TW201512197A - 吡咯并吡啶或吡唑并吡啶衍生物 - Google Patents
吡咯并吡啶或吡唑并吡啶衍生物 Download PDFInfo
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- TW201512197A TW201512197A TW103129408A TW103129408A TW201512197A TW 201512197 A TW201512197 A TW 201512197A TW 103129408 A TW103129408 A TW 103129408A TW 103129408 A TW103129408 A TW 103129408A TW 201512197 A TW201512197 A TW 201512197A
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- Prior art keywords
- pyridine
- methyl
- pyrrolo
- benzyl
- fluoro
- Prior art date
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- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 title 1
- 150000005229 pyrazolopyridines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 109
- -1 cyano, phenyl Chemical group 0.000 claims abstract description 69
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 61
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 40
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 17
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 17
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 11
- 150000002367 halogens Chemical class 0.000 claims abstract description 9
- 208000028698 Cognitive impairment Diseases 0.000 claims abstract description 7
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 208000027520 Somatoform disease Diseases 0.000 claims abstract description 6
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 208000027753 pain disease Diseases 0.000 claims abstract description 6
- 208000019116 sleep disease Diseases 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 5
- 230000003287 optical effect Effects 0.000 claims abstract description 4
- HTKSECLBTOEFQD-UHFFFAOYSA-N FC1=C(CN2C=C(C3=NC=CC=C32)C(=O)O)C=CC(=C1)C=1C=NN(C1)C Chemical compound FC1=C(CN2C=C(C3=NC=CC=C32)C(=O)O)C=CC(=C1)C=1C=NN(C1)C HTKSECLBTOEFQD-UHFFFAOYSA-N 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 28
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 235000005152 nicotinamide Nutrition 0.000 claims description 11
- 239000011570 nicotinamide Substances 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- PQMCFTMVQORYJC-WDSKDSINSA-N (1s,2s)-2-aminocyclohexan-1-ol Chemical compound N[C@H]1CCCC[C@@H]1O PQMCFTMVQORYJC-WDSKDSINSA-N 0.000 claims description 3
- NGXJDZCYCQIPPU-RDJZCZTQSA-N 1-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]pyrrolo[3,2-b]pyridine-3-carboxamide Chemical compound ClC1=CC=C(C=N1)CN1C=C(C2=NC=CC=C21)C(=O)N[C@@H]1[C@H](CCCC1)O NGXJDZCYCQIPPU-RDJZCZTQSA-N 0.000 claims description 3
- IYPGNPVPGKHSSI-UHFFFAOYSA-N 1-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]-N-(2-hydroxy-2-methylcyclohexyl)pyrrolo[3,2-b]pyridine-3-carboxamide Chemical compound FC1=C(CN2C=C(C3=NC=CC=C32)C(=O)NC2C(CCCC2)(C)O)C=CC(=C1)C=1C=NN(C=1)C IYPGNPVPGKHSSI-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- PZVWPEIFLVAEAV-UHFFFAOYSA-N Cn1cc(cn1)-c1ccc(Cn2cc(C(=O)NC3CCOCC3O)c3ncccc23)cn1 Chemical compound Cn1cc(cn1)-c1ccc(Cn2cc(C(=O)NC3CCOCC3O)c3ncccc23)cn1 PZVWPEIFLVAEAV-UHFFFAOYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- ARXNYUWFHDFBSN-IFMALSPDSA-N FC1=C(CN2C=C(C3=NC=CC=C32)C(=O)N[C@@H]2COCC[C@H]2O)C=CC(=C1)C=1C=NN(C=1)C Chemical compound FC1=C(CN2C=C(C3=NC=CC=C32)C(=O)N[C@@H]2COCC[C@H]2O)C=CC(=C1)C=1C=NN(C=1)C ARXNYUWFHDFBSN-IFMALSPDSA-N 0.000 claims description 2
- QYGIGBVQQKRBFA-ICSRJNTNSA-N FC=1C=C(CN2C=C(C3=NC=CC=C32)C(=O)N[C@@H]2[C@H](CCCC2)O)C=CC=1C Chemical compound FC=1C=C(CN2C=C(C3=NC=CC=C32)C(=O)N[C@@H]2[C@H](CCCC2)O)C=CC=1C QYGIGBVQQKRBFA-ICSRJNTNSA-N 0.000 claims description 2
- WZJGOLWNRSXEIM-GMAHTHKFSA-N O[C@@H]1[C@H](CCCC1)NC(=O)C1=CN(C=2C1=NC=CC=2)CC1=CC(=CC=C1)C=1C=NN(C=1)C Chemical compound O[C@@H]1[C@H](CCCC1)NC(=O)C1=CN(C=2C1=NC=CC=2)CC1=CC(=CC=C1)C=1C=NN(C=1)C WZJGOLWNRSXEIM-GMAHTHKFSA-N 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- GHLITDDQOMIBFS-UHFFFAOYSA-H cerium(3+);tricarbonate Chemical compound [Ce+3].[Ce+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O GHLITDDQOMIBFS-UHFFFAOYSA-H 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 2
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- 239000011664 nicotinic acid Substances 0.000 claims 2
- HTNOSEJBESHNND-UNMCSNQZSA-N Cn1cc(cn1)-c1ccc(Cn2cc(C(=O)N[C@H]3CCCC[C@@H]3O)c3ncccc23)cn1 Chemical compound Cn1cc(cn1)-c1ccc(Cn2cc(C(=O)N[C@H]3CCCC[C@@H]3O)c3ncccc23)cn1 HTNOSEJBESHNND-UNMCSNQZSA-N 0.000 claims 1
- DCDZENLPBPSVBL-UHFFFAOYSA-N FC1=C(CN2C=C(C3=NC=CC=C32)C(=O)NCC3(CC3)O)C=CC(=C1)C=1C=NN(C1)C Chemical compound FC1=C(CN2C=C(C3=NC=CC=C32)C(=O)NCC3(CC3)O)C=CC(=C1)C=1C=NN(C1)C DCDZENLPBPSVBL-UHFFFAOYSA-N 0.000 claims 1
- LKHOWSWHCJVABM-FPOVZHCZSA-N FC1=C(CN2N=C(C3=NC=CC=C32)C(=O)N[C@@H]2[C@H](CCCC2)O)C=CC(=C1)C=1C=NN(C=1)C Chemical compound FC1=C(CN2N=C(C3=NC=CC=C32)C(=O)N[C@@H]2[C@H](CCCC2)O)C=CC(=C1)C=1C=NN(C=1)C LKHOWSWHCJVABM-FPOVZHCZSA-N 0.000 claims 1
- YCWDQUXMRHWDMX-UHFFFAOYSA-N N-(2-fluorocyclohexyl)-1-[[2-fluoro-4-(1-methylpyrazol-4-yl)phenyl]methyl]pyrrolo[3,2-b]pyridine-3-carboxamide Chemical compound FC1=C(CN2C=C(C3=NC=CC=C32)C(=O)NC2C(CCCC2)F)C=CC(=C1)C=1C=NN(C=1)C YCWDQUXMRHWDMX-UHFFFAOYSA-N 0.000 claims 1
- ICRDIACDNOZOII-FPOVZHCZSA-N O[C@@H]1[C@H](CCCC1)NC(=O)C1=CN(C=2C1=NC=CC2)CC2=CC=C(C=C2)C=2SC=CN2 Chemical compound O[C@@H]1[C@H](CCCC1)NC(=O)C1=CN(C=2C1=NC=CC2)CC2=CC=C(C=C2)C=2SC=CN2 ICRDIACDNOZOII-FPOVZHCZSA-N 0.000 claims 1
- YJDBWBNVHMDFHU-RXVVDRJESA-N O[C@@H]1[C@H](CCCC1)NC(=O)C1=CN(C=2C1=NC=CC2)CC=2C=C1C=NN(C1=CC2)C Chemical compound O[C@@H]1[C@H](CCCC1)NC(=O)C1=CN(C=2C1=NC=CC2)CC=2C=C1C=NN(C1=CC2)C YJDBWBNVHMDFHU-RXVVDRJESA-N 0.000 claims 1
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
本發明係關於如下式之化合物，
□其中：R1係鹵素、低碳數烷基、低碳數烷氧基、氰基、苯基、C(O)NHCH3、C(O)NH2、經鹵素取代之低碳數烷基或為視情況經低碳數烷基取代之五員雜芳基；Y1係N或CH；Y2係CH；且若Y1為CH，則Y1及Y2可與其等所附接之C原子一起形成包含-CH=N-N(CH3)-、-CH=N-N(H)-之環。
X係CH或N；R係(CH2)m-環烷基，視情況經羥基、低碳數烷氧基或低碳數烷基取代，或為四氫吡喃，視情況經羥基取代，或為低碳數烷氧基，經羥基取代，或為經一個或兩個羥基取代之低碳數烷基，或為
(CH2)m-吡啶基，視情況經羥基、低碳數烷基或經羥基取代之低碳數烷基取代，或為L-苯基，視情況經羥基、低碳數烷基或經羥基取代之低碳數烷基取代，及：L係鍵、-CH(CH2OH)-或-CH2CH(OH)-；n係0、1或2；m係0或1；或其醫藥上可接受之酸加成鹽、外消旋混合物或其相應的對映異構體及/或其光學異構體。
本發明之化合物為毒蕈鹼M1受體正異位調節劑(PAM)且因此可用於治療由毒蕈鹼M1受體介導之疾病，諸如阿茲海默氏病(Alzheimer's disease)、認知損傷、精神分裂症、疼痛或睡眠障礙。
Description
本發明係關於如下通式之化合物，
其中：R1係鹵素、低碳數烷基、低碳數烷氧基、氰基、苯基、C(O)NHCH3、C(O)NH2、經鹵素取代之低碳數烷基或為視情況經低碳數烷基取代之五員雜芳基；Y1係N或CH；Y2係CH；且若Y1為CH，Y1及Y2可與其等所附接之C原子一起形成包含-CH=N-N(CH3)-、-CH=N-N(H)-之環。
X係CH或N；R係(CH2)m-環烷基，視情況經羥基、低碳數烷氧基或低碳數烷基取代，或為四氫吡喃，視情況經羥基取代，或為低碳數烷氧基，經羥基取代，或為經一個或兩個羥基取代之低碳數烷基，或為(CH2)m-吡啶基，視情況經羥基、低碳數烷基或經羥基取代之低碳數烷基取代，或為L-苯基，視情況經羥基、低碳數烷基或經羥基取代之
低碳數烷基取代，及：L係鍵、-CH(CH2OH)-或-CH2CH(OH)-；n係0、1或2；m係0或1；或其醫藥上可接受之酸加成鹽、外消旋混合物或其相應的對映異構體及/或其光學異構體。
本發明之化合物為毒蕈鹼M1受體正異位調節劑(PAM)且因此可用於治療由毒蕈鹼M1受體介導之疾病，諸如阿茲海默氏病(Alzheimer's disease)、認知損傷、精神分裂症、疼痛或睡眠障礙。
乙醯膽鹼(ACh)為激活CNS中及外周中之菸鹼(配體閘控之離子通道)及毒蕈鹼(代謝型)受體之神經傳遞素。
毒蕈鹼受體(mAChR)為A類G蛋白偶聯受體之成員。迄今為止，已有5種不同子類型之mAChR(M1至M5)經選殖及定序。毒蕈鹼M1受體主要分佈在大腦中，在皮層、丘腦、紋狀體及海馬體中有最高表現。在臨床研究中，呫諾美林(Xanomeline)(一種M1/M4優先激動劑)對精神分裂症患者之陽性、陰性及認知症狀展現強大功效並改善認知得分及減小罹患阿茲海默氏病(AD)患者之精神病類似行為。M1受體已與記憶及學習過程，多巴胺及NMDA受體活性之調節有牽連及因此被提出可作為用於治療AD及精神分裂症之潛在標靶。
AD係晚年癡呆最常見原因。病理學上，AD之特徵為類澱粉以細胞外斑塊及細胞內神經元纖維纏結沉積於大腦中。類澱粉斑塊主要由起源自藉由一系列蛋白質水解裂解步驟的β-類澱粉前驅蛋白質(APP)之類澱粉肽(Abeta肽)組成。現已識別APP之若干種形式，其中最大量為695、751及770個胺基酸長度之蛋白質。其全部自單基因經差異剪接產生。Abeta肽起源自APP之相同結構域但在其N-及C-端不同，主要種類藉由β-類澱粉蛋白質裂解酶處理β-類澱粉前驅蛋白質(APP)具
有40及42個胺基酸長度。該處理導致大腦中Abeta之積聚。
M1受體以突觸後方式大量地表現於為涉及認知之重要大腦區域的皮層、海馬體及紋狀體。基於膽鹼能假設(即海馬體及皮層區域中突觸前膽鹼能神經末端退化)，M1活化應減緩AD中出現之認知缺陷，因此提供此神經退化性病症之症狀治療。AD皮層組織之死後研究已證明M1受體之表現未減低，因此為在皮層大腦區域中之標靶可用性提供證據。此外，臨床前研究已證明M1活化藉由改變APP處理朝向非類澱粉蛋白α-分泌酶路徑及減低tau蛋白過度磷酸化而具有作為針對AD之疾病改良療法之潛力。因此，M1 PAM提供一種靶向AD之症狀及疾病改良治療之方法。
精神分裂症係一種嚴重、致殘、終生病症，其影響1%之人口且特徵為陽性症狀(諸如幻覺、錯覺及妄想)、陰性症狀(諸如社會退縮及冷漠)及認知損傷(例如工作記憶、執行功能及注意力缺陷)。精神分裂症係一種具有遺傳風險因素及神經病理學變化之神經發育病症。異常活性發生於精神分裂症患者之大腦中前額-海馬體-丘腦網路中。精神分裂症之陽性症狀被表明由多巴胺系統功能障礙，尤其係皮層下大腦區域諸如紋狀體之多巴胺活性增強引起。陰性症狀之發生被認為係歸因於腹側被蓋區及腹側紋狀體之神經電路中削弱之信號傳導。在椎體神經元中減低之NMDA受體功能結合在重要區域(諸如前額葉皮質)中次佳之多巴胺釋放可係一些認知缺陷的原因。
M1受體位於精神分裂症受影響之區域，諸如海馬體、皮層及紋狀體，尤其係在中型棘狀神經元中。若干報告顯示在精神分裂症患者之子集中，M1密集表現之區域，前額皮層及海馬體中減低之毒蕈鹼受體。此外，臨床前研究顯示M1基因剔除小鼠具有增强之安非他命(amphetamine)誘導之活性及增強之紋狀體多巴胺含量。電生理學研究已揭示M1受體之活化增強NMDA介導之海馬體活性，調節中型棘狀
神經元之活性及增強內側前額葉皮層神經元之活性。總言之，M1受體之活化應調節基礎神經電路中功能失調之多巴胺能及谷胺酸能信號傳導，從而導致改進精神分裂症之症狀。
然而，呫諾美林及其他毒蕈鹼M1激動劑之臨床作用總是與歸因於其不足之M1毒蕈鹼受體子類型選擇性之不良作用相關聯。典型觀測到之副作用(包括出汗、流涎、腸胃痛及心搏徐緩)歸因於外周M2及M3 mAChR之非特異性活化。儘管有來自許多公司的巨大努力，但是針對高M1選擇性激動劑之研究已失敗，此係因為在其原立體乙醯膽鹼配體結合位點之毒蕈鹼受體子類型之間的高度守恆。為了規避與靶向高守恆性之原立體ACh位點相關聯之選擇性及安全問題，一備選方法在於開發在較低高守恆性之異位結合位點起作用之M1 PAM。
目前，據默克及范德比爾特大學報告，來自不同化學等級之M1 PAM合理地展現良好程度之M1子類型選擇性。重要地，與呫諾美林及其他無選擇性M1激動劑之臨床前特性類似，該等M1異位劑展現促認知作用(在小鼠、莨菪鹼削弱之非人類靈長動物及轉殖基因AD小鼠之莨菪鹼引起之記憶缺陷)。已顯示，PQCA及ML169促進非類澱粉蛋白APP處理。電生理學研究已顯示M1 PAM加強在內側前額葉皮質及中型棘狀神經元中之卡巴可(carbachol)引起之活性。此外，與無選擇性激動劑不同，M1 PAM不顯示產生副作用，諸如以治療上有效劑量之流涎症。此外，它們預期缺乏不利因素，諸如先前針對原立體受體激動劑所報導之慢性投與後之受體脫敏化/內部化。簡言之，藉由以真正選擇性方式活化M1受體的該PAM方法係一種遞送用於治療精神分裂症(陽性、陰性及認知症狀)及AD(症狀及疾病改良)之有效及安全治療劑的有前景之新穎策略。
因此，咸信本發明之化合物(為毒蕈鹼M1受體正異位調節劑)可用於治療阿茲海默氏病及由毒蕈鹼M1受體介導之其他疾病而無副作
用。
因此，本發明之目標係識別為毒蕈鹼M1受體正異位調節劑之化合物。現已發現，式I之化合物在此領域有活性且因此其可用於治療阿茲海默氏病、認知損傷、精神分裂症、疼痛或睡眠障礙。
本發明係關於式I之化合物及其醫藥上可接受之鹽、作為醫藥上活性物質之該等化合物、其製備方法及其於治療或預防與毒蕈鹼M1受體正異位調節劑有關之病症之用途及含有式I之化合物之醫藥組合物。
用於本發明描述之一般術語之以下定義適用，不論所討論之術語是單獨出現或組合出現。
如本文使用，術語「低碳數烷基」表示包括具有1至7個碳原子之直鏈或分支鏈碳鏈的飽和，即脂族烴基。「烷基」之實例為甲基、乙基、正丙基、異丙基、正丁基、異丁基、2-丁基、第三丁基及類似者。具有1至4個碳原子之烷基較佳。
如本文使用，術語「環烷基」表示包含3至6個碳環原子之飽和碳環，例如環丙基、環丁基、環戊基或環己基。
術語「烷氧基」表示基團-O-R’，其中R’係如上定義之低碳數烷基。
術語「鹵素」表示氯、溴、氟或碘。
術語「經鹵素取代之低碳數烷基」表示其中至少一個氫原子經鹵素置換之如上定義之烷基，例如CF3、CH2F、CH2CF3、CH2CH2CF3、CH2CF2CF3及類似者。
術語「經羥基取代之低碳數烷基」表示其中至少一個氫原子經羥基置換之如上定義之烷基，例如CH2OH、CH2CH2OH、C(CH3)2OH、CH(CH3)CH2OH、CH2CH(OH)CH3、CH2C(OH)(CH3)2、CH(CH2CH3)CH2OH、CH2(CH2OH)C(CH3)3、
CH(CH2OH)CH(CH3)CH2CH3、CH2CH(OH)CH2CH3、CH2CH(OH)CH2OH、CH(CH2OH)CH(CH3)2、CH(CH2OH)CH2CH2CH3、CH(CH2OH)CH2CH(CH3)2及類似者。
術語「五員雜芳基」表示含有至少一N、S或O原子之具有5個環原子之芳族環，例如噻唑基或吡唑基。
術語「雜芳基」表示具有6個環原子之六員芳族環，例如吡啶基，其中環N原子可在不同位置。
術語「醫藥上可接受之鹽」或「醫藥上可接受之酸加成鹽」包括無機酸及有機酸之鹽，諸如鹽酸、硝酸、硫酸、磷酸、檸檬酸、甲酸、富馬酸、馬來酸、乙酸、琥珀酸、酒石酸、甲磺酸、對甲苯磺酸及類似者。
本發明之一實施例為式I-A之化合物，
其中R1係吡唑基或噻唑基，其可視情況經低碳數烷基取代及R係(CH2)m-環烷基，其可視情況經羥基、低碳數烷氧基或低碳數烷基取代，及n與m係如上所述，例如以下化合物：
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1R,2R)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-
3-羧酸[(1R,2R)-2-羥基-環戊基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(1S,2S)-2-羥基-環戊基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(1S,2R)-2-羥基-環戊基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(1-羥基-環戊基甲基)-醯胺
N-環己基-1-(2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1SR,2RS)-2羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(1S,2S)-2-甲氧基-環己基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1SR,2SR)-2-羥基-2-甲基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1SR,2RS)-2-羥基-2-甲基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
N-[(1S,2S)-2-羥基環己基]-1-[3-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
N-[(1S,2S)-2-羥基環己基]-1-[4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1SR,2SR)-2-氟環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
N-[(1S,2S)-2-羥基環己基]-1-[4-(噻唑-2-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1-羥基環丙基)甲
基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
本發明之另一實施例為式I-A之化合物，其中R1係鹵素、低碳數烷基、低碳數烷氧基、氰基、苯基、C(O)NHCH3、C(O)NH2、經鹵素取代之低碳數烷基及R係視情況經羥基、低碳數烷氧基或低碳數烷基取代之(CH2)m-環烷基或係視情況經羥基取代之四氫吡喃，及n與m係如上所述，例如以下化合物：
1-(5-溴-2-氟苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2b]吡啶-3-甲醯胺及(1S,2S)-2-胺基環己醇
N-[(1S,2S)-2-羥基環己基]-1-(4-甲基苯甲基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-(3-氟-4-甲氧基苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-(4-氰苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-(3-氟-4-甲基苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
N-[(1S,2S)-2-羥基環己基]-1-(4-甲氧基苯甲基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-(聯苯-4-基甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-(4-溴苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-(4-氰基-2-氟苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-(4-氯苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
N-[(1S,2S)-2-羥基環己基]-1-[4-(甲基胺甲醯)苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-(4-胺基甲醯苯甲基)-N-[(3S,4R)-3-羥基四氫-2H-吡喃-4-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或1-(4-胺基甲醯苯甲基)-N-[(3R,4S)-3-羥基四氫-2H-吡喃-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
本發明之另一實施例為式I-A之化合物，其中R1係視情況經低碳數烷基取代的吡唑基及R係視情況經羥基取代的四氫吡喃，及n與m係如上所述，例如以下化合物：
1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-N-[(3RS,4SR)-3-羥基四氫-2H-吡喃-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
1-{[2-氟-4-(1-甲基吡唑-4-基)苯基]甲基}-N-[(3S,4S)-4-羥基oxan-3-基]吡咯并[3,2-b]吡啶-3-甲醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(3R,4R)-4-羥基四氫-2H-吡喃-3-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或1-{[2-氟-4-(1-甲基吡唑-4-基)苯基]甲基}-N-[(3R,4S)或(3S,4R)-3-羥基氧雜環己烷-4-基]吡咯并[3,2-b]吡啶-3-甲醯胺。
本發明之一實施例為式I-A之化合物，其中R1係吡唑基，視情況經低碳數烷基取代及R係低碳數烷氧基，經羥基、經一個或兩個羥基取代之低碳數烷基取代，或係(CH2)m-吡啶基，視情況經羥基、低碳數烷基或經羥基取代之低碳數烷基取代，或係L-苯基，視情況經羥基、低碳數烷基或經羥基取代之低碳數烷基取代，且L係鍵、-CH(CH2OH)-或-CH2CH(OH)-，及n與m係如上所述，例如以下化合物：
外消旋-1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基-3-甲氧基-丙基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-2-羥基-1-甲基-乙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(R)-2-羥基-丙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-2-羥基-丙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基-2-甲基-丙基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-丙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(1-羥基甲基-丙基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基-丁基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(R)-2,3-二羥基-丙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-2-甲基-丙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(1-羥基甲基-丁基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(R)-1-羥基甲基-2-甲基-丙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(1-羥基甲基-2-甲基-丙基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-丁基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-3-甲基-丁基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(1S,2S)-1-羥基甲基-2-甲基-丁基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-2,2-二甲基-丙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基甲基-苯基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(3-羥基甲基-吡啶-2-基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基-2-苯基-乙基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-2-羥基-1-苯基-乙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基甲基-4-甲基-苯基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-2-羥基-2-苯基-乙基]-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(3-甲基-吡啶-2-基)-醯胺
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(3-羥基-吡啶-2-基)-醯胺或1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1-羥基環丙基)甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
本發明之一實施例為式I-B之化合物，
其中R、R1及n係如上所定義，例如以下化合物：
1-[(6-氯吡啶-3-基)甲基]-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
N-[(1S,2S)-2-羥基環己基]-1-{[6-(三氟甲基)吡啶-3-基]甲基}-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
N-[(1S,2S)-2-羥基環己基]-1-{[6-(1-甲基-1H-吡唑-4-基)吡啶-3-基]甲基}-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或N-[(3RS,4SR)-3-羥基四氫-2H-吡喃-4-基]-1-{[6-(1-甲基-1H-吡唑-4-基)吡啶-3-基]甲基}-1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
本發明之另一實施例為式I-C之化合物，
其中R、R1及n係如上所定義，例如以下化合物：
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1S,2S)-2-羥基環己基]-1H-吡唑并[4,3-b]吡啶-3-甲醯胺。
本發明之一實施例為式I-D之化合物，
其中R、R1及n係如上所定義及R’係氫或低碳數烷基，例如以下化合物：
N-[(1S,2S)-2-羥基環己基]-1-[(1-甲基-1H-吲唑-5-基)甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或N-[(1S,2S)-2-羥基環己基]-1-[4-(甲基胺甲醯基)苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
本發明之式I之化合物及其醫藥上可接受之鹽可藉由相關技術已知之方法，例如，藉由以下描述之方法製備，該方法包括：a)使下式之化合物，
與下式之化合物，RNH2
在活化劑諸如BOP六氟磷酸(苯并三唑-1-基氧基)三(二甲胺基)鏻或亞硫醯氯之存在下，反應以生成下式之化合物：
其中取代基係如上所定義，或b)使下式之化合物，
與下式之化合物，
在例如碳酸銫之鹼之存在下反應以生成下式之化合物：
其中Hal係鹵素及其他取代基係如上所定義。
式I之化合物可依照方法變型a)或b)及以下流程圖1至2製備。起始物質可購得或可依照已知方法製備。
流程圖1
通式I之化合物可藉由使式IV之酯衍生物與烷基化劑在鹼諸如氫化鈉之存在下反應以獲得V，隨後V在鹼諸如氫氧化鋰之存在下皂化，及將所得酸II與胺RNH2偶合而製得。
通式I之化合物可藉由將式VI之酸衍生物與胺RNH2偶合以獲得醯胺III，隨後III與烷基化劑在鹼諸如碳酸銫之存在下反應而製得。
一些取代基R1可源自在反應順序結束之另一前驅物取代基。例如，式I之化合物可經合成為攜帶酯基如R1，該酯基藉由標準程序轉化為甲醯胺取代基。
通常於合適溶劑及在氬氣或氮氣之氛圍下實施所有反應。
因其製法未描述於實例中，式(I)之化合物及所有中間產物可依照類似之方法或依照上述之方法製備。起始物質可購得且已為相關技術已知或可藉由相關技術習知之方法或其類似之方法製得。
化合物之單離及純化
本文描述之化合物及中間產物之單離及純化如有需要可藉由任何合適之分離或純化程序(諸如例如過濾、萃取、結晶、管柱層析、薄層層析、厚層層析、製備型低壓或高壓液相層析或該等程序之組合)實現。合適之分離及單離程序之具體說明可參考以下本文製法及實例而得到。然而，當然亦可使用其他相當之分離或單離程序。
式I之化合物之鹽
式I之化合物為鹼性並可被轉化為對應之酸加成鹽。該轉化係藉由以至少化學計量量之合適之酸(諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸及類似者)，及有機酸(諸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、蘋果酸、丙二酸、琥珀酸、馬來酸、富馬酸、酒石酸、檸檬酸、安息香酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、對甲苯磺酸、水楊酸及類似者)之處理而達成。典型地，將游離鹼溶解於惰性有機溶劑諸如乙醚、乙酸乙酯、氯仿、乙醇或甲醇及類似者，且在相似之溶劑中加入酸。溫度保持在0℃與50℃之間。所得鹽自發地沉澱出或用極性較小之溶劑從溶液中帶出。
式I之鹼性化合物之酸加成鹽可藉由用至少化學計量相等之合適
之鹼(諸如氫氧化鈉或氫氧化鉀、碳酸鉀、碳酸氫鈉、氨及類似者)處理而被轉化為對應之游離鹼。
式I之化合物及其醫藥上可用之加成鹽具有有價值之醫藥性質。明確言之，已發現本發明之化合物具有作為神經源性藥物之活性。
依照下文給出之測試研究該等化合物。
M1 PAM分析
該分析經設計為藉由用螢光成像板閱讀器系統(FLIPR，Molecular Devices)測量細胞內鈣以選擇具有在CHO細胞中表現之乙醯膽鹼毒蕈鹼受體之調節活性之化合物。該分析使用FLIPR研究若干種濃度之測試化合物對基礎或經乙醯膽鹼刺激之Ca2+水平之影響。
在實驗開始前一日，將CHO人類M1以2 x 105細胞/ml置於PDL BioCoat 96孔黑/透明板(Becton 35 4640)中。細胞於37℃及5% CO2下於以下培養基中生長：F12 Nut Mix(Gibco 21765)、10%熱滅活FCS(GIBCO 16000-044)、1% Pen Strep(Gibco,15140)及200μg/ml Geneticin(Gibco 11811)。在實驗當日，移除培養基並用含有漢克平衡鹽溶液(HBSS，14065-049，Gibco)及20mM HEPES(Gibco 15630-056)、2mM丙磺舒(Probenicid)(Sigma P8761)、2mM Fluo-4AM酯(Molecular Probes F-14202)、10%普朗尼克酸(Molecular Probes P-3000)pH=7.4之100μl染料負載緩衝劑替換並在37℃下培養。60分鐘後，移除細胞外染料，用含有在37℃下預熱之HBSS(Gibco 14065-049)及20mM HEPES(Gibco,15630-056)、2mM丙磺舒(Sigma P8761)之FLIPR緩衝劑及使用Ebml細胞清洗器洗滌細胞五次，在每個孔中留有100μl FLIPR緩衝劑。將細胞板及稀釋化合物(1% DMSO最終濃度)置於FLIPR之平臺上且門關閉。實施檢查背景螢光及基礎螢光信號的信號測試。若需要則調整雷射強度。提供用稀釋之測試化合物預培育兩分鐘，以藉由與30nM乙醯膽鹼對照之比較來測定對M1受體之任
何激動劑活性。為了測定任何調節劑活性，向細胞中加入稀釋之化合物，且在預培育兩分鐘後，加入EC20之乙醯膽鹼，隨後在用FLIPR(Molecular Devices)測量細胞內Ca2+之前再預培育兩分鐘。
61種式(I)之化合物及其醫藥上可接受之鹽可用作藥物，例如以醫藥製劑之形式。醫藥製劑可經口投與，例如以錠劑、包衣錠劑、糖衣片、硬及軟明膠膠囊、溶液、乳液或懸浮液之形式。然而，投藥亦可經直腸達成，例如以栓劑之形式，或非經腸達成，例如以注射溶液之形式。
因此，式I之化合物及其醫藥上可接受之鹽可與醫藥上惰性的無機或有機載劑一起加工以製備醫藥製劑。乳糖、玉米澱粉或其衍生物、滑石、硬脂酸或其鹽及類似者可被用作例如錠劑、包衣錠劑、糖衣片及硬明膠膠囊之該等載劑。合適的軟明膠膠囊載劑為例如植物油、蠟、脂肪、半固體及液體多元醇及類似者，此取決於活性物質之性質，但在軟明膠膠囊的情況中一般不需要任何載劑。用於製備溶液及糖漿之合適的載劑為例如水、多元醇、蔗糖、轉化糖、葡萄糖及類似者。佐劑(諸如醇、多元醇、甘油、植物油及類似者)可用於式(I)之化合物之水溶性鹽之注射水溶液，但通常不必要。用於栓劑之合適的載劑為例如天然或硬化油、蠟、脂肪、半液體或液體多元醇及類似者。
此外，醫藥製劑可包含防腐劑、增溶劑、穩定劑、潤濕劑、乳
化劑、甜味劑、著色劑、矯味劑、改變滲透壓之鹽、緩衝劑、掩蔽劑或抗氧化劑。其亦可包含其他治療上有價值之物質。
如之前所提及，包含式(I)之化合物或其醫藥上可接受之鹽及治療上惰性之賦形劑之藥物亦係本發明之一目標，正如一種製備該等藥物之方法，該方法包括使一或多種式(I)之化合物或其醫藥上可接受之鹽與如有需要的一或多種其他治療上有價值之物質及一或多種治療上惰性載劑一起形成蓋倫劑型。
如之前所進一步提及，式(I)之化合物於製備用於預防及/或治療上述疾病之藥物的用途亦為本發明之一目標。
劑量可在寬泛限制中變化，當然亦將適於每個特定情況中的個別需求。一般而言，對於所有所述適應症而言，口服或非經腸投與的有效劑量在0.01至20mg/kg/天之間，以0.1至10mg/kg/天為較佳。70kg體重成人的日劑量相應地位於0.7至1400mg/天之間，較佳地位於7至700mg/天之間。
包含本發明之化合物之醫藥组合物：
錠劑調配物(濕法製粒)
製造程序
1．混合項目1、2、3及4並用純化水造粒。
2．在50℃下乾燥顆粒。
3．使顆粒通過合適的研磨設備。
4．加入項目5並混合3分鐘；在合適的壓製機上壓製。
膠囊調配物
製造程序
1．於合適的混合器中混合項目1、2及3達30分鐘。
2．加入項目4及5並混合3分鐘。
3．填充於合適的膠囊中。
實驗部分
中間產物之製備
實例A.1
1-(5-溴-2-氟苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸之製備
a)步驟1：1-(5-溴-2-氟苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸甲酯
於0℃在氮氣下，向含於DMF(20ml)中之1H-吡咯并[3,2-b]吡啶-3-羧酸甲酯(200mg，1.14mmol)溶液中加入氫化鈉(90.8mg，2.27mmol)。用力攪拌反應混合物30分鐘。加入4-溴-2-(溴甲基)-1-氟苯(335mg，1.25mmol)。允許歷時3小時加熱反應混合物至室溫並用水(20ml)淬滅。用乙酸乙酯(3 x 26ml)萃取水相。經硫酸鈉乾燥合併之有機相並濃縮。用利用自正庚烷及乙酸乙酯構成之梯度(0至70%)洗脫之在矽(10g)上之急驟管柱層析純化粗黃色油，以獲得39mg(產率：9.46%)呈黃色油之標題化合物。
b)步驟2：1-(5-溴-2-氟苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸
向含於四氫吡喃(380μl)、甲醇(190μl)及水(190μl)中之1-(5-溴-2-氟苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸甲酯(38mg，105μmol)溶液中加入一水合氫氧化鋰(13.2mg，314μmol)。在室溫下攪拌混合物24小時，在冰浴中冷卻並用HCl 5N(80ul)酸化。用水稀釋懸浮液。固體經過濾、用水洗滌並乾燥以獲得23mg(產率：63%)呈白色固體之標題化合物。MS(m/e)：349.3(M+H)
實例A.2
1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸之製備
a)步驟1：1-(4-溴-2-氟苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸甲酯
與針對合成實例A.1(步驟：1)描述之程序類似，從1H-吡咯并[3,2-b]吡啶-3-羧酸甲酯及4-溴-1-(溴甲基)-2-氟苯製得標題化合物。MS(m/e)：363(M+H+)。
b)步驟2：1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸甲酯
向含於水(250μl)中之磷酸三鉀(29.2mg，138μmol)溶液中加入1-(4-溴-2-氟苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸甲酯(50mg，138μmol)、二噁烷(500μl)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環己烷-2-基)-1H-吡唑(35.4mg，165μmol)、Pd2(dba)3(1.3mg，1.38μmol)及三環己基膦(995μg，3.44μmol)。在微波下照射下，於140℃下加熱混合物30分鐘。用水及乙酸乙酯稀釋混合物。分離有機相並用乙酸乙酯萃取水相一次。經硫酸鈉乾燥合併之有機相，過濾並在真空中濃縮。在利用自正庚烷及乙酸乙酯構成之梯度(0至100%)洗脫之矽上純化粗物質，以獲得37mg(74%)呈白色固體之標題化合物。MS(m/e)：365.5(M+H)+。
c)步驟3：1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸
與針對合成實例A.1(步驟：2)描述之程序類似，從1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸甲酯製得標題化合物。MS(m/e)：351.5(M+H)+。
實例A.3
1-[(6-氯吡啶-3-基)甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸鹽酸鹽之製備
與針對合成實例A.1(步驟：1-2)描述之程序類似，從1H-吡咯并[3,2-b]吡啶-3-羧酸甲酯及5-(溴甲基)-2-氯吡啶並隨後用氫氧化鋰處理而製得標題化合物。MS(m/e)：288.4(M+H)+。
實例A.4
1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-1H-吡咯并[3,2-b]吡啶-3-甲醯氯鹽酸鹽之製備
於室溫在氮氣下，向含於二氯乙烷(5.00ml)中之1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸(實例A2)(500mg，1.43mmol)溶液中加入1滴N,N-二甲基甲醯胺，隨後逐滴加入草醯氯(555mg，375μl，4.28mmol)。在50℃油浴下攪拌反應混合物5.5小時。蒸發混合物至乾燥以獲得581mg(100%)呈灰白色固體之標題化合物。
實例A.5
1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-1H-吡咯并[4,3-b]吡啶-3-羧酸鹽酸鹽之製備
a)步驟1：(2-氟-4-(1-甲基-1H-吡唑-4-基)苯基)甲醇
向含於二噁烷(104ml)中之(4-溴-2-氟苯基)甲醇(7.3g，34.9mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環己烷-2-基)-1H-吡唑(15.1g，71.3mmol)及1,1'-雙(二苯基膦)二茂鐵-二氯化鈀(II)二氯甲烷錯合物(1.42g，1.74mmol)之混合物中加入水(83.4ml)及2M碳酸鈉溶液(52.3ml，105mmol)。在80℃下加熱反應混合物，攪拌2.5小時，冷卻至室溫並經玻璃纖維紙過濾。用乙酸乙酯及水之混合物洗滌固體。用乙酸乙酯萃取濾液並用水洗滌有機相，經硫酸鎂乾燥並在真空中濃縮。在利用自正庚烷及乙酸乙酯構成之梯度(0至80%)洗脫之矽上純化粗物質，以獲得7.07g(98%)呈灰白色固體之標題化合物。MS(m/e)：207.5(M+H)+。
b)步驟2：4-[4-(氯甲基)-3-氟苯基]-1-甲基-1H-吡唑
將[2-氟-4-(1-甲基-1H-吡唑-4-基)苯基]甲醇(7.07g，34.3mmol)
以二氯甲烷(389ml)溶解於1L梨形燒瓶中並加入亞硫醯氯(8.16g，5.00ml，68.6mmol)。在40℃下加熱反應混合物並攪拌2.5小時。在真空中濃縮粗反應混合物並用乙醚萃取。用碳酸氫鈉飽和溶液洗滌有機相兩次，經硫酸鈉乾燥並在真空中濃縮以獲得7.7g(100%)呈灰白色固體之標題化合物。
c)步驟3：1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-1H-吡唑并[4,3-b]吡啶-3-羧酸鹽酸鹽
與針對合成實例A.1(步驟：1至2)描述之程序類似，從1H-吡唑并[4,3-b]吡啶-3-羧酸乙酯及4-[4-(氯甲基)-3-氟苯基]-1-甲基-1H-吡唑並隨後用氫氧化鋰處理而製得標題化合物。MS(m/e)：352.4(M+H)+。
實例A.6
N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
在100ml梨形燒瓶中，將1H-吡咯并[3,2-b]吡啶-3-羧酸(863mg，5.32mmol)、(1S,2S)-(+)-2-胺基環己醇鹽酸鹽(888mg，5.85mmol)及BOP(3.06g，6.92mmol)與二氯甲烷(31.9ml)及三乙胺(2.15g，2.97ml，21.3mmol)組合。在室溫下攪拌反應混合物整夜，用二氯甲烷萃取三次。用水洗滌有機相並在真空中濃縮。在利用自二氯甲烷及甲醇構成之梯度(0至10%)洗脫之矽上純化粗物質，以獲得0.86g(62%)呈白色固體之標題化合物。MS(m/e)：260.5(M+H)+。
實例A.7
N-四氫吡喃-4-基-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
向含於DMF(8ml)中之1H-吡咯并[3,2-b]吡啶-3-羧酸(0.4g，2.5mmol)、四氫-2H-吡喃-4-胺(274mg，281μl，2.7mmol)及BOP(1.42g，3.2mmol)之溶液中加入TEA(374mg，516μl，3.7mmol)。在25℃下攪拌所得混合物5小時。用水淬滅混合物並用乙酸乙酯萃取。用水及鹽水洗滌有機層，然後經硫酸鎂乾燥並濃縮以獲得無需進一步純化用於下一步驟中之粗產物。MS(m/e)：281.4(M+H)+。
實例A.8
N-[(3RS,4SR)-3-羥基四氫吡喃-4-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
用三乙胺(749mg，1.03ml，7.4mmol)處理含於二氯甲烷(11ml)中之1H-吡咯并[3,2-b]吡啶-3-羧酸(300mg，1.85mmol)、(3RS,4SR)-4-胺基四氫-2H-吡喃-3-醇鹽酸鹽(284mg，1.85mmol)及BOP(1.06g，2.41mmol)之溶液以獲得灰白色懸浮液。在室溫下攪拌反應混合物4小時。用二氯甲烷及EtOAc萃取反應混合物。用水及鹽水洗滌有機層，然後濃縮。藉由利用CH2Cl2/MeOH梯度作為洗脫液之急驟層析純化粗物質，以獲得呈無色固體之標題化合物(183mg，38%)。MS(m/e)：262.1(M+H)+。
實例之描述：
實例1
1-(5-溴-2-氟苯甲基)-N-((1S,2S)-2-羥基環己基)-1H-吡咯并[3,2b]吡啶-3-甲醯胺及(1S,2S)-2-胺基環己醇鹽酸鹽
向含於二氯甲烷(400μl)中之1-(5-溴-2-氟苯甲基)-1H-吡咯并[3,2-b]吡啶-3-羧酸(實例A.1)(21mg，60.1μmol)之懸浮液中加入(1S,2S)-2-胺基環己醇鹽酸鹽(10.9mg，72.2μmol)、六氟磷酸(苯并三唑-1-氧基)叁(二甲胺基)鏻(BOP)(34.6mg，78.2μmol)及三乙胺(24.3mg，33.5μl，241μmol)。在室溫下攪拌黃色溶液4小時。用二氯甲烷稀釋溶液並用水洗滌一次。分離水層並用二氯甲烷萃取兩次。經硫酸鈉乾燥合併之有機餾份，過濾並在真空中濃縮。在矽上利用自正庚烷及乙酸乙酯構成之梯度(0至100%)洗脫純化粗物質，以獲得17mg(63%)呈白色固體之標題化合物。MS(m/e)：448.4(M+H)+。
與實例1類似，下表之實例2至36係藉由將酸衍生物與胺偶合而製得。
實例37
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1SR,2RS)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
於室溫在氮氣下，向含於N,N-二甲基甲醯胺(1.00ml)中之1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-1H-吡咯并[3,2-b]吡啶-3-甲醯氯鹽酸鹽(實例A4)(100mg，247μmol)之懸浮液中加入三乙胺(99.9mg，137μl，987μmol)。5分鐘後，加入順-2-胺基環己醇鹽酸鹽(41.6mg，271μmol)並在室溫下攪拌反應混合物30分鐘。藉由製備型HPLC純化混合物。純產物在乙醚中結晶並乾燥以獲得49mg(產率：44.4%)呈白色固體之標題化合物。MS(m/e)：448.5(M+H)+。
與實例37類似，下表之化合物38至42係從1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯氯鹽酸鹽(實例A4)及胺衍生物製得：
實例43
N-[(1S,2S)-2-羥基環己基]-1-(4-甲基苯甲基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
在封閉管中，將N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺(實例A6)(30mg，116μmol)、1-(溴甲基)-4-甲苯(21.8mg，116μmol)及碳酸銫(37.7mg，116μmol)與DMA(700μl)組合。在室溫下攪拌反應混合物整夜，用水淬滅，用乙酸乙酯萃取。用水洗滌合併之有機層，經硫酸鎂乾燥並在真空中濃縮。HPLC純化獲得24mg(57%)呈淡黃色固體之標題化合物。MS(m/e)：364.5(M+H)+。
與實例43類似，下表之化合物44至55係藉由N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺(實例A6)與烷基化劑之反應而製得。
實例56
N-[(1S,2S)-2-羥基環己基]-1-{[6-(1-甲基-1H-吡唑-4-基)吡啶-3-基]甲基}-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
與針對合成實例A.2(步驟：2)描述之程序類似，從1-[(6-氯吡啶-3-基)甲基]-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺(實例5)及1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環己烷-2-基)-1H-吡唑製得標題化合物。MS(m/e)：431.6(M+H)+。
實例57
N-[(3RS,4SR)-3-羥基四氫-2H-吡喃-4-基]-1-{[6-(1-甲基-1H-吡唑-4-基)吡啶-3-基]甲基}-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
a)步驟1：1-((6-氯吡啶-3-基)甲基)-N-((3RS,4SR)-3-羥基四氫-2H-吡喃-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
與針對合成實例1描述之程序類似，從1-[(6-氯吡啶-3-基)甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸鹽酸鹽(實例A3)及(3RS,4SR)-4-胺基四氫-2H-吡喃-3-醇(CAS：215940-92-4)製得標題化合物。MS(m/e)：387.5(M+H)+。
a)步驟2：N-[(3RS,4SR)-3-羥基四氫-2H-吡喃-4-基]-1-{[6-(1-甲基-1H-吡唑-4-基)吡啶-3-基]甲基}-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
與針對合成實例A.2(步驟：2)描述之程序類似，從1-[(6-氯吡啶-3-基)甲基]-N-[(3RS,4SR)-3-羥基四氫-2H-吡喃-4-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺及1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環己烷-2-基)-1H-吡唑製得標題化合物。MS(m/e)：433.5(M+H)+。
實例58
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1SR,2SR)-2-氟環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
於0℃在氮氣下，向含於1,2-二氯乙烷(800μl)中之1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1SR,2RS)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺(實例37)(40mg，89.4μmol)之懸浮液中逐滴加入含於1,2-二氯乙烷(100μl)中之雙(2-甲氧基乙基)胺基三氟化硫(22.9mg，19.1μl，98.3μmol)之溶液。在0℃下攪拌澄清溶液2小時並允許其加熱至室溫。攪拌混合物2小時。在冰浴中冷卻澄清溶液並用飽和碳酸氫鈉溶液淬滅保持其溫度低於10℃。用水及二氯甲烷稀釋混合物。分離水層並用二氯甲烷萃取兩次。合併之有機層經硫酸鈉乾燥，過濾並在真空中濃縮。HPLC純化獲得3.2mg(產率：7.96%)呈白色固體之標題化合物。MS(m/e)：450.4(M+H)+。
實例59
1-{[2-氟-4-(1-甲基吡唑-4-基)苯基]甲基}-N-[(3R,4S)或(3S,4R)-3-羥基氧雜環己烷-4-基]吡咯并[3,2-b]吡啶-3-甲醯胺
標題化合物係藉由外消旋物：1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(3RS,4SR)-3-羥基四氫-2H-吡喃-4-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺(實例4)在Reprosil對掌性NR管柱上之對掌性HPLC分離而製
得，第二洗脫對映異構體，呈淡黃色固體。MS(m/e)：450.5(M+H)+。
實例60
N-[(1S,2S)-2-羥基環己基]-1-[4-(噻唑-2-基)苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
與實例43類似，藉由N-[(1S,2S)-2-羥基-環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺(實例A6)與2-[4-(氯甲基)苯基]噻唑反應而製得標題化合物。MS(m/e)：433.3(M+H)+。
實例61
N-[(1S,2S)-2-羥基環己基]-1-[4-(甲基胺甲醯)苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
步驟1：4-((3-((1S,2S)-2-羥基環己基胺基甲醯)-1H-吡咯并[3,2-b]吡啶-1-基)甲基)苯甲酸乙酯
與實例43類似，藉由N-[(1S,2S)-2-羥基-環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺(實例A6)與4-(溴甲基)-苯甲酸乙酯反應而製得標題化
合物。MS(m/e)：422.3(M+H)+。
步驟2：N-[(1S,2S)-2-羥基環己基]-1-[4-(甲基胺甲醯)苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
於室溫在氬氣氛圍下，向含於1,4-二噁烷(5ml)中之甲胺鹽酸鹽(27.9mg，413μmol)之經攪拌懸浮液中一次加入三甲基鋁(含於甲苯中之2M溶液；206μl，413μmol)。在室溫下攪拌2小時，一次加入4-((3-((1S,2S)-2-羥基環己基胺基甲醯)-1H-吡咯并[3,2-b]吡啶-1-基)甲基)苯甲酸乙酯(58mg，138μmol)。加熱混合物至100℃並攪拌整夜。冷卻混合物至室溫並用H2O(0.5ml)處理。在室溫下攪拌15分鐘後，加入MgSO4，并繼續在室溫下攪拌15分鐘。過濾混合物並用MeOH洗滌。濃縮濾液。藉由利用CH2Cl2/MeOH梯度作為洗脫液之矽膠層析純化粗產物以獲得呈灰白色固體之標題化合物(18mg，29%)。MS(m/e)：407.3(M+H)+。
實例62
N-[(1S,2S)-2-羥基環己基]-1-[4-(甲基胺甲醯)苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
與實例43中描述之程序類似，藉由N-(四氫-2H-吡喃-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺(實例A.7)與5-(溴甲基)-1H-吲唑氫溴酸鹽反應而製得標題化合物。灰白色固體。MS(m/e)：376.2(M+H)+。
實例63
1-(4-胺基甲醯苯甲基)-N-[(3S,4R)-3-羥基四氫-2H-吡喃-4-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺及1-(4-胺基甲醯苯甲基)-N-[(3R,4S)-3-羥基四氫-2H-吡喃-4-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
步驟1：1-(4-胺基甲醯苯甲基)-N-[(3RS,4SR)-3-羥基四氫-2H-吡喃-4-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺
與實例43類似，藉由N-[(3RS,4SR)-3-羥基四氫吡喃-4-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺(實例A.8)與4-(氯甲基)-苯甲醯胺(CAS 220875-88-7)反應而製得標題化合物。無色固體。MS(m/e)：422.3(M+H)+。
步驟2：1-(4-胺基甲醯苯甲基)-N-((3S,4R)-3-羥基四氫-2H-吡喃-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺63a及1-(4-胺基甲醯苯甲基)-N-((3R,4S)-3-羥基四氫-2H-吡喃-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺63b
與實例59類似，藉由外消旋物之對掌性分離而獲得標題化合物。灰白色固體，MS(m/e)：395.3(M+H)+及灰白色固體，MS(m/e)：395.2(M+H)+。
實例64
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1-羥基環丙基)甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
與實例1中描述之程序類似，藉由將中間產物A.2與吡啶-3-基甲胺偶合而獲得標題化合物。白色固體。MS(m/e)：441.2(M+H)+。
實例65
1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1-羥基環丙基)甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺之製備
與實例1中描述之程序類似，藉由將中間產物A.2與1-(胺甲基)環丙醇偶合而獲得標題化合物。白色泡沫。MS(m/e)：420.3(M+H)+。
Claims (22)
- 一種下式之化合物，
- 如請求項1之式I-A之化合物，
- 如請求項2之式I-A之化合物，其中該等化合物為：1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1R,2R)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(1R,2R)-2-羥基-環戊基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(1S,2S)-2-羥基-環戊基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(1S,2R)-2-羥基-環戊基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡 啶-3-羧酸(1-羥基-環戊基甲基)-醯胺N-環己基-1-(2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1SR,2RS)-2羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(1S,2S)-2-甲氧基-環己基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1SR,2SR)-2-羥基-2-甲基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1SR,2RS)-2-羥基-2-甲基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺N-[(1S,2S)-2-羥基環己基]-1-[3-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺N-[(1S,2S)-2-羥基環己基]-1-[4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1SR,2SR)-2-氟環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺N-[(1S,2S)-2-羥基環己基]-1-[4-(噻唑-2-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或1-(2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-N-[(1-羥基環丙基)甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
- 如請求項1或2之式I-A之化合物，其中R1係鹵素、低碳數烷基、低碳數烷氧基、氰基、苯基、C(O)NHCH3、C(O)NH2、經鹵素取代之低碳數烷基及R係視情況經羥基、低碳數烷氧基或低碳數烷基取代之(CH2)m-環烷基或係視情況經羥基取代之四氫吡喃，及n與m係如請求項1中所描述。
- 如請求項4之式I-A之化合物，其中該等化合物為1-(5-溴-2-氟苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2b]吡啶-3-甲醯胺及(1S,2S)-2-胺基環己醇N-[(1S,2S)-2-羥基環己基]-1-(4-甲基苯甲基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-(3-氟-4-甲氧基苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-(4-氰苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-(3-氟-4-甲基苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺N-[(1S,2S)-2-羥基環己基]-1-(4-甲氧基苯甲基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-(聯苯-4-基甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-(4-溴苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-(4-氰基-2-氟苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-(4-氯苯甲基)-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺N-[(1S,2S)-2-羥基環己基]-1-[4-(甲基胺甲醯)苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-(4-胺基甲醯苯甲基)-N-[(3S,4R)-3-羥基四氫-2H-吡喃-4-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或1-(4-胺基甲醯苯甲基)-N-[(3R,4S)-3-羥基四氫-2H-吡喃-4-基)- 1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
- 如請求項1或2之式I-A之化合物，其中R1係視情況經低碳數烷基取代之吡唑基及R係視情況經羥基取代之四氫吡喃，及n與m係如請求項1中所描述。
- 如請求項6之式I-A之化合物，其中該等化合物為：1-(2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基)-N-[(3RS,4SR)-3-羥基四氫-2H-吡喃-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲醯胺1-{[2-氟-4-(1-甲基吡唑-4-基)苯基]甲基}-N-[(3S,4S)-4-羥基氧雜環己烷-3-基]吡咯并[3,2-b]吡啶-3-甲醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(3R,4R)-4-羥基四氫-2H-吡喃-3-基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或1-{[2-氟-4-(1-甲基吡唑-4-基)苯基]甲基}-N-[(3R,4S)或(3S,4R)-3-羥基氧雜環己烷-4-基]吡咯并[3,2-b]吡啶-3-甲醯胺。
- 如請求項1或2之式I-A之化合物，其中R1係視情況經低碳數烷基取代之吡唑基及R係低碳數烷氧基，經羥基、經一個或兩個羥基取代之低碳數烷基取代，或係(CH2)m-吡啶基，視情況經羥基、低碳數烷基或經羥基取代之低碳數烷基取代，或係L-苯基，視情況經羥基、低碳數烷基或經羥基取代之低碳數烷基取代，且L係鍵、-CH(CH2OH)-或-CH2CH(OH)-，及n與m係如請求項1中所描述。
- 如請求項8之式I-A之化合物，其中該等化合物為：外消旋-1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基-3-甲氧基-丙基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-2-羥基-1-甲基-乙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡 啶-3-羧酸[(R)-2-羥基-丙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-2-羥基-丙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基-2-甲基-丙基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-丙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(1-羥基甲基-丙基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基-丁基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(R)-2,3-二羥基-丙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-2-甲基-丙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(1-羥基甲基-丁基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(R)-1-羥基甲基-2-甲基-丙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(1-羥基甲基-2-甲基-丙基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-丁基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-3-甲基-丁基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡 啶-3-羧酸[(1S,2S)-1-羥基甲基-2-甲基-丁基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-1-羥基甲基-2,2-二甲基-丙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基甲基-苯基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(3-羥基甲基-吡啶-2-基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基-2-苯基-乙基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-2-羥基-1-苯基-乙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(2-羥基甲基-4-甲基-苯基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸[(S)-2-羥基-2-苯基-乙基]-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(3-甲基-吡啶-2-基)-醯胺1-[2-氟-4-(1-甲基-1H-吡唑-4-基)-苯甲基]-1H-吡咯并[3,2-b]吡啶-3-羧酸(3-羥基-吡啶-2-基)-醯胺或1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1-羥基環丙基)甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
- 如請求項1之式I-B之化合物，
- 如請求項10之式I-B之化合物，其中該等化合物為：1-[(6-氯吡啶-3-基)甲基]-N-[(1S,2S)-2-羥基環己基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺N-[(1S,2S)-2-羥基環己基]-1-{[6-(三氟甲基)吡啶-3-基]甲基}-1H-吡咯并[3,2-b]吡啶-3-甲醯胺N-[(1S,2S)-2-羥基環己基]-1-{[6-(1-甲基-1H-吡唑-4-基)吡啶-3-基]甲基}-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或N-[(3RS,4SR)-3-羥基四氫-2H-吡喃-4-基]-1-{[6-(1-甲基-1H-吡唑-4-基)吡啶-3-基]甲基}-1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
- 如請求項1之式I-C之化合物，
- 如請求項12之式I-C之化合物，其中該化合物為1-[2-氟-4-(1-甲基-1H-吡唑-4-基)苯甲基]-N-[(1S,2S)-2-羥基環己基]-1H-吡唑并[4,3-b]吡啶-3-甲醯胺。
- 如請求項1之式I-D之化合物，
- 如請求項14之式I-D之化合物，其中該等化合物為：N-[(1S,2S)-2-羥基環己基]-1-[(1-甲基-1H-吲唑-5-基)甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺或N-[(1S,2S)-2-羥基環己基]-1-[4-(甲基胺甲醯基)苯甲基]-1H-吡咯并[3,2-b]吡啶-3-甲醯胺。
- 一種製造如請求項1至15中任一項所定義之式I之化合物的方法，該方法包括：a)使下式之化合物，
- 如請求項1至3及10至15中任一項之化合物，當其係藉由如請求項16之方法製造時。
- 一種醫藥組合物，其包含如請求項1至15中任一項之化合物及醫藥上可接受之載劑及/或佐劑。
- 一種醫藥組合物，其包含如請求項1至15中任一項之化合物及醫藥上可接受之載劑及/或佐劑，其用於治療阿茲海默氏病(Alzheimer's disease)、認知損傷、精神分裂症、疼痛或睡眠障礙。
- 如請求項1至3及10至15中任一項之化合物，其用作治療活性物質。
- 如請求項1至3及10至15中任一項之化合物，其用作用於治療阿 茲海默氏病、認知損傷、精神分裂症、疼痛或睡眠障礙之治療活性物質。
- 一種如請求項1至15中任一項之化合物之用途，其用於製備用於治療及/或預防治療阿茲海默氏病、認知損傷、精神分裂症、疼痛或睡眠障礙之藥物。
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| TW (1) | TW201512197A (zh) |
| WO (1) | WO2015028483A1 (zh) |
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| GB201317363D0 (en) * | 2013-10-01 | 2013-11-13 | Eisai Ltd | Novel compounds |
| KR102349237B1 (ko) | 2014-04-23 | 2022-01-07 | 다케다 야쿠힌 고교 가부시키가이샤 | 알츠하이머 병의 치료를 위한 콜린작동성 무스카린 ｍ１ 수용체 양성 알로스테릭 조절인자 활성을 갖는 이소인돌린-1-온 유도체 |
| EP3144308B1 (en) | 2014-05-16 | 2020-06-24 | Takeda Pharmaceutical Company Limited | Nitrogen-containing heterocyclic compound |
| TR201904639T4 (tr) * | 2015-06-08 | 2019-05-21 | Suven Life Sciences Ltd | Muskarinik M1 reseptörü pozitif allosterik modülatörler. |
| PT3347349T (pt) | 2015-09-10 | 2019-10-30 | Suven Life Sciences Ltd | Derivados de fluoroindole como moduladores alostéricos positivos para recetor m1 muscarínico |
| AU2017221404A1 (en) * | 2016-02-16 | 2018-08-23 | Vanderbilt University | Positive allosteric modulators of the muscarinic acetylcholine receptor M1 |
| KR102017786B1 (ko) * | 2016-09-02 | 2019-09-03 | 수벤 라이프 사이언시스 리미티드 | 무스카린 m1 수용체 포지티브 알로스테릭 조절제 |
| WO2018063552A1 (en) | 2016-09-30 | 2018-04-05 | Vanderbilt University | Positive allosteric modulators of the muscarinic acetylcholine receptor m1 |
| WO2019000238A1 (en) | 2017-06-27 | 2019-01-03 | Merck Sharp & Dohme Corp. | 5- (PYRIDIN-3-YL) OXAZOLE ALLOSTERIC MODULATORS OF M4 ACETYLCHOLINE MUSCARINIC RECEPTOR |
| WO2019000237A1 (en) | 2017-06-27 | 2019-01-03 | Merck Sharp & Dohme Corp. | ALLOSTERIC MODULATORS OF 3- (1H-PYRAZOL-4-YL) PYRIDINE FROM THE M4 ACETYLCHOLINE MUSCARINIC RECEPTOR |
| WO2019000236A1 (en) * | 2017-06-27 | 2019-01-03 | Merck Sharp & Dohme Corp. | ALLOSTERIC MODULATORS OF 3- (1H-PYRAZOL-4-YL) PYRIDINE FROM THE M4 ACETYLCHOLINE MUSCARINIC RECEPTOR |
| NZ764004A (en) * | 2017-10-18 | 2023-03-31 | Suven Life Sciences Ltd | Heteroaryl compounds as muscarinic m1 receptor positive allosteric modulators |
| AU2018354969B2 (en) * | 2017-10-27 | 2020-09-17 | Suven Life Sciences Limited | Polycyclic amides as muscarinic M1 receptor positive allosteric modulators |
| CN112543757A (zh) * | 2018-06-15 | 2021-03-23 | 卡迪拉保健有限公司 | 对结核菌具有抗菌活性的缩合氮杂杂芳基化合物 |
| WO2020086864A1 (en) | 2018-10-24 | 2020-04-30 | Vanderbilt University | Positive allosteric modulators of the muscarinic acetylcholine receptor m1 |
| CN116102549B (zh) * | 2021-11-09 | 2025-02-11 | 暨南大学 | 5-醛基杂环酰胺类化合物及其应用 |
| WO2023082044A1 (zh) * | 2021-11-09 | 2023-05-19 | 暨南大学 | 5-醛基杂环酰胺类化合物及其应用 |
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| US5461067A (en) * | 1993-02-25 | 1995-10-24 | Abbott Laboratories | Retroviral protease inhibiting compounds |
| US8012992B2 (en) * | 2008-06-30 | 2011-09-06 | Allergan, Inc. | Aza-indoles and related compounds having sphingosine-1-phosphate (S1P) receptor antagonist biological activity |
| CA2733588A1 (en) * | 2008-08-12 | 2010-02-18 | Merck Sharp & Dohme Corp. | N-heterocyclic m1 receptor positive allosteric modulators |
| EP2483275B1 (en) * | 2009-10-01 | 2014-10-15 | Merck Sharp & Dohme Corp. | HETEROCYCLIC-FUSED PYRAZOLO[4,3-c]PYRIDIN-3-ONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS |
| ME02421B (me) * | 2009-12-17 | 2016-09-20 | Merck Sharp & Dohme | Pozitivni alosterni modulatori m1 receptora na bazi hinolin amida |
| EP2575454B1 (en) * | 2010-05-28 | 2018-08-29 | Merck Sharp & Dohme Corp. | Naphthalene carboxamide m1 receptor positive allosteric modulators |
| WO2013106795A1 (en) * | 2012-01-12 | 2013-07-18 | Vanderbilt University | Substituted 4-(1h~pyrazol-4.yl)benzyl analogues as positive allosteric modulators of machr m1 receptors |
| EA028611B1 (ru) * | 2013-07-17 | 2017-12-29 | Глоубал Элаенс Фор Тб Драг Дивелопмент | Азаиндольные соединения, их получение и способы их применения |
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- 2014-08-27 MX MX2015017343A patent/MX2015017343A/es unknown
- 2014-08-27 BR BR112015032637A patent/BR112015032637A2/pt not_active Application Discontinuation
- 2014-08-27 WO PCT/EP2014/068114 patent/WO2015028483A1/en not_active Ceased
- 2014-08-27 HK HK16103515.2A patent/HK1215575A1/zh unknown
- 2014-08-27 RU RU2016110483A patent/RU2016110483A/ru unknown
- 2014-08-27 CN CN201480038043.7A patent/CN105358559A/zh active Pending
- 2014-08-27 KR KR1020167005141A patent/KR20160035068A/ko not_active Abandoned
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| US20160194321A1 (en) | 2016-07-07 |
| BR112015032637A2 (pt) | 2017-07-25 |
| US9932335B2 (en) | 2018-04-03 |
| CN108558867A (zh) | 2018-09-21 |
| EP3039024A1 (en) | 2016-07-06 |
| HK1215575A1 (zh) | 2016-09-02 |
| AR099640A1 (es) | 2016-08-10 |
| MX2015017343A (es) | 2016-04-06 |
| CA2915952A1 (en) | 2015-03-05 |
| JP6434516B2 (ja) | 2018-12-05 |
| WO2015028483A1 (en) | 2015-03-05 |
| KR20160035068A (ko) | 2016-03-30 |
| RU2016110483A (ru) | 2017-10-04 |
| JP2016529268A (ja) | 2016-09-23 |
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