TW202108135A - 治療睡眠呼吸中止症之α2-腎上腺素受體亞型C (α-2C)拮抗劑與TASK1/3通道阻斷劑之組合 - Google Patents
治療睡眠呼吸中止症之α2-腎上腺素受體亞型C (α-2C)拮抗劑與TASK1/3通道阻斷劑之組合 Download PDFInfo
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- TW202108135A TW202108135A TW109114789A TW109114789A TW202108135A TW 202108135 A TW202108135 A TW 202108135A TW 109114789 A TW109114789 A TW 109114789A TW 109114789 A TW109114789 A TW 109114789A TW 202108135 A TW202108135 A TW 202108135A
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- Prior art keywords
- methyl
- alkyl
- imidazo
- methanone
- pyridin
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- 238000011282 treatment Methods 0.000 title claims abstract description 28
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 title abstract description 26
- 239000005557 antagonist Substances 0.000 title abstract description 17
- 102000015006 alpha2-adrenergic receptor activity proteins Human genes 0.000 title abstract 2
- 201000002859 sleep apnea Diseases 0.000 title description 5
- 208000001797 obstructive sleep apnea Diseases 0.000 claims abstract description 39
- 206010041235 Snoring Diseases 0.000 claims abstract description 29
- 208000003417 Central Sleep Apnea Diseases 0.000 claims abstract description 27
- 230000000414 obstructive effect Effects 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 208000035475 disorder Diseases 0.000 claims abstract description 7
- -1 NH 2 Chemical group 0.000 claims description 169
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 156
- 150000001875 compounds Chemical class 0.000 claims description 106
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 91
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 80
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
- 208000023504 respiratory system disease Diseases 0.000 claims description 30
- 229910052731 fluorine Inorganic materials 0.000 claims description 27
- 239000011737 fluorine Substances 0.000 claims description 27
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 21
- 239000000460 chlorine Substances 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
- 229910052794 bromium Inorganic materials 0.000 claims description 15
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 14
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 13
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 230000002265 prevention Effects 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 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
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 206010003119 arrhythmia Diseases 0.000 claims description 7
- 230000006793 arrhythmia Effects 0.000 claims description 7
- 150000002460 imidazoles Chemical class 0.000 claims description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 7
- 125000006413 ring segment Chemical group 0.000 claims description 7
- HJCFDCKEUGZLPS-UHFFFAOYSA-N 2-(4-chlorophenyl)-1h-imidazole Chemical compound C1=CC(Cl)=CC=C1C1=NC=CN1 HJCFDCKEUGZLPS-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 6
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 230000001703 neuroimmune Effects 0.000 claims description 6
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 6
- VDKJCAWGDJJKNL-UHFFFAOYSA-N (3-chloro-6-methoxypyridin-2-yl)-[3-[[2-(4-propan-2-ylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone Chemical compound ClC=1C(=NC(=CC=1)OC)C(=O)N1C2CN(CC1CC2)CC1=C(N=C2N1C=CC=N2)C1=CC=C(C=C1)C(C)C VDKJCAWGDJJKNL-UHFFFAOYSA-N 0.000 claims description 5
- VEVCQRNNUZFZRI-UHFFFAOYSA-N (3-chloro-6-methoxypyridin-2-yl)-[5-[[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl]-2,5-diazabicyclo[2.2.2]octan-2-yl]methanone Chemical compound ClC=1C(=NC(=CC=1)OC)C(=O)N1C2CN(C(C1)CC2)CC1=C(N=C2N1C=CC=C2)C1=NC=C(C=C1)Cl VEVCQRNNUZFZRI-UHFFFAOYSA-N 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- CROTXORBJIXBSO-UHFFFAOYSA-N [4-[[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-(6-methoxypyridin-2-yl)methanone Chemical compound ClC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CCN(CC1)C(=O)C1=NC(=CC=C1)OC CROTXORBJIXBSO-UHFFFAOYSA-N 0.000 claims description 5
- 229940083712 aldosterone antagonist Drugs 0.000 claims description 5
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 5
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000002837 carbocyclic group Chemical group 0.000 claims description 5
- 231100000252 nontoxic Toxicity 0.000 claims description 5
- 230000003000 nontoxic effect Effects 0.000 claims description 5
- GWCXCQVXKXFHMH-UHFFFAOYSA-N (3-chloro-6-methoxypyridin-2-yl)-[3-[[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone Chemical compound ClC=1C(=NC(=CC=1)OC)C(=O)N1C2CN(CC1CC2)CC1=C(N=C2N1C=CC=N2)C1=CC=C(C=C1)Cl GWCXCQVXKXFHMH-UHFFFAOYSA-N 0.000 claims description 4
- OGGHXOJOVOYBOH-UHFFFAOYSA-N (3-fluoro-6-methoxypyridin-2-yl)-[3-[[2-(4-propan-2-ylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone Chemical compound FC=1C(=NC(=CC=1)OC)C(=O)N1C2CN(CC1CC2)CC1=C(N=C2N1C=CC=N2)C1=CC=C(C=C1)C(C)C OGGHXOJOVOYBOH-UHFFFAOYSA-N 0.000 claims description 4
- GMWJNQNMIMYTPB-UHFFFAOYSA-N (6-methoxypyridin-2-yl)-[2-[[2-(4-propan-2-ylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]methanone Chemical compound COC1=NC(=CC=C1)C(=O)N1CC2CN(CC3=C(N=C4C=CC=CN34)C3=CC=C(C=C3)C(C)C)CC2C1 GMWJNQNMIMYTPB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 4
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical group C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims description 4
- LMEIPAPPZIABHG-UHFFFAOYSA-N ClC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CC2C(C1)CN(C2)C(=O)C1=NC(=CC=C1)OC Chemical compound ClC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CC2C(C1)CN(C2)C(=O)C1=NC(=CC=C1)OC LMEIPAPPZIABHG-UHFFFAOYSA-N 0.000 claims description 4
- OPWVZOMCGJLMFL-PMACEKPBSA-N ClC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1[C@@H]2CN([C@H](C1)CC2)C(=O)C1=NC(=CC=C1F)OC Chemical compound ClC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1[C@@H]2CN([C@H](C1)CC2)C(=O)C1=NC(=CC=C1F)OC OPWVZOMCGJLMFL-PMACEKPBSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- DWBFFVUVIXJXHA-SFTDATJTSA-N [(1S,4S)-5-[[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]-2,5-diazabicyclo[2.2.2]octan-2-yl]-(6-methoxypyridin-2-yl)methanone Chemical compound C1=C(N=C(C=C1)OC)C(=O)N1[C@H]2CC[C@H](N(C2)CC=2N3C(=NC=2C2=CC=C(Cl)C=C2)C=CC=C3)C1 DWBFFVUVIXJXHA-SFTDATJTSA-N 0.000 claims description 4
- LFPZVWHVFXUWFL-UHFFFAOYSA-N [2-[[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-(6-methoxy-3-methylpyridin-2-yl)methanone Chemical compound C1=CC(=C(N=C1OC)C(=O)N1CC2C(C1)CN(C2)CC=1N2C(=NC=1C1=CC=C(Cl)C=C1)C=CC=C2)C LFPZVWHVFXUWFL-UHFFFAOYSA-N 0.000 claims description 4
- SMVLTESEHRAPDU-UHFFFAOYSA-N [3-[[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-(3-fluoro-6-methoxypyridin-2-yl)methanone Chemical compound ClC1=CC=C(C=C1)C=1N=C2N(C=CC=N2)C=1CN1CC2CCC(C1)N2C(=O)C1=NC(=CC=C1F)OC SMVLTESEHRAPDU-UHFFFAOYSA-N 0.000 claims description 4
- YJADTYIFXPYAMV-UHFFFAOYSA-N [3-[[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-(6-methoxypyridin-2-yl)methanone Chemical compound ClC1=CC=C(C=C1)C=1N=C2N(C=CC=N2)C=1CN1CC2CCC(C1)N2C(=O)C1=NC(=CC=C1)OC YJADTYIFXPYAMV-UHFFFAOYSA-N 0.000 claims description 4
- NABAWQRCDXXOMF-UHFFFAOYSA-N [4-[[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-(2-fluorophenyl)methanone Chemical compound BrC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CCN(CC1)C(=O)C1=C(C=CC=C1)F NABAWQRCDXXOMF-UHFFFAOYSA-N 0.000 claims description 4
- RWCKYFYFNKRFHA-UHFFFAOYSA-N [4-[[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-cyclopentylmethanone Chemical compound BrC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CCN(CC1)C(=O)C1CCCC1 RWCKYFYFNKRFHA-UHFFFAOYSA-N 0.000 claims description 4
- SIFMANNOUHDCIV-UHFFFAOYSA-N [4-[[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-[6-(trifluoromethoxy)pyridin-2-yl]methanone Chemical compound ClC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CCN(CC1)C(=O)C1=NC(=CC=C1)OC(F)(F)F SIFMANNOUHDCIV-UHFFFAOYSA-N 0.000 claims description 4
- OJTQAPGPBFFNOG-UHFFFAOYSA-N [4-[[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl]piperazin-1-yl]-cyclopentylmethanone Chemical compound ClC1=CC=C(C=C1)C=1N=C2N(C=CC=C2)C=1CN1CCN(CC1)C(=O)C1CCCC1 OJTQAPGPBFFNOG-UHFFFAOYSA-N 0.000 claims description 4
- CPNNJLTVWFNGNR-UHFFFAOYSA-N [5-[[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl]-2,5-diazabicyclo[2.2.2]octan-2-yl]-(3-fluoro-6-methoxypyridin-2-yl)methanone Chemical compound COc1ccc(F)c(n1)C(=O)N1CC2CCC1CN2Cc1c(nc2ccccn12)-c1ccc(Cl)cn1 CPNNJLTVWFNGNR-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 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 4
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- SHNUDJJIKQNRCO-UHFFFAOYSA-N (3-fluoro-6-methoxypyridin-2-yl)-[2-[[2-(4-propan-2-ylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]methanone Chemical compound COC1=NC(C(=O)N2CC3CN(CC4=C(N=C5C=CC=CN45)C4=CC=C(C=C4)C(C)C)CC3C2)=C(F)C=C1 SHNUDJJIKQNRCO-UHFFFAOYSA-N 0.000 claims description 3
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- QOSRXQONARTPFE-UHFFFAOYSA-N COC1=NC(C(=O)N2C3CCC2CN(CC2=C(N=C4N=CC=CN24)C2=CC=C(C=C2)C2CC2)C3)=C(F)C=C1 Chemical compound COC1=NC(C(=O)N2C3CCC2CN(CC2=C(N=C4N=CC=CN24)C2=CC=C(C=C2)C2CC2)C3)=C(F)C=C1 QOSRXQONARTPFE-UHFFFAOYSA-N 0.000 claims description 3
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- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims 11
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Abstract
本發明係關於TASK-1及TASK-3通道之選擇性阻斷劑、尤其二氮雜雙環取代之咪唑并[1,2-a]嘧啶衍生物及α2-腎上腺素受體亞型C (α-2C)拮抗劑、尤其式(I)之芳基喹嗪衍生物之組合,其用於治療及/或防治睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾。
Description
本發明係關於TASK-1及TASK-3通道之選擇性阻斷劑、尤其二氮雜雙環取代之咪唑并[1,2-a]嘧啶衍生物及α2-腎上腺素受體亞型C (α-2C)拮抗劑、尤其式(I)之芳基喹嗪衍生物之組合,其用於治療及/或防治睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾。
阻塞性睡眠呼吸中止症(OSA)係一種睡眠相關性呼吸病症,其特徵在於上氣道阻塞之重複發作。在吸氣時,藉由兩種相反力之相互作用來確保上氣道通暢。上氣道肌肉組織之擴張效應抵消了使管腔收縮之官腔內負壓。橫膈膜及其他輔助呼吸肌肉之主動收縮會在氣道中生成負壓,由此構成呼吸驅動力。上呼吸道之穩定性實質上取決於上氣道之擴張肌之協調性及收縮性。
據信,OSA中之上氣道塌陷發生於睡眠開始時,此乃因若干上氣道擴張肌之活性有所減小,由此不能使解剖學脆弱之氣道維持開放。然而,一些上氣道擴張肌(包含頦舌肌,其係上呼吸氣道之最重要擴張肌且由舌下神經神經支配)可在睡眠期間因應於呼吸刺激物而增加活性,從而潛在地抵消睡眠開始時之一些此類變化。據觀察,OSA患者具有無呼吸中止症間隔,在該等間隔中頦舌肌活性僅高於具有頻繁阻塞性呼吸中止症之睡眠期25-40% (Jordan AS, White DP, Lo YL 等人 , Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep 2009, 32(3): 361-8
)。去甲腎上腺素係舌下運動神經元活性之最強力神經調節劑之一(Horner R.L. Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008, 164 (1-2): 179-196
)。據信,減少去甲腎上腺素能驅動使得舌下運動神經元興奮性發生睡眠依賴性降低,從而減小上氣道擴張肌活性、尤其減小頦舌肌活性。
α2C腎上腺素受體調控去甲腎上腺素來自中樞去甲腎上腺素能神經元之釋放,其係涉及去甲腎上腺素之突觸前反饋抑制之自體受體(Hein L.等人,Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission Nature 1999, 402(6758): 181-184)
。經由α2c腎上腺素受體拮抗作用來增加舌下神經之運動神經元活性可穩定上氣道且保護其免於塌陷及堵塞。此外,亦可經由上呼吸氣道之穩定機制來抑制打鼾。
對於單純打鼾而言,上氣道並不阻塞。因上氣道變窄,吸入及呼出空氣之流度有所增加。此狀態以及肌肉鬆弛導致口腔及喉嚨之軟組織在氣流中撲動。此輕微振動會生成典型打鼾聲。
阻塞性打鼾(上氣道阻力症候群、重度打鼾、呼吸減弱症候群)係由上氣道在睡眠期間之復發性部分阻塞所引起。此會增加氣道阻力且由此增加具有顯著胸內壓波動之呼吸工作。在吸氣期間產生之胸內負壓可由此達到因OSA中之完全氣道阻塞而產生之值。對心臟、循環及睡眠品質之病理生理學效應與阻塞性睡眠呼吸中止症中相同。發病機制可能與OSA相同。阻塞性打鼾通常提供OSA之先兆(Hollandt J.H. 等人 , Upper airway resistance syndrome (UARS)-obstructive snoring. HNO 2000, 48(8): 628-634
)。
中樞性睡眠呼吸中止症(CSA)係因腦功能紊亂或呼吸調控受損而發生。CSA之特徵在於在睡眠期間缺乏呼吸驅動力,從而產生通氣不足或缺乏且氣體交換受損之重複期。存在若干CSA表現。該等表現包含高海拔誘導性週期性呼吸、特發性CSA (ICSA)、麻醉性中樞性呼吸中止症、肥胖症換氣不足症候群(OHS)及陳-施二氏呼吸(Cheyne-Stokes breathing,CSB)。儘管各類CSA中所涉及之精確促成機制可廣泛變化,但睡眠期間之不穩定通氣驅動係主要潛在下伏特徵(Eckert D.J. 等人 , Central sleep apnea: Pathophysiology and treatment. Chest 2007, 131(2): 595-607
)。
US 2018/0235934 A1
闡述使用用於促進舌下運動神經元興奮性之藥劑治療病症(例如阻塞性睡眠呼吸中止症)之方法。關於促進舌下運動神經元興奮性之藥劑,闡述了中樞去甲腎上腺素神經元之抑制解除劑及/或刺激劑。在一些實施例中,中心去甲腎上腺素能神經元之抑制解除劑係α2-腎上腺素受體拮抗劑,例如育亨賓(yohimbine)或α2-腎上腺素受體亞型A (α-2A)拮抗劑或α2-腎上腺素受體亞型C (α-2C)拮抗劑。α2-腎上腺素受體拮抗劑係選自由以下組成之群:阿替美唑(Atipamezole)、MK-912、RS-79948、RX 821002、[3H]2-甲氧基-依達唑烷(idazoxan)及JP-1302。
α2C腎上腺素受體屬G蛋白偶合受體之家族。除不同α1-腎上腺素受體外,亦存在三個不同α2-腎上腺素受體亞型(α2A、α2B及α2C)。在藉由衍生自突觸或經由血液之內源性兒茶酚胺(腎上腺素、降腎上腺素)刺激時,其參與調介不同組織中之若干不同生理學效應。α2腎上腺素受體主要在心血管系統及中樞神經系統中發揮重要生理學作用。α2A-及α2C-腎上腺素受體係涉及中樞神經系統中去甲腎上腺素之突觸前反饋抑制之主要自體受體。去甲腎上腺素針對α2C-腎上腺素受體之功效及親和力高於針對α2A-腎上腺素受體者。α2C-腎上腺素受體在低內源性去甲腎上腺素濃度下抑制去甲腎上腺素釋放,而α2A -腎上腺素受體在高內源性去甲腎上腺素濃度下抑制去甲腎上腺素釋放(Uys M.M. 等人 , Therapeutic Potential of Selectively Targeting the α 2C-Adrenoceptor in Cognition, Depression, and Schizophrenia - New Developments and Future Perspective. Frontiers in Psychiatry 2017, Aug 14;8:144. doi: 10.3389/fpsyt.2017.00144. eCollection 2017
)。
維持氣道通暢之另一機制依賴於位於咽黏膜負壓敏感性神經末梢/機械刺激感受器。在呼吸循環期間檢測到較小負壓時,該等受體會經由負壓反射將興奮性運動神經輸出至頦舌肌。
頦舌肌在阻塞性睡眠呼吸中止症之發病機制中發揮決定作用。在擴張補償機制之意義上,此肌肉之活性隨咽中壓力之降低而增加。在藉由舌下神經神經支配下,其驅動舌向前及向下,由此擴大了咽氣道[Verse等人,Somnologie 3, 14-20 (1999)]。尤其經由鼻腔/咽中之機械刺激感受器/牽張感受器來調節上氣道擴張肌之伸張[Bouillette等人,J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 46, 772-779 (1979)]。對於患有嚴重睡眠呼吸中止症之睡眠患者而言,在上氣道之局部麻醉下,可觀察到頦舌肌活性之額外減小[Berry等人,Am. J. Respir. Crit. Care Med. 156, 127-132 (1997)]。
在經麻醉豬之睡眠呼吸中止症模型中,經鼻內投與鉀通道阻斷劑(其阻斷毫微莫耳範圍內之TASK-1通道)可抑制咽呼吸肌肉組織之塌陷性且敏化上氣道之負壓反射。可假設,經鼻內投與鉀通道阻斷劑會使上氣道中之機械刺激感受器去極化且經由活化負壓反射來增加上氣道肌肉組織之活性,由此穩定上氣道且預防塌陷。藉助上氣道之此穩定化,TASK通道阻斷可能對於阻塞性睡眠呼吸中止症亦及打鼾極為重要[Wirth等人,Sleep 36, 699-708 (2013);Kiper等人,Pflugers Arch. 467, 1081-1090 (2015)]。
尤其關注TASK (TWIK相關性酸敏性K+通道)亞家族之TASK-1 (KCNK3或K2P3.1)及TASK-3 (KCNK9或K2P9.1)。在功能上,該等通道之特徵在於,在維持電壓獨立性動力學期間,其具有流經其之「洩漏」或「背景」流,且其藉由增加或降低諸多生理學及病理學影響之活性來對該等影響作出反應。TASK通道之特徵性特徵係對細胞外pH變化具有敏感反應:在酸性pH下,該等通道受到抑制;且在鹼性pH下,其發生活化。
TASK-1及TASK-3通道亦在呼吸調控中發揮作用。兩種通道表現於腦幹中呼吸中樞之呼吸神經元、尤其生成呼吸節律之神經元(具有前包欽格複合體(pre-Bötzinger complex)之腹部呼吸群)中,且表現於去甲腎上腺素能藍斑核(Locus caeruleus)亦及脊核之血清素能神經元中。因pH依賴性,TASK通道在此處具有將細胞外pH變化轉變成相應細胞信號之感測器之功能[Bayliss等人,Pflugers Arch. 467, 917-929 (2015)]。TASK-1及TASK-3亦表現於頸動脈球中,頸動脈球係量測血液之pH、O2及CO2含量且將信號傳輸至腦幹中之呼吸中樞中以調控呼吸之周邊化學感受器。已展示,TASK-1敲低小鼠對低氧及常氧高碳酸血症之通氣反應有所降低(呼吸速率及潮氣量增加) [Trapp等人,J. Neurosci. 28, 8844-8850 (2008)]。另外,TASK-1及TASK-3通道顯示於舌下神經(第七顱神經,其在保持上氣道開放中具有重要作用)之運動神經元中[Berg等人,J. Neurosci. 24, 6693-6702 (2004)]。
作為α2-腎上腺素受體亞型C (α-2C)拮抗劑之芳基六氫吡嗪以及其製備及其作為藥劑之用途可自WO 03/082866 A1
獲知,其中該等化合物揭示為可用於治療諸如以下等病症:由應激傳播之病症、帕金森氏病(Parkinson's disease)、抑鬱症、精神***症、注意力缺失過動病症、創傷後應激病症、強迫性病症、妥瑞氏症候群(Tourette's syndrome)、瞼痙攣或其他灶性肌張力障礙、顳葉性癲癇伴精神病、藥物誘導性精神病、亨廷頓氏病(Huntington's disease)、由性激素含量波動引起之病症、恐慌病症、阿茲海默氏病(Alzheimer's disease)或輕度認知損傷。並未揭示該等化合物在治療睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾中之應用。
用於OSA患者之當前金標準治療係連續氣道正壓通氣(CPAP)。由氣流渦輪幫浦夾板生成之正氣流壓力可打開上氣道,從而逆轉咽塌陷之所有潛在原因,由此預防呼吸減弱、呼吸中止症及睡眠片段化。不幸的是,所有OSA患者之高達50%並不長期耐受CPAP(M. Kohler, D. Smith, V. Tippett 等人 , Thorax 2010 65(9):829-32: Predictors of long-term compliance with continuous positive airway pressure)
。因此,仍需要探尋用於治療及/或防治睡眠相關性呼吸病症(例如阻塞性睡眠呼吸中止症)之有效治療劑。因此,本發明之目標係提供用於治療及/或防治睡眠相關性呼吸病症(例如阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症及打鼾)之有效治療劑。
令人吃驚地,現已發現,α2-腎上腺素受體亞型C (α-2C)拮抗劑與TASK1/3通道阻斷劑之組合可以優於每一單獨治療之效能抑制上氣道塌陷性,且由此適於產生用於治療及/或防治睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾之藥劑。已發現,α2-腎上腺素受體亞型C (α-2C)拮抗劑與TASK1/3通道阻斷劑之組合之協同作用容許每一治療之劑量低於每一單獨治療。
本發明係關於以下化合物之組合:式(I)化合物
X 係CR2
R2
'、O、S或NR2
;
Z 係-CHR8
-(CH2
)n-或單鍵;
R1
係羥基、(C1
-C6
)烷基、(C1
-C6
)烷氧基、鹵素、鹵代(C1
-C6
)烷基、(C1
-C6
)烷氧基-(C=O)-、CO-、CN、NO2
、NH2
、單-或二(C1
-C6
)烷基胺基或羧基;
R2
及R2
'獨立地係H、羥基或(C1
-C6
)烷基或R2
及R2
'與其所連接之碳環原子一起形成羰基;
R3
係H、羥基、(C1
-C6
)烷基、(C2
-C6
)烯基、羥基(C1
-C6
)烷基、(C1
-C6
)烷氧基、(C1
-C6
)烷氧基(C1
-C6
)烷基、羥基(C1
-C6
)烷氧基(C1
-C6
)烷基、(C3
-C7
)環烷基、(C3
-C7
)環烷基(C1
-C6
)烷基、芳基、芳基(C1
-C6
)烷基、芳基氧基、芳基(C1
-C6
)烷氧基、芳基氧基(C1
-C6
)烷基、芳基(C1
-C6
)烷氧基(C1
-C6
)烷基、鹵代(C1
-C6
)烷基、NH2
、胺基(C1
-C6
)烷基、單-或二(C1
-C6
)烷基胺基、單-或二(C1
-C6
)烷基胺基(C1
-C6
)烷基、(C1
-C6
)烷基-CO-、(C1
-C6
)烷基-CO-O-、(C1
-C6
)烷基-CO-O-(C1
-C6
)烷基、(C1
-C6
)烷氧基-CO-、(C1
-C6
)烷氧基-CO-(C1
-C6
)烷基、(C1
-C6
)烷氧基-CO-(C1
-C6
)烷氧基(C1
-C6
)烷基、胺甲醯基、單-或二(C1
-C6
)烷基胺甲醯基、羧基或(C1
-C6
)烷基-S-(C1
-C6
)烷基,其中該(C3
-C7
)環烷基或芳基未經取代或經1或2個各自獨立地係羥基、(C1
-C6
)烷基、鹵素、(C1
-C6
)烷氧基、NH2
、CN或NO2
之取代基取代,或R3
或R4
中之一者及R6
一起在其所連接之環原子之間形成鍵;
R4
係H、羥基、(C1
-C6
)烷基、羥基(C1
-C6
)烷基、(C1
-C6
)烷氧基或(C1
-C6
)烷氧基(C1
-C6
)烷基;
R5
係H、羥基、(C1
-C6
)烷基、(C2
-C6
)烯基、羥基(C1
-C6
)烷基、(C1
-C6
)烷氧基、(C1
-C6
)烷氧基(C1
-C6
)烷基、羥基(C1
-C6
)烷氧基(C1
-C6
)烷基、(C3
-C7
)環烷基、(C3
-C7
)環烷基(C1
-C6
)烷基、芳基、芳基(C1
-C6
)烷基、芳基氧基、芳基(C1
-C6
)烷氧基、芳基氧基(C1
-C6
)烷基、芳基(C1
-C6
)烷氧基(C1
-C6
)烷基、鹵代(C1
-C6
)烷基、(C1
-C6
)烷基-CO-、(C1-C6)烷基-CO-O-、(C1
-C6
)烷基-CO-O-(C1
-C6
)烷基、(C1
-C6
)烷氧基-CO-、(C1
-C6
)烷氧基-CO-(C1
-C6
)烷基、(C1
-C6
)烷氧基-CO-(C1
-C6
)烷氧基(C1
-C6
)烷基、胺甲醯基、單-或二(C1
-C6
)烷基胺甲醯基、羧基或(C1
-C6
)烷基-S-(C1
-C6
)烷基,其中該(C3
-C7
)環烷基或芳基未經取代或經1或2個各自獨立地係羥基、(C1
-C6
)烷基、鹵素、(C1
-C6
)烷氧基、NH2
、CN或NO2
之取代基取代,或R4
及R5
與其所連接之碳環原子一起形成未經取代或經1至3個取代基R9
取代之縮合5至7員飽和碳環,R9
各自獨立地係羥基、(C1
-C6
)烷基、鹵素、NH2
、NO2
、(C3
-C7
)環烷基、羥基(C1
-C6
)烷基、鹵代(C1
-C6
)烷基、胺基(C1
-C6
)烷基、單-或二(C1
-C6
)烷基胺基、單-或二(C1
-C6
)烷基胺基(C1
-C6
)烷基、(C1
-C6
)烷氧基、(C1
-C6
)烷氧基(C1
-C6
)烷基、羧基、(C1
-C6
)烷基-CO-、(C1
-C6
)烷基-CO-O-、(C1
-C6
)烷氧基-CO-、(C1
-C6
)烷氧基-CO-(C1
-C6
)烷基、胺甲醯基、單-或二(C1
-C6
)烷基胺甲醯基或側氧基;
R6
係H、羥基、(C1
-C6
)烷基、羥基(C1
-C6
)烷基、(C1
-C6
)烷氧基或(C1
-C6
)烷氧基(C1
-C6
)烷基,或R6
在其所連接之環原子與R7
所連接之環原子之間形成鍵;
R7
係H、羥基、(C1
-C6
)烷基、羥基(C1
-C6
)烷基、(C1
-C6
)烷氧基或(C1
-C6
)烷氧基(C1
-C6
)烷基;
R8
係H、羥基、(C1
-C6
)烷基、羥基(C1
-C6
)烷基、(C1
-C6
)烷氧基或(C1
-C6
)烷氧基(C1
-C6
)烷基,或僅在n為0時R7
及R8
與其所連接之碳環原子一起形成未經取代或經1至3個取代基R10
取代之縮合5至7員飽和碳環,R10
各自獨立地係羥基、(C1
-C6
)烷基、鹵素、NH2
、NO2
、(C3
-C7
)環烷基、羥基(C1
-C6
)烷基、鹵代(C1
-C6
)烷基、胺基(C1
-C6
)烷基、單-或二(C1
-C6
)烷基胺基、單-或二(C1
-C6
)烷基胺基(C1
-C6
)烷基、(C1
-C6
)烷氧基、(C1
-C6
)烷氧基(C1
-C6
)烷基、羧基、(C1
-C6
)烷基-CO-、(C1
-C6
)烷基-CO-O-、(C1
-C6
)烷氧基-CO-、(C1
-C6
)烷氧基-CO-(C1
-C6
)烷基、胺甲醯基、單-或二(C1
-C6
)烷基胺甲醯基或側氧基;
R15
係H、(C1
-C6
)烷基、(C2
-C6
)烯基、羥基(C1
-C6
)烷基、(C1
-C6
)烷氧基(C1
-C6
)烷基、羥基(C1
-C6
)烷氧基(C1
-C6
)烷基、鹵代(C1
-C6
)烷基、胺基(C1
-C6
)烷基、單-或二(C1
-C6
)烷基胺基(C1
-C6
)烷基、(C1
-C6
)烷基-CO-、(C1
-C6
)烷基-CO-O-(C1
-C6
)烷基、(C1
-C6
)烷氧基-CO-、(C1
-C6
)烷氧基-CO-(C1
-C6
)烷基、(C1
-C6
)烷氧基-CO-(C1
-C6
)烷氧基(C1
-C6
)烷基、胺甲醯基、單-或二(C1
-C6
)烷基胺甲醯基或羧基;
R16
係H或(C1
-C6
)烷基;
R7
及R8
連接至毗鄰碳環原子;
m 為0至2;且
n 為0或1,
與式(II)化合物
其中
環Q代表六氫吡嗪或下式之二氮雜雜雙環系統: 或
其中*表示至毗鄰CHR’2
基團之鍵且**表示至羰基之鍵,
W1
、W2
或W3
代表CH或N,
R’1
代表鹵素、氰基、(C1
-C4
)-烷基、環丙基或環丁基
其中(C1
-C4
)-烷基可最多由氟三取代且環丙基及環丁基可最多由氟二取代,
且
R’2
代表(C4
-C6
)-環烷基,其中環CH2
基團可由-O-代替,
或
R’2
代表式(a)之苯基、式(b)或(c)之吡啶基或式(d)、(e)、(f)或(g)之唑基,
其中***標記至毗鄰羰基之鍵且
R’3
代表氫、氟、氯、溴或甲基,
R’4
代表氫、氟、氯、溴、氰基、(C1
-C3
)-烷基或(C1
-C3
)-烷氧基,
其中(C1
-C3
)-烷基及(C1
-C3
)-烷氧基可各自最多由氟三取代,
R’5
代表氫、氟、氯、溴或甲基,
R6
代表氫、(C1
-C3
)-烷氧基、環丁基氧基、環氧丙烷-3-基氧基、四氫呋喃-3-基氧基、四氫-2H
-吡喃-4-基氧基、單-(C1
-C3
)-烷基胺基、二-(C1
-C3
)-烷基胺基或(C1
-C3
)-烷基硫基,
其中(C1
-C3
)-烷氧基可最多由氟三取代,
R7
代表氫、氟、氯、溴、(C1
-C3
)-烷基或(C1
-C3
)-烷氧基,
R8A
及R8B
相同或不同且彼此獨立地代表氫、氟、氯、溴、(C1
-C3
)-烷基、環丙基或(C1
-C3
)-烷氧基
其中(C1
-C3
)-烷基及(C1
-C3
)-烷氧基可各自最多由氟三取代,
R9
代表氫、(C1
-C3
)-烷基或胺基
且
其中在子式(d)中
Y 代表O、S或N(CH3
),
其中在子式(e)及(f)中
Y 代表O或S,
或
R’2
代表-OR10
或-NR11
R12
基團,其中
R10
代表(C1
-C6
)-烷基、(C4
-C6
)-環烷基或[(C3
-C6
)-環烷基]甲基,
R11
代表氫或(C1
-C3
)-烷基
且
R12
代表(C1
-C6
)-烷基、(C3
-C6
)-環烷基、苯基或苄基、1-苯基乙基或2-苯基乙基,
其中(C1
-C6
)-烷基可最多由氟三取代,
且
其中苯基及苄基、1-苯基乙基及2-苯基乙基中之苯基可最多由選自由以下組成之群之相同或不同基團三取代:氟、氯、甲基、乙基、三氟甲基、甲氧基、乙氧基、三氟甲氧基及(三氟甲基)硫基,
或
R11
及R12
彼此連接且與其所鍵結之氮原子一起形成吡咯啶、六氫吡啶、嗎啉或硫嗎啉環,或
R11
及R12
彼此連接且與其所鍵結之氮原子一起形成式(c)之四氫喹啉環或式(d)之四氫異喹啉環,
其中**標記至羰基之鍵,
及其鹽、溶劑合物及鹽之溶劑合物。
在式I化合物之可能子組中,X係NR2
。
在式I化合物之另一可能子組中,
m為0;n為0;
R2
係H;
R3
係H、羥基、(C1
-C6
)烷基、羥基(C1
-C6
)烷基、(C1
-C6
)烷氧基(C1
-C6
)烷基、(C3
-C7
)環烷基、鹵代(C1
-C6
)烷基、(C1
-C6
)烷基-CO-、(C1
-C6
)烷基-COO-(C1
-C6
)烷基、(C1
-C6
)烷氧基-CO-或(C1
-C6
)烷氧基-CO-( C1
-C6
)烷基;
R4
係H、羥基、(C1
-C6
)烷基或羥基(C1
-C6
)烷基;
R5
係H、羥基、(C1
-C6
)烷基、羥基(C1
-C6
)烷基、(C1
-C6
)烷氧基或(C1
-C6
)烷基-CO-;
R6
係H或(C1
-C6
)烷基且
R7
係H、(C1
-C6
)烷基或羥基(C1
-C6
)烷基。
在式I化合物之另一可能子組中,
R3
係H或(C1
-C6
)烷基且
R4
係羥基或羥基(C1
-C6
)烷基。
在式I化合物之另一可能子組中,R4
及R5
與其所連接之碳環原子一起形成縮合6員飽和碳環。
在式I化合物之另一可能子組中,R4
及R6
一起在其所連接之環原子之間形成鍵或R6
在其所連接之環原子及R7
所連接之環原子之間形成鍵。
在式I化合物之另一可能子組中,化合物係1α-乙基-1,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-1-醇、(1β-乙基-1,2,3,4,6,7,12,12bα-八氫-吲哚并[2,3-a
]喹嗪-1-基)-甲醇、1α-甲基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-1-醇、(1α-甲基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-1-基)-甲醇、1,2,3,4,4aβ,5,6,7,8,13,13bβ,13cα-十二氫-6a,13-二氮雜-茚并-[1,2-c
]菲、1,2,3,4,4aβ,5,6,7,8,13,13bβ,13cβ-十二氫-6a,13-二氮雜-茚并[1,2-c
]菲或3,4,4aβ,5,6,7,8,13,13bβ,13cα-十氫-2H-6a,13-二氮雜-茚并[1,2-c
]菲-1-酮。
在式I化合物之另一可能子組中,X係CR2
R2
'。
在式I化合物之另一可能子組中,X係S。
在式I化合物之又一可能子組中,X係O。
在X係O時,式I化合物之一種可能子組包含如在闡述上述式I化合物之用途時所定義之R5
及R6
。
在X係O時式I化合物之另一可能子組中,R5
係H、羥基、(C1
-C6
)烷基、(C2
-C6
)烯基、(C1
-C6
)烷氧基、(C1
-C6
)烷氧基(C1
-C6
)烷基、(C3
-C7
)環烷基、(C3
-C7
)環烷基(C1
-C6
)烷基、芳基、芳基(C1
-C6
)烷基、芳基氧基、芳基(C1
-C6
)烷氧基、芳基氧基(C1
-C6
)烷基、芳基(C1
-C6
)烷氧基(C1
-C6
)烷基、鹵代(C1
-C6
)烷基、(C1
-C6
)烷基-CO-O-、(C1
-C6
)烷基-CO-O-( C1
-C6
)烷基、(C1
-C6
)烷氧基-CO-(C1
-C6
)烷氧基(C1
-C6
)烷基、胺甲醯基、單-或二(C1
-C6
)烷基胺甲醯基、羧基或(C1
-C6
)烷基-S-(C1
-C6
)烷基且R6
係H、羥基、(C1
-C6
)烷基、(C1
-C6
)烷氧基或(C1
-C6
)烷氧基(C1
-C6
)烷基。
在式I化合物之另一可能子組中,化合物係1α-甲基-1,3,4,5,6,11b-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-醇、(1α-甲基-1,3,4,5,6,11bβ-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-基)-甲醇、(-)-(1α-甲基-1,3,4,5,6,11bβ-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-基)-甲醇、(+)-(1α-甲基-1,3,4,5,6,11-bβ六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-基)-甲醇、1α-異丙基-1,3,4,5,6,11b-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-醇、1α-乙基-1,3,4,5,6,11bβ-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-醇、(1α-乙基-1,3,4,5,6,11bβ-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-基)-甲醇、5,6,7,7aβ,8,9,10,11,11aβ,11bα-十氫-12-氧雜-6a-氮雜-茚并[l,2-a
]茀、1-甲基-1α,3,4,6,11bβ-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀、(1-羥甲基-1,3,4,5,6,11b-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-基]-甲醇、1-甲氧基甲基-1α-甲基-1,3,4,5,6,11bβ-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀、(-)-1-甲氧基甲基-1a-甲基-1,3,4,5,6,11bβ-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀、(+)-1-甲氧基甲基-1α-甲基-1,3,4,5,6,11bβ-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀、2,3,4,4aβ,5,6,7,8,13bβ,13cβ-十氫-1H-13-氧雜-6a-氮雜-茚并[1,2-c
]菲、2,3,4,4aβ,5,6,7,8,13b(,13cβ-十氫-1H-13-氧雜-6a-氮雜-茚并[1,2-c
]菲、1α-甲基-1,3,4,5,6,11bα-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-甲酸乙酯、1-乙氧基甲基-1α-甲基-1,3,4,5,6,11bβ-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀、(1α-甲基-1,3,4,5,6,11bα-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-基)-甲醇、(-)-(1α-甲基-1,3,4,5,6,11bα-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-l-基)-甲醇、(+)-(1α-甲基-1,3,4,5,6,11bα-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-基)-甲醇、1α-乙基-1,3,4,5,6,11bα-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-甲酸甲酯、1-甲氧基甲基-1α-甲基-1,3,4,5,6,11bα-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀、(-)-1-甲氧基甲基-1α-甲基-1,3,4,5,6,11bα-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀、(+)-1-甲氧基甲基-1α-甲基-1,3,4,5,6,11bα-六氫-2H11-氧雜-4a-氮雜-苯并[a
]茀、(1α-乙基-1,3,4,5,6,11bα-六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-基)-甲醇、乙酸1α-甲基-1,3,4,5,6,11bβ六氫-2H-11-氧雜-4a-氮雜-苯并[a
]茀-1-基甲酯、(1α-甲基-1,2,3,4,6,7,12,12bα-八氫茚并[2,1-a
]喹嗪-1-基)-甲醇或(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪。
在式I化合物之另一可能子組中,化合物係1α-乙基-12-甲基-1,2,3,4,6,7,12bβ-八氫吲哚并[2,3-a
]喹嗪-1-醇或1α-乙基-12-乙基-1,2,3,4,6,7,12bβ-八氫吲哚并[2,3-a
]喹嗪-1-醇。
在式I化合物之另一可能子組中,化合物係2,3,4,4aβ,5,6,7,8,13,13bβ-十氫-1H-6a,13-二氮雜-茚并[1,2-c
]菲-13cβ-醇、(-)-2,3,4,4aβ,5,6,7,8,13,13bβ-十氫-1H-6a,13-二氮雜-茚并[1,2-c
]菲-13cβ-醇、(+)-2,3,4,4aβ,5,6,7,8,13,13bβ十氫-1H-6a,13-二氮雜-茚并[1,2-c
]菲-13cβ-醇、(2,3,4,4aβ,5,6,7,8,13,l3bβ-十氫-1H-6a,13-二氮雜-茚并[1,2-c
]菲基)-13cβ-甲醇、5,6,7,7a,11,11b,12-十氫-6a,12-二氮雜-茚并[1,2-a
]茀11a-醇、3,4,4aβ,5,6,7,8,13,13bβ,13cα-十氫-2H-6a,13-二氮雜-茚并[1,2-c
]菲-1-酮、1,2,3,4,5,6,7,8,13,13b-十氫-6a,13-二氮雜-茚并[1,2-c
]菲、乙酸1α,2,3,4,4aβ,5,6,7,8,13,13bβ,13cα-十二氫-6a,13-二氮雜-茚并[1,2-c
]菲-1-基酯或乙酸1β,2,3,4,4aβ,5,6,7,8,13,13bβ,13cα-十二氫-6a,13-二氮雜-茚并[1,2-c
]菲-1-基酯。
本發明之另一實施例提供如下新化合物:2,3,4,5,7,8,13,13b-八氫-1H-氮呯并[1',2':1,2]吡啶并[3,4-b
]吲哚、2β-甲氧基-1,2,3,4,6,7,12,12bα-八氫-吲哚并[2,3-a
]喹嗪、2(-甲氧基-1,2,3,4,6,7,12,12bα-八氫-吲哚并[2,3-a
]喹嗪、1a
-乙基-2(-甲基-1,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-1-醇、1α-異丙基-1,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-l-醇、(-)-1α-異丙基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-1-醇、(+)-1α-異丙基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-l-醇、1β-異丙基-1,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪、(1α-異丙基-1,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-1-基)-甲醇、(1α-正丙基-1,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-1-基)-甲醇、2-(1α,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-1-基)-丁烷-2-醇、1-(1,2α,3,4,6,7,12,12bα-八氫-吲哚并[2,3-a
]喹嗪-2-基)-丙烷-1-醇、2-(1α,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-1-基)-丙烷-2-醇、1-s
-丁基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-l-醇、1-環己基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-1-醇、9-氟-1a-異丙基-1,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-l-醇、(1α-甲基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-1-基)-甲醇、(-)-(1α-甲基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a]喹嗪-1-基)-甲醇、(+)-(1α-甲基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-1-基)-甲醇、(1α-乙基-1,4,6,7,12,12bβ-六氫吲哚并[2,3-a
]喹嗪-1-基)-甲醇、3β,4(-二甲基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪、(1,2α,3,4,6,7,12,12bα-八氫吲哚并[2,3-a
]喹嗪-2-基)-丙烷-2-醇、(1,2α,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-2-基)-丙烷-2-醇、(2α-乙基-1,2,3,4,6,7,12,12bα-八氫吲哚并[2,3-a
]喹嗪-2-基)-甲醇、(2α-乙基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-2-基)-甲醇、(1-(乙基-1,2,3,4,6,7,12,12bβ-八氫吲哚并[2,3-a
]喹嗪-1-基甲氧基)-乙酸乙酯、1-(2α-乙基-1,2,3,4,6,7,12,12bα-八氫-吲哚并[2,3-a
]喹嗪-2-基)-乙酮、1-(2α-乙基-1,2,3,4,6,7,12,12bα-八氫-吲哚并[2,3-a
]喹嗪-2-基)-乙醇、2-(2α-乙基-1,2,3,4,6,7,12,12bα-八氫-吲哚并[2,3-a
]喹嗪-2-基)-丙烷-2-醇、2-(3-乙基-1,2α,3α,4,6,7,12,12bα-八氫-吲哚并[2,3-a
]喹嗪-2-基)-丙烷-2-醇、(3-乙基-2-甲基-1α,2β,3β,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-l-基)-甲醇、3-乙基-1,2-二甲基-1α,2β,3β,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪、1,2-二甲基-1,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-1β-醇、(1-乙基-2-甲基-1β,2β,3β,4,6,7,12,12bα-八氫-吲哚并[2,3-a
]喹嗪-3-基)-甲醇或1-β-羥甲基-1-甲基-1,2,3,4,6,7,12,12bβ-八氫-吲哚并[2,3-a
]喹嗪-6β-甲酸甲酯。
較佳式(I)化合物係(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪。
本發明之另一實施例係關於以下化合物之組合:作為式(I)化合物之(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪
及式(II)化合物
其中
環Q代表六氫吡嗪或下式之二氮雜雜雙環系統: 或
其中*表示至毗鄰CHR2
基團之鍵且**表示至羰基之鍵,
W2
代表CH,
W1
、W3
代表CH或N,
R’1
代表氟、氯、溴、甲基、第三丁基、異丙基、環丙基或環丁基,
且
R’2
代表環丁基、環戊基或環己基,
或
R’2
代表式(a)之苯基、式(b)之吡啶基或式(d)或式(g)之唑基
其中***標記至毗鄰羰基之鍵且
R’3
代表氫、氟或氯,
R’4
代表氟、氯、甲基、異丙基、甲氧基或乙氧基,
R’5
代表氫、氟、氯、溴或甲基,
R6
代表甲氧基、二氟甲氧基、三氟甲氧基、異丙氧基、環丁基氧基或甲基硫基,
R8A
及R8B
相同或不同且彼此獨立地代表氫、甲基、三氟甲基、乙基、異丙基或環丙基,
且
R9
代表甲基或胺基
Y 代表O或S或N(CH3
)
及其鹽、溶劑合物及鹽之溶劑合物。
本發明之一較佳實施例係關於以下化合物之組合:作為式(I)化合物之(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪
及選自由以下組成之群之式(II)化合物:
(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-氟苯基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(3-甲氧基苯基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-氯-5-氟苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-氟苯基)甲酮、(4-{[2-(4-氟苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環己基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環己基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(四氫呋喃-3-基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環丁基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-甲氧基苯基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(5-氟-2-甲氧基苯基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-甲基苯基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(5-氟-2-甲基苯基)甲酮、(2-氯-5-氟苯基)(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環己基)甲酮、((4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環丁基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(3-甲氧基苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-甲氧基苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(5-氟-2-甲氧基苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-甲基苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(5-氟-2-甲基苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[3-(三氟甲氧基)苯基]甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[3-(三氟甲基)苯基]甲酮、((4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(吡啶-2-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-氟-5-甲氧基苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-乙氧基苯基)甲酮、(2-氯-5-甲氧基苯基)(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(四氫-2H-吡喃-2-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(3-異丙氧基苯基)甲酮、2-[(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)羰基]苯甲腈、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(3-異丙基苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-異丙基苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(四氫呋喃-2-基)甲酮、(3-氯苯基)(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(2-氯苯基)(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[6-(2,2,2-三氟乙氧基)吡啶-2-基]甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-異丙氧基吡啶-2-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基-4-甲基吡啶-2-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[6-(環丁基氧基)吡啶-2-基]甲酮、(3-溴-6-甲氧基吡啶-2-基)(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[6-(二氟甲氧基)吡啶-2-基]甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-乙氧基吡啶-2-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[6-(四氫-2H-吡喃-4-基氧基)吡啶-2-基]甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-氟苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氟苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環丁基)甲酮、(5-氟-2-甲氧基苯基)(4-{[2-(4-氟苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(2-氯-5-氟苯基)(4-{[2-(4-氟苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(4-{[2-(4-氟苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-甲氧基苯基)甲酮、(2-氟苯基)(4-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、環戊基(4-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(4-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、環戊基(4-{[2-(4-甲基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、環己基(4-{[2-(4-甲基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(2-甲氧基苯基)(4-{[2-(4-甲基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(6-甲氧基吡啶-2-基)(4-{[2-(4-甲基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)甲酮、(4-(3-{[4-(2-氟苯甲醯基)六氫吡嗪-1-基]甲基}咪唑并[1,2-a]吡啶-2-基)苯甲腈、4-[3-({4-[(6-甲氧基吡啶-2-基)羰基]六氫吡嗪-1-基}甲基)咪唑并[1,2-a]吡啶-2-基]苯甲腈、4-(3-{[4-(環戊基羰基)六氫吡嗪-1-基]甲基}咪唑并[1,2-a]吡啶-2-基)苯甲腈、4-(3-{[4-(環己基羰基)六氫吡嗪-1-基]甲基}咪唑并[1,2-a]吡啶-2-基)苯甲腈、(4-{[2-(4-第三丁基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-第三丁基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-氟苯基)甲酮、(4-{[2-(4-第三丁基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[6-(三氟甲氧基)吡啶-2-基]甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-環丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-氟苯基)甲酮、4-(3-{[4-(2-氟-5-甲氧基苯甲醯基)六氫吡嗪-l-基]甲基}咪唑并[1-2-a]吡啶-2-基)苯甲腈、4-[3-({4-[(6-甲氧基-3-甲基吡啶-2-基)羰基]六氫吡嗪-l-基}甲基)咪唑并[1,2-a]吡啶-2-基)苯甲腈、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3 yl]¬甲基}六氫吡嗪-1-基)(6-甲氧基-3-甲基吡啶-2-基)甲酮、(4-{[2-(4-第三丁基苯基)咪唑并[1,2-a]-吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基-3-甲基吡啶-2-基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基-3-甲基-吡啶-2-基)甲酮、5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H)-甲酸第三丁基酯、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-甲酸第三丁基酯、5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-甲酸第三丁基酯、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](6-甲氧基吡啶-2-基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](環戊基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](2-氟苯基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](2-氯-5-氟苯基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](環己基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](環丁基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](3-甲氧基苯基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](2-甲氧基苯基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](5-氟-2-甲氧基苯基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](2-甲基苯基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](2-氟苯基)甲酮、(2-氯-5-氟苯基)[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H)-基]甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](環己基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](3-甲氧基苯基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](2-甲氧基苯基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H)-基](5-氟-2-甲氧基苯基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H)-基](2-甲基苯基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](5-氟-2-甲基苯基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基][3-(三氟甲氧基)苯基]甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基][3-(三氟甲基)苯基]甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](6-甲氧基吡啶-2-基)甲酮、[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H)-基](6-甲氧基吡啶-2-基)甲酮、(2-氟苯基)[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H)-基]甲酮、[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](3-甲氧基苯基)甲酮、環戊基[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基]甲酮、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-甲基-N
-苯基六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](3,4-二氫喹啉-1(2H
)-基)甲酮、[5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](3,4-二氫異喹啉-2(1H
)-基)甲酮、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-甲酸異丁基酯、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-甲酸苄基酯、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-甲酸環戊基酯、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-甲酸異丙基酯、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-甲酸3-(三氟甲基)苯基酯、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-甲酸氟乙基酯、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2,4-二氟苯基)六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2,6-二氟苄基)六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2,6-二甲基苯基)六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2-氟苯基)六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2-乙氧基苯基)六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(4-氯-3-(三氟甲基)苯基]六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-[2-氯-5-(三氟甲基)苯基]六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(環己基)六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺,外消旋-5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(1-苯基乙基)六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(4-氟苯基)六氫吡咯并[3,4-c]吡咯-2(1H
)-甲醯胺、(3-氟-6-甲氧基吡啶-2-基)[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基]甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](6-甲氧基-3-甲基吡啶-2-基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](3-氟-6-甲氧基吡啶-2-基)甲酮、3-氯-6-甲氧基吡啶-2-基)[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基]甲酮、5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲酸第三丁基酯、8-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-3-甲酸第三丁基酯、8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-3-甲酸第三丁基酯、8-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-3-甲酸第三丁基酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚烷-6-甲酸第三丁基酯、3-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚烷-6-甲酸第三丁基酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、3-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、3-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、(-)-[(1S
,4S
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](6-甲氧基吡啶-2-基)甲酮、(-)-(3-氯-6-甲氧基吡啶-2-基)[(1S
,4S
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基]甲酮、(-)-[(1S
,4S
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(-)-(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(5-{[2-(6-異丙基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)(5-{[2-(6-異丙基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(6-甲氧基吡啶-2-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)[6-(環丁基氧基)吡啶-2-基]甲酮、(3-氯-6-甲氧基吡啶-2-基)(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)甲酮、(3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(6-甲氧基吡啶-2-基)甲酮、(+)-[(1R
,4R
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](6-甲氧基吡啶-2-基)甲酮、(-)-(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(2-氟苯基)甲酮、(+)-(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(2-氟苯基)甲酮、5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(環戊基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(環戊基)甲酮、(-)-(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-甲氧基苯基)甲酮、(+)-(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-甲氧基苯基)甲酮、(2-氯-5-氟苯基)(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(環己基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(環丁基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(2-甲氧基苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(5-氟-2-甲氧基苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(2-甲基苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(5-氟-2-甲基苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)[3-(三氟甲氧基)苯基]甲酮、(3-氯苯基)(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)[3-(三氟甲基)苯基]甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(吡啶-2-基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(1-甲基-1H
-咪唑-2-基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-甲基苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-乙氧基苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(吡啶-4-基)甲酮、(-)-(2-氟苯基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(+)-(2-氟苯基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(-)-(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-甲氧基苯基)甲酮、(+)-(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-甲氧基苯基)甲酮、(-)-(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(+)-(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、環戊基(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、環戊基(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(-)-(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(2-氟苯基)甲酮、(+)-(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(2-氟苯基)(5-{[2-(6-異丙基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(2-氟苯基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(3-甲氧基苯基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(環戊基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)[3-(三氟甲氧基)苯基]甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(2-異丙基苯基)甲酮、(2-氯-5-甲氧基苯基)(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(5-氟-2-甲氧基苯基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(3-異丙基苯基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)[6-(2,2,2-三氟乙氧基)吡啶-2-基]甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(四氫呋喃-3-基)甲酮、(3-氯苯基)(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)[6-(三氟甲氧基)吡啶-2-基]甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(6-甲氧基-3-甲基吡啶-2-基)甲酮、(8-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(2-氟苯基)甲酮、(8-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(6-甲氧基吡啶-2-基)甲酮、(8-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(3-甲氧基苯基)甲酮、(8-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(環戊基)甲酮、(8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(環戊基)甲酮、(8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(2-氟苯基)甲酮、(8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(5-氟-2-甲基苯基)甲酮、(8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(5-氟-2-甲氧基苯基)甲酮、(8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(2-甲基苯基)甲酮、(8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(2-甲氧基苯基)甲酮、(8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(6-甲氧基吡啶-2-基)甲酮、(8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(環己基)甲酮、(2-氟苯基)(8-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)甲酮、(8-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(6-甲氧基吡啶-2-基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(環戊基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-氟苯基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(6-甲氧基吡啶-2-基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-甲氧基苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-甲基苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(環丁基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-氟苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(5-氟-2-甲氧基苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(6-甲氧基吡啶-2-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(環己基)甲酮、(2-氯-5-氟苯基)(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(5-氟-2-甲基苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-甲氧基苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-甲氧基苯基)甲酮、(2-氟苯基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-氟苯基)甲酮、(3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-甲氧基苯基)甲酮、(3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(環戊基)甲酮、(3-氯苯基)(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)(四氫呋喃-2-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)(環戊基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)(2-氟苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)(環己基)甲酮、(2-氯-5-氟苯基)(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)[3-(三氟甲氧基)苯基]甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)(環丁基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)(3-乙氧基苯基)甲酮、環戊基(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)甲酮、(5-{[2-(6-異丙基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)(5-{[2-(6-異丙基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(2-氟苯基)(5-{[2-(6-異丙基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、7-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲酸第三丁基酯、3-{[2-(6-異丙基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、5-{[2-(6-異丙基吡啶-3-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、(7-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)[6-(三氟甲氧基)吡啶-2-基]甲酮、(3-氯-6-甲氧基吡啶-2-基)(7-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)甲酮、5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](6-甲氧基-3-甲基吡啶-2-基)甲酮、5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](6-甲氧基-3-甲基吡啶-2-基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-氯-6-甲氧基吡啶-2-基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-異丙基苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.1.1]庚-6-基)(6-甲氧基-3-甲基吡啶-2-基)甲酮、(8-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(6-甲氧基-3-甲基吡啶-2-基)甲酮、(8-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-3-基)(6-甲氧基-3-甲基吡啶-2-基)甲酮、(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(6-甲氧基-3-甲基吡啶-2-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(4-異丙基-1,3-噻唑-2-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(1,3-噻唑-2-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(4-甲基-1,3-噻唑-2-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(5-甲基-1,3-噻唑-2-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(4,5-二甲基-1,3-噻唑-2-基)甲酮、(5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(2-氟苯基)甲酮、(5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-異丙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2-氟苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2,6-二氯苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2,6-二甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-戊基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2-甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-[2-氯-5-(三氟甲基)苯基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、N
-(4-氯苯基)-3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2-乙基-6-甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2,5-二甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-環己基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、N
-(2-氯-6-甲基苯基)-3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2,6-二氟苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-(2,4-二甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-異丙基-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲醯胺、N
-(2-氯-6-甲基苯基)-7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-環丙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、N
-(2-氯苯基)-3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-甲基-N
-苯基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(嗎啉-4-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N,N
-二異丙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-環己基-N
-乙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(吡咯啶-1-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-乙基-N
-苯基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-異丙基-N
-甲基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(六氫吡啶-1-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N,N
-二甲基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-乙基-N
-(4-甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、N
-(4-氯苯基)-3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-異丙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(硫基嗎啉-4-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸甲酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸乙酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸環戊基酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸環己基酯、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N,N
-二乙基-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲醯胺、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(嗎啉-4-基)甲酮、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N,N
-二異丙基-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲醯胺、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-環己基-N
-乙基-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲醯胺、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(吡咯啶-1-基)甲酮、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-乙基-N
-苯基-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲醯胺、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-N
-異丙基-N
-甲基-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲醯胺、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲酸乙酯、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲酸環戊基酯、7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲酸丙酯、(7-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(六氫吡啶-1-基)甲酮、(5-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氯-6-甲氧基吡啶-2-基)甲酮、(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)[6-(二氟甲氧基)吡啶-2-基]甲酮、7-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲酸第三丁基酯、7-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬烷-9-甲酸第三丁基酯、5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、3-{1-[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]乙基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、5-{[2-(4-溴苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛烷-2-甲酸第三丁基酯、3-{[2-(4-溴苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、(7-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(7-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)[6-(甲基硫基)吡啶-2-基]甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(環戊基)甲酮、(3-氟-6-甲氧基吡啶-2-基)(7-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)甲酮、[6-(二氟甲氧基)吡啶-2-基](7-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基-3-甲基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(5-環丙基-1,3-噁唑-4-基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(2-氟苯基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(3-甲氧基苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-氟苯基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)[6-(甲基硫基)吡啶-2-基]甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(環戊基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)[6-(甲基胺基)吡啶-2-基]甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-甲氧基苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(環戊基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-甲氧基苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(2-氟苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(2-氟苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-甲氧基苯基)甲酮、(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(7-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(5-環丙基-1,3-噁唑-4-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-環丙基-1,3-噁唑-4-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(5-甲基-1,3-噁唑-4-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(5-異丙基-1,3-噁唑-4-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2,4-二甲基-1,3-噁唑-5-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(5-乙基-1,3-噁唑-4-基)甲酮、(4-溴-5-甲基-1,3-噻唑-2-基)(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(5-環丙基-1,3-噁唑-4-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-異丙基-1,3-噻唑-4-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(1,3-噻唑-5-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2,5-二甲基-1,3-噁唑-4-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)[2-甲氧基-4-(三氟甲基)-1,3-噻唑-5-基]甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)[2-(三氟甲基)-1,3-噻唑-4-基]甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(5-甲基-1,3-噻唑-4-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)[4-(三氟甲基)-1,3-噻唑-2-基]甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(1,3-噻唑-4-基)甲酮、(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)[6-(甲基胺基)吡啶-2-基]甲酮、(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(6-甲氧基吡啶-2-基)甲酮、(2-氟苯基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{1-[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]乙基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(7-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)(6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(7-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)甲酮、(2-氟苯基)(7-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3-氧雜-7,9-二氮雜雙環[3.3.1]壬-9-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(5-環丙基-1,3-噁唑-4-基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、[6-(二氟甲氧基)吡啶-2-基](5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基-3-甲基吡啶-2-基)甲酮、(5-{[2-(4-溴苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(2-氟苯基)甲酮、(5-{[2-(4-溴苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(環戊基)甲酮、(5-{[2-(4-溴苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(2-氟苯基)甲酮、(3-{[2-(4-溴苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(環戊基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2,4-二氟苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-異丙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-環丙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2,5-二氯-4-甲氧基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、N
-(3-氯苯基)-3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2,6-二氟苄基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2,6-二氯苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2,6-二甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2-氟苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2,3-二氯苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2-乙基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、N
-(2-氯苯基)-3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-[2-氯-5-(三氟甲基)苯基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2-乙基-6-甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2,5-二甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-環己基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-異丁基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(3,4-二甲氧基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-{4-[(三氟甲基)硫基]苯基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(3-氟苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2,6-二氟苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-[4-氯-2-(三氟甲基)苯基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(2-甲基苄基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-甲基-N
-苯基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N,N
-二乙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(嗎啉-4-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N,N
-二異丙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-環己基-N
-乙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(吡咯啶-1-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-乙基-N
-苯基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-異丙基-N
-甲基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(六氫吡啶-1-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-乙基-N
-(4-甲基苯基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、N
-(4-氯苯基)-3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-異丙基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N,N
-二甲基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(4-乙氧基苯基)-N
-甲基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-N
-(3-甲氧基苄基)-N
-甲基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲醯胺、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(硫基嗎啉-4-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸甲酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸乙酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸環戊基酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸丙酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸環己基甲基酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸環己基酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸2,2-二甲基丙基酯、3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、(5-環丙基-1,3-噁唑-4-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁基酯、(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)(2-氟苯基)甲酮、環戊基(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)甲酮、(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)甲酮、(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)(6-甲氧基吡啶-2-基)甲酮、(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)[6-(二氟甲氧基)吡啶-2-基]甲酮、(5-環丙基-1,3-噁唑-4-基)(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)甲酮、6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬烷-2-甲酸第三丁基酯、6-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬烷-2-甲酸第三丁基酯、6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬烷-2-甲酸第三丁基酯、(-)-6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬烷-2-甲酸第三丁基酯、9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬烷-3-甲酸第三丁基酯、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[6-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](6-甲氧基吡啶-2-基)甲酮、[6-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)[6-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](6-甲氧基吡啶-2-基)甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](2-氟苯基)甲酮、(3-氯-6-甲氧基吡啶-2-基)[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、(4-胺基-1,2-噁二唑-3-基)[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](2-氟苯基)甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](6-甲氧基吡啶-2-基)甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、(4-胺基-1,2,5-噁二唑-3-基)[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、[6-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](2-氟苯基)甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](2-氟苯基)甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](6-甲氧基吡啶-2-基)甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、(4-胺基-1,2,5-噁二唑-3-基)[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](2-氟苯基)甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](6-甲氧基吡啶-2-基)甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、(4-胺基-1,2,5-噁二唑-3-基)[6-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、(3-氯-6-甲氧基吡啶-2-基)[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、環戊基[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、[6-(二氟甲氧基)吡啶-2-基][6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、(2-氟苯基)[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、(2-氟苯基)[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基](6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、(3-氯-6-甲氧基吡啶-2-基)[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、[6-(二氟甲氧基)吡啶-2-基][6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、環戊基[6-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基]甲酮、(3-氟-6-甲氧基吡啶-2-基)[9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基]甲酮、(3-氯-6-甲氧基吡啶-2-基)[9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基]甲酮、[9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基](6-甲氧基吡啶-2-基)甲酮、[6-(二氟甲氧基)吡啶-2-基][9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基]甲酮、環戊基[9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基]甲酮、(3-氟-6-甲氧基吡啶-2-基)[9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基]甲酮、(3-氯-6-甲氧基吡啶-2-基)[9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基]甲酮、[9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基](6-甲氧基吡啶-2-基)甲酮、[6-(二氟甲氧基)吡啶-2-基][9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基]甲酮、環戊基[9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基]甲酮、(-)-(2-氟苯基)[9-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-3-基]甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基][6-(三氟甲氧基)吡啶-2-基]甲酮、[6-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,6-二氮雜雙環[3.2.2]壬-2-基][6-(二氟甲氧基)吡啶-2-基]甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](2-氟苯基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](6-甲氧基吡啶-2-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](2-氟苯基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](4-甲基-1,2,5-噁二唑-3-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](2-氟苯基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](4-甲基-1,2,5-噁二唑-3-基)甲酮、(4-胺基-1,2,5-噁二唑-3-基)[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基]甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](2-氟苯基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](2-氟苯基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.2.2]壬-6-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.2.2]壬-6-基](6-甲氧基吡啶-2-基)甲酮、[3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,6-二氮雜雙環[3.2.2]壬-6-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,6-二氮雜雙環[3.2.2]壬-6-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,6-二氮雜雙環[3.2.2]壬-6-基](6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)[3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬烷-9-基]甲酮、(3-氟-6-甲氧基吡啶-2-基)[3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬烷-9-基]甲酮、[3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬烷-9-基](6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)[3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬烷-9-基]甲酮。
本發明之一更佳實施例係關於以下化合物之組合:作為式(I)化合物之(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪;及
選自由以下組成之群之式(II)化合物:
(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-氟苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-異丙氧基吡啶-2-基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[6-(三氟甲氧基)吡啶-2-基]甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](6-甲氧基吡啶-2-基)甲酮、[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H)-基](6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基]甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](6-甲氧基-3-甲基吡啶-2-基)甲酮、(-)-[(1S
,4S
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](6-甲氧基吡啶-2-基)甲酮、(-)-(3-氯-6-甲氧基吡啶-2-基)[(1S
,4S
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基]甲酮、(-)-[(1S
,4S
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(-)-(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)[6-(二氟甲氧基)吡啶-2-基]甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)[3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬烷-9-基]甲酮。
本發明之一最佳實施例係關於以下化合物之組合:作為式(I)化合物之(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪
及
選自由以下組成之群之式(II)化合物:
(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-氟苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-異丙氧基吡啶-2-基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[6-(三氟甲氧基)吡啶-2-基]甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](6-甲氧基吡啶-2-基)甲酮、[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H)-基](6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基]甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H
)-基](6-甲氧基-3-甲基吡啶-2-基)甲酮、(-)-[(1S
,4S
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](6-甲氧基吡啶-2-基)甲酮、(-)-(3-氯-6-甲氧基吡啶-2-基)[(1S
,4S
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基]甲酮、(-)-[(1S
,4S
)-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(-)-(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)[6-(二氟甲氧基)吡啶-2-基]甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)[3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬烷-9-基]甲酮。
另一實施例本發明係關於以下化合物之組合:
(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪及
(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮或(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮。
本文所採用之術語具有下文所指示之含義。下文含義中所採用之術語「至少一個」係指一個或若干個,例如一個。
本文所採用之術語「羥基」 (本身或作為另一基團之一部分)係指-OH基團。
在本發明之上下文中,(C1
-C6
)- 烷基
係具有1至6個碳原子之直鏈或具支鏈烷基。實例包含:甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、2-戊基、3-戊基、新戊基、正己基、2-己基及3-己基。
在本發明之上下文中,(C1
-C4
)- 烷基
係具有1至4個碳原子之直鏈或具支鏈烷基。實例包含:甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基及第三丁基。
在本發明之上下文中,(C1
-C3
)- 烷基
係具有1至3個碳原子之直鏈或具支鏈烷基。實例包含:甲基、乙基、正丙基及異丙基。
本文所採用之術語(C1
-C6
) 烷氧基
(本身或作為另一基團之一部分)係指經由氧原子附加至母體分子部分之如本文所定義之(C1
-C6
)烷基。(C1
-C6
)烷氧基之代表性實例包含(但不限於)甲氧基、乙氧基、正丙氧基、正丁氧基、異丁氧基、第二丁氧基、第三丁氧基、2,2-二甲基丙氧基、3-甲基丁氧基及正己氧基。
本文所採用之術語「鹵基
」或「鹵素
」 (本身或作為另一基團之一部分)係指氟、氯、溴或碘。
本發明上下文中之單 -(C1
-C3
)- 烷基胺基
係具有含有1至3個碳原子之直鏈或具支鏈烷基取代基之胺基。實例包含:甲基胺基、乙基胺基、正丙基胺基及異丙基胺基。
本發明上下文中之二 -(C1
-C3
)- 烷基胺基
係具有兩個各自具有1至3個碳原子之相同或不同直鏈或具支鏈烷基取代基之胺基。實例包含:N,N
-二甲基胺基、N,N
-二乙基胺基、N
-乙基-N
-甲基胺基、N
-甲基-N
-正丙基胺基、N
-異丙基-N
-甲基胺基、N,N
-二-正丙基胺基、N
-異丙基-N
-正丙基胺基及N,N
-二異丙基胺基。
本發明上下文中之(C1
-C3
)- 烷基硫基
[亦稱為(C1
-C3
)-烷硫基]係經由硫原子連接至分子之其他部分之具有1至3個碳原子的直鏈或具支鏈烷基。實例包含:甲基硫基、乙基硫基、正丙基硫基及異丙基硫基。
本發明上下文中之(C3
-C6
)- 環烷基
係具有3至6個環碳原子之單環飽和環烷基。實例包含:環丙基、環丁基、環戊基及環己基。
本發明上下文中之(C4
-C6
)- 環烷基
係具有4至6個碳原子之單環飽和環烷基。實例包含:環丁基、環戊基及環己基。
本文所採用之術語羥基 (C1
-C6
) 烷基
(本身或作為另一基團之一部分)係指如本文所定義經由如本文所定義之(C1
-C6
)烷基附加至母體分子部分之至少一個羥基。羥基(C1
-C6
)烷基之代表性實例包含(但不限於)羥甲基、1-羥乙基、2-羥乙基、2,2-二羥基乙基、1-羥丙基、3-羥丙基、1-羥基-1-甲基乙基及1-羥基-1-甲基丙基。
本文所採用之術語(C1
-C6
) 烷氧基 (C1
-C6
) 烷基
(本身或作為另一基團之一部分)係指如本文所定義經由如本文所定義之(C1
-C6
)烷基附加至母體分子部分之至少一個(C1
-C6
)烷氧基。在存在若干(C1
-C6
)烷氧基時,(C1
-C6
)烷氧基可相同或不同。
(C1
-C6
) 烷氧基 (C1
-C6
) 烷基
之代表性實例包含(但不限於)甲氧基甲基、乙氧基甲基、丙氧基甲基、2-甲氧基乙基、2-乙氧基乙基、2,2-二甲氧基乙基、1-甲基-2-丙氧基乙基、1-甲氧基-1-甲基乙基及4-甲氧基丁基。
本文所採用之術語羥基 (C1
-C6
) 烷氧基
(本身或作為另一基團之一部分)係指如本文所定義經由如本文所定義之(C1
-C6
)烷氧基附加至母體分子部分之至少一個羥基。羥基(C1
-C6
)烷氧基之代表性實例包含(但不限於)羥基甲氧基、二羥基甲氧基、2-羥基乙氧基、2-羥基丙氧基、3-羥基丙氧基、2-羥基丁氧基及2-羥基-1-甲基乙氧基。
本文所採用之術語(C1
-C6
) 烷氧基 (C1
-C6
) 烷氧基
(本身或作為另一基團之一部分)係指如本文所定義經由如本文所定義之(C1
-C6
)烷氧基附加至母體分子部分之至少一個(C1
-C6
)烷氧基。(C1
-C6
)烷氧基可相同或不同。(C1
-C6
)烷氧基(C1
-C6
)烷氧基之代表性實例包含(但不限於)甲氧基甲氧基、丙氧基甲氧基、2-甲氧基乙氧基、2-乙氧基乙氧基、2-丁氧基乙氧基、2,2-二甲氧基乙氧基、1-甲基-2-丙氧基乙氧基、2-甲氧基丙氧基及4-甲氧基丁氧基。
本文所採用之術語鹵代 (C1
-C6
) 烷氧基
(本身或作為另一基團之一部分)係指如本文所定義經由如本文所定義之(C1
-C6
)烷氧基附加至母體分子部分之至少一個鹵素。在存在若干鹵素時,鹵素可相同或不同。鹵代(C1
-C6
)烷氧基之代表性實例包含(但不限於)氟甲氧基、氯甲氧基、二氟甲氧基、三氟甲氧基、2-溴乙氧基、2,2,2-三氯乙氧基、3-溴丙氧基、2-氯丙氧基及4-氯丁氧基。
本文所採用之表達「本發明化合物」係指式I化合物。
使用有機酸及無機酸二者形成之醫藥上可接受之鹽(例如酸加成鹽)在醫藥領域中已眾所周知。醫藥上可接受之酸加成鹽之代表性實例包含(但不限於)氯化物、溴化物、硫酸鹽、硝酸鹽、磷酸鹽、磺酸鹽、甲磺酸鹽、甲酸鹽、酒石酸鹽、馬來酸鹽、檸檬酸鹽、苯甲酸鹽、水楊酸鹽、抗壞血酸鹽、乙酸鹽及草酸鹽。
水合物或溶劑合物在本發明中指定為式(I)化合物以固態或液態藉由與水水合或與溶劑分子配位而形成分子化合物或複合物之彼等形式。水合物之實例係倍半水合物、單水合物、二水合物或三水合物。同樣,本發明化合物之鹽之水合物或溶劑合物亦適宜。
在適用時,可藉由已知方法使用醫藥領域中常用之醫藥上可接受之酸來製備醫藥上可接受之酯且保留游離形式之藥理學性質。該等酯之非限制性實例包含脂肪族或芳香族醇之酯。醫藥上可接受之酯之代表性實例包含(但不限於)甲酯、乙酯、正丙基酯、異丙基酯、正丁基酯、異丁基酯、第二丁基酯、第三丁基酯及苄基酯。
本發明在其範圍內包含化合物之所有可能幾何異構體(例如Z及E異構體(順式及反式異構體))以及化合物之所有可能光學異構體(例如非對映異構體及對映異構體)。另外,本發明在其範圍內包含個別異構體及其任何混合物(例如外消旋混合物)二者。個別異構體可使用起始材料之相應異構體形式來獲得,或其可在製備最終化合物之後根據習用分離方法予以分離。為自混合物分離光學異構體(例如對映異構體),可使用習用拆分方法(例如分段結晶)。
式(I)化合物、其產生及其作為α2C拮抗劑來治療周邊或中樞神經系統之疾病或病狀之作用通常揭示於WO-A 2010/
058060中,且尤其而言,該等化合物特定地係本發明說明之明確部分且以引用方式併入本文中。
式(II)化合物、其產生及其作為TASK-1及TASK-3通道之選擇性阻斷劑用於治療呼吸病症、睡眠相關性呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、神經退化性病症、神經發炎性病症及神經免疫性病症之作用通常揭示於WO 2017/097792 A1、WO 2017/097671 A1、WO 2018/015196 A1、WO 2018/228907 A1及WO 2018/228909 A1中,且尤其地,該等化合物特定地係本發明說明之明確部分且以引用方式併入本文中。
本文所用之術語有效量係指有效治療及/或防治睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾之式(I)化合物之量。
本發明係關於本發明之式(I)化合物及式(II)化合物之組合,其用於治療及/或預防呼吸病症、睡眠相關性呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、神經退化性病症、神經發炎性病症及神經免疫性病症之方法中。
本發明亦係關於本發明之式(I)化合物及式(II)化合物之組合之用途,其用以產生用於治療及/或預防呼吸病症、睡眠相關性呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、神經退化性病症、神經發炎性病症及神經免疫性病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾之藥劑。
此外,本發明係關於一或多種TASK-1及TASK-3通道之選擇性阻斷劑與一或多種α2-腎上腺素受體亞型C (α-2C)拮抗劑之組合之用途,其用以製備用於治療睡眠相關性呼吸病症之醫藥組合物。
本發明之另一標的物係本發明之式(I)化合物及式(II)化合物與一或多種其他活性化合物之組合之用途,其用於用以治療及/或防治睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾之方法中。
本發明之另一標的物係包括至少一種本發明之式(I)化合物及式(II)化合物之組合與一或多種惰性無毒醫藥適宜賦形劑之組合的藥劑,其用於用以治療及/或防治睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾之方法中。
本發明另外係關於包括至少一種本發明之式(I)化合物及式(II)化合物之組合以及一或多種其他活性化合物與一或多種惰性無毒醫藥適宜賦形劑之組合的藥劑,其用於用以治療及/或防治睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾之方法中。
本發明亦係關於治療及/或防治睡眠相關性呼吸病症之方法,其係藉由全身性及/或局部性投與治療有效量之至少一種式(I)化合物及式(II)化合物之組合或包括至少一種本發明之式(I)化合物及式(II)化合物之組合與惰性、無毒、醫藥上可接受之添加劑之組合的藥劑來達成。
本發明之式(I)化合物及式(II)化合物之組合可單獨使用或視需要與一或多種其他藥理學活性物質組合,條件係此組合不會產生不期望及不可接受之副效應。適用於治療睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾之目的之組合之較佳實例包含:
• 呼吸刺激劑,例如(藉由實例方式且較佳地)茶鹼(theophylline)、多沙普侖(doxapram)、尼可刹米(nikethamide)或咖啡因(caffeine);
• 精神刺激劑,例如(藉由實例方式且較佳地)莫達非尼(modafinil)或阿莫達非尼(armodafinil);
• ***(amphetamine)及***衍生物,例如(藉由實例方式且較佳地)***、甲基***(metamphetamine)或甲基芬尼定(methylphenidate);
• 血清素再攝取抑制劑,例如(藉由實例方式且較佳地)氟西汀(fluoxetine)、帕羅西汀(paroxetine)、西酞普蘭(citalopram)、依他普侖(escitalopram)、舍曲林(sertraline)、氟伏沙明(fluvoxamine)或曲唑酮(trazodone);
• 血清素前體,例如(藉由實例方式且較佳地) L-色胺酸;
• 選擇性血清素去甲腎上腺素再攝取抑制劑,例如(藉由實例方式且較佳地)文拉法辛(venlafaxine)或度洛西汀(duloxetine);
• 去甲腎上腺素能及特定血清素能抗抑鬱劑,例如(藉由實例方式且較佳地)米氮平(mirtazapine);
• 選擇性去甲腎上腺素再攝取抑制劑,例如(藉由實例方式且較佳地)瑞波西汀(reboxetine)或阿托莫西汀(atomoxetine);
• 三環抗抑鬱劑,例如(藉由實例方式且較佳地)阿米替林(amitriptyline)、普羅替林(protriptyline)、多慮平(doxepine)、曲米帕明(trimipramine)、伊米帕明(imipramine)、氯米帕明(clomipramine)或地昔帕明(desipramine);
• 蕈毒鹼受體拮抗劑,例如(且較佳地)奧昔布寧(oxybutynin);
• GABA激動劑,例如(藉由實例方式且較佳地)巴氯芬(baclofen);
• 糖皮質激素,例如(藉由實例方式且較佳地)氟替卡松(fluticasone)、布***(budesonide)、倍氯米松(beclometasone)、莫米松(mometasone)、替可的松(tixocortol)或曲安奈德(triamcinolone);
• ***素受體激動劑;
• 碳酸酐酶抑制劑,例如(藉由實例方式且較佳地)乙醯唑胺(acetazolamide)、醋甲唑胺(methazolamide)或雙氯非那胺(diclofenamide);
• 類鴉片及苯并二氮呯受體拮抗劑,例如(藉由實例方式且較佳地)氟馬西尼(flumazenil)、納洛酮(naloxone)或那曲酮(naltrexone);
• 膽鹼酯酶抑制劑,例如(藉由實例方式且較佳地)新斯的明(neostigmine)、吡啶斯的明(pyridostigmine)、毒扁豆鹼(physostigmine)、多奈派齊(donepezil)、加蘭他敏(galantamine)或利凡斯的明(rivastigmine);
• 食欲抑制劑,例如(藉由實例方式且較佳地)***(sibutramin)、托吡酯(topiramate)、苯丁胺(phentermine)、脂肪酶抑制劑或***素受體拮抗劑;
• 鹽皮質激素受體拮抗劑。
包括如技術方案1至5中任一項所定義之組合與一或多種選自由以下組成之群之其他活性成分之組合的藥劑:蕈毒鹼受體拮抗劑、鹽皮質激素受體拮抗劑、利尿劑、皮質類固醇。
本發明之較佳標的物係包括本發明之式(I)化合物及式(II)化合物之組合及一或多種選自由蕈毒鹼受體拮抗劑、鹽皮質激素受體拮抗劑、利尿劑、皮質類固醇組成之群之其他活性化合物的組合,其用於用以治療及/或防治睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾之方法中。
本發明之另一較佳標的物係包括本發明之式(I)化合物及式(II)化合物之組合與一或多種選自由蕈毒鹼受體拮抗劑組成之群之其他活性化合物之組合的藥劑
在本發明之一較佳實施例中,組合投與本發明組合與蕈毒鹼受體拮抗劑(例如(且較佳地)奧昔布寧)。
在本發明之一較佳實施例中,組合投與本發明組合與鹽皮質激素受體拮抗劑(例如(且較佳地)螺內酯(spironolactone)、依普利酮(eplerenone)或非奈利酮(finerenone))。
在本發明之一較佳實施例中,組合投與本發明組合與利尿劑(例如(且較佳地)呋塞米(furosemide)、布美他尼(bumetanide)、托拉塞米(torsemide)、苄氟噻嗪(bendroflumethiazide)、***(chlorothiazide)、氫***(hydrochlorothiazide)、氫氟噻嗪(hydroflumethiazide)、甲***(methyclothiazide)、泊利噻嗪(polythiazide)、三***(trichlormethiazide)、氯噻酮(chlorthalidone)、吲達帕胺(indapamide)、美托拉宗(metolazone)、喹乙宗(quinethazone)、乙醯唑胺、雙氯非那胺(dichlorphenamide)、醋甲唑胺、甘油、異山梨醇、甘露醇、阿米洛利(amiloride)或胺苯蝶啶(triamterene))。
在本發明之一較佳實施例中,組合投與本發明化合物與皮質類固醇(例如(且較佳地)普賴松(prednisone)、普賴蘇濃(prednisolone)、甲基普賴蘇濃(methylprednisolone)、曲安奈德(triamcinolone)、***(dexamethasone)、倍他米松(betamethasone)、倍氯米松(beclomethasone)、氟尼縮松(flunisolide)、布***或氟替卡松)。
若需要,則亦可採用本發明之式(I)之芳基六氫吡嗪且聯合使用一或多種醫學技術裝置或輔件,條件係此不會產生不期望及不可接受之副效應。適用於此一組合應用之醫學裝置及輔件係(舉例而言且較佳地):
• 用於氣道正壓通氣之裝置,例如(藉由實例方式且較佳地) CPAP (連續氣道正壓)裝置、BiPAP (雙相氣道正壓)裝置及IPPV (間歇正壓通氣)裝置;
• 舌下神經之神經剌激器;
• 口內輔件,例如(藉由實例方式且較佳地)突出支架;
• 鼻用一次性瓣膜;
• 鼻支架。
本發明之式(I)之芳基六氫吡嗪及式(II)化合物可全身性及/或局部性發揮作用。出於此目的,其可以適宜方式投與,例如經由經口、非經腸、經肺、經肺內(吸入性)、經鼻、經鼻內、經咽、經舌、經舌下、經頰、經直腸、經皮、經真皮、結膜或耳部途徑或作為植入物或支架。
本發明之另一標的物係包括本發明之式(I)化合物及式(II)化合物之組合的醫藥組合物,其用於藉由經口、非經腸、經肺、經肺內(吸入性)、經鼻、經鼻內、經咽、經舌、經舌下、經頰、經直腸、經皮、經真皮、結膜或耳部途徑或作為植入物或支架來全身性及/或局部性投與。較佳投與係經口、經鼻及經咽途徑。
對於該等投與途徑而言,本發明化合物可以適宜投與形式來投與。
對於經口投與而言,適宜投與形式如下:根據最新技術發揮作用,快速及/或以改良方式釋放本發明化合物,且含有呈結晶及/或非晶形及/或溶解形式之本發明化合物,例如錠劑(未包衣或經包衣錠劑,例如具有控制本發明化合物之釋放之抗胃液或延遲溶解或不溶解包衣)、在口腔中快速崩解之錠劑或膜/糯米紙囊劑、膜/凍乾物、膠囊(例如硬質或軟質明膠膠囊)、糖衣錠、粒劑、丸劑、粉劑、乳液、懸浮液、氣溶膠或溶液。
可在省略吸收步驟(例如靜脈內、動脈內、心臟內、脊柱內或腰內投與)或涉及吸收(例如肌內、皮下、皮內、經皮或腹膜腔內投與)之情形下實現非經腸投與。適於非經腸投與之形式包含呈溶液、懸浮液、乳液、凍乾物或無菌粉末形式之注射及輸注製劑。
對於其他投與途徑而言,舉例而言,吸入調配物(包含粉末吸入器及噴霧器)、滴鼻劑、溶液或噴霧、咽噴霧、用於經舌、舌下或經頰投與之錠劑、錠劑、膜/糯米紙囊劑或膠囊、栓劑、耳部或眼部製劑、***膠囊、水性懸浮液(洗劑、可搖動混合物)、親脂性懸浮液、軟膏、乳霜、經皮治療系統(例如硬膏劑)、牛乳、膏糊、發泡體、撒粉、植入體或支架係適宜的。
經口或經鼻及經咽投與較佳。
可將本發明化合物轉化成所述投與形式。此可以本身已知之方式藉由與惰性、無毒、醫藥上適宜之添加劑混合來實現。該等添加劑包含載劑(例如微晶纖維素、乳糖、甘露醇)、溶劑(例如液體聚乙二醇)、乳化劑及分散劑或潤濕劑(例如十二烷基硫酸鈉、聚氧山梨醇酐油酸酯)、黏合劑(例如聚乙烯基吡咯啶酮)、合成及天然聚合物(例如白蛋白)、穩定劑(例如氧化劑,例如抗壞血酸)、著色劑(例如無機顏料,例如氧化鐵)及矯味劑或矯臭劑。
一般而言,為在口服投與中達成有效結果,已發現,可有利地投與約0.01 mg/kg體重至100 mg/kg體重、較佳地約0.01 mg/kg體重至10 mg/kg體重之量。在經鼻或經咽投與中,劑量為約0.01 µg/kg體重至1000 µg/kg體重、較佳地約0.1 µg/kg體重至10 µg/kg體重。然而,可能有時需要偏離該等量,亦即其取決於體重、投與途徑、個體對活性物質之反應、製劑性質及發生投與之時間或間隔。因此,在一些情形下,在小於上述最小量下即可足以達成效應,而在其他情形下則必須超過所述上限。在投與較大量之情形下,在全天內將該等量分成若干個別投與可為明智的。
本發明之另一標的物係全身性投與式(I)化合物與局部投與式(II)化合物之組合。
出於此目的,可以適宜方式(例如藉由經口、非經腸、經肺、經肺內(吸入性)、經鼻、經鼻內、經咽、經舌、經舌下、經頰、經直腸、經皮、經真皮、結膜或耳部途徑或作為植入物或支架)投與式(I)化合物,且可(例如)藉由經鼻、鼻內、經咽、經舌、舌下及經頰途徑投與式(II)化合物。
較佳投與係式(I)化合物之經口途徑及式(II)化合物之經鼻及經咽途徑。
對於經口投與而言,適宜投與形式如下:根據最新技術發揮作用,快速及/或以改良方式釋放本發明化合物,且含有呈結晶及/或非晶形及/或溶解形式之本發明化合物,例如錠劑(未包衣或經包衣錠劑,例如具有控制本發明化合物之釋放之抗胃液或延遲溶解或不溶解包衣)、在口腔中快速崩解之錠劑或膜/糯米紙囊劑、膜/凍乾物、膠囊(例如硬質或軟質明膠膠囊)、糖衣錠、粒劑、丸劑、粉劑、乳液、懸浮液、氣溶膠或溶液。
對於經鼻及經咽投與途徑而言,舉例而言,鼻滴劑、溶液或噴霧、咽噴霧、用於經舌、舌下或經頰投與之錠劑、錠劑、膜/糯米紙囊劑或膠囊、栓劑或口服製備係適宜的。
下列實踐實例闡釋本發明。本發明並不限於該等實例。
實例 A. 實驗方法 可藉由下列方法測定α2-腎上腺素受體亞型C (α-2C)拮抗劑與TASK1/3通道阻斷劑之組合之有利藥理學性質。
可在臨床前於阻塞性睡眠呼吸中止症(OSA)之豬模型中評價本發明之α2-腎上腺素受體亞型C (α-2C)拮抗劑與TASK1/3通道阻斷劑之組合在睡眠呼吸中止症中之治療潛力。
使用負壓,可誘導經麻醉、自發呼吸豬中之上呼吸道之塌陷且由此使其阻塞(Wirth K.J.等人,Sleep 36(5) (2013) 第699-708頁)。
該模型使用德國藍瑞斯豬(German Landrace pig)。將豬麻醉且切開氣管。將兩根氣管插管***氣管中,一根***氣管之吻部部分中且另一根***尾部部分中。使用連接件將吻部插管連接至負壓裝置之管及遠端氣管插管。遠端氣管插管另外經由連接件連接至具有至大氣之開口端之管,此用於氣管自由呼吸,從而繞過上氣道。藉由適當地打開及夾緊彼等管子,可使呼吸自鼻呼吸切換至經由尾部氣管插管呼吸(繞過上氣道),且可使(經隔離)上氣道連接至負壓裝置,從而產生沿吸氣方向之氣流。
在某些時間點,藉由使豬經由尾部插管呼吸且向上呼吸道施加-50、-100及-150 cm水頭(cm H2O)之負壓來測試上呼吸道塌陷性。此會導致上呼吸道塌陷,其本身表現為氣流中斷及管系統中之壓力降。在投與測試物質之前及在投與測試物質之後以一定間隔實施此測試。適當之有效測試物質可防止吸氣階段中之此呼吸道塌陷。
在此OSA豬模型中,在-50-、100及-150 cm水頭(cm H2
O)之所有負壓下全身性施加式(I)之α2-腎上腺素受體亞型C (α-2C)拮抗劑(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪(0.015 µg/kg之靜脈內濃注,隨後以0.005 µg/kg/h進行靜脈內輸注4小時)在濃注及輸注開始之後之任一時間點皆不抑制上氣道塌陷性。在濃注及輸注開始之後之90 min時間點,在-100及-150 cm水頭(cm H2O)之負壓下誘導上氣道塌陷性,上氣道塌陷性僅在-50 cm水頭(cm H2O)之負壓下得以抑制。在-50、-100及-150 cm水頭(cm H2
O)之所有負壓下,此非有效劑量之式(I)之α2-腎上腺素受體亞型C (α-2C)拮抗劑(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪與非有效劑量之TASK1/TASK3通道阻斷劑(0.3 µg (4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮)之組合皆抑制上氣道塌陷性4小時以上(參見表 1 、 2
及3
及圖 1
)。
圖 1
:在開始實驗之後式(I)之α2-腎上腺素受體亞型C (α-2C)拮抗劑(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪之0.015 µg/kg靜脈內濃注及隨後4小時0.005 µg/kg/h靜脈內輸注(在時間點0 min下給予)與0.3 µg TASK1/TASK3通道阻斷劑 (4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮(在時間點90 min下給予)之鼻內投與之組合在不同負壓值下對上氣道塌陷性的效應。給出無塌陷豬之百分比。平均值。表 1
: 非有效劑量之(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪與有效劑量之0.3 µg (4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮之組合在-50 cm水頭(cm H2
O)之負壓下抑制上氣道塌陷性
表 2
: 非有效劑量之(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪與有效劑量之0.3 µg (4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮之組合在-100 cm水頭(cm H2
O)之負壓下抑制上氣道塌陷性
表 3
: 非有效劑量之(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪與有效劑量之0.3 µg (4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮之組合在-150 cm水頭(cm H2
O)之負壓下抑制上氣道塌陷性
表 4 、 5 及 6 及圖 2 :
經鼻內投與0.3 µg TASK1/TASK3通道阻斷劑(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮(在時間點0 min下給予)在不同負壓值下對上氣道塌陷性之效應。給出無塌陷豬之百分比。平均值。表 4
:在-50 cm水頭(cm H2
O)之負壓下0.3 µg TASK1/TASK3通道阻斷劑(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮之經鼻內投與
表 5
:在-100 cm水頭(cm H2
O)之負壓下0.3 µg TASK1/TASK3通道阻斷劑(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮之經鼻內投與
表 6
:在-150 cm水頭(cm H2
O)之負壓下0.3 µg TASK1/TASK3通道阻斷劑(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮之經鼻內投與
自上文所提及數據可推斷出,式(I)之α2-腎上腺素受體亞型C (α-2C)拮抗劑與TASK1/3通道阻斷劑之組合可抑制上氣道塌陷性且與每一單獨治療相比具有改良效能,並由此適於治療睡眠相關性呼吸病症、較佳地阻塞性及中樞性睡眠呼吸中止症以及打鼾。
時間, min | 無塌陷豬之百分比 -50 cm H2 O, % | |
0 | 0 | |
30 | 0 | |
60 | 100 | |
經鼻施加 TASK1/3通道阻斷劑 | 90 | 100 |
100 | 100 | |
120 | 100 | |
150 | 100 | |
180 | 100 | |
210 | 100 | |
240 | 100 | |
300 | 100 | |
330 | 100 | |
360 | 100 |
時間, min | 無塌陷豬之百分比 -100 cm H2 O, % | |
0 | 0 | |
30 | 0 | |
60 | 0 | |
經鼻施加 TASK1/3通道阻斷劑 | 90 | 0 |
100 | 100 | |
120 | 100 | |
150 | 100 | |
180 | 100 | |
210 | 100 | |
240 | 100 | |
300 | 100 | |
330 | 100 | |
360 | 100 |
時間, min | 無塌陷豬之百分比 -150 cm H2 O, % | |
0 | 0 | |
30 | 0 | |
60 | 0 | |
經鼻施加 TASK1/3通道阻斷劑 | 90 | 0 |
100 | 100 | |
120 | 100 | |
150 | 100 | |
180 | 100 | |
210 | 100 | |
240 | 100 | |
300 | 100 | |
330 | 100 | |
360 | 100 |
時間, min | 無塌陷豬之百分比 -50 cm H2 O, % |
0 | 0 |
10 | 0 |
30 | 0 |
60 | 0 |
時間, min | 無塌陷豬之百分比 -100 cm H2 O, % |
0 | 0 |
10 | 0 |
30 | 0 |
60 | 0 |
時間, min | 無塌陷豬之百分比 -150 cm H2 O, % |
0 | 0 |
10 | 0 |
30 | 0 |
60 | 0 |
圖 1
:在開始實驗之後式(I)之α2-腎上腺素受體亞型C (α-2C)拮抗劑(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪之0.015 µg/kg靜脈內濃注及隨後4小時0.005 µg/kg/h靜脈內輸注(在時間點0 min下給予)與0.3 µg TASK1/TASK3通道阻斷劑(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮(在時間點90 min下給予)之鼻內投與之組合在不同負壓值下對上氣道塌陷性的效應。給出無塌陷豬之百分比。平均值。圖 2 :
經鼻內投與0.3 µg TASK1/TASK3通道阻斷劑(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮(在時間點0 min下給予)在不同負壓值下對上氣道塌陷性之效應。給出無塌陷豬之百分比。平均值。
Claims (13)
- 一種式(I)化合物及式(II)化合物之組合, X 係CR2 R2 '、O、S或NR2 ; Z 係-CHR8 -(CH2 )n-或單鍵; R1 係羥基、(C1 -C6 )烷基、(C1 -C6 )烷氧基、鹵素、鹵代(C1 -C6 )烷基、(C1 -C6 )烷氧基-(C=O)-、CO-、CN、NO2 、NH2 、單-或二(C1 -C6 )烷基胺基或羧基; R2 及R2 '獨立地係H、羥基或(C1 -C6 )烷基或R2 及R2 '與其所連接之碳環原子一起形成羰基; R3 係H、羥基、(C1 -C6 )烷基、(C2 -C6 )烯基、羥基(C1 -C6 )烷基、(C1 -C6 )烷氧基、(C1 -C6 )烷氧基(C1 -C6 )烷基、羥基(C1 -C6 )烷氧基(C1 -C6 )烷基、(C3 -C7 )環烷基、(C3 -C7 )環烷基(C1 -C6 )烷基、芳基、芳基(C1 -C6 )烷基、芳基氧基、芳基(C1 -C6 )烷氧基、芳基氧基(C1 -C6 )烷基、芳基(C1 -C6 )烷氧基(C1 -C6 )烷基、鹵代(C1 -C6 )烷基、NH2 、胺基(C1 -C6 )烷基、單-或二(C1 -C6 )烷基胺基、單-或二(C1 -C6 )烷基胺基(C1 -C6 )烷基、(C1 -C6 )烷基-CO-、(C1 -C6 )烷基-CO-O-、(C1 -C6 )烷基-CO-O-(C1 -C6 )烷基、(C1 -C6 )烷氧基-CO-、(C1 -C6 )烷氧基-CO-(C1 -C6 )烷基、(C1 -C6 )烷氧基-CO-(C1 -C6 )烷氧基(C1 -C6 )烷基、胺甲醯基、單-或二(C1 -C6 )烷基胺甲醯基、羧基或(C1 -C6 )烷基-S-(C1 -C6 )烷基,其中該(C3 -C7 )環烷基或芳基未經取代或經1或2個各自獨立地為羥基、(C1 -C6 )烷基、鹵素、(C1 -C6 )烷氧基、NH2 、CN或NO2 之取代基取代,或R3 或R4 中之一者及R6 一起在其所連接之環原子之間形成鍵; R4 係H、羥基、(C1 -C6 )烷基、羥基(C1 -C6 )烷基、(C1 -C6 )烷氧基或(C1 -C6 )烷氧基(C1 -C6 )烷基; R5 係H、羥基、(C1 -C6 )烷基、(C2 -C6 )烯基、羥基(C1 -C6 )烷基、(C1 -C6 )烷氧基、(C1 -C6 )烷氧基(C1 -C6 )烷基、羥基(C1 -C6 )烷氧基(C1 -C6 )烷基、(C3 -C7 )環烷基、(C3 -C7 )環烷基(C1 -C6 )烷基、芳基、芳基(C1 -C6 )烷基、芳基氧基、芳基(C1 -C6 )烷氧基、芳基氧基(C1 -C6 )烷基、芳基(C1 -C6 )烷氧基(C1 -C6 )烷基、鹵代(C1 -C6 )烷基、(C1 -C6 )烷基-CO-、(C1-C6)烷基-CO-O-、(C1 -C6 )烷基-CO-O-(C1 -C6 )烷基、(C1 -C6 )烷氧基-CO-、(C1 -C6 )烷氧基-CO-(C1 -C6 )烷基、(C1 -C6 )烷氧基-CO-(C1 -C6 )烷氧基(C1 -C6 )烷基、胺甲醯基、單-或二(C1 -C6 )烷基胺甲醯基、羧基或(C1 -C6 )烷基-S-(C1 -C6 )烷基,其中該(C3 -C7 )環烷基或芳基未經取代或經1或2個各自獨立地為羥基、(C1 -C6 )烷基、鹵素、(C1 -C6 )烷氧基、NH2 、CN或NO2 之取代基取代,或R4 及R5 與其所連接之碳環原子一起形成未經取代或經1至3個取代基R9 取代之縮合5至7員飽和碳環,R9 各自獨立地係羥基、(C1 -C6 )烷基、鹵素、NH2 、NO2 、(C3 -C7 )環烷基、羥基(C1 -C6 )烷基、鹵代(C1 -C6 )烷基、胺基(C1 -C6 )烷基、單-或二(C1 -C6 )烷基胺基、單-或二(C1 -C6 )烷基胺基(C1 -C6 )烷基、(C1 -C6 )烷氧基、(C1 -C6 )烷氧基(C1 -C6 )烷基、羧基、(C1 -C6 )烷基-CO-、(C1 -C6 )烷基-CO-O-、(C1 -C6 )烷氧基-CO-、(C1 -C6 )烷氧基-CO-(C1 -C6 )烷基、胺甲醯基、單-或二(C1 -C6 )烷基胺甲醯基或側氧基; R6 係H、羥基、(C1 -C6 )烷基、羥基(C1 -C6 )烷基、(C1 -C6 )烷氧基或(C1 -C6 )烷氧基(C1 -C6 )烷基,或R6 在其所連接之環原子與R7 所連接之環原子之間形成鍵; R7 係H、羥基、(C1 -C6 )烷基、羥基(C1 -C6 )烷基、(C1 -C6 )烷氧基或(C1 -C6 )烷氧基(C1 -C6 )烷基; R8 係H、羥基、(C1 -C6 )烷基、羥基(C1 -C6 )烷基、(C1 -C6 )烷氧基或(C1 -C6 )烷氧基(C1 -C6 )烷基,或僅在n為0時R7 及R8 與其所連接之碳環原子一起形成未經取代或經1至3個取代基R10 取代之縮合5至7員飽和碳環,R10 各自獨立地係羥基、(C1 -C6 )烷基、鹵素、NH2 、NO2 、(C3 -C7 )環烷基、羥基(C1 -C6 )烷基、鹵代(C1 -C6 )烷基、胺基(C1 -C6 )烷基、單-或二(C1 -C6 )烷基胺基、單-或二(C1 -C6 )烷基胺基(C1 -C6 )烷基、(C1 -C6 )烷氧基、(C1 -C6 )烷氧基(C1 -C6 )烷基、羧基、(C1 -C6 )烷基-CO-、(C1 -C6 )烷基-CO-O-、(C1 -C6 )烷氧基-CO-、(C1 -C6 )烷氧基-CO-(C1 -C6 )烷基、胺甲醯基、單-或二(C1 -C6 )烷基胺甲醯基或側氧基; R15 係H、(C1 -C6 )烷基、(C2 -C6 )烯基、羥基(C1 -C6 )烷基、(C1 -C6 )烷氧基(C1 -C6 )烷基、羥基(C1 -C6 )烷氧基(C1 -C6 )烷基、鹵代(C1 -C6 )烷基、胺基(C1 -C6 )烷基、單-或二(C1 -C6 )烷基胺基(C1 -C6 )烷基、(C1 -C6 )烷基-CO-、(C1 -C6 )烷基-CO-O-(C1 -C6 )烷基、(C1 -C6 )烷氧基-CO-、(C1 -C6 )烷氧基-CO-(C1 -C6 )烷基、(C1 -C6 )烷氧基-CO-(C1 -C6 )烷氧基(C1 -C6 )烷基、胺甲醯基、單-或二(C1 -C6 )烷基胺甲醯基或羧基; R16 係H或(C1 -C6 )烷基; R7 及R8 連接至毗鄰碳環原子; m 為0至2;且 n 為0或1; 其中 該環Q代表六氫吡嗪或下式之二氮雜雜雙環系統: 或 其中*表示至毗鄰CHR’2 基團之鍵且**表示至羰基之鍵, W1 、W2 或W3 代表CH或N, R’1 代表鹵素、氰基、(C1 -C4 )-烷基、環丙基或環丁基 其中(C1 -C4 )-烷基可最多由氟三取代且環丙基及環丁基可最多由氟二取代, 且 R’2 代表(C4 -C6 )-環烷基,其中環CH2 基團可由-O-代替, 或 R’2 代表式(a)之苯基、式(b)或(c)之吡啶基或式(d)、(e)、(f)或(g)之唑基, 其中***標記至毗鄰羰基之鍵且 R’3 代表氫、氟、氯、溴或甲基, R’4 代表氫、氟、氯、溴、氰基、(C1 -C3 )-烷基或(C1 -C3 )-烷氧基, 其中(C1 -C3 )-烷基及(C1 -C3 )-烷氧基可各自最多由氟三取代, R’5 代表氫、氟、氯、溴或甲基, R’6 代表氫、(C1 -C3 )-烷氧基、環丁基氧基、環氧丙烷-3-基氧基、四氫呋喃-3-基氧基、四氫-2H -吡喃-4-基氧基、單-(C1 -C3 )-烷基胺基、二-(C1 -C3 )-烷基胺基或(C1 -C3 )-烷基硫基, 其中(C1 -C3 )-烷氧基可最多由氟三取代, R7 代表氫、氟、氯、溴、(C1 -C3 )-烷基或(C1 -C3 )-烷氧基, R8A 及R8B 相同或不同且彼此獨立地代表氫、氟、氯、溴、(C1 -C3 )-烷基、環丙基或(C1 -C3 )-烷氧基 其中(C1 -C3 )-烷基及(C1 -C3 )-烷氧基可各自最多由氟三取代, R9 代表氫、(C1 -C3 )-烷基或胺基 且 其中在子式(d)中 Y 代表O、S或N(CH3 ), 其中在子式(e)及(f)中 Y 代表O或S, 或 R’2 代表-OR10 或-NR11 R12 基團,其中 R10 代表(C1 -C6 )-烷基、(C4 -C6 )-環烷基或[(C3 -C6 )-環烷基]甲基, R11 代表氫或(C1 -C3 )-烷基 且 R12 代表(C1 -C6 )-烷基、(C3 -C6 )-環烷基、苯基或苄基、1-苯基乙基或2-苯基乙基, 其中(C1 -C6 )-烷基可最多由氟三取代, 且 其中苯基及苄基、1-苯基乙基及2-苯基乙基中之苯基可最多由選自由以下組成之群之相同或不同基團三取代:氟、氯、甲基、乙基、三氟甲基、甲氧基、乙氧基、三氟甲氧基及(三氟甲基)硫基, 或 R11 及R12 彼此連接且與其所鍵結之氮原子一起形成吡咯啶、六氫吡啶、嗎啉或硫嗎啉環,或 R11 及R12 彼此連接且與其所鍵結之氮原子一起形成式(c)之四氫喹啉環或式(d)之四氫異喹啉環, 其中**標記至羰基之鍵, 及其鹽、溶劑合物及鹽之溶劑合物。
- 如請求項1之組合,其中該式(I)化合物係(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪 且對於式(II)化合物 其中該環Q代表六氫吡嗪或下式之二氮雜雜雙環系統: 或 其中*表示至毗鄰CHR2 基團之鍵且**表示至羰基之鍵, W2 代表CH, W1 、W3 代表CH或N, R’1 代表氟、氯、溴、甲基、第三丁基、異丙基、環丙基或環丁基, 且 R’2 代表環丁基、環戊基或環己基, 或 R’2 代表式(a)之苯基、式(b)之吡啶基或式(d)或式(g)之唑基 其中***標記至毗鄰羰基之鍵且 R’3 代表氫、氟或氯, R’4 代表氟、氯、甲基、異丙基、甲氧基或乙氧基, R’5 代表氫、氟、氯、溴或甲基, R6 代表甲氧基、二氟甲氧基、三氟甲氧基、異丙氧基、環丁基氧基或甲基硫基, R8A 及R8B 相同或不同且彼此獨立地代表氫、甲基、三氟甲基、乙基、異丙基或環丙基, 且 R9 代表甲基或胺基 Y 代表O或S或N(CH3 ) 及其鹽、溶劑合物及鹽之溶劑合物。
- 如請求項1之組合,其中該式(I)化合物係(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪 且式(II)化合物係選自由以下組成之群: (4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(環戊基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(2-氟苯基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-異丙氧基吡啶-2-基)甲酮、(4-{[2-(4-溴苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)[6-(三氟甲氧基)吡啶-2-基]甲酮、(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H )-基](6-甲氧基吡啶-2-基)甲酮、[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H)-基](6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)[5-{[2-(4-異丙基苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H )-基]甲酮、[5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡咯并[3,4-c]吡咯-2(1H )-基](6-甲氧基-3-甲基吡啶-2-基)甲酮、(-)-[(1S ,4S )-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](6-甲氧基吡啶-2-基)甲酮、(-)-(3-氯-6-甲氧基吡啶-2-基)[(1S ,4S )-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基]甲酮、(-)-[(1S ,4S )-5-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(-)-(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)(6-甲氧基吡啶-2-基)甲酮、(5-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)[6-(二氟甲氧基)吡啶-2-基]甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(5-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-2,5-二氮雜雙環[2.2.2]辛-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮、(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)(3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-環丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛烷-8-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、3-{[2-(4-氯苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-8-氧雜-3,10-二氮雜雙環[4.3.1]癸-10-基](3-氟-6-甲氧基吡啶-2-基)甲酮、[3-{[2-(5-氯吡啶-2-基)咪唑并[1,2-a]吡啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬-9-基](3-氟-6-甲氧基吡啶-2-基)甲酮、(3-氟-6-甲氧基吡啶-2-基)[3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,9-二氮雜雙環[4.2.1]壬烷-9-基]甲酮。
- 如請求項1之組合,其中該式(I)化合物係(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪且式(II)化合物選自由以下組成之群: (4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮及(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮。
- 如請求項1之組合,其中該式(I)化合物係(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪且其中該式(II)化合物係(4-{[2-(4-氯苯基)咪唑并[1,2-a]吡啶-3-基]甲基}六氫吡嗪-1-基)(6-甲氧基吡啶-2-基)甲酮。
- 如請求項1之組合,其中該式(I)化合物係(-)-(1S,12bS)-1-(甲氧基甲基)-1-甲基-1,3,4,6,7,12b-六氫-2H-[1]苯并呋喃并[2,3-a]喹嗪且其中該式(II)化合物係(3-氯-6-甲氧基吡啶-2-基)(3-{[2-(4-異丙基苯基)咪唑并[1,2-a]嘧啶-3-基]甲基}-3,8-二氮雜雙環[3.2.1]辛-8-基)甲酮。
- 如請求項1至6中任一項之組合,其用於治療及/或預防呼吸病症、睡眠相關性呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、神經退化性病症、神經發炎性病症及神經免疫性病症之方法中。
- 一種如請求項1至6中任一項之組合之用途,其用以產生用於治療及/或預防呼吸病症、睡眠相關性呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、神經退化性病症、神經發炎性病症及神經免疫性病症之藥劑。
- 一種藥劑,其包括如請求項1至6中任一項之組合與一或多種惰性、無毒、醫藥上適宜之賦形劑之組合。
- 一種藥劑,其包括如請求項1至6中任一項之組合與一或多種選自由以下組成之群之其他活性成分的組合:蕈毒鹼受體拮抗劑、鹽皮質激素受體拮抗劑、利尿劑、皮質類固醇。
- 如請求項9或10之藥劑,其用於治療及/或預防呼吸病症、睡眠相關性呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、神經退化性病症、神經發炎性病症及神經免疫性病症。
- 一種治療及/或預防人類及動物之呼吸病症、睡眠相關性呼吸病症、阻塞性睡眠呼吸中止症、中樞性睡眠呼吸中止症、打鼾、心律不整、神經退化性病症、神經發炎性病症及神經免疫性病症之方法,其係藉由投與有效量之至少一種如請求項1至4中任一項之組合或如請求項9至11中任一項之藥劑來達成。
- 如請求項8之用途,其中該睡眠相關性呼吸病症係阻塞性及中樞性睡眠呼吸中止症以及打鼾。
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