施例2，得白色固体化合物(I-9)(0.100g，收率59％)。
1H NMR(800MHz,DMSO-d
6)δ8.55(d,J＝8.6Hz,1H),8.30(s,1H),7.81(d,J＝2.9Hz,1H),7.22–7.18(m,1H),7.20–7.13(m,2H),7.11–7.07(m,1H),6.87(dd,J＝3.6,1.4Hz,1H),6.85(t,J＝3.2Hz,1H),5.02–4.97(m,1H),4.70and 4.62(ABq,J＝16.4Hz,2H),2.78–2.68(m,2H),1.93–1.84(m,2H),1.77–1.65(m,2H).
13C NMR(201MHz,DMSO-d
6)δ166.15,144.63,137.18,137.05,132.37,128.74,128.12,126.79,125.86,125.69,117.04,115.87,109.57,53.12,46.74,29.81,28.73,20.06.HRMS(ESI)C
18H
19N
4O
2
+[M+H]
+计算值:322.1503,实测值:322.1502。
实施例10：N-(2-(二甲基氨基)-1-苯基乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-10)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成N1,N1-二甲基-2-苯基乙烷-1,2-二胺，其余所需原料，试剂及制备方法同实施例7，得棕色泡沫状固体化合物(I-10)(0.050g，收率28％)。
1H NMR(800MHz,DMSO-d
6)δ8.80(d,J＝9.0Hz,1H),8.30(s,1H),7.79(d,J＝2.3Hz,1H),7.46–7.39(m,4H),7.34(t,J＝6.9Hz,1H),6.88(dd,J＝3.7,1.4Hz,1H),6.86(t,J＝3.6Hz,1H),5.41–5.27(m,1H),4.82and 4.76(ABq,J＝16.6Hz,2H),3.48–3.32(m,2H),2.82(brs,6H).
13C NMR(201MHz,DMSO-d
6)δ166.03,144.58,142.08,132.28,128.20(2C),126.87,126.66(2C),125.58,117.04,115.91,109.62,64.44,52.84,50.95,45.14(2C).HRMS(ESI)C
18H
22N
5O
2
+[M+H]
+计算值:340.1768,实测值:340.1767。
实施例11：(S)-N-(1-(4-氟苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-11)的制备
步骤1：5-甲基吡咯-2-甲醛的制备
将二氯甲烷(12mL)加入三颈圆底烧瓶，然后向其中加入DMF(0.854g,11.7mmol)，置换氮气。在0℃下向其滴加POCl
3(1.79g，11.7mmol)，室温搅拌15分钟，然后在0℃条件下加入2-甲基吡咯(1.0g，12.3mmol)，室温搅拌30分钟。将无水醋酸钠(4.6g，56.0mmol)溶解于13mL水中，在室温条件下缓慢加入圆底烧瓶中，80℃搅拌20分钟。反应液加水稀释，二氯甲烷萃取两次，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至20％EA/PE)，得淡黄色固体标题化合物(0.600g，收率44％)。
1H NMR(800MHz,DMSO-d
6)δ11.86(s,1H),9.30(s,1H),6.89–6.86(m,1H),6.03–5.99(m,1H),2.24(s,3H).HRMS(ESI)C
6H
8NO
+[M+H]
+计算值:110.0600，实测值:110.0599。
步骤2：6-甲基吡咯并[1,2-d][1,2,4]三嗪-4-酮的制备
将5-甲基吡咯-2-甲醛(2.00g，18.33mmol)和肼基甲酸乙酯(2.29g,21.99mmol)溶于DMF(20mL)中，90℃搅拌24小时。冷却至室温之后在0℃条件下加入NaH(60％在矿物油中，0.733g，9.16mmol)，90℃搅拌12小时。反应液加水稀释，以乙酸乙酯萃取三次，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至10％EA/PE)，得黄色固体标题化合物(1.70g，收率62％)。
1H NMR(800MHz,DMSO-d
6)δ11.82(s,1H),8.04(s,1H),6.64(d,J＝3.6Hz,1H),6.47(d,J＝3.6Hz,1H),2.69(s,3H).HRMS(ESI)C
7H
8N
3O
+[M+H]
+计算值:150.0662，实测值:150.0662。
步骤3：2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯的制备
将碳酸钾(4.73g，34.19mmol)溶解在丙酮溶液(35mL)，然后将6-甲基吡咯并[1,2-d][1,2,4]三嗪-4-酮(1.70g，11.40mmol)加入上述溶液中。在搅拌状态下加入溴乙酸乙酯(3.81g，5.62mmol)，55℃搅拌过夜。反应液加水稀释，乙酸乙酯萃取，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5％EA/PE)，得淡黄色固体标题化合物(2.25g，收率81％)。
1H NMR(800MHz,DMSO-d
6)δ8.13(s,1H),6.71(d,J＝3.7Hz,1H),6.53(dd,J＝3.7,1.0Hz,1H),4.74(s,2H),4.17and 4.15(ABq,J＝7.2Hz,2H),2.68(s,3H),1.21(t,J＝7.1Hz,3H).HRMS(ESI)C
11H
14N
3O
3
+[M+H]
+计算值:236.1030，实测值:236.1029。
步骤4：2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸的制备
将2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯(2.25g，9.56mmol)溶解在THF:H
2O(1:1,20mL)溶液中，在0℃条件下加入氢氧化锂(1.20g,28.69mmol)，室温搅拌2小时。使用1M盐酸调节PH至2左右，减压蒸干溶剂，得相应固体标题化合物(1.7g,粗品)，其不经进一步纯化使用。HRMS(ESI)C
9H
10N
3O
3
+[M+H]
+计算值:208.0717，实测值:208.0717。
步骤5：(S)-N-(1-(4-氟苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-11)的制备
将2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.120g，0.57mmol)溶解于DMF(7mL)溶液中，然后加入HATU(0.440g，1.14mmol)室温搅拌30分钟。依次加入DIPEA(0.187g，1.71mmol)和(S)-1-(4-氟苯基)乙胺(0.089g，0.62mmol)，室温搅拌过夜。反应液加水稀释，乙酸乙酯萃取两次，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至50％EA/PE)，得白色固体化合物(I-11)(0.110g，收率57％)。
1H NMR(800MHz,DMSO-d
6)δ8.58(d,J＝7.9Hz,1H),8.08(s,1H),7.38–7.34(m,2H),7.17–7.12(m,2H),6.67(d,J＝3.7Hz,1H),6.51(dd,J＝3.7,1.0Hz,1H),4.96–4.91(m,1H),4.58and 4.56(ABq,J＝16.5Hz,2H),2.69(s,3H),1.36(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.02,161.03(d,J＝242.1Hz),146.22,140.54(d,J＝2.9Hz),132.65,130.75,127.90(2C,d,J＝8.1Hz),125.73,115.42,114.91(2C,d,J＝21.3Hz),108.28,52.70,47.48,22.43,14.67.HRMS(ESI)C
17H
18FN
4O
2
+[M+H]
+计算值:329.1408，实测值:329.1409。
实施例12：(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(对甲苯基)乙基)乙酰胺(化合物I-12)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-甲基苯基)乙胺，其余所需原料，试剂及制备方法同实施例11步骤5，得白色固体化合物(I-12)(0.080g，收率42％)。
1H NMR(800MHz,DMSO-d
6)δ8.52(d,J＝7.9Hz,1H),8.07(s,1H),7.20(d,J＝8.0Hz,2H),7.13(d,J＝7.7Hz,2H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.7,1.0Hz,1H),4.92–4.87(m,1H),4.57and 4.55(ABq,J＝16.4Hz,2H), 2.69(s,3H),2.27(s,3H),1.35(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.88,146.23,141.32,135.70,132.62,130.74,128.77(2C),125.90(2C),125.74,115.41,108.26,52.67,47.77,22.43,20.61,14.68.HRMS(ESI)C
18H
21N
4O
2
+[M+H]
+计算值:325.1659，实测值:325.1659。
实施例13：(S)-N-(1-(4-甲氧基苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-13)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-甲氧基苯基)乙胺，其余所需原料，试剂及制备方法同实施例11步骤5，得白色固体化合物(I-13)(0.118g，收率59％)。
1H NMR(800MHz,DMSO-d
6)δ8.49(d,J＝8.0Hz,1H),8.07(s,1H),7.25–7.22(m,2H),6.90–6.87(m,2H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.7,1.0Hz,1H),4.92–4.87(m,1H),4.57and 4.54(ABq,J＝16.3Hz,2H),3.73(s,3H),2.69(s,3H),1.35(d,J＝6.9Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.81,158.07,146.23,136.26,132.62,130.74,127.14(2C),125.73,115.41,113.61(2C),108.25,55.06,52.65,47.44,22.43,14.68.HRMS(ESI)C
18H
20NaN
4O
3
+[M+Na]
+计算值:363.1428，实测值:363.1428。
实施例14：(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯乙基)乙酰胺(化合物I-14)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-苯乙胺，其余所需原料，试剂及制备方法同实施例11步骤5，得白色固体化合物(I-14)(0.085g，收率47％)。
1H NMR(800MHz,DMSO-d
6)δ8.57(d,J＝7.9Hz,1H),8.08(s,1H),7.35–7.30(m,4H),7.25–7.21(m,1H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.6,1.0Hz,1H),4.97–4.91(m,1H),4.59and 4.57(ABq,J＝16.3Hz,2H),2.69(s,3H),1.37(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.97,146.23,144.34,132.63,130.74,128.25(2C),126.67,125.96(2C),125.73,115.42,108.26,52.68,48.05,22.45,14.67.HRMS(ESI)C
17H
19N
4O
2
+[M+H]
+计算值:311.1503,实测值:311.1503。
实施例15：(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲氧基)苯基)乙基)乙酰胺(化合物I-15)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-4-(三氟甲氧基)苯乙胺，其余所需原料，试剂及制备方法同实施例11步骤5，得白色固体化合物(I-15)(0.125g，收率54％)。
1H NMR(800MHz,DMSO-d
6)δ8.64(d,J＝7.7Hz,1H),8.08(s,1H),7.46–7.43(m,2H),7.32(d,J＝7.9Hz,2H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.6,1.0Hz,1H),4.99–4.94(m,1H),4.59(s,2H),2.69(s,3H),1.38(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.17,147.04,146.23,143.90,132.68,130.76,127.84(2C),125.73,120.90(2C),120.11(q,J＝255.7Hz),115.43,108.31,52.72,47.60,22.28,14.66.HRMS(ESI)C
18H
17NaF
3N
4O
3
+[M+Na]
+计算值:417.1145,实测值:417.1145。
实施例16：(S)-N-1-(4-氯苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-16)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-氯苯基)乙胺盐酸盐，其余所需原料，试剂及制备方法同实施例11步骤5，得白色固体化合物(I-16)(0.088g，收率44％)。
1H NMR(800MHz,DMSO-d
6)δ8.61(d,J＝7.8Hz,1H),8.08(s,1H),7.40–7.37(m,2H),7.36–7.33(m,2H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.6,1.0Hz,1H),4.95–4.90(m,1H),4.59and 4.57(ABq,J＝16.3Hz,2H),2.69(s,3H),1.36(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.11,146.22,143.44,132.66,131.20,130.75,128.17(2C),127.88(2C),125.72,115.42,108.29,52.70,47.59,22.26,14.67.HRMS(ESI)C
17H
18Cl
4N
4O
2
+[M+H]
+计算值:345.1113,实测值:345.1118。
实施例17：(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-氟苯基)乙基)乙酰胺(化合物I-17)的制备
步骤1：6,8-二甲基吡咯并[1,2-d][1,2,4]三嗪-4-酮的制备
将3,5-二甲基-2-吡咯甲醛(1.00g,8.12mmol)和肼基甲酸乙酯(1.01g,9.74mmol)溶于DMF(10mL)中，90℃搅拌24小时。冷却至室温之后在0℃条件下加入NaH(60％在矿物油中,0.325g,8.12mmol)，90℃搅拌12小时。反应液加水稀释，以乙酸乙酯萃取三次，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至10％EA/PE)，得淡黄色固体标题化合物(0.85g，收率64％)。
1H NMR(800MHz,DMSO-d
6)δ11.64(s,1H),8.07(s,1H),6.32(s,1H),2.65(s,3H),2.20(s,3H).
13C NMR(201MHz,DMSO-d
6)δ146.49,131.66,129.34,122.65,117.86,116.86,14.33,10.01.HRMS(ESI)C
8H
10N
3O
+[M+H]
+计算值:164.0818；实测值:164.0817。
步骤2：2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯的制备
将碳酸钾(4.32g,31.25mmol)溶解在丙酮溶液(35mL)，然后将6,8-二甲基吡咯并[1,2-d][1,2,4]三嗪-4-酮(1.70g,10.42mmol)加入上述溶液中。在搅拌状态下加入溴乙酸乙酯(3.48g,20.84mmol)，55℃搅拌过夜。反应液加水稀释，乙酸乙酯萃取，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5％EA/PE)，得黄色固体标题化合物(2.20g,收率84％)。
1H NMR(800MHz,DMSO-d
6)δ8.17(s,1H),6.39(s,1H),4.71(s,2H),4.17and 4.15(ABq,J＝7.2Hz,2H),2.64(s,3H),2.22(s,3H),1.21(t,J＝7.1Hz,3H).HRMS(ESI)C
12H
16N
3O
3
+[M+H]
+计算值:250.1186；实测值:250.1186。
步骤3：2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸的制备
将2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸乙酯(2.10g,8.42mmol)溶解在THF:H
2O(1:1,10mL)溶液中，在0℃条件下加入氢氧化锂(1.06g，25.27mmol)，室温搅拌2小时。使用1M盐酸调节PH至2左右，减压蒸干溶剂，得相应固体标题化合物(1.8g,粗品)，其不经进一步纯化使用。HRMS(ESI)C
10H
12N
3O
3
+[M+H]
+计算值:222.0873；实测值:222.0874。
步骤4：(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-氟苯基)乙基)乙酰胺(I-17)的制备
将2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.200g，0.90mmol)溶解于DMF(7mL)溶液中，然后加入HATU(0.688g,1.80mmol)室温搅拌30分钟。依次加入DIPEA(0.292g,2.25mmol)和(S)-1-(4-氟苯基)乙胺(0.138g，0.99mmol)，室温搅拌过夜。反应液加水稀释，乙酸乙酯萃取两次，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至50％EA/PE)，得白色固体化合物I-17(0.160g，收率51％)。
1H NMR(800MHz,DMSO-d
6)δ8.55(d,J＝7.9Hz,1H),8.11(s,1H),7.39–7.32(m,2H),7.14(t,J＝8.9Hz,2H),6.36(s,1H),4.97–4.91(m,1H),4.55and 4.53(ABq,J＝16.4Hz,2H),2.64(s,3H),2.21(s,3H),1.36(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.13,161.02(2C,d,J＝242.5Hz),146.22,140.56,131.60,130.04,127.90(2C,d,J＝8.1Hz),122.83,118.39,117.29,114.91(d,J＝21.3Hz),52.55,47.44,22.43,14.49,9.97.HRMS(ESI)C
18H
20FN
4O
2
+[M+H]
+计算值:343.1565；实测值:343.1567。
实施例18：(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(对甲苯基)乙基)乙酰胺(化合物I-18)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-甲基苯基)乙胺，其余所需原料，试剂及制备方法同实施例17步骤4，得白色固体化合物(I-18)(0.180g，收率58％)。
1H NMR(800MHz,DMSO-d
6)δ8.49(d,J＝8.0Hz,1H),8.10(s,1H),7.20(d,J＝8.0Hz,2H),7.12(d,J＝7.9Hz,2H),6.36(s,1H),4.93–4.86(m,1H),4.54and 4.52(ABq,J＝16.2Hz,2H),2.64(s,3H),2.27(s,3H),2.21(s,3H),1.35(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.97,146.21,141.34,135.68,131.56,130.02,128.76(2C),125.90(2C),122.83,118.35,117.28,52.52,47.73,22.43,20.61,14.49,9.96.HRMS(ESI)C
19H
23N
4O
2
+[M+H]
+计算值:339.1816；实测值:339.1818。
实施例19：(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-甲氧基苯基)乙基)乙酰胺(化合物I-19)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-甲氧基苯基)乙胺，其余所需原料，试剂及制备方法同实施例17步骤4，得淡黄色固体化合物(I-19)(0.150g，收率46％)。
1H NMR(800MHz,DMSO-d
6)δ8.47(d,J＝8.0Hz,1H),8.10(s,1H),7.27–7.19(m,2H),6.90–6.86(m,2H),6.35(s,1H),4.92–4.87(m,1H),4.54and 4.51(ABq,J＝14.3Hz,2H),3.73(s,3H),2.64(d,J＝0.9Hz,3H),2.21(s,3H),1.35(d,J＝6.9Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.90,158.05,146.20,136.27,131.53,130.01,127.13(2C),122.82,118.33,117.25,113.59(2C),55.05,52.50,47.39,22.40,14.46,9.94.HRMS(ESI)C
19H
23N
4O
3
+[M+H]
+计算值:355.1765；实测值:355.1764。
实施例20：(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯乙基)乙酰胺(化合物I-20)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-苯乙胺，其余所需原料，试剂及制备方法同实施例17步骤4，得白色固体化合物(I-20)(0.130g，收率44％)。
1H NMR(800MHz,DMSO-d
6)δ8.55(d,J＝8.0Hz,1H),8.11(s,1H),7.32(d,J＝4.4Hz,4H),7.26–7.20(m,1H),6.35(s,1H),4.97–4.92(m,1H),4.56and 4.54(ABq,J＝16.2Hz,2H),2.64(s,3H),2.21(s,3H),1.37(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.06,146.20,144.34,131.55,130.01,128.22(2C),126.64,125.95(2C),122.82,118.34,117.25,52.52,48.00,22.42,14.46,9.94.HRMS(ESI)C
18H
21N
4O
2
+[M+H]
+计算值:325.1659；实测值:325.1659。
实施例21：(S)-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲氧基)苯基)乙基)乙酰胺(化合物I-21)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-4-(三氟甲氧基)苯乙胺，其余所需原料，试剂及制备方法同实施例17步骤4，得白色固体化合物(I-21)(0.240g，收率65％)。
1H NMR(800MHz,DMSO-d
6)δ8.61(d,J＝7.7Hz,1H),8.11(s,1H),7.47–7.43(m,2H),7.32(d,J＝8.1Hz,2H),6.36(s,1H),5.00–4.94(m,1H),4.56(s,2H),2.64(s,3H),2.21(s,3H),1.38(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.26,147.02,146.20,143.89,131.59,130.04,127.83(2C),122.82,120.87(2C),120.10(q,J＝256.7Hz),118.38,117.27,52.55,47.54,22.25,14.44,9.93.HRMS(ESI)C
19H
20F
3N
4O
3
+[M+H]
+计算值:409.1482；实测值:409.1483。
实施例22：(S)-N-1-(4-氯苯基)乙基-2-(6,8-二甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-22)的制备
将实施例17步骤4中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-氯苯基)乙胺盐酸盐，其余所需原料，试剂及制备方法同实施例17步骤4，得白色固体化合物(I-22)(0.140g，收率43％)。
1H NMR(800MHz,DMSO-d
6)δ8.58(d,J＝7.8Hz,1H),8.11(s,1H),7.40–7.36(m,2H),7.36–7.33(m,2H),6.36(s,1H),4.95–4.89(m,1H),4.55and 4.53(ABq,J＝16.3Hz,2H),2.64(s,3H),2.21(s,3H),1.36(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.22,146.21,143.47,131.61,131.18,130.05,128.17(2C),127.89(2C),122.83,118.40,117.29,52.55,47.56,22.26,14.48,9.97.HRMS(ESI)C
18H
20ClN
4O
2
+[M+H]
+计算值:359.1269；实测值:359.1268。
实施例23：(S)-N-(1-(萘-1-乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-23)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(1-萘基)乙胺，其余所需原料，试剂及制备方法同实施例2，得白色固体化合物(I-23)(0.130g，收率72％)。
1H NMR(800MHz,DMSO-d
6)δ8.74(d,J＝7.9Hz,1H),8.28(s,1H),7.90–7.87(m,3H),7.83–7.78(m,2H),7.53–7.49(m,2H),7.49–7.47(m,1H),6.86(dd,J＝3.6,1.4Hz,1H),6.84(t,J＝3.3Hz,1H),5.14–5.09(m,1H),4.73and 4.71(ABq,J＝16.3Hz,2H),1.47(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.94,144.62,141.74,132.85,132.33,132.06,127.89,127.65,127.45,126.15,125.65,125.63,124.89,124.00,117.03,115.89,109.60,53.01,48.24,22.18.HRMS(ESI)C
20H
19N
4O
2
+[M+H]
+计算值:347.1503,实测值:347.1507。
实施例24：(S)-N-(1-(4-溴苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I- 24)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(4-溴苯)乙胺，其余所需原料，试剂及制备方法同实施例2，得白色固体化合物(I-24)(0.130g，收率66％)。
1H NMR(800MHz,DMSO-d
6)δ8.65(d,J＝7.7Hz,1H),8.27(s,1H),7.78(d,J＝2.1Hz,1H),7.53–7.50(m,2H),7.30–7.26(m,2H),6.86(dd,J＝3.6,1.4Hz,1H),6.84(t,J＝3.3Hz,1H),4.93–4.88(m,1H),4.68and 4.65(ABq,J＝16.8Hz,2H),1.35(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.93,144.60,143.83,132.35,131.12(2C),128.27(2C),125.61,119.69,117.05,115.91,109.64,52.92,47.70,22.18.HRMS(ESI)C
16H
16BrN
4O
2
+[M+H]
+计算值:375.0451,实测值:375.0450。
实施例25：(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-吡啶-2-基)乙基)乙酰胺(化合物I-25)的制备
将实施例2中的(S)-1-(4-甲基苯基)乙胺替换成(S)-1-(吡啶-2-基)乙胺，其余所需原料，试剂及制备方法同实施例2，得白色固体化合物(I-25)(0.110g，收率71％)。
1H NMR(800MHz,DMSO-d
6)δ8.69(d,J＝7.9Hz,1H),8.52(dd,J＝4.7,0.9Hz,1H),8.28(s,1H),7.79(dd,J＝1.5,0.8Hz,1H),7.78–7.75(m,1H),7.37(d,J＝7.9Hz,1H),7.28–7.25(m,1H),6.86(dd,J＝3.7,1.4Hz,1H),6.85–6.83(m,1H),5.01–4.96(m,1H),4.73and 4.70(ABq,J＝16.4Hz,2H),1.40(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.11,162.20,148.79,144.61,136.81,132.34,125.62,122.14,120.30,117.03,115.90,109.62,52.95,49.91,21.08.HRMS(ESI)C
15H
16N
5O
2
+[M+H]
+计算值:298.1299,实测值:298.1299。
实施例26：(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-萘-1-基)乙基)乙酰胺(化合物I-26)的制备
将实施例11步骤5中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(1-萘基)乙胺，其余所需原料，试剂及制备方法同实施例11步骤5，得白色固体化合物(I-26)(0.130g，收率74％)。
1H NMR(800MHz,DMSO-d
6)δ8.71(d,J＝7.8Hz,1H),8.09(s,1H),7.90–7.86(m,3H),7.82(d,J＝2.0Hz,1H),7.52–7.49 (m,2H),7.49–7.46(m,1H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.7,1.0Hz,1H),5.13–5.08(m,1H),4.64and 4.61(ABq,J＝16.4Hz,2H),2.70(s,3H),1.47(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.17,146.25,141.82,132.86,132.65,132.05,130.73,127.87,127.63,127.46,126.13,125.75,125.64,124.92,123.98,115.42,108.27,52.85,48.22,22.22,14.68.HRMS(ESI)C
21H
21N
4O
2
+[M+H]
+计算值:361.1659,实测值:361.1656。
实施例27：(S)-N-1-(4-溴苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-27)的制备
将实施例11步骤3中(S)-1-(4-氟苯基)乙胺替换成(S)-1-(4-溴苯)乙胺，其余所需原料，试剂及制备方法同实施例11步骤5，得白色固体化合物(I-27)(0.140g，收率74％)。
1H NMR(800MHz,DMSO-d
6)δ8.62(d,J＝7.8Hz,1H),8.08(s,1H),7.54–7.49(m,2H),7.30–7.27(m,2H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.7,1.0Hz,1H),4.93–4.88(m,1H),4.59and 4.56(ABq,J＝16.3Hz,2H),2.69(s,3H),1.35(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.12,146.21,143.89,132.66,131.09(2C),130.75,128.27(2C),125.72,119.67,115.42,108.29,52.69,47.66,22.21,14.67.HRMS(ESI)C
17H
18B
rN
4O
2
+[M+H]
+计算值:388.0608,实测值:388.0609。
实施例28：(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(吡啶-2-基)乙基)乙酰胺(化合物I-28)的制备
将实施例11步骤3中11步骤3替换成(S)-1-(吡啶-2-基)乙胺，其余所需原料，试剂及制备方法同实施例11步骤3，得白色固体化合物(I-28)(0.080g，收率53％)。
1H NMR(800MHz,DMSO-d
6)δ8.65(d,J＝7.8Hz,1H),8.52(d,J＝5.7Hz,1H),8.08(s,1H),7.77(td,J＝7.6,1.8Hz,1H),7.38(d,J＝7.8Hz,1H),7.28–7.24(m,1H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.7,1.0Hz,1H),5.01–4.96(m,1H),4.63and 4.60(ABq,J＝16.3Hz,2H),2.69(s,3H),1.40(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.31,162.26,148.77,146.23,136.79,132.65,130.74,125.72,122.13,120.31,115.43,108.29,52.73,49.87,21.11,14.67.HRMS(ESI)C
16H
18N
5O
2
+[M+H]
+计算值:312.1455,实测值:312.1454。
实施例29：(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(吡啶-3-基)乙基)乙酰胺(化合物I-29)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-1-(吡啶-3-基)乙胺，其余所需原料，试剂及制备方法同实施例7，得白色固体化合物(I-29)(0.064g，收率41％)。
1H NMR(800MHz,DMSO-d
6)δ8.71(d,J＝7.7Hz,1H),8.54(d,J＝2.4Hz,1H),8.45(dd,J＝4.8,1.7Hz,1H),8.28(s,1H),7.79(d,J＝2.2Hz,1H),7.73–7.71(m,1H),7.37–7.35(m,1H),6.86(dd,J＝3.6,1.4Hz,1H),6.84(t,J＝3.3Hz,1H),5.00–4.96(m,1H),4.70and 4.68(ABq,J＝16.6Hz,2H),1.41(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.08,148.00,147.74,144.61,139.51,133.58,132.37,125.62,123.41,117.05,115.92,109.65,52.97,46.26,21.98.HRMS(ESI)C
15H
16N
5O
2
+[M+H]
+计算值:298.1299,实测值:298.1295。
实施例30：N-(2-吗啉-1-苯乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-30)的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.08g，0.41mmol)溶解于DMF(6mL)溶液中，然后加入HATU(0.315g，0.83mmol)室温搅拌30分钟。依次加入DIPEA(0.134g，1.03mmol)和2-吗啉-4-基-1-苯基乙胺(CAS#38060-08-1，0.094g，0.45mmol)，室温搅拌过夜。反应液加水稀释，乙酸乙酯萃取，合并的有机相用盐水洗涤，经无水Na
2SO
4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5％MeOH/DCM)，得棕色泡沫状化合物I-30(0.035g，收率22％)。
1H NMR(800MHz,DMSO-d
6)δ8.27(s,1H),7.92(t,J＝5.7Hz,1H),7.79(d,J＝1.9Hz,1H),7.36–7.31(m,2H),7.30–7.26(m,1H),7.25–7.21(m,2H),6.88–6.86(m,1H),6.85–6.83(m,1H),4.59and 4.57(ABq,J＝16.3Hz,2H),3.73–3.67(m,1H),3.56–3.51(m,4H),3.49(d,J＝6.8Hz,1H),3.32(d,J＝6.1Hz,1H),2.38–2.24(m,4H).
13C NMR(201MHz,DMSO-d
6)δ166.62,144.52,137.71,132.35,128.54(2C),128.02(2C),127.33,125.59,117.07,115.94,109.66,67.92,66.37(2C)52.86,50.10(2C),40.27.HRMS(ESI)C
20H
24N
5O
3
+[M+H]
+计算值:382.1874,实测值:382.1875。
实施例31：(R)-N-(1-(4-氟苯基)乙基-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-31)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(R)-1-(4-氟苯基)乙胺，其余所需原料，试剂及制备方法同实施例7，得白色固体化合物I-31(0.130g，收率79％)。
1H NMR(800MHz,DMSO-d
6)δ8.62(d,J＝7.9Hz,1H),8.27(s,1H),7.78(d,J＝2.2Hz,1H),7.37–7.34(m,2H),7.17–7.13(m,2H),6.86(dd,J＝3.7,1.4Hz,1H),6.84(t,J＝3.3Hz,1H),4.96–4.92(m,1H),4.68and 4.65(ABq,J＝16.4Hz,2H),1.36(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ165.83,161.04(d,J＝242.1Hz),144.61,140.48,132.33,127.89(2C,d,J＝8.1Hz),125.62,117.04,115.90,114.93(2C,d,J＝21.3Hz),109.61,52.92,47.51,22.38.HRMS(ESI)C
16H
16FN
4O
2
+[M+H]
+计算值:315.1252,实测值:315.1252。
实施例32：(S)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲基)苯基)乙基)乙酰胺(化合物I-32)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-1-[4-(三氟甲基)苯基]乙胺盐酸盐，其余所需原料，试剂及制备方法同实施例7，得白色固体化合物I-32(0.105g，收率79％)。
1H NMR(800MHz,DMSO-d
6)δ8.75(d,J＝7.7Hz,1H),8.28(s,1H),7.79(d,J＝2.9Hz,1H),7.70(d,J＝8.3Hz,2H),7.55(d,J＝8.4Hz,2H),6.86(dd,J＝3.7,1.4Hz,1H),6.85–6.83(m,1H),5.03–4.98(m,1H),4.70(s,2H),1.39(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.10,149.25,144.61,132.37,127.41(q,J＝31.5Hz),126.74(2C),125.62,125.20(2C,q,J＝3.7Hz),124.33(q,J＝271.8Hz),117.05,115.91,109.64,52.93,48.07,22.16.HRMS(ESI)C
17H
16F
3N
4O
2
+[M+H]
+计算值:365.1220,实测值:365.1219。
实施例33：(S)-N-(1-(4-氰基苯乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-33)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-4-(1-氨基乙基)苯甲氰盐酸盐，其余所需原料，试剂及制备方法同实施例7，得白色固体化合物I-33(0.060g，收率72％)。
1H NMR(800MHz,DMSO- d
6)δ8.75(d,J＝7.7Hz,1H),8.28(s,1H),7.82–7.80(m,2H),7.78(d,J＝2.3Hz,1H),7.53–7.51(m,2H),6.86(dd,J＝3.7,1.4Hz,1H),6.85–6.83(m,1H),5.01–4.96(m,1H),4.70(s,2H),1.38(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.17,150.20,144.61,132.38,132.33(2C),126.95(2C),125.61,118.88,117.06,115.92,109.66,109.52,52.95,48.19,22.03.HRMS(ESI)C
17H
16N
5O
2
+[M+H]
+计算值:322.1299,实测值:322.1297。
实施例34：(S)-N-(2-甲基-1-苯丙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-34)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-2-甲基-1-苯基丙-1-胺盐酸盐，其余所需原料，试剂及制备方法同实施例7，得白色固体化合物I-34(0.035g,收率41％)。
1H NMR(800MHz,DMSO-d
6)δ8.53(d,J＝9.0Hz,1H),8.26(s,1H),7.78(d,J＝4.7Hz,1H),7.34–7.31(m,2H),7.29–7.27(m,2H),7.25–7.22(m,1H),6.85(dd,J＝3.7,1.4Hz,1H),6.84(t,J＝3.4Hz,1H),4.74and 4.65(ABq,J＝15.9Hz,2H),4.56(t,J＝8.6Hz,1H),1.98–1.93(m,1H),0.91(d,J＝6.7Hz,3H),0.73(d,J＝6.7Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.02,144.55,142.33,132.21,128.08(2C),127.09(2C),126.71,125.59,117.00,115.90,109.57,58.83,52.85,32.99,19.77,18.91.HRMS(ESI)C
18H
21N
4O
2
+[M+H]
+计算值:325.1659,实测值:325.1659。
实施例35：(S)-N-(2-(4-甲基哌嗪)-1-苯基乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-35)的制备
将2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.05g,0.25mmol)溶解于DMF(6mL)溶液中，然后加入HATU(0.197g,0.51mmol)室温搅拌30分钟。依次加入DIPEA(0.084g,0.64mmol)和2-(4-甲基哌嗪-1-基)-1-苯基乙烷-1-胺(CAS#775349-54-7,0.063g,0.28mmol)，室温搅拌过夜。反应液加水稀释，乙酸乙酯萃取，合并的有机相用盐水洗涤，经无水Na2SO4干燥，过滤并真空浓缩。剩余固体用硅胶柱层析分离纯化(0至5％MeOH/DCM)，得棕色泡沫状化合物I-35(0.025g,收率24％)。
1H NMR(800MHz,DMSO-d
6)δ8.19(s,1H),7.86(t,J＝5.7Hz,1H),7.79(d,J＝1.8Hz,1H),7.33(t,J＝7.4Hz,2H),7.28–7.26(m,1H),7.24–7.22(m,2H),6.88–6.86(m,1H),6.86–6.84(m,1H),4.59and 4.57(ABq, J＝15.6Hz,2H),3.69–3.65(m,1H),3.53(t,J＝7.0Hz,1H),3.35–3.31(m,1H),2.50–2.18(m,8H),2.16(s,3H).HRMS(ESI)C
21H
27N
6O
2
+[M+H]
+计算值:395.2190,实测值:395.2192。
实施例36：(S)-N-(1-环己基乙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-36)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-1-环己基乙胺，其余所需原料，试剂及制备方法同实施例7，得淡黄色固体化合物I-36(0.090g，收率57％)。
1H NMR(800MHz,DMSO-d
6)δ8.27(s,1H),7.91(d,J＝8.7Hz,1H),7.80–7.77(m,1H),6.87–6.83(m,2H),4.66and 4.58(ABq,J＝16.2Hz,2H),3.65–3.59(m,1H),1.76-1.64(m,4H),1.62–1.54(m,1H),1.33–1.22(m,1H),1.20–1.05(m,3H),1.00(d,J＝6.7Hz,3H),0.97–0.82(m,2H).
13C NMR(201MHz,DMSO-d
6)δ166.13,145.04,132.70,126.10,117.47,116.33,109.99,53.35,49.35,42.90,29.26,29.22,26.48,26.23,26.21,18.16.HRMS(ESI)C
16H
23N
4O
2
+[M+H]
+计算值:303.1816,实测值:303.1815。
实施例37：(S)-N-(1-(4-氟苯基)-2-甲基丙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-37)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-1-(4-氟苯基)-2-甲基丙-1-胺盐酸盐，其余所需原料，试剂及制备方法同实施例7，得白色固体化合物I-37(0.100g，收率80％)。
1H NMR(800MHz,DMSO-d
6)δ8.55(d,J＝8.9Hz,1H),8.26(s,1H),7.78(d,J＝2.3Hz,1H),7.34–7.30(m,2H),7.17–7.13(m,2H),6.85(dd,J＝3.6,1.4Hz,1H),6.84–6.82(m,1H),4.74and 4.65(ABq,J＝16.4Hz,2H),4.56(t,J＝8.6Hz,1H),1.97–1.91(m,1H),0.91(d,J＝6.7Hz,3H),0.72(d,J＝6.7Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.08,161.03(d,J＝242.5Hz),144.56,138.58,132.25,128.94(2C,d,J＝8.1Hz),125.60,117.03,115.92,114.80(2C,d,J＝20.9Hz),109.61,58.19,52.87,32.99,19.68,18.92.HRMS(ESI)C
18H
20FN
4O
2
+[M+H]
+计算值:343.1565,实测值:343.1564。
实施例38：(S)-N-(2-甲基-1-(4-三氟甲基)苯丙基)-2-(4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-38)的制备
将实施例7中的(S)-4-(1-氨基乙基)苯酚替换成(S)-2-甲基-1-(4-(三氟甲基)苯基)丙-1-胺，其余所需原料，试剂及制备方法同实施例7，得白色固体化合物I-38(0.110g,收率77％)。
1H NMR(800MHz,DMSO-d
6)δ8.66(d,J＝8.7Hz,1H),8.26(s,1H),7.79–7.76(m,1H),7.70(d,J＝8.4Hz,2H),7.52(d,J＝8.3Hz,2H),6.86–6.84(m,1H),6.84–6.82(m,1H),4.76and 4.68(ABq,J＝16.1Hz,2H),4.65(t,J＝8.4Hz,1H),2.04–1.95(m,1H),0.93(d,J＝6.7Hz,3H),0.74(d,J＝6.7Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.83,147.69,145.02,132.73,128.36(2C),127.89(q,J＝31.5Hz),126.05,125.48(2C,q,J＝3.7Hz),124.13(q,J＝264.9Hz),117.50,116.39,110.09,59.06,53.32,33.20,20.08,19.22.HRMS(ESI)C
19H
20F
3N
4O
2
+[M+H]
+计算值:393.1533,实测值:393.1535。
实施例39：(S)-N-(1-(4-氟苯基)-2-甲基丙基)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-39)的制备
将2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酸(0.080g,0.39mmol)溶解于DMF(5mL)溶液中，然后加入HATU(0.295g,0.78mmol)室温搅拌20分钟。依次加入DIPEA(0.125g,0.98mmol)和(S)-1-(4-氟苯基)-2-甲基丙-1-胺盐酸盐(0.089g,0.62mmol)，室温搅拌过夜。制备方法同实施例26，得白色固体化合物I-39(0.110g,收率79％)。
1H NMR(800MHz,DMSO-d
6)δ8.50(d,J＝8.9Hz,1H),8.06(s,1H),7.35–7.29(m,2H),7.17–7.12(m,2H),6.66(d,J＝3.6Hz,1H),6.50(d,J＝2.6Hz,1H),4.64(d,J＝16.3Hz,1H),4.58–4.54(m,2H),2.67(s,3H),1.96–1.88(m,1H),0.91(d,J＝6.6Hz,3H),0.72(d,J＝6.8Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.25,161.02(d,J＝242.5Hz),146.18,138.63(d,J＝2.9Hz),132.57,130.73,128.93(2C,d,J＝8.1Hz),125.70,115.43,114.78(2C,d,J＝21.3Hz),108.28,58.16,52.57,33.00,19.67,18.91,14.67.HRMS(ESI)C
19H
22FN
4O
2
+[M+H]
+计算值:357.1721,实测值:357.1722。
实施例40：(S)-N-(2-甲基-1-(4-三氟甲基)苯丙基)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-40)的制备
将实施例I-39中的(S)-1-(4-氟苯基)-2-甲基丙-1-胺盐酸盐替换成(S)-2-甲基-1-(4-(三氟甲基)苯基)丙-1-胺，其余所需原料，试剂及制备方法同实施例26，得白色固体化合物I-40(0.120g,收率76％)。
1H NMR(800MHz,DMSO-d
6)δ8.61(d,J＝8.7Hz,1H),8.06(s,1H),7.70(d,J＝8.4Hz,2H),7.52(d,J＝8.3Hz,2H),6.66(d,J＝3.6Hz,1H),6.50(dd,J＝3.7,1.0Hz,1H),4.68–4.63(m,2H),4.59(d,J＝16.3Hz,1H),2.67(s,3H),2.02–1.97(m,1H),0.92(d,J＝6.6Hz,3H),0.74(d,J＝6.7Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.54,147.29,146.18,132.60,130.74,129.02(q,J＝35.1Hz)127.91(2C),125.70,124.99(2C,q,J＝8.2Hz),124.33(q,J＝271.7Hz),115.44,108.30,58.58,52.58,32.74,19.61,18.75,14.66.HRMS(ESI)C
20H
22F
3N
4O
2
+[M+H]
+计算值:407.1689,实测值:407.1690。
实施例41：(S)-2(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-苯丙基)乙酰胺(化合物I-41)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(S)-1-苯基丙胺，其余所需原料，试剂及制备方法同实施例26，得白色固体化合物I-41(0.05g，收率31％)。
1H NMR(800MHz,DMSO-d
6)δ8.51(d,J＝8.4Hz,1H),8.07(s,1H),7.34–7.28(m,4H),7.25–7.21(m,1H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.7,1.1Hz,1H),4.73–4.69(m,1H),4.62and 4.57(ABq,J＝16.2Hz,2H),2.68(d,J＝1.0Hz,3H),1.73–1.66(m,2H),0.85(t,J＝7.3Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.29,146.21,143.38,132.61,130.73,128.20(2C),126.70,126.44(2C),125.73,115.41,108.25,54.28,52.65,29.25,14.67,10.97.HRMS(ESI)C
18H
21N
4O
2
+[M+H]
+计算值:325.1659,实测值:325.1659。
实施例42：(S)-2(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1,2,3,4-四氢萘-1-基)乙酰胺(化合物I-42)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(S)-1,2,3,4-四氢-1-萘胺，其余所需原料，试剂及制备方法同实施例26，得白色固体化合物I-42(0.085g，收率63％)。
1H NMR(800MHz,DMSO-d
6)δ8.51(d,J＝8.7Hz,1H),8.10(s,1H),7.22–7.19(m,1H),7.17–7.14(m,2H),7.10–7.08(m,1H),6.67(d,J＝3.6 Hz,1H),6.51(dd,J＝3.7,1.0Hz,1H),5.02–4.97(m,1H),4.60and 4.57(ABq,J＝16.4Hz,2H),2.78–2.68(m,5H),1.92–1.84(m,2H),1.77–1.66(m,2H).
13C NMR(201MHz,DMSO-d
6)δ166.33,146.25,137.24,137.04,132.70,130.74,128.71,128.12,126.76,125.83,125.80,115.39,108.23,52.87,46.72,29.82,28.74,20.09,14.70.HRMS(ESI)C
19H
21N
4O
2
+[M+H]
+计算值:337.1659,实测值:337.1657。
实施例43：(S)-2(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(吡啶-3-基)乙基)乙酰胺(化合物I-43)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(S)-1-(吡啶-3-基)乙胺，其余所需原料，试剂及制备方法同实施例26，得白色固体化合物I-43(0.065g,收率52％)。
1H NMR(800MHz,DMSO-d
6)δ8.67(d,J＝7.7Hz,1H),8.54(d,J＝2.3Hz,1H),8.45(dd,J＝4.7,1.6Hz,1H),8.08(s,1H),7.73–7.71(m,1H),7.37–7.35(m,1H),6.67(d,J＝3.6Hz,1H),6.51(dd,J＝3.7,1.1Hz,1H),5.00–4.96(m,1H),4.60(s,2H),2.69(d,J＝0.9Hz,3H),1.41(d,J＝7.0Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.26,147.98,147.75,146.23,139.57,133.59,132.69,130.76,125.73,123.40,115.43,108.32,52.75,46.23,22.01,14.67.HRMS(ESI)C
16H
18N
5O
2
+[M+H]
+计算值:312.1455,实测值:312.1454。
实施例44：N-(2-(二甲基氨基)-1-苯基乙基)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-44)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成N
1,N
1-二甲基-2-苯基乙烷-1,2-二胺，其余所需原料，试剂及制备方法同实施例26，得棕色泡沫状固体化合物I-44(0.055g,收率40％)。
1H NMR(800MHz,DMSO-d
6)δ8.56(d,J＝5.3Hz,1H),8.07(s,1H),7.33(d,J＝4.4Hz,4H),7.26–7.23(m,1H),6.67(d,J＝3.7Hz,1H),6.51(dd,J＝3.7,1.0Hz,1H),4.96(s,1H),4.61and 4.58(ABq,J＝16.2Hz,2H),2.68(s,4H),2.21(brs,6H),1.26–1.22(m,1H).
13C NMR(201MHz,DMSO-d
6)δ166.76,149.59,146.68,133.09,131.22,128.68(2C),127.40,127.15(2C),126.16,115.92,108.78,64.66,53.08,51.23,45.48(2C),15.14.HRMS(ESI)C
19H
24N
5O
2
+[M+H]
+计算值:354.1925,实测值:354.1927。
实施例45：(R)-N-(1-(4-氟苯基)乙基-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)乙酰胺(化合物I-45)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(R)-1-(4-氟苯基)乙胺，其余所需原料，试剂及制备方法同实施例26，得白色固体化合物I-45(0.040g，收率18％)。
1H NMR(800MHz,DMSO-d
6)δ8.59(d,J＝7.9Hz,1H),8.08(s,1H),7.38–7.34(m,2H),7.17–7.13(m,2H),6.67(d,J＝3.6Hz,1H),6.50(d,J＝2.6Hz,1H),4.96–4.92(m,1H),4.58and 4.55(ABq,J＝16.0Hz,2H),2.69(s,3H),1.36(d,J＝6.9Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.02,161.03(d,J＝242.1Hz),146.23,140.54(d,J＝3.3Hz),132.65,130.75,127.90(d,J＝8.1Hz,2C),125.73,115.43,114.91(2C,d,J＝20.9Hz),108.29,52.69,47.48,22.43,14.67.HRMS(ESI)C
17H
18FN
4O
2
+[M+H]
+计算值:329.1408,实测值:329.1407。
实施例46：(S)-2-(6-甲基-4-氧代吡咯并[1,2-d][1,2,4]三嗪-3(4H)基)-N-(1-(4-(三氟甲基)苯基)乙基)乙酰胺(化合物I-46)的制备
将实施例26中(S)-1-(1-萘基)乙胺替换成(S)-1-[4-(三氟甲基)苯基]乙胺盐酸盐，其余所需原料，试剂及制备方法同实施例26，得白色固体化合物I-46(0.092g，收率71％)。
1H NMR(800MHz,DMSO-d
6)δ8.71(d,J＝7.6Hz,1H),8.08(s,1H),7.69(d,J＝8.5Hz,2H),7.55(d,J＝8.3Hz,2H),6.67(d,J＝3.6Hz,1H),6.50(dd,J＝3.7,1.0Hz,1H),5.03–4.98(m,1H),4.61(s,2H),2.69(s,3H),1.39(d,J＝7.2Hz,3H).
13C NMR(201MHz,DMSO-d
6)δ166.30,149.32,146.23,132.69,130.77,127.32(q,J＝31.5Hz),126.75(2C),125.73,125.19(2C,q,J＝3.7Hz),124.34(q,J＝271.8Hz),115.44,108.32,52.71,48.04,22.20,14.66.HRMS(ESI)C
18H
18F
3N
4O
2
+[M+H]
+计算值:379.1376,实测值:379.1377。
生物测试实施例1：本发明化合物对GPR139的激动活性测定
本发明化合物对GPR139的激动活性采用钙流检测实验(Molecular Devices)来测定。具体操作方法如下：
(1)细胞培养(CHO-K1细胞系，细胞培养基：Ham’s F12+10％FBS+1％PS(青链霉素Penicillin-Streptomycin)。
(2)在10cm培养皿中，用2mL PBS缓冲液(HyClone,Cat#SH30028.02)洗涤细胞，去除缓冲液，再加入1mL胰酶(Thermo,Cat#25300054)消化细胞2分钟；加入2mL细胞培养基终止消化，吹打混匀，1000rmp离心3分钟。
(3)将细胞重悬并调整细胞密度为3×10
6/mL，取1mL的细胞液于10cm培养皿(10mL细胞培 养基)，过夜培养。
(4)待细胞密度至60％进行转染，转染前1小时细胞换液；将GPR139质粒和TransIT-2020分别加入Opti-MEM(转染比例：1μg GPR139质粒+16μL TransIT-2020+1000μL Opti-MEM)，吹打混匀室温孵育20分钟；逐滴加入含细胞的培养皿中轻轻混匀，转染16至20小时。
(5)细胞经胰酶消化之后用17mL细胞培养基重悬，铺入黑色底透384孔板(Greiner,Cat#781091)中，每孔加入40μL细胞液，细胞数为15000～20000个/孔；37℃，5％CO
2孵育16小时。
(6)配制试剂：将待测化合物用DMSO配制成10mM浓度的储存液，然后用0.1％BSA(牛血清白蛋白)溶液稀释至30μM,再3倍梯度稀释，16个浓度点；激动剂阳性对照TAK-041和空白对照DMSO均为30μM起始，16个浓度点。
(7)用排枪将不同浓度的待测化合物转移到384孔板(Greiner,Cat#784201)上，每孔20μL，1000rmp离心1分钟。
(8)去除384孔黑板中的细胞培养液，向每孔中加入20μL 1×染料(FLIPR Calcium6 Assay Explorer Kit,Cat#R8190,含2.5mM丙磺舒)溶液后，37℃孵育60分钟；室温平衡15分钟。
(9)使用FLIPR(Molecular Devices)将不同浓度的待测化合物转移到384孔黑板上，每孔10μL，用FLIPR读取钙流信号(最大激发光：470～495nm，最大发射光515～575nm)。
(10)使用GraphPad Prism(版本8.0)分析数据，数据显示为平均值±标准差，浓度响应曲线的拟合采用非线性回归，计算出EC
50值。
结果：本发明化合物对GPR139的激动活性如表1所示。
表1.
| 化合物 | EC 50(nM) | E max(％) |
| TAK-041 | 61±2 | 100 |
| I-1 | 56±13 | 101 |
| I-2 | 28±4 | 112 |
| I-3 | 60±1 | 114 |
| I-4 | 111±4 | 99 |
| I-5 | 25±2 | 105 |
| I-6 | 30±6 | 111 |
| I-7 | NT | NT |
| I-8 | 45±1 | 98 |
| I-9 | NT | NT |
| I-10 | NT | NT |
| I-11 | 19±3 | 109 |
| I-12 | 21±5 | 114 |
| I-13 | 24±6 | 116 |
| I-14 | 13±2 | 111 |
| I-15 | 75±11 | 96 |
| I-16 | 23±5 | 116 |
| I-17 | 95±14 | 95 |
| I-18 | 93±15 | 105 |
| I-19 | 34±6 | 104 |
| I-20 | 19±3 | 103 |
| I-21 | 96±14 | 98 |
| I-22 | 56±11 | 104 |
| I-23 | 23±5 | 110 |
| I-24 | 33±5 | 108 |
| I-25 | NT | NT |
| I-26 | 42±1 | 110 |
| I-27 | 15±3 | 108 |
| I-28 | NT | NT |
| I-29 | NT | NT |
| I-30 | NT | NT |
| I-31 | NT | NT |
| I-32 | 61±4 | 105 |
| I-33 | NT | NT |
| I-34 | 57±5 | 92 |
| I-35 | NT | NT |
| I-36 | NT | NT |
| I-37 | 120 | 92 |
| I-38 | 61 | 93 |
| I-39 | 26 | 94 |
| I-40 | 125 | 80 |
| I-41 | 22±2 | 107 |
| I-42 | NT | NT |
| I-43 | NT | NT |
| I-44 | NT | NT |
| I-45 | NT | NT |
| I-46 | 68±8 | 102 |
注：上表中，E
max＝本申请化合物的最大效应/TAK-041的最大效应；NT，未测试。
生物测试实施例2：化合物腹腔注射给药后在小鼠体内药代动力学研究
化合物在雄性小鼠体内单剂量腹腔注射给药后，于不同时间点采集血样和脑组织，LC-MS/MS测定小鼠血浆和脑组织中化合物的浓度并计算相关药代参数，考察化合物在小鼠体内药代特征及脑分布。
2.1实验设计
36只雄性C57小鼠按体重随机分为4组，每组9只。给药前1天禁食不禁水12～14h，给药后4h给食。化合物溶媒：10％DMSO+10％solutol(聚乙二醇-12羟基硬脂酸酯)+80％生理盐水。
2.2样品采集
于给药前及给药后异氟烷麻醉经眼眶取血0.1mL，置于EDTAK2离心管中并放置冰浴上。5000rpm，4℃离心10min，收集血浆。IP血浆和脑组织采集时间点：0.5h、2h和4h，分析检测前，所有血浆样品存于-80℃。脑组织采集时间点0.5h、2h和4h，小鼠放血安乐死后取脑组织清洗干净，准确称量后用50％甲醇水按照1:4匀浆，匀浆液样品存于-80℃待分析。
2.3数据处理
数据采集及控制系统软件为Analyst1.5.1软件(Applied Biosystem)。图谱样品峰积分方式为自动积分；采用样品峰面积和内标峰面积的比值作为指标，和样品的浓度进行回归。回归方式：线性回归，权重系数为1/X
2。药代动力学参数用WinNonlin Professional v6.3(Pharsight,USA)用非房室模型分析处理。C
max为实测的最大血药浓度，血药浓度-时间曲线下面积AUC
(0→t)由梯形法计算得到，t
max为给药后血药浓度达峰时间。实验数据“均数”(Mean,n＝3)表示。
2.4实验结果
注：NA表示无法计算。
生物测试实施例3：化合物给药后对BALB/c小鼠的行为学研究
对BALB/c小鼠腹腔注射不同剂量的I-5，通过社会交互实验来验证所开发化合物对于精神分裂症阴性症状的治疗效果
3.1实验对象
实验对象为6周龄、体重约22克的雄性BALB/c野生型小鼠，采购自上海灵畅生物科技有限公司。饲养在SPF级饲养设施，每笼2只，12小时明暗循环，随意获取食物和水。本项目中所有行为实验均在光循环期间完成。本实验全程遵守实验动物福利伦理相关法规和各项规定，并接受伦理委员会和实验室动物管理者的监督与检查。
3.2行为系统
本实验所使用的行为箱长、宽、高均为40厘米。实验过程中，4只小鼠同时在4个行为箱中进行试验。本实验使用EthoVision XT进行实验设置和视频录制。
3.3实验流程
将小鼠随机分为6组，分别是阴性对照组；阳性对照组：TAK-041(3mg/kg),TAK-041(1mg/kg)；实验组：I-5(3mg/kg),I-5(1mg/kg),I-5(0.3mg/kg)，每组≥12只。
小鼠购入时为5周龄，观察一周后，待其6周龄，并且体重长至22克左右时开始实验。每次实验前，提前18小时对实验鼠进行限食。实验当天，提前1小时，将小鼠转移至行为学实验室中熟悉环境。接下来通过腹腔注射给药，每只小鼠给药后放回原鼠笼。20分钟后，将实验鼠放入行为箱中适应10分钟，然后将刺激鼠(同批次BALB/c)放入行为箱中远离实验鼠的角落，任两只小鼠自由探索10分钟，通过摄像机监测记录小鼠活动，并存档。
对实验数据进行分析。计算每只实验鼠在10分钟内的社交交互时间(包括接近、嗅、理毛、追逐、攻击等)，通过单因素方差分析对不同组之间每只小鼠总社交时间进行分析。在分析过程中，未进行社交和社交时间低于10秒的小鼠被排除在外。
3.4实验结果
实验结果如图1和下表：
实验结果表明，化合物I-5在3mg/kg剂量下，对小鼠社交障碍具有显著的改善作用。
Claims (13)
- 一种如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐；
其中，R 1、R 2、R 3和R 4独立地为H、卤素、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、被1个、2个或3个R 1-1取代的C 1-6烷基、被1个、2个或3个R 1-2取代的C 3-6环烷基或被1个、2个或3个R 1-3取代的-O-C 1-6烷基；R 1-1、R 1-2和R 1-3独立地为卤素；R 5为H或C 1-6烷基；R 6和R 7独立地为H、C 1-6烷基、C 3-6环烷基、被1个、2个或3个R 6-1取代的C 1-6烷基或被1个、2个或3个R 6-2取代的C 3-6环烷基；R 6-1独立地为卤素、-O-C 1-6烷基或-NR aR b；R 6-2独立地为卤素、-O-C 1-6烷基或-NR aR b；R a和R b独立地为C 1-6烷基；或，R a和R b与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个R a-1取代的5-6元杂环烷基；所述5-6元杂环烷基独立地为杂原子独立地选自N、O和S中的1种、2种或3种，杂原子的个数为1个、2个或3个的5-6元杂环烷基；R a-1独立地为C 1-6烷基；Q为C 6-10芳环、5-10元杂芳环、C 3-6环烷基或5-6元杂环烷基；所述5-10元杂芳环为杂原子独立地选自N、O和S中的1种、2种或3种，杂原子的个数为1个、2个或3个的5-10元杂芳环；n为0、1、2、3、4或5；R 8独立地为卤素、-OH、-CN、-NH 2、C 1-6烷基、-O-C 1-6烷基、被1个、2个或3个R 8-1取代的C 1-6烷基或被1个、2个或3个R 8-2取代的-O-C 1-6烷基；R 8-1和R 8-2独立地为卤素；或，R 8与R 7一起形成-(CH 2) m-，m为2或3；带“*”、“#”的碳原子为非手性碳原子或手性碳原子，当为手性碳原子时，独立地为S构型和/或R构型。 - 如权利要求1所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐；其特征在于，
其中，R 1、R 2、R 3和R 4独立地为H、卤素、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、被1个、2个或3个R 1-1取代的C 1-6烷基、被1个、2个或3个R 1-2取代的C 3-6环烷基或被1个、2个或3个R 1-3取代的-O-C 1-6烷基；R 1-1、R 1-2和R 1-3独立地为卤素；R 5为H或C 1-6烷基；R 6和R 7独立地为H、C 1-6烷基、C 3-6环烷基、被1个、2个或3个R 6-1取代的C 1-6烷基或被1个、2个或3个R 6-2取代的C 3-6环烷基；R 6-1独立地为卤素、-O-C 1-6烷基或-NR aR b；R 6-2独立地为卤素、-O-C 1-6烷基或-NR aR b；R a和R b独立地为C 1-6烷基；或，R a和R b与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个R a-1取代的5-6元杂环烷基；所述5-6元杂环烷基独立地为杂原子独立地选自N、O和S中的1种、2种或3种，杂原子的个数为1个、2个或3个的5-6元杂环烷基；R a-1独立地为C 1-6烷基；Q为C 6-10芳环或5-10元杂芳环；所述5-10元杂芳环为杂原子独立地选自N、O和S中的1种、2种或3种，杂原子的个数为1个、2个或3个的5-10元杂芳环；n为0、1、2、3、4或5；R 8独立地为卤素、-OH、-CN、-NH 2、C 1-6烷基、-O-C 1-6烷基、被1个、2个或3个R 8-1取代的C 1-6烷基或被1个、2个或3个R 8-2取代的-O-C 1-6烷基；R 8-1和R 8-2独立地为卤素；或，R 8与R 7一起形成-(CH 2) m-，m为2或3；带“*”、“#”的碳原子为非手性碳原子或手性碳原子，当为手性碳原子时，独立地为S构型和/或R构型。 - 如权利要求1或2所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐，其特征在于，为
例如
为
其中，*、#、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、Q和n的定义如权利要求1或2所述。
- 如权利要求1-3中至少一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐，其特征在于，其满足以下条件中的一种或多种：(1)R 1、R 2和R 3独立地为H或C 1-6烷基；(2)R 4独立地为H；(3)R 5为H；(4)R 6为H；(5)R 7为C 1-6烷基或被1个、2个或3个R 6-1取代的C 1-6烷基；(6)R 6-1独立地为-NR aR b；(7)R a和R b独立地为C 1-6烷基；(8)n为0或1；和(9)R 8为卤素、-OH、-CN、C 1-6烷基、-O-C 1-6烷基、被1个、2个或3个R 8-1取代的C 1-6烷基或被1个、2个或3个R 8-2取代的-O-C 1-6烷基；或，R 8与R 7一起形成-(CH 2) m-，m为2或3；例如，R 8为卤素、-OH、C 1-6烷基、-O-C 1-6烷基或被1个、2个或3个R 8-2取代的-O-C 1-6烷基；或，R 8与R 7一起形成-(CH 2) m-，m为2或3。
- 如权利要求1-3中至少一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐，其特征在于，其满足以下条件中的一种或多种：(1)R 1、R 2、R 3和R 4中，所述C 1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；(2)R 1-1、R 1-2和R 1-3中，所述卤素为F、Cl、Br或I；(3)R 6和R 7中，所述C 1-6烷基和被1个、2个或3个R 6-1取代的C 1-6烷基中的C 1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；(4)R a和R b中，所述C 1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；(5)Q中，所述C 6-10芳环为苯环或萘环；(6)Q中，所述5-10元杂芳环为5-6元杂芳环；(7)R 8中，所述卤素独立地为F、Cl、Br或I；(8)R 8中，所述C 1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；(9)R 8中，所述-O-C 1-6烷基和被1个、2个或3个R 8-2取代的-O-C 1-6烷基中的-O-C 1-6烷基独立地为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基；(10)R 8-1和R 8-2中，所述卤素独立地为F、Cl、Br或I；(11)当R 8与R 7一起形成-(CH 2) m-，m为3；(12)当R a和R b与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个R a-1取代的5-6元杂环烷基，所述的5-6元杂环烷基或被1个、2个或3个R a-1取代的5-6元杂环烷基中的5-6元杂环烷基独立地为杂原子独立地选自N和O，杂原子的个数为1个或2个的5-6元杂环烷基；(13)R a-1中，所述C 1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，和(14)Q中，所述C 3-6环烷基为环丙基、环丁基、环戊基或环已基。
- 如权利要求5所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐，其特征在于，其满足以下条件中的一种或多种：(1)R 1、R 2、R 3和R 4中，所述C 1-6烷基为甲基；(2)R 6和R 7中，所述C 1-6烷基和被1个、2个或3个R 6-1取代的C 1-6烷基中的C 1-6烷基独立地为甲基或乙基；(3)R a和R b中，所述C 1-6烷基为甲基；(4)Q中，所述C 6-10芳环为苯环；(5)Q中，所述5-10元杂芳环为吡啶环，例如为
(6)R 8中，所述卤素为F、Cl或Br；(7)R 8中，所述C 1-6烷基为甲基；(8)R 8中，所述-O-C 1-6烷基和被1个、2个或3个R 8-2取代的-O-C 1-6烷基中的-O-C 1-6烷基为甲氧基；(9)R 8-1和R 8-2中，所述卤素为F；(10)当R a和R b与其相连的氮原子一起形成5-6元杂环烷基或被1个、2个或3个R a-1取代的5-6元杂环烷基，所述的5-6元杂环烷基为
(11)R a-1中，所述C 1-6烷基为甲基；和(12)Q中，所述C 3-6环烷基为环己基。 - 如权利要求1-3中至少一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐，其特征在于，其满足以下条件中的一种或多种：(1)当Q为苯环时，为
R 8-a、R 8-b、R 8-c和R 8-d独立地为H、卤素、-OH、-CN、-NH 2、C 1-6烷基、-O-C 1-6烷基、被1个、2个或3个R 8-1取代的C 1-6烷基或被1个、2个或3个R 8-2取代的-O-C 1-6烷基；
R 8-e为H、卤素、-OH、-CN、-NH 2、C 1-6烷基、-O-C 1-6烷基、被1个、2个或3个R 8-1取代的C 1- 6烷基或被1个、2个或3个R 8-2取代的-O-C 1-6烷基；或者，R 8-e与R 7一起形成-(CH 2) m-，m为2或3；(2)为
(3)R 6为H；(4)R 7为-CH 3、-CH 2CH 3、例如为-CH 3、-CH 2CH 3
- 如权利要求1-3中至少一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐，其特征在于，R 8独立地为F、Cl、Br、-OH、-CH 3、-OCH 3、-OCF 3、-CF 3或CN，例如为F、Cl、Br、-OH、-CH 3、-OCH 3或-OCF 3；较佳地，为
例如为
更佳地，为
- 如权利要求1或2所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐，其特征在于，所述如式I所示的吡咯并三嗪酮类化合物选自以下任一化合物：
- 一种药物组合物，其特征在于，所述药物组合物包含如权利要求1-9至少一项所述的如式I所示的吡咯并三嗪酮类化合物或其药学上可接受的盐，以及药用辅料。
- 如权利要求1-9至少一项所述的如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐的制备方法，其特征在于，其包括以下步骤：化合物II和化合物III发生缩合反应；
其中，*、#、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、Q和n的定义如权利要求1-9至少一项所述。 - 如权利要求1-9至少一项所述的如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐或如权利要求10所述的药物组合物在制备药物中的应用，所述药物用于治疗和/或预防GPR139受体相关的疾病；所述GPR139受体相关的疾病可为精神分裂症、双相情感障碍、抑郁症、认知障碍、自闭症谱系障碍、睡眠障碍、注意缺陷多动障碍、创伤后应激障碍、物质滥用、吸毒成瘾、饮食失调、强迫症、焦虑症、疼痛或纤维肌痛。
- 如权利要求1-9至少一项所述的如式I所示的吡咯并三嗪酮类化合物及其药学上可接受的盐或如权利要求10所述的药物组合物在制备药物中的应用，所述药物用于治疗和/或预防精神分裂症、双相情感障碍、抑郁症、认知障碍、自闭症谱系障碍、睡眠障碍、注意缺陷多动障碍、创伤后应激障碍、物质滥用、吸毒成瘾、饮食失调、强迫症、焦虑症、疼痛或纤维肌痛。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210195902 | 2022-03-01 | ||
| CN202210195902.X | 2022-03-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023165263A1 true WO2023165263A1 (zh) | 2023-09-07 |
Family
ID=87836298
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2023/071042 WO2023165263A1 (zh) | 2022-03-01 | 2023-01-06 | 吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN116693536A (zh) |
| WO (1) | WO2023165263A1 (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107108531A (zh) * | 2014-11-20 | 2017-08-29 | 武田药品工业株式会社 | 作为gpr139的调节剂的4‑氧代‑3,4‑二氢‑1,2,3‑苯并三嗪类 |
| WO2020097609A1 (en) * | 2018-11-09 | 2020-05-14 | Blackthorn Therapeutics, Inc. | Gpr139 receptor modulators |
| WO2021055326A1 (en) * | 2019-09-16 | 2021-03-25 | Takeda Pharmaceutical Company Limited | Azole-fused pyridazin-3(2h)-one derivatives |
| WO2021224680A1 (en) * | 2020-05-08 | 2021-11-11 | Takeda Pharmaceutical Company Limited | Substituted benzotriazinone metabolites of a gpr139 agonist |
-
2023
- 2023-01-06 WO PCT/CN2023/071042 patent/WO2023165263A1/zh unknown
- 2023-01-06 CN CN202310020896.9A patent/CN116693536A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107108531A (zh) * | 2014-11-20 | 2017-08-29 | 武田药品工业株式会社 | 作为gpr139的调节剂的4‑氧代‑3,4‑二氢‑1,2,3‑苯并三嗪类 |
| WO2020097609A1 (en) * | 2018-11-09 | 2020-05-14 | Blackthorn Therapeutics, Inc. | Gpr139 receptor modulators |
| WO2021055326A1 (en) * | 2019-09-16 | 2021-03-25 | Takeda Pharmaceutical Company Limited | Azole-fused pyridazin-3(2h)-one derivatives |
| WO2021224680A1 (en) * | 2020-05-08 | 2021-11-11 | Takeda Pharmaceutical Company Limited | Substituted benzotriazinone metabolites of a gpr139 agonist |
Non-Patent Citations (3)
| Title |
|---|
| DATABASE Registry 4 July 2012 (2012-07-04), ANONYMOUS: "Pyrrolo[1,2-d][1,2,4]triazine-3(4H)-acetamide, N-[(4-fluorophenyl)methyl]-4-oxo-1-(trifluoromethyl)- (CA INDEX NAME)", XP093088830, retrieved from STNext Database accession no. 1381460-52-1 * |
| REICHARD, HOLLY A. ET AL.: "Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia", JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 15, 14 July 2021 (2021-07-14), pages 11527 - 11542, XP055874804, DOI: 10.1021/acs.jmedchem.1c00820 * |
| SHEHATA MOHAMED A., NØHR ANNE C., LISSA DELPHINE, BISIG CHRISTOPH, ISBERG VIGNIR, ANDERSEN KIRSTEN B., HARPSØE KASPER, BJÖRKLING F: "Novel Agonist Bioisosteres and Common Structure-Activity Relationships for The Orphan G Protein-Coupled Receptor GPR139", SCIENTIFIC REPORTS, vol. 6, no. 1, 10 November 2016 (2016-11-10), pages 36681, XP093088518, DOI: 10.1038/srep36681 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116693536A (zh) | 2023-09-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6736559B2 (ja) | トリアゾロピリミジン化合物およびその使用 | |
| JP7169469B2 (ja) | Ｂｒａｆ関連疾患および障害を処置するために有用なキナゾリン－４－オン誘導体 | |
| JP5883399B2 (ja) | ｍＧｌｕＲ４アロステリック増強剤としてのピラゾロピリジン、ピラゾロピラジン、ピラゾロピリミジン、ピラゾロチオフェンおよびピラゾロチアゾール化合物、組成物、および神経機能不全を治療する方法 | |
| RU2486188C9 (ru) | СОЕДИНЕНИЯ ИМИДАЗО[1,2-B]ПИРИДАЗИНА (ВАРИАНТЫ), СПОСОБ ПОЛУЧЕНИЯ СОЕДИНЕНИЙ ИМИДАЗО[1,2-b]ПИРИДАЗИНА (ВАРИАНТЫ), ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И ЛЕКАРСТВЕННОЕ СРЕДСТВО ДЛЯ ЛЕЧЕНИЯ И/ИЛИ ПРЕДУПРЕЖДЕНИЯ ЗАБОЛЕВАНИЙ, СВЯЗАННЫХ С ИНГИБИРОВАНИЕМ ГАМКА РЕЦЕПТОРОВ | |
| JP2016169231A (ja) | Ｍｇｌｕｒ５の負のアロステリック調節剤としての６−アルキル−ｎ−（ピリジン−２−イル）−４−アリールオキシピコリンアミド類似体ならびにそれを作製および使用する方法 | |
| CN108558831B (zh) | 取代吡咯-4-烷基胺类化合物及其用途 | |
| WO2022166817A1 (zh) | 一种杂环化合物、其中间体、其制备方法及其应用 | |
| WO2022001767A1 (zh) | 一种杂环化合物及其应用 | |
| CN110267945A (zh) | 氰基取代的吲哚化合物及其作为lsd1抑制剂的用途 | |
| MX2012009381A (es) | Metodos y sistema para retirar componentes del gas a partir de los gases de proceso. | |
| JP2013508413A (ja) | ｍＧｌｕＲ４アロステリック増強剤、組成物、および神経機能不全を治療する方法 | |
| JP6392352B2 (ja) | リーシュマニア症などの寄生虫病を処置するための原生動物のプロテアソーム阻害剤としての［１，２，４］トリアゾロ［１，５−ａ］ピリミジン誘導体 | |
| WO2020182159A1 (zh) | Jak激酶抑制剂及其制备方法和在医药领域的应用 | |
| WO2023066377A1 (zh) | 一种含氮化合物、其制备方法及应用 | |
| WO2020156271A1 (zh) | 两面神激酶jak家族抑制剂及其制备和应用 | |
| WO2020020377A1 (zh) | 用作fgfr4抑制剂的稠环衍生物 | |
| WO2023165263A1 (zh) | 吡咯并三嗪酮类化合物、含其的药物组合物、其制备方法及其应用 | |
| WO2023165262A1 (zh) | 噻吩并含氮杂环类化合物、含其的药物组合物、其制备方法及其应用 | |
| WO2022206730A1 (zh) | 嘧啶并吡嗪酮化合物及其用途 | |
| WO2021228217A1 (zh) | 可用作RORγ调节剂的苯胺类化合物 | |
| WO2021218863A1 (zh) | 1,5-二氢-2,4-苯二氮䓬-3-酮衍生物及其应用 | |
| TWI828489B (zh) | 具有mat2a抑制活性的嘧啶-2(1h)-酮并二環類化合物及其用途 | |
| WO2022161493A1 (zh) | 氮杂麦角林类衍生物及其制备方法和应用 | |
| RU2797606C1 (ru) | Производные хиназолин-4-она, полезные для лечения braf-ассоциированных заболеваний и нарушений | |
| EP4234544A1 (en) | Fused ring-containing compound, application thereof, and composition containing same |
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: 23762664 Country of ref document: EP Kind code of ref document: A1 |