CN112584898A - P2x3受体拮抗剂 - Google Patents
P2x3受体拮抗剂 Download PDFInfo
- Publication number
- CN112584898A CN112584898A CN201980046603.6A CN201980046603A CN112584898A CN 112584898 A CN112584898 A CN 112584898A CN 201980046603 A CN201980046603 A CN 201980046603A CN 112584898 A CN112584898 A CN 112584898A
- Authority
- CN
- China
- Prior art keywords
- pyrido
- pyrimidin
- morpholin
- chlorobenzyl
- triazolo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000005557 antagonist Substances 0.000 title abstract description 5
- 101710189970 P2X purinoceptor 3 Proteins 0.000 title description 2
- 102100040460 P2X purinoceptor 3 Human genes 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 306
- 238000011282 treatment Methods 0.000 claims abstract description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 208000002193 Pain Diseases 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 13
- 208000035475 disorder Diseases 0.000 claims abstract description 11
- 230000002265 prevention Effects 0.000 claims abstract description 9
- 208000000094 Chronic Pain Diseases 0.000 claims abstract description 7
- 206010020853 Hypertonic bladder Diseases 0.000 claims abstract description 7
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims abstract description 7
- 229940035676 analgesics Drugs 0.000 claims abstract description 7
- 239000000730 antalgic agent Substances 0.000 claims abstract description 7
- 208000020629 overactive bladder Diseases 0.000 claims abstract description 7
- 210000001835 viscera Anatomy 0.000 claims abstract description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- 230000004064 dysfunction Effects 0.000 claims abstract description 6
- 208000005615 Interstitial Cystitis Diseases 0.000 claims abstract description 5
- 206010013990 dysuria Diseases 0.000 claims abstract description 5
- 208000023504 respiratory system disease Diseases 0.000 claims abstract description 5
- -1 hydroxy, mercapto Chemical class 0.000 claims description 267
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 claims description 134
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 117
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 74
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 60
- 150000003839 salts Chemical class 0.000 claims description 52
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 46
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 35
- 125000004432 carbon atom Chemical group C* 0.000 claims description 32
- 239000008194 pharmaceutical composition Substances 0.000 claims description 29
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 22
- 125000002619 bicyclic group Chemical group 0.000 claims description 21
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 21
- 150000003254 radicals Chemical class 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 150000001204 N-oxides Chemical class 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000002950 monocyclic group Chemical group 0.000 claims description 17
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 206010011224 Cough Diseases 0.000 claims description 9
- 201000009273 Endometriosis Diseases 0.000 claims description 9
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- IJLCBANUTUIXFU-UHFFFAOYSA-N 8-[(4-methoxyphenyl)methyl]-11-morpholin-4-yl-5-propan-2-yl-3,6,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,10,12-tetraen-7-one Chemical compound COC1=CC=C(CN2C(N3C(C4=C2C=C(C=N4)N2CCOCC2)=NCC3C(C)C)=O)C=C1 IJLCBANUTUIXFU-UHFFFAOYSA-N 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- YHPVIBUEXBEHPV-UHFFFAOYSA-N 2,6-dihydro-1h-pyrimidin-5-one Chemical compound O=C1CNCN=C1 YHPVIBUEXBEHPV-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 6
- 125000004043 oxo group Chemical group O=* 0.000 claims description 6
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 4
- 206010068065 Burning mouth syndrome Diseases 0.000 claims description 4
- 208000003251 Pruritus Diseases 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- RRQCWBHRLMOOKD-UHFFFAOYSA-N 4-[5-tert-butyl-8-[(4-chlorophenyl)methyl]-3,4,6,7,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-11-yl]morpholine Chemical compound C(C)(C)(C)C1=NN=C2N1N=C(C1=C2N=CC(=C1)N1CCOCC1)CC1=CC=C(C=C1)Cl RRQCWBHRLMOOKD-UHFFFAOYSA-N 0.000 claims description 3
- SNVKRKHHQNUVTN-UHFFFAOYSA-N 8-[(4-chlorophenyl)methyl]-5-[(2-methylpyridin-3-yl)methyl]-11-morpholin-4-yl-3,4,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound ClC1=CC=C(CN2C(N3C(C4=C2C=C(C=N4)N4CCOCC4)=NN=C3CC=3C(=NC=CC3)C)=O)C=C1 SNVKRKHHQNUVTN-UHFFFAOYSA-N 0.000 claims description 3
- 206010058019 Cancer Pain Diseases 0.000 claims description 3
- 208000019695 Migraine disease Diseases 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 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 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 3
- 206010027599 migraine Diseases 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 2
- XRSUHXLZFMPECA-UHFFFAOYSA-N 11-(4-acetylpiperazin-1-yl)-8-[(4-chlorophenyl)methyl]-5-propan-2-yl-3,4,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound C(C)(=O)N1CCN(CC1)C1=CC2=C(C=3N(C(N2CC2=CC=C(C=C2)Cl)=O)C(=NN3)C(C)C)N=C1 XRSUHXLZFMPECA-UHFFFAOYSA-N 0.000 claims description 2
- YSJKWHTUDKWRGF-UHFFFAOYSA-N 11-bromo-5-tert-butyl-8-[(4-chlorophenyl)methyl]-3,4,6,7,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene Chemical compound BrC1=CC2=C(C=3N(N=C2CC2=CC=C(C=C2)Cl)C(=NN3)C(C)(C)C)N=C1 YSJKWHTUDKWRGF-UHFFFAOYSA-N 0.000 claims description 2
- UFLSIVNVGOXOOH-UHFFFAOYSA-N 12-methoxy-8-[(4-methoxyphenyl)methyl]-5-(oxan-4-ylmethyl)-3,4,6,8,11,13-hexazatricyclo[7.4.0.02,6]trideca-1(13),2,4,9,11-pentaen-7-one Chemical compound COC=1N=CC2=C(C=3N(C(N2CC2=CC=C(C=C2)OC)=O)C(=NN3)CC3CCOCC3)N1 UFLSIVNVGOXOOH-UHFFFAOYSA-N 0.000 claims description 2
- CFQPRKFZWFPCIF-UHFFFAOYSA-N 4-[8-[(3,5-dimethoxyphenyl)methyl]-5-(2-methylpropyl)-3,4,6,7,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-11-yl]morpholine Chemical compound COC=1C=C(CC=2C3=C(C=4N(N2)C(=NN4)CC(C)C)N=CC(=C3)N3CCOCC3)C=C(C1)OC CFQPRKFZWFPCIF-UHFFFAOYSA-N 0.000 claims description 2
- UHOURYWXLYTVRS-UHFFFAOYSA-N 4-[8-[(4-chlorophenyl)methyl]-5-[1-(oxan-4-yl)ethyl]-3,4,6,7,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-11-yl]morpholine Chemical compound ClC1=CC=C(CC=2C3=C(C=4N(N2)C(=NN4)C(C)C4CCOCC4)N=CC(=C3)N3CCOCC3)C=C1 UHOURYWXLYTVRS-UHFFFAOYSA-N 0.000 claims description 2
- CKRGZHBVHFHZKC-UHFFFAOYSA-N 4-[8-[(4-methylphenyl)methyl]-5-(oxan-4-ylmethyl)-3,4,6,7,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-11-yl]morpholine Chemical compound CC1=CC=C(CC=2C3=C(C=4N(N2)C(=NN4)CC4CCOCC4)N=CC(=C3)N3CCOCC3)C=C1 CKRGZHBVHFHZKC-UHFFFAOYSA-N 0.000 claims description 2
- YGSNWKAMBXMHKJ-UHFFFAOYSA-N 4-tert-butyl-8-[(4-chlorophenyl)methyl]-11-piperazin-1-yl-3,5,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound C(C)(C)(C)C1=NN2C(N(C3=C(C2=N1)N=CC(=C3)N3CCNCC3)CC3=CC=C(C=C3)Cl)=O YGSNWKAMBXMHKJ-UHFFFAOYSA-N 0.000 claims description 2
- BDTRIDKONHOQQN-UHFFFAOYSA-N 4h-pyrimidin-5-one Chemical compound O=C1CN=CN=C1 BDTRIDKONHOQQN-UHFFFAOYSA-N 0.000 claims description 2
- UTZKGYIHGNFEAJ-UHFFFAOYSA-N 5-tert-butyl-8-[(4-chlorophenyl)methyl]-11-(oxan-4-ylamino)-3,4,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound C(C)(C)(C)C1=NN=C2N1C(N(C1=C2N=CC(=C1)NC1CCOCC1)CC1=CC=C(C=C1)Cl)=O UTZKGYIHGNFEAJ-UHFFFAOYSA-N 0.000 claims description 2
- SMYSUZPOBKXESF-UHFFFAOYSA-N 5-tert-butyl-8-[(4-chlorophenyl)methyl]-11-morpholin-4-yl-3,4,6,8,12-pentazatricyclo[7.4.0.02,6]trideca-1(13),2,4,9,11-pentaen-7-one Chemical compound C(C)(C)(C)C1=NN=C2N1C(N(C1=C2C=NC(=C1)N1CCOCC1)CC1=CC=C(C=C1)Cl)=O SMYSUZPOBKXESF-UHFFFAOYSA-N 0.000 claims description 2
- NJNAXQCZIPNREB-UHFFFAOYSA-N 5-tert-butyl-8-[(4-chlorophenyl)methyl]-11-piperazin-1-yl-3,4,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound C(C)(C)(C)C1=NN=C2N1C(N(C1=C2N=CC(=C1)N1CCNCC1)CC1=CC=C(C=C1)Cl)=O NJNAXQCZIPNREB-UHFFFAOYSA-N 0.000 claims description 2
- VFWHQXYGVPQCMT-UHFFFAOYSA-N 5-tert-butyl-8-[(5-methylthiophen-2-yl)methyl]-11-morpholin-4-yl-3,4,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound C(C)(C)(C)C1=NN=C2N1C(N(C1=C2N=CC(=C1)N1CCOCC1)CC=1SC(=CC1)C)=O VFWHQXYGVPQCMT-UHFFFAOYSA-N 0.000 claims description 2
- CKEJSZZUWJSXLW-UHFFFAOYSA-N 8-[(3,5-dimethoxyphenyl)methyl]-4,5-dimethyl-11-morpholin-4-yl-3,6,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound COC=1C=C(CN2C(N3C(C4=C2C=C(C=N4)N4CCOCC4)=NC(=C3C)C)=O)C=C(C1)OC CKEJSZZUWJSXLW-UHFFFAOYSA-N 0.000 claims description 2
- OADCPTCJUFQLKT-UHFFFAOYSA-N 8-[(4-chlorophenyl)methyl]-11-morpholin-4-yl-5-(oxan-4-ylmethyl)-3,4,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound ClC1=CC=C(CN2C(N3C(C4=C2C=C(C=N4)N4CCOCC4)=NN=C3CC3CCOCC3)=O)C=C1 OADCPTCJUFQLKT-UHFFFAOYSA-N 0.000 claims description 2
- DRZGHCMFVWIFNU-UHFFFAOYSA-N 8-[(4-chlorophenyl)methyl]-11-morpholin-4-yl-5-(oxan-4-yloxymethyl)-3,4,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound ClC1=CC=C(CN2C(N3C(C4=C2C=C(C=N4)N4CCOCC4)=NN=C3COC3CCOCC3)=O)C=C1 DRZGHCMFVWIFNU-UHFFFAOYSA-N 0.000 claims description 2
- ZHSJCRIAOINOBH-UHFFFAOYSA-N 8-[(4-chlorophenyl)methyl]-11-morpholin-4-yl-5-[(2-oxo-1H-pyridin-3-yl)methyl]-3,4,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound ClC1=CC=C(CN2C(N3C(C4=C2C=C(C=N4)N4CCOCC4)=NN=C3CC=3C(=NC=CC3)O)=O)C=C1 ZHSJCRIAOINOBH-UHFFFAOYSA-N 0.000 claims description 2
- ANOQBHLBUDERAM-UHFFFAOYSA-N 8-[(4-chlorophenyl)methyl]-12-methoxy-5-(1-methylcyclopropyl)-3,4,6,8,11,13-hexazatricyclo[7.4.0.02,6]trideca-1(13),2,4,9,11-pentaen-7-one Chemical compound ClC1=CC=C(CN2C(N3C(C4=C2C=NC(=N4)OC)=NN=C3C3(CC3)C)=O)C=C1 ANOQBHLBUDERAM-UHFFFAOYSA-N 0.000 claims description 2
- VBERFSLHBOSIJH-UHFFFAOYSA-N 8-[(4-chlorophenyl)methyl]-4-cyclopropyl-11-morpholin-4-yl-3,6,8,13-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,10,12-tetraen-7-one Chemical compound ClC1=CC=C(CN2C(N3C(C4=C2C=C(C=N4)N4CCOCC4)=NC(C3)C3CC3)=O)C=C1 VBERFSLHBOSIJH-UHFFFAOYSA-N 0.000 claims description 2
- BMDXGUWPPOEIRD-UHFFFAOYSA-N 8-[(4-chlorophenyl)methyl]-5-(1-ethylpyrazol-3-yl)-11-morpholin-4-yl-3,4,6,8,13-pentazatricyclo[7.4.0.02,6]trideca-1(9),2,4,10,12-pentaen-7-one Chemical compound ClC1=CC=C(CN2C(N3C(C4=C2C=C(C=N4)N4CCOCC4)=NN=C3C3=NN(C=C3)CC)=O)C=C1 BMDXGUWPPOEIRD-UHFFFAOYSA-N 0.000 claims description 2
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- JQSVFCJLQUHVFP-UHFFFAOYSA-N COC=1C=C(CC=2C3=C(C=4N(N2)C(=NN4)CC(C)C)N=CC(=C3)N3CC(C3)COC)C=C(C1)OC Chemical compound COC=1C=C(CC=2C3=C(C=4N(N2)C(=NN4)CC(C)C)N=CC(=C3)N3CC(C3)COC)C=C(C1)OC JQSVFCJLQUHVFP-UHFFFAOYSA-N 0.000 claims description 2
- MAGUNAYMBHTVEC-UHFFFAOYSA-N COC=1C=C(CC=2C3=C(C=4N(N2)C(=NN4)COC(C)C)N=CC(=C3)N3CCOCC3)C=C(C1)OC Chemical compound COC=1C=C(CC=2C3=C(C=4N(N2)C(=NN4)COC(C)C)N=CC(=C3)N3CCOCC3)C=C(C1)OC MAGUNAYMBHTVEC-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明涉及式(I)化合物,及其作为P2X3和P2X2/3受体活性的拮抗剂的用途、包含这样的化合物的药物组合物、以及用其进行治疗的方法。本发明的化合物可用于治疗和/或预防疼痛和慢性疼痛以及对镇痛剂的耐受、呼吸系统病症和功能障碍,以及治疗膀胱过度活动症、膀胱疼痛综合征、排尿困难,以及一般性地用于泌尿生殖系统疾病、心血管病症中,并且更一般性地用于以P2X3和P2X2/3受体参与为特征的内脏器官疾病和病症的潜在治疗。
Description
技术领域
本发明涉及包含4-亚氨基-1H-吡啶并[3,2-d]嘧啶-2-酮和7H-吡啶并[2,3-d]哒嗪-8-亚胺衍生物的稠合杂环衍生物、及其作为P2X3和P2X2/3受体活性的拮抗剂的用途、包含这样的化合物的药物组合物、以及用其进行治疗的方法。
背景技术
腺苷-5’-三磷酸(ATP)充当在从健康或受损细胞中释放后对两种不同类型的嘌呤能受体(离子型P2X受体和G蛋白偶联的P2Y受体)发挥作用的胞外信号传导分子(G.Burnstock,“Discovery of purinergic signalling,the initial resistance andcurrent explosion of interest”,Br.J.Pharmacol.(2012),No.167,pp.238-55)。
P2X受体是由七种P2X1-7亚基缔合为同源或异源三聚体而产生的离子通道(R.A.North,“Molecular physiology of P2X receptors”,Physiol.Rev.(2002),No.82,pp.1013-67)。
同源三聚体P2X3受体和异源三聚体P2X2/3受体主要定位在背根神经节和颅感觉神经节内的中小直径C纤维和Aδ纤维感觉神经元上,以及在在包括皮肤、关节和内脏的组织中的其周围神经末端上。P2X3受体也存在于脊髓背角内和脑干中的感觉神经元的中央投影上,在那里其在增加谷氨酸和P物质的释放中发挥作用。由于其特定且受限的位置,P2X3受体亚型因此提供了独特的机会来研究感觉和伤害感受机制(C.Volontè,G.Burnstock,“P2X3 receptor-a novel′CASKade′of signalling”,J.Neurochem.(2013),No.126,pp.1-3)。
P2X3受体还参与了许多病症,其中疼痛症状源自外周传入途径的慢性致敏(例如,膀胱过度活动症、肠易激综合征(irritable bowel syndrome)、慢性瘙痒和咳嗽、气道高反应性)。
引起咳嗽的传入纤维几乎完全限于迷走神经,并且临床前研究表明C纤维(化学感受器)和Aδ纤维(机械感受器)二者均发挥关键作用。P2X3受体是ATP门控的离子通道,其选择性地定位在由颅和背根神经节二者产生的初级传入神经的群体中。
在豚鼠中,支配气道的迷走神经C纤维表达P2X3受体,并可被释放到气道中的ATP激活。此外,当豚鼠暴露于ATP和组胺气雾剂时,通过P2X受体提高了对咳嗽刺激的咳嗽响应。P2X3R还参与了许多病症,其中疼痛症状源自外周传入途径的慢性致敏(例如,膀胱过度活动症、肠易激综合征、慢性瘙痒和咳嗽、气道高反应性)。
P2X3离子通道受体由三叉神经系统中的小直径初级伤害性感受器的亚群表达,并且当被三磷酸腺苷(ATP)激活时,其可引起灼痛感。在灼口综合征(Burning MouthSyndrome)中,伴随着瞬时受体电位亚家族成员V1(TRPV1)离子通道以及神经生长因子NGF的上调,P2X3受体上调。由于这个原因,因此作用于P2X3受体的化合物可能在灼口综合征的治疗中具有潜在作用(“Burning Mouth Syndrome:Aetiopathogenesis and Principlesof Management”,L.Feller,J.Fourie,M.Bouckaert,R.A.G.Khammissa,R.Ballyram,andJ.Lemmer,Pain Research and Management,Vol.2017,Article ID 1926269,6页)。
与单独的吗啡相比,每日全身注射正构P2X3受体拮抗剂减弱了吗啡诱导的对冯弗雷(von Frey)和热刺激的抗伤害感受性耐受,表明P2X3受体拮抗剂能够逆转对吗啡的耐受,并且其可能是预防对吗啡诱导的抗伤害感受的耐受的新的治疗靶点(“Blockade andreversal of spinal morphine tolerance by P2X3 receptor antagonist”,Ma X andXu T,Xu H,Jiang W,Behavioural Pharmacology,(2015),Vol.26(3),pp.260-267)。在吗啡耐受大鼠中,P2X3受体拮抗剂对吗啡的耐受减弱可能归因于突触体膜中N-甲基-D-天冬氨酸受体亚基NR1和NR2B表达的下调以及对兴奋性氨基酸释放的抑制(“Purinergic P2XReceptor Regulates N-Methyl-D-aspartate Receptor Expression and SynapticExcitatory Amino Acid Concentration in Morphine-tolerant Rats”,Yueh-Hua Tai,Pao-Yun Cheng,Ru-Yin Tsai,Yuh-Fung Chen,Chih-Shung Wong,Anesthesiology,(2010),Vol.113(5),pp.1163-75)。
当前,由于在高血压大鼠和人中交感兴奋响应被增强,因此考虑将颈动脉体作为高血压的治疗靶标。此外,导致高血压的异常信号传导可通过大鼠颈动脉去神经而正常化。P2X3受体mRNA表达在高血压大鼠的化学感受性岩神经节神经元中上调。这些神经元在高血压大鼠中产生强直性驱动和反射亢进二者,并且这两种现象均通过P2X3受体拮抗剂得以正常化。P2X3受体的拮抗作用还降低了清醒的高血压大鼠的动脉压和基础交感神经活动,并使颈动脉体反射亢进正常化。颈动脉体中存在的嘌呤能受体可被视为控制人高血压的潜在新靶点(Wioletta Pijacka,Davi J A Moraes,Laura E K Ratcliffe,Angus KNightingale,Emma C Hart,Melina P da Silva,Benedito H Machado,Fiona D McBryde,Ana P Abdala,Anthony P Ford&Julian FR Paton)。
子宫内膜异位症是一种常见的妇科疾病,其特征在于子宫腔外存在功能性子宫内膜,导致痛经、性交疼痛、骨盆疼痛和不育症,缺乏有效的临床治疗(Strathy JH,MolgaardCA,Coulam CB,Melton LJ 3rd.“Endometriosis and infertility:a laparoscopicstudy of endometriosis among fertile and infertile women”,Fertility andsterility,(1982),Vol.38(6),pp.667-72)。子宫内膜异位症被认为是一种炎性和神经性疼痛,越来越多的证据表明三磷酸腺苷(ATP)和P2X3受体在子宫内膜异位症疼痛致敏性和转导中的重要性。P2X3在子宫内膜上皮细胞和子宫内膜基质细胞上表达。P2X3在子宫内膜异位症子宫内膜和子宫内膜异位病灶中过表达,二者与对照子宫内膜相比均显著升高,并且与疼痛以及患有子宫内膜异位症女性的疼痛严重程度均呈正相关。与用白介素(IL)-1β或三磷酸腺苷(ATP)分别处理后的初始水平相比,子宫内膜异位基质细胞(ESC)中的磷酸化±ERK(p-ERK)、磷酸化cAMP反应元件结合蛋白(p-CREB)和P2X3的表达水平均显著提高,并且所述水平在用ERK1/2抑制剂预处理ESC后没有提高。P2X3受体可能代表了子宫内膜异位症非激素治疗的高度创新靶标(“P2X3 receptor involvement in endometriosis pain viaERK signaling pathway”,Shaojie Ding,Libo Zhu,Yonghong Tian,Tianhong Zhu,Xiufeng Huang,Xinmei Zhang;PLoS ONE,(2017),Vol.12(9):e0184647)。
已显示数种P2X受体亚型,包括P2X2、P2X3、P2X4和P2X7,在中枢神经痛的发病机制中发挥多种作用,包括在周围神经系统中介导快速传递和在中枢神经系统中调节神经元活性。P2X3受体在神经性和炎性疼痛中发挥重要作用。通过鞘内施用ATP产生的持久性痛觉超敏(allodynia)可能通过P2X2/3受体发生。据报道,脊髓P2X2和P2X3受体参与了慢性压迫性损伤小鼠模型的神经性疼痛(“Nociceptive transmission and modulation via P2Xreceptors in central pain syndrome.”,Kuan,Y.H.,and Shyu,B.C.Mol.Brain(2016),Vol.9,pp.58)。P2X3受体表现出快速脱敏开始和缓慢恢复的结合。P2X3受体代表了通过促进脱敏以抑制慢性疼痛而开发新的镇痛剂的有吸引力的靶标,所述慢性疼痛例如:炎性和神经性疼痛、偏头痛和三叉神经痛,以及癌性疼痛(“Desensitization properties of P2X3receptors shaping pain signalling,Rashid Giniatullin and Andrea Nistri”,Front.Cell.Neurosci.,(2013),Vol.7,pp.245)。
发明内容
本发明提供了根据通式I的化合物或者其对映体、非对映体、N-氧化物或可药用盐或组合:
其中:
每个A独立地表示选自C、N、S或O的原子;
X和Y选自C和N原子,其中单元X-Y分别表示N-C基团或C=N基团;
每个R1独立地表示氢、卤素原子,或任选取代的羟基、羰基、羧基、氨基、酰胺基、C1-C6烷基或C1-C6烷氧基,任选取代的单环、双环或三环C6-C14芳基,或包含1至5个选自N、O或S的杂原子的任选取代的单环、双环或三环的C1-C13杂环基;
R2表示氢,或任选取代的C1-C6烷基、C1-C6烷氧基、C4-C14芳基烷基、C4-C14杂芳基烷基、C3-C7环烷基,单环、双环或三环C6-C14芳基,或者包含1至5个选自N、O或S的杂原子的单环、双环或三环C1-C13杂环基;
基团R3和R4,或者作为替代地基团R3和R5彼此连接以形成五元或六元杂环,所述杂环包含选自N、O和S的2至3个杂原子,任选地被一个或更多个基团nR6取代,前提是剩余的不与基团R3连接以形成杂环的R4或R5不存在,或是独立地选自N、O或S的直接与含X-Y环双键键合的原子;
每个R6独立地表示氢,选自F、Cl、Br或I的卤素原子,或任选取代的羰基、氧代、C1-C6烷基、C1-C6烷氧基或C3-C7环烷基,任选取代的单环、双环或三环C6-C14芳基,或包含1至5个选自N、O或S的杂原子的任选取代的单环、双环或三环C1-C13杂环基团,或者作为替代地,两个R6基团彼此连接以形成式-(Zp)-的基团,其中p为3至5的整数,并且每个Z独立地表示氧原子或任选取代的亚甲基,前提是没有两个相邻的Y部分表示氧原子;并且
n是独立地选自0至3的整数。
优选地,本发明的化合物可用于治疗和/或预防疼痛和慢性疼痛以及对镇痛剂的耐受、呼吸系统病症和功能障碍,以及治疗膀胱过度活动症、膀胱疼痛综合征、排尿困难,以及一般性地用于泌尿生殖系统疾病、心血管病症中,并且更一般性地用于以P2X3和P2X2/3受体参与为特征的内脏器官疾病和病症的潜在治疗。
优选地,所述任选的取代基独立地选自卤素原子、C1-C6烷基、C1-C6烷氧基、羟基、巯基、硝基、氰基、氧代、卤代(C1-C6)烷基、卤代(C1-C6)烷氧基、C1-C6烷硫基、C1-C6烷基磺酰基、C1-C6烷基羰基、氨基磺酰基、C1-C6烷基氨基磺酰基、二(C1-C6)烷基氨基磺酰基、(C1-C6)烷氧基羰基和(C1-C6)烷基羰基(C1-C6)烷基,以及选自式-NR*R*、-C(=O)-NR*R*、-D、-O-D、-C(=O)-D、-(CH2)q-D、-NR**-D、-C(=O)-NR**-D、-NR**C(=O)-D和-O-C(=O)-D的基团,其中每个R*独立地表示氢原子或C1-C6烷基、C1-C6烷氧基、C1-C6烷基羰基、苯基或苄基,R**表示氢原子或C1-C6烷基,q为1至6的整数,并且D表示苯基或包含1至3个选自N、O和S的杂原子的C1-C8杂环基,C1-C6环烷基,每个基团D还任选地被1至3个独立地选自卤素、羟基、氰基、硝基和C1-C6烷基的基团取代,优选其中所述任选的取代基选自卤素原子和C1-C6烷基。
本发明的优选化合物是其中A基团之一包含杂原子而其余三个A基团包含碳原子的化合物。一个非限制性实例包括这样的情况,其中A基团之一包含氮原子,而其余三个A基团各自包含碳原子,使得如此形成的杂环为吡啶环。
本发明的优选化合物是其中两个A基团包含杂原子而其余两个A基团包含碳原子的化合物。非限制性实例包括这样的情况,其中两个A基团包含氮原子,而其余两个A基团各自包含碳原子,使得如此形成的杂环为哒嗪、嘧啶或吡嗪环。
本发明的优选化合物是其中三个A基团包含杂原子而其余的A基团包含碳原子的化合物。非限制性实例包括这样的情况,其中三个A基团包含氮原子,而其余的A基团包含碳原子,使得如此形成的杂环为1,2,3-三嗪或1,2,4-三嗪环。
本发明的优选化合物是其中所有四个A基团均包含杂原子的化合物。一个非限制性实例包括这样的情况,其中所有四个A基团均包含氮原子,使得如此形成的杂环为1,2,3,4-四嗪环。
本领域技术人员将理解,对于上述每个实例,包含碳或其他杂环原子的每个A基团或者如此形成的杂环还可包含直接连接至一个或更多个环原子的一个或更多个氢原子和/或n个R1基团(如上所限定),以满足与原子键合和化合价相关的通常规则。
本发明还提供了杂原子的其他这样的组合,包括但不限于由每个独立地由选自C、N、S或O的原子代表的A基形成的杂环,使得所得的所形成的杂环是哌啶、吡啶、四氢吡喃、吡喃、噻吩、噻喃、吗啉、嗪、硫代吗啉、噻嗪、二烷、二英、二噻烷、二噻英(dithiin)、三烷或三噻烷衍生物。
优选的非限制性实例包括所得的如此形成的杂环,其为2H-1,2-嗪、4H-1,2-嗪、6H-1,2-嗪、2H-1,3-嗪、4H-1,3-嗪、6H-1,3-嗪、2H-1,4-嗪、4H-1,4-嗪、硫代吗啉、1,2-噻嗪、1,3-噻嗪、1,4-噻嗪、1,4-二烷、1,2-二英、1,4-二英、1,2-二噻烷、1,3-二噻烷、1,4-二噻烷、1,2-二噻英和1,4-二噻英、1,2,3-三烷或1,2,4-三烷衍生物。
本发明的优选化合物是这样的化合物,其中基团X-Y表示N-C基团,使得如此形成的六元中心杂环为嘧啶环。
本发明的优选化合物是这样的化合物,其中基团X-Y表示C=N基团,使得如此形成的六元中心杂环为哒嗪环。
本发明的优选化合物是这样的化合物,其中基团X-Y表示N-C基团,基团R3和R4彼此连接以形成包含2至3个氮杂原子的五元或六元杂环,任选被具有一个或更多个如上所限定的基团nR6取代,并且R5是羰基。
本发明的优选化合物是这样的化合物,其中基团X-Y表示N-C基团,并且基团R3和R4彼此连接以形成包含2至3个氮杂原子的五元或六元杂环(例如2-咪唑啉、咪唑、1,2,4-三唑或嘧啶),其选自但不限于吡啶并[2,3-e]咪唑并[1,2-d]嘧啶、吡啶并[2,3-e]咪唑并[1,2-d]嘧啶、吡啶并[2,3-e]1,2,4-三唑并[1,2-d]嘧啶或1,4,5,6-四氢嘧啶并[2,1-f]吡啶并[3,2-d]嘧啶衍生物,并且R5为羰基。
本发明的优选化合物是这样的化合物,其中基团X-Y表示N-C基团,基团R3和R5彼此连接以形成包含2至3个氮杂原子的五元杂环,其任选地被一个或更多个如上所限定的基团nR6取代,并且R4为羰基。
本发明的优选化合物是这样的化合物,其中基团X-Y表示N-C基团,并且基团R3和R5彼此连接以形成包含2至3个氮杂原子的五元杂环(例如1,2,4-三唑),其选自但不限于吡啶并[2,3-e]1,2,4-三唑并[2,1-b]嘧啶衍生物,并且R4为羰基。
本发明的优选化合物是这样的化合物,其中基团X-Y表示C=N基团,基团R3和R4彼此连接以形成包含2至3个氮杂原子的五元或六元杂环,其任选地被一个或更多个如上所限定的基团nR6取代,并且R5不存在。
本发明的优选化合物是这样的化合物,其中基团X-Y表示C=N基团,并且基团R3和R4彼此连接以形成包含2至3个氮杂原子的五元或六元杂环(例如1,2,4-三唑),其选自但不限于吡啶并[3,2-d]1,2,4-三唑并[1,2-d]1,4,5,6-四氢哒嗪衍生物,并且R5为羰基。
本发明的优选化合物是其中R1选自包含以下的组的化合物:H、Br、羟基、羧基、甲氧基、甲氧基乙基氨基、2-羟基乙基氨基、叔丁氧基羰基氨基、2-羟基乙基氨基羰基,任选取代的氮杂环丁烷基、吗啉基、氧杂环丁烷基、哌嗪基、哌啶基、吡喃基或吡咯烷基部分、或其衍生物,或任选取代的包含1至5个选自N、O或S的杂原子的螺稠合的双环或三环C1-C13杂环基。
本发明的高度优选的化合物是这样的化合物,其中R1选自包含以下的组:2-氧杂-6-氮杂螺[3.3]庚烷-6-基、3-甲氧基甲基氮杂环丁烷-1-基、3-甲氧基吡咯烷-1-基、4-乙酰基哌嗪-1-基、4-氨基哌啶-1-基、4-羟基哌啶-1-基、4-羟基哌啶-1-基-羰基、4-甲氧基哌啶-1-基、4-吗啉基、二甲基氨基哌啶-1-基、羟甲基哌啶-1-基、吗啉-4-基羰基、四氢-2H-吡喃-4-基氨基或四氢-2H-吡喃-4-基氨基羰基。
本发明的优选化合物是其中R2是氢原子或任选取代的苄基或其衍生物的化合物。
本发明的高度优选的化合物是这样的化合物,其中R2是氢原子,或选自包含以下的组:3,5-二甲氧基苄基、4-甲氧基苄基、4-甲基苄基、4-氯苄基或4-氯-2,6-二氟苄基。
本发明的优选化合物是这样的化合物,其中R6选自包含以下的组:苯基、(1-苯基)乙基、1-乙基-1H-吡唑-3-基、1-乙基-1H-吡唑-5-基、(四氢-2H-吡喃-4-基)甲基、(四氢-2H-吡喃-4-基氧基)甲基、(四氢-2H-吡喃-4-基)乙基、3,5-二甲基-1,2唑-4-基、2-羟基吡啶-3-基、2-甲基吡啶-3-基、吗啉-4-基-羰基、吡啶-3-基-甲基、氧代、甲基、乙基、异丙基、叔丁基、甲基丙基、2,2-二甲基丙基、3-甲基丁基、2,2,2-三氟乙基、甲氧基甲基、甲氧基乙基、(丙烷-2-基氧基)甲基、叔丁氧基甲基、丙-1-烯-2-基、丙烷-2-基-乙酰胺、环丙基、环丁基、环己基、1-甲基环丙基。
本发明的优选化合物是这样的化合物,其中-(Zp)-表示选自以下的基团:-O-(CH2)2-O-、-O-(CH2)3-O-、-O-(CH2)2-、-O-(CH2)3-、-CH2-O-CH2-或-(CH2)2-O-(CH2)2。
本发明的优选化合物是这样的化合物,其中A基团之一是氮原子而其余三个A基团是碳原子,X-Y单元是N-C基团,基团R3和R4彼此连接以形成包含2个氮杂原子的五元杂环,R5是直接与含X-Y环双键键合的氧原子(羰基),使得如此形成的化合物是吡啶并[2,3-e]咪唑并[1,2-d]嘧啶衍生物,并具有根据下式1a的结构:
其中基团R1、R2、R6和n如上式I所限定。
本发明的优选化合物是这样的化合物,其中A基团之一是氮原子而其余三个A基团是碳原子,X-Y单元是N-C基团,基团R3和R4彼此连接以形成包含2个氮杂原子的五元杂环,R5是直接与含X-Y环双键键合的氧原子(羰基),使得如此形成的化合物是吡啶并[2,3-e]咪唑并[1,2-d]嘧啶衍生物,并具有根据下式1b的结构:
其中基团R1、R2、R6和n如上式I所限定。
本发明的优选化合物是这样的化合物,其中A基团之一是氮原子而其余三个A基团是碳原子,X-Y单元是N-C基团,基团R3和R4彼此连接以形成包含3个氮杂原子的五元杂环,R5是直接与含X-Y环双键键合的氧原子(羰基),使得如此形成的化合物是吡啶并[2,3-e]1,2,4-三唑并[1,2-d]嘧啶衍生物,并具有根据下式1c的结构:
其中基团R1、R2、R6和n如上式I所限定。
本发明的优选化合物是这样的化合物,其中A基团之一是氮原子而其余三个A基团是碳原子,X-Y单元是N=C基团,基团R3和R4彼此连接以形成包含3个氮杂原子的五元杂环,R5是直接与含X-Y环双键键合的氧原子(羰基),使得如此形成的化合物是吡啶并[3,2-d]1,2,4-三唑并[1,2-d]1,4,5,6-四氢哒嗪衍生物,并具有根据下式1d的结构:
其中基团R1、R2、R6和n如上式I所限定。
本发明的优选化合物是这样的化合物,其中A基团之一是氮原子而其余三个A基团是碳原子,X-Y单元是N-C基团,基团R3和R4彼此连接以形成包含2个氮杂原子的六元杂环,并且R5是直接与含X-Y环双键键合的氧原子(羰基),使得如此形成的化合物是1,4,5,6-四氢嘧啶并[2,1-f]吡啶并[3,2-d]嘧啶衍生物,并具有根据下式1e的结构:
其中基团R1、R2、R6和n如上式I所限定。
本发明的优选化合物是这样的化合物,其中A基团之一是氮原子而其余三个A基团是碳原子,X-Y单元是N-C基团,基团R3和R5彼此连接以形成包含3个氮杂原子的五元杂环,R4是直接与含X-Y环双键键合的氧原子(羰基),使得如此形成的化合物是吡啶并[2,3-e]1,2,4-三唑并[2,1-b]嘧啶衍生物,并具有根据下式1f的结构:
其中基团R1、R2、R6和n如上式I所限定。
本发明的优选化合物是这样的化合物,其中A基团之一是氮原子而其余三个A基团是碳原子,X-Y单元是N-C基团,基团R3和R4彼此连接以形成包含2个氮杂原子的五元杂环,R5是直接与含X-Y环双键键合的氧原子(羰基),并且至少一个基团nR6是直接与R3/R4所连接的五元杂环(咪唑啉)环双键键合的氧原子,使得如此形成的化合物是吡啶并[2,3-e]咪唑并[1,2-d]嘧啶二酮衍生物,并具有根据下式1g的结构:
其中基团R1、R2、R6和n如上式I所限定。
根据本发明的优选化合物是化合物或者其对映体、非对映体、N-氧化物或可药用盐或组合,其根据通式1a或1g选自下表1的化合物而提供:
表1:根据式1a和1g选择的本发明化合物。
根据本发明的优选化合物是化合物或者其对映体、非对映体、N-氧化物或可药用盐或组合,其根据通式1b或1c选自下表2的化合物而提供:
表2:根据式1b和1c选择的本发明化合物。
根据本发明的优选化合物是化合物或者其对映体、非对映体、N-氧化物或可药用盐或组合,其根据通式1d选自下表3的化合物而提供:
表3:根据式1d选择的本发明化合物。
根据本发明的优选化合物是化合物或者其对映体、非对映体、N-氧化物或可药用盐或组合,其根据通式1e选自下表4的化合物而提供:
表4:根据式1e选择的本发明化合物。
根据本发明的优选化合物是化合物或者其对映体、非对映体、N-氧化物或可药用盐或组合,其根据通式1a至1f选自下表5的化合物而提供:
表5:根据式1a至1f选择的本发明化合物。
本发明还提供了药物组合物,其包含式I化合物:
或者其对映体、非对映体、N-氧化物或可药用盐或组合,以及可药用载体,其中A、X、Y、R1至R6和n具有与上述相同的含义,其用于治疗和/或预防疼痛、慢性疼痛和对镇痛剂的耐受、呼吸系统病症和功能障碍、膀胱过度活动症、膀胱疼痛综合征、排尿困难,以及一般性地用于泌尿生殖系统疾病、心血管病症中,并且更一般性地用于以P2X3和P2X2/3参与为特征的内脏器官疾病和病症的潜在治疗。
本发明还提供了药物组合物,其包含式1a至1g中的任一种的化合物:
或者其对映体、非对映体、N-氧化物或可药用盐或组合,以及可药用载体,其中A、X、Y、R1至R6和n具有与上述相同的含义,其用于治疗和/或预防疼痛、慢性疼痛和对镇痛剂的耐受、呼吸系统病症和功能障碍、泌尿生殖系统疾病和心血管病症,并且一般性地用于以P2X3和P2X2/3参与为特征的内脏器官疾病和病症的潜在治疗。
本发明还提供了根据以上所示出的式I或式1a至1g中任一种的化合物,其用于治疗和/或预防功能障碍,包括但不限于涉及ATP释放,并且一般性地用于以P2X3和P2X2/3受体参与为特征的感觉器官和内脏器官疾病和病症的潜在治疗;用于治疗和/或预防疼痛、慢性疼痛和癌性疼痛、对镇痛剂的成瘾和耐受;用于治疗哮喘、咳嗽、COPD和难治性慢性咳嗽,以及一般性的呼吸系统病症和功能障碍;用于治疗膀胱过度活动症、尿失禁、膀胱疼痛综合征、排尿困难和子宫内膜异位症,以及一般性地用于泌尿生殖系统疾病中;用于治疗心血管病症、肠易激综合征(IBS)、灼口综合征(BMS)偏头痛和瘙痒。
使用的术语和定义
除非另有说明,否则以下定义在整个本说明书和权利要求书中适用。无论术语是单独使用还是与其他术语组合使用,这些定义均适用。例如,“烷基”的定义不仅适用于烷基本身,而且适用于烷氧基、烷基氨基、烷基硫基或烷基羰基等的烷基部分。此外,针对化学基团描述的所有范围,例如“1至13个碳原子”或“C1-C6烷基”包括其中碳原子的范围和特定数目的所有组合和子组合。
技术人员将意识到,基团A、X、Y、R1至R6和n均具有如本文所述赋予它们的含义。例如,“基团X和Y选自C和N原子,其中单元X-Y分别表示N-C基团或C=N基团”。
“烷基”意指在链中具有1至20个碳原子的直链或支链脂肪族烃基。优选的烷基在链中具有1至12个碳原子。更优选的烷基在链中具有1至6个碳原子。“低级烷基”意指在链中具有约1至约6个碳原子的烷基,其可以是直链或支链的。合适的烷基的实例包括甲基、乙基、正丙基、异丙基、仲丁基、正丁基和叔丁基。
“烯基”意指在链中具有至少一个碳-碳双键并且具有2至15个碳原子的直链或支链脂肪族烃基。优选的烯基在链中具有2至12个碳原子。更优选的烯基在链中具有2至6个碳原子。“低级烯基”意指在链中具有2至约6个碳原子的烯基,其可以是直链或支链的。合适的烯基的实例包括乙烯基、丙烯基、异丙烯基、正丁烯基、1-己烯基和3-甲基丁-2-烯基。
“炔基”意指在链中具有至少一个碳-碳三键并且具有2至15个碳原子的直链或支链脂肪族烃基。优选的炔基在链中具有2至12个碳原子。更优选的炔基在链中具有2至6个碳原子。“低级炔基”意指在链中具有2至约6个碳原子的炔基,其可以是直链或支链的。合适的炔基的实例包括乙炔基、丙炔基和2-丁炔基。
“单环、双环或三环杂环”意指芳族或非芳族饱和单环、双环或三环系统,其具有2至14个环碳原子并且包含1至5个选自N、O和S的环原子,单独或组合。双环和三环杂环基团在2个或4个点处稠合,或者通过键或杂原子接头(O、S、NH或N(C1-C6烷基)在一个点处连接。通过用一个或更多个可相同或不同的取代基替代环上的可用氢,“单环、双环或三环杂环”可任选地在环上被取代。杂环的氮或硫原子可任选被氧化成相应的N-氧化物、S-氧化物或S-二氧化物。合适的杂环的实例包括呋喃基、咪唑基、异唑基、二唑基、唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、三唑基、四唑基、噻吩基、咔唑基、苯并咪唑基、苯并噻吩基、苯并呋喃基、吲哚基、喹啉基、苯并三唑基、苯并噻唑基、苯并唑基、苯并咪唑基、异喹啉基、异吲哚基、吖啶基和苯并异唑基、吖丙啶基、哌啶基、吡咯烷基、哌嗪基、四氢吡喃基、四氢呋喃基、四氢噻吩基、吗啉基和硫代吗啉基。
具有芳族特性的杂环可被称为杂芳基或杂芳族。合适的杂芳族的实例包括呋喃基、咪唑基、异唑基、二唑基、唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、三唑基、四唑基、噻吩基、咔唑基、苯并咪唑基、苯并噻吩基、苯并呋喃基、吲哚基、喹啉基、苯并三唑基、苯并噻唑基、苯并唑基、苯并咪唑基、异喹啉基、异吲哚基、吖啶基、苯并异唑基、四氢喹啉基、四氢异喹啉基、3-苯基吡啶、3-环己基吡啶、3-(吡啶-3-基)吗啉、3-苯基异唑和2-(哌啶-1-基)嘧啶。
“单环、双环或三环芳基”意指包含6至14个碳原子的芳族单环、双环或三环系统。双环和三环芳基在2个或4个点处稠合,或者通过键或杂原子接头(O、S、NH或N(C1-C6烷基))在一个点处连接(例如,联苯基、1-苯基萘基)。芳基可在环上任选地被一个或更多个取代基,优选1至6个取代基取代,其可以是相同或不同的。合适的芳基的实例包括苯基和萘基。
“环烷基”意指具有3至14个碳原子,优选3至6个碳原子的单环或双环碳环系统。通过用一个或更多个可相同或不同的取代基替代环上的可得氢,环烷基可任选地在环上被取代。合适的单环环烷基的实例包括环丙基、环戊基、环己基和环庚基。合适的多环环烷基的实例包括1-癸烯基、降冰片基和金刚烷基。
“环烯基”具有与环烷基相对应的含义,但在环内具有一个或两个双键(例如,环己烯基、环己二烯)。
“胺”是氨的衍生物,其中一个或更多个氢原子已被取代基如烷基或芳基替代。这些可分别称为烷基胺和芳基胺;两种类型的取代基与一个氮原子相连的胺可称为烷基芳基胺。
胺可进一步组织成四个子类别。当氨中三个氢原子之一被烷基或芳族基团替代(分别为N-烷基氨基或N-芳基氨基)时,会出现伯胺。合适的伯烷基胺的实例包括甲胺或乙醇胺,或作为芳族胺的实例的苯胺(苯胺)。仲胺具有两个与一个氢原子一起与氮原子结合的有机取代基(独立地为烷基或芳基)(如果一个取代基键为双键,则没有氢)。合适的仲胺的实例包括二甲胺和甲基乙醇胺,而芳族胺的实例为二苯胺。根据取代基的性质,这样的化合物也可被称为“N,N-二烷基氨基”、“N,N-二芳基氨基”或“N,N-烷基芳基氨基”。如本文所定义的被烷氧基取代的仲胺例如将被称为“N-烷基-N-烷氧基氨基”化合物。在叔胺中,所有三个氢原子均被有机取代基替代(例如三甲胺)。最终的子类是环胺,其为仲胺或叔胺。合适的环胺的实例包括三元环氮丙啶和六元环哌啶。N-甲基哌啶和N-苯基哌啶是环状叔胺的合适实例。
“酰胺”是具有与羰基相连的氮原子,因此具有结构R-CO-NR’R”的化合物,其中基团R’和R”独立地选自如本文中所定义的烷基或芳族基团。例如,当R’为氢且R”为3-吡啶基时,所得酰胺具有3-吡啶基氨基取代基。或者,当R’为氢且R”为环戊基时,所得酰胺具有环戊基氨基取代基。
“卤素”、“卤化物”或“卤代”意指氟、氯、溴或碘。优选的卤素是氟、氯或溴,最优选是氟和氯。
术语“酰基”,无论是单独使用还是在例如“酰基氨基”的术语中使用,均表示从有机酸中除去羟基后,由残基提供的基团。术语“酰基氨基”是指被酰基取代的氨基基团。“酰基氨基”基团的实例是CH3C(=O)-NH-,其中胺可进一步被烷基、芳基或芳烷基取代。
术语“稠环”是指分子中的多环系统,其中两个环共享两个或更多个共同原子。认为只有两个共同原子和一个共同键的两个环是邻位稠合的,例如萘。在多环化合物中,一个与其他两个本身邻位稠合在一起的环的不同侧边邻位稠合的环(即第一个环与另外两个环之间存在三个共同原子)被称为与另外两个环邻位和迫位稠合。非那烯被认为是由三个苯环构成的,每个苯环都与另外两个苯环邻位和迫位稠合。稠合命名法涉及具有最大数量的非累积双键的多环系统的二维表示。另外,该系统可以是桥接的,或包含在装配体或螺系统中(见下文)。对于环系统,必须对在所有侧边都与其他环稠合的任何环本身命名(即,不将其视为内多边形)。出于命名目的,可将具有两个共同原子和一个共同键的两个环视为来源于作为独立的实体的两个环。以这种方式连接环的过程称为稠合。本文中所举例说明或描述的任何稠合化合物均根据并参考“Nomenclature of fused and bridged fused ringsystems”(IUPAC Recommendations 1998)”,IUPAC,Pure Appl.Chem.,(1999),Vol.70,pp.143-216来命名。
螺环化合物具有两个(或三个)环,它们仅具有一个共同的原子,并且两个(或三个)环不通过桥连接。这些环可形成其他环系统(稠环,桥连稠环,以冯·拜尔命名法命名的系统等)的一部分。共同原子称为螺原子,螺稠合也称为螺接。具有两个单环的单螺烃通过前缀螺随后是置于方括号中的冯·拜尔描述符(表示每个环中与螺原子相连的碳原子数,按升序排列并以句号分隔),随后是表示骨架原子的总数的母体烃的名称,例如螺[4.4]壬烷。具有两个单环的单螺烃从小环中在螺原子旁的原子处开始,围绕小环返回螺原子,然后环绕第二个环进行连续编号。杂原子用替代前缀表示,不饱和度通常用词尾烯、二烯等表示。低位次分配给基团位置,或者,如果环系统是取代基,则分配给其连接点。如果可选择数字,则选择给出螺原子的较低位次的名称。本文中所举例说明或描述的任何螺化合物均根据并参考“Extension and revision of the nomenclature for spiro compounds”(IUPAC Recommendations 1999)”,IUPAC,Pure Appl.Chem.,(1999),Vol.71,pp.531.538来命名。
星号可用于亚属通式或基团中,以指示连接至如本文中定义的母体或核芯分子的键。
如本文中所用,术语“治疗”等涵盖消除或减轻疾病或病症的症状并使它们免于恶化(稳定化),并且更一般性地带来期望的生理或药理作用。如本文中所用,术语“预防”等涵盖抑制或延缓这样的疾病或病症的症状表现或者降低(或视情况而提高)或消除其标志物中的异常值。
立体化学
除非特别指出,否则在整个说明书和权利要求书中,给定的化学式或名称应涵盖其互变异构体及所有立体、光学和几何异构体(例如对映体、非对映体、+/-、R/S、E/Z异构体等)、外消旋混合物和外消旋物。这包括不同比例的单独对映体的混合物、非对映体的混合物或存在这样的异构体和对映体的任何前述形式的混合物,以及盐,包括其可药用盐及溶剂合物,例如游离化合物的水合物、溶剂合物或者化合物盐的溶剂合物。
本发明化合物的衍生物
本发明还包括式I化合物的盐、溶剂合物、水合物、N-氧化物、前药和活性代谢物。
本文中所用的短语“可药用”是指这样的化合物、材料、组合物和/或剂型,其在合理的医学判断范围内适合与人和动物的组织接触使用而没有过度毒性、刺激性、变应性反应或其他问题或并发症,并与合理的效益/风险比相称。
如本文中所用,“可药用盐”是指所公开化合物的衍生物,其中母体化合物通过制备其酸式或碱式盐而被修饰。可药用盐的实例包括但不限于碱性残基例如胺的无机或有机酸盐;酸性残基例如羧酸的碱金属盐或有机盐;等等。例如,这样的盐包括来自以下的盐:氨、L-精氨酸、甜菜碱、苯乙苄胺(benethamine)、苄星(benzathine)、氢氧化钙、胆碱、地亚诺(deanol)、二乙醇胺(2,2’-亚氨基双(乙醇))、二乙胺、2-(二乙基氨基)-乙醇、2-氨基乙醇、乙二胺、N-乙基葡糖胺、海巴明(hydrabamine)、1H-咪唑、赖氨酸、氢氧化镁、4-(2-羟基乙基)-吗啉、哌嗪、氢氧化钾、1-(2-羟基乙基)-吡咯烷、氢氧化钠、三乙醇胺(2,2’,2”-次氮基三(乙醇))、氨丁三醇、氢氧化锌、乙酸、2,2-二氯乙酸、己二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、2,5-二羟基苯甲酸、4-乙酰氨基-苯甲酸、(+)-樟脑酸、(+)-樟脑-10-磺酸、碳酸、肉桂酸、柠檬酸、环拉酸、癸酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、乙二胺四乙酸、甲酸、富马酸、半乳糖二酸、龙胆酸、D-葡糖庚酸、D-葡糖酸、D-葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、甘氨酸、乙醇酸、己酸、马尿酸、氢溴酸、盐酸、异丁酸、DL-乳酸、乳糖酸、月桂酸、赖氨酸、马来酸、(-)-L-苹果酸、丙二酸、DL-扁桃酸、甲磺酸、半乳糖二酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、辛酸、油酸、乳清酸、草酸、棕榈酸、扑酸(扑酸(embonic acid))、磷酸、丙酸、(-)-L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸和十一碳烯酸。进一步地,可药用盐可用来自金属(例如铝、钙、锂、镁、钾、钠、锌等)的阳离子形成(参见Pharmaceutical salts,Berge,S.M.et al.,J.Pharm.Sci.,(1977),Vol.66,pp.1-19)。
本发明的可药用盐可通过常规化学方法由含有碱性或酸性部分的母体化合物合成。通常来说,可通过使这些化合物的游离酸或碱形式与足量的适当碱或酸在水中或在例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈或者其混合物的有机稀释剂中反应来制备这样的盐。
除上述提及的那些以外的其他酸的盐,例如可用于纯化或分离本发明的化合物的盐(例如三氟乙酸盐),也构成本发明的一部分。
通常来说,通过适当地使用所需的酸或碱,可容易地制备式I化合物的可药用盐。该盐可从溶液中沉淀出来并通过过滤收集,或者可通过蒸发溶剂来回收。例如,可将酸的水溶液例如盐酸添加至式I化合物的水悬浮液,并将所得混合物蒸发至干(冻干)以获得为固体的酸加成盐。或者,可将式I化合物溶于合适的溶剂,例如醇,例如异丙醇中,并将酸添加至相同溶剂或另外的合适的溶剂。然后可将所得的酸加成盐直接沉淀,或通过添加极性较小的溶剂例如二异丙醚或己烷沉淀,并通过过滤分离。
式I化合物的酸加成盐可通过使游离碱形式与足够量的所需酸接触从而以常规方式产生该盐来制备。可通过使盐形式与碱接触并以常规方式分离游离碱来使游离碱形式再生。游离碱形式在某些物理性质(例如在极性溶剂中的溶解性)方面与它们各自的盐形式有所不同,但是出于本发明的目的,在其他方面中盐等同于它们各自的游离碱。
还包括全部和部分盐,即每摩尔式I的酸具有1、2或3当量,优选2当量的碱的盐或者每摩尔式I的酸具有1、2或3当量,优选1当量的碱的盐。
可药用碱加成盐是与金属或胺,例如碱金属和碱土金属或有机胺形成的。用作阳离子的金属的实例是钠,钾,镁,钙等。合适的胺的实例是N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、二环己胺、乙二胺、N-甲基葡糖胺和普鲁卡因。
所述酸性化合物的碱加成盐是通过使游离酸形式与足够量的所需碱接触从而以常规方式产生盐而制备的。可通过使盐形式与酸接触并分离出游离酸来使游离酸形式再生。
本发明的化合物可同时具有碱性和酸性中心,因此可以是两性离子或内盐的形式。
通常来说,通过适当地使用所需的酸或碱,可容易地制备式I化合物的可药用盐。该盐可从溶液中沉淀出来并通过过滤收集,或者可通过蒸发溶剂来回收。例如,可将酸的水溶液例如盐酸添加至式I化合物的水悬浮液中,并将所得混合物蒸发至干(冻干)以获得作为固体的酸加成盐。或者,可将式I化合物溶于合适的溶剂,例如醇,例如异丙醇中,并将酸添加至相同溶剂或另外的合适的溶剂。然后可直接沉淀所得的酸加成盐,或通过添加极性较小的溶剂例如二异丙醚或己烷沉淀,并通过过滤分离。
有机化学领域的技术人员将理解,许多有机化合物可与其与之反应或其从中沉淀或结晶的溶剂形成配合物。这些配合物被称为“溶剂合物”。例如,与水的配合物被称为“水合物”。本发明化合物的溶剂合物在本发明的范围内。式I化合物的盐可形成溶剂合物(例如水合物),并且本发明也包括所有这样的溶剂合物。词语“溶剂合物”的含义对于本领域技术人员而言是公知的,其是通过溶剂和溶质的相互作用(即,溶剂化)形成的化合物。制备溶剂合物的技术在本领域中是建立良好的(例如,参见Brittain.Polymorphism inPharmaceutical solids.Marcel Decker,New York,1999.)。
本发明还涵盖了式I化合物的N-氧化物。术语“N-氧化物”意指对于含有在其他情况下未被取代的sp2N原子的杂环,N原子可带有共价键合的O原子,即-N→O。这种N-氧化物取代的杂环的实例包括吡啶基N-氧化物、嘧啶基N-氧化物、吡嗪基N-氧化物和吡唑基N-氧化物。
本发明还涵盖了式I化合物的前药,即当施用于哺乳动物对象时在体内释放根据式I的活性母体药物的化合物。前药是具有药理学活性的或更通常是无活性的化合物,其通过代谢转化被转化为药理学活性剂。式I化合物的前药是通过以这样的方式修饰式I化合物中存在的官能团而制备的:该修饰可在体内裂解以释放母体化合物。在体内,前药在生理条件下容易经历化学变化(例如,被天然存在的一种或更多种酶所作用),从而导致药理学活性剂的释放。前药包括式I化合物,其中式I化合物的羟基、氨基或羧基与可在体内裂解以分别使游离羟基、氨基或羧基再生的任何基团键合。前药的实例包括式I化合物的酯(例如乙酸酯、甲酸酯和苯甲酸酯衍生物)或任何其他在达到生理pH后或通过酶作用转化为活性母体药物的衍生物。选择和制备合适的前药衍生物的常规方法在本领域中描述(参见,例如,Bundgaard.Design of Prodrugs.Elsevier,1985)。
前药可以以与它们转化为的活性成分相同的方式和等同的有效量施用,或者其可以以储库形式例如经皮贴剂或其他适于允许(通过提供酶或其他合适的药剂)将前药随时间缓慢转化为活性成分,并将该活性成分递送给患者的储库。
本发明还涵盖代谢物。本文中公开的化合物的“代谢物”是当化合物代谢时形成的化合物的衍生物。术语“活性代谢物”是指化合物被代谢时形成的该化合物的生物活性衍生物。术语“代谢”是指生物体内特定物质发生变化的过程的总和。简言之,体内存在的所有化合物都被体内的酶操纵,以获取能量和/或将其从体内清除。特定的酶对化合物产生特定的结构改变。例如,细胞色素P450催化多种氧化和还原反应,而尿苷二磷酸葡糖醛酸基转移酶催化活化的葡糖醛酸分子转移至芳族醇、脂肪族醇、羧酸、胺和游离巯基。关于代谢的更多信息可从The Pharmacological Basis of Therapeutics,9th Edition,McGraw-Hill(1996),pages 11-17中获得。
本文中公开的化合物的代谢物可通过将化合物施用于宿主并分析来自宿主的组织样品,或通过将化合物与肝细胞在体外孵育并分析所得化合物来鉴定。两种方法都是本领域公知的。
术语“载体”是指与活性化合物一起施用的稀释剂、赋形剂和/或载剂。本发明的药物组合物可包含多于一种载体的组合。这样的药物载体可以是无菌液体,例如水、盐水溶液、右旋糖水溶液、甘油水溶液和油,包括石油,动物、植物或合成来源的油,例如花生油、大豆油、矿物油、芝麻油等。优选将水或水溶液、盐水溶液和右旋糖水溶液和甘油溶液用作载体,特别是对于可注射溶液。合适的药物载体在E.W.Martin的“Remington’sPharmaceutical Sciences”(第18版)中描述。
“可药用赋形剂”意指可用于制备通常是安全、无毒且生物学上或其他方面均期望的药物组合物的赋形剂,并且包括兽医学用途以及人药物用途可接受的赋形剂。如本申请中所使用的“可药用赋形剂”包括一种或多于一种这样的赋形剂二者。
本发明的化合物可被配制为以任何方便的方式施用用于人或兽用药物中,因此,本发明在其范围内包括药物组合物,其包含适用于人或兽用药物的本发明化合物。这样的组合物可借助于一种或更多种合适的载体以常规方式应用来呈现。可接受的用于治疗用途的载体在制药领域是公知的,并且例如在Remington’s Pharmaceutical Sciences,MackPublishing Co.(A.R.Gennaro edit.1985)中进行了描述。可根据预期的施用途径和标准药物实践选择药物载体。除载体之外,药物组合物还可包含任何合适的黏合剂、润滑剂、助悬剂、包衣剂和/或增溶剂。
包含式I化合物的药物组合物
尽管可将化合物I作为本体物质施用,但优选使活性成分以药物制剂的形式存在,例如,其中所述物质与针对预期的施用途径和标准药物实践选择的可药用载体混合。
因此,本发明还提供了药物组合物,其包含与可药用载体混合的式I化合物或其溶剂合物、水合物、异构体(例如,对映体、非对映体等)、N-氧化物或可药用盐。术语“载体”是指与活性化合物一起施用的稀释剂、赋形剂和/或载剂。
式I化合物可与其他治疗和/或活性剂组合使用。因此,在另一方面中,本发明提供了药物组合物,其包含式I化合物或其溶剂合物、水合物、异构体(例如对映体、非对映体等)、N-氧化物或可药用盐,第二活性成分,以及可药用载体。
除了载体之外,药物组合物还可包含任何合适的黏合剂、润滑剂、悬浮剂、包衣剂和/或增溶剂。
药物组合物中也可提供防腐剂、稳定剂、染料和矫味剂。也可使用抗氧化剂和助悬剂。
可将本发明的化合物还原成细颗粒形式(例如,使用已知的研磨程序例如湿磨进行研磨)以获得适合于片剂形成和其他制剂类型的粒径。本发明化合物的细分(纳米粒)制剂可通过本领域已知的方法制备,例如参见WO02/00196。
施用途径和单位剂量形式
施用途径包括经口(例如,作为片剂、胶囊剂或可吸收溶液剂)、表面(topical)、黏膜(例如,作为鼻喷雾剂或吸入用气雾剂)、经鼻、肠胃外(例如,通过可注射形式)、胃肠道、椎管内、腹膜内、肌内、静脉内、子宫内、眼内、真皮内、颅内、鞘内、气管内、阴道内、脑室内、脑内、皮下、经眼(包括玻璃体内或前房内(intracameral))、经皮、直肠、口含、硬膜外和舌下。本发明的组合物可特别地配制用于那些施用途径中的任何一种。在优选的实施方案中,本发明的药物组合物以适于经口递送的形式配制。
取决于不同的递送系统,可能存在不同的组成/配方要求。应当理解,并非所有化合物都需要通过相同途径施用。同样,如果组合物包含多于一种活性组分,则可通过不同途径施用那些组分。举例来说,本发明的药物组合物可配制成使用微型泵或通过黏膜途径递送,例如作为鼻喷雾剂或用于吸入的气雾剂或可摄入溶液剂,或肠胃外施用,其中组合物为通过注射形式配制的,用于通过例如静脉内、肌内或皮下途径递送。或者,可将制剂设计为通过多种途径递送。
当药剂通过胃肠道黏膜经黏膜递送时,其应能够在通过胃肠道的转运过程中保持稳定;例如,其应能抵抗蛋白水解降解、在酸性pH值下稳定并能抵抗胆汁的清洁作用。例如,式I化合物可用肠溶衣层包衣。肠溶衣层材料可分散或溶解在水或合适的有机溶剂中。可单独或组合使用使用以下中的一种或更多种作为肠溶衣聚合物;例如,以下的溶液或分散体:甲基丙烯酸共聚物、邻苯二甲酸乙酸纤维素、乙酸丁酸纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、聚乙酸乙烯邻苯二甲酸酯、偏苯三酸乙酸纤维素、羧甲基乙基纤维素、虫胶或其他一种或更多种合适的肠溶衣层聚合物。出于环境原因,水性包衣方法可能是优选的。在这种水性方法中,最优选甲基丙烯酸共聚物。
适当时,药物组合物可通过吸入施用,以栓剂或阴道栓剂的形式施用,以洗剂、溶液剂、霜剂、软膏剂或扑粉剂(dusting powder)的形式表面施用,通过皮肤贴剂施用,以含有赋形剂(例如淀粉或乳糖)的片剂的形式经口施用,或者以单独或与赋形剂混合的胶囊剂或胚珠剂(ovule)形式施用,或以含有矫味剂或着色剂的酏剂、溶液剂或混悬剂形式施用,或者它们可肠胃外注射,例如静脉内、肌内或皮下注射。对于口含或舌下施用,组合物可以以片剂或锭剂的形式施用,其可以常规方式配制。
当本发明的组合物肠胃外施用时,这种施用包括以下中的一种或更多种:静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内或皮下施用药剂;和/或使用输注技术。
本发明的药物组合物可肠胃外施用,例如通过输注或注射。适用于注射或输注的药物组合物可以是无菌水溶液剂、分散体或含有活性成分的无菌粉末剂的形式,如果需要的话,可对所述活性成分进行调节以制备这样的适合于输注或注射的无菌溶液剂或分散体。该制剂可任选地被包封在脂质体中。在所有情况下,最终制剂在生产和储存条件下必须是无菌、液体且稳定的。为了提高储存稳定性,这样的制剂还可包含防腐剂以防止微生物的生长。可通过添加多种抗细菌剂和抗真菌剂来预防微生物的作用,例如对羟基苯甲酸酯、氯丁醇、乙酸钠、乳酸钠、柠檬酸钠或抗坏血酸。在许多情况下,建议使用等张物质,例如糖、缓冲液和氯化钠,以确保与体液特别是血液类似的渗透压。可通过引入吸收延迟剂(例如单硬脂酸铝或明胶)来延长这样的可注射混合物的吸收。
分散体可在液体载体或中间体例如甘油、液体聚乙二醇、三醋精油及其混合物中制备。液体载体或中间体可以是溶剂或液体分散介质,其包含例如水、乙醇、多元醇(例如甘油、丙二醇等)、植物油、无毒甘油酯及其合适的混合物。可通过产生脂质体,在分散体的情况下施用合适的粒径或通过添加表面活性剂来维持合适的流动性。
对于肠胃外施用,该化合物最好以无菌水溶液剂的形式使用,该无菌水溶液剂可包含其他物质,例如,足够的盐或葡萄糖以使该溶液剂与血液等张。如有必要,应适当对水溶液进行缓冲(优选缓冲至pH 3至9)。无菌条件下合适的肠胃外制剂的制备可通过本领域技术人员公知的标准制药技术容易地完成。
无菌可注射溶液可通过将式I化合物与适当的溶剂和一种或更多种上述载体混合,随后进行无菌过滤来制备。在适用于制备无菌可注射溶液的无菌粉末的情况下,优选的制备方法包括真空干燥和冻干,这提供了醛固酮受体拮抗剂和所需赋形剂的粉状混合物,用于随后制备无菌溶液。
根据本发明的化合物可配制成通过注射(例如,通过静脉推注或输注或者通过肌内、皮下或鞘内途径)用于人或兽用药物中,并且可以以单位剂量形式存在于安瓿或其他单位剂量的容器中,或多剂量的容器中(必要时添加防腐剂)。用于注射的组合物可以是在油性或水性载剂中的悬浮剂、溶液剂或乳剂的形式,并且可包含配制剂,例如助悬剂、稳定剂、增溶剂和/或分散剂。或者,活性成分可以是无菌粉末剂形式,以便在使用前用合适的载剂例如无菌、无热原的水重构。
本发明的化合物可以以片剂、胶囊剂、胚珠剂、酏剂、溶液剂或混悬剂的形式(例如经口或表面)施用,其可包含矫味剂或着色剂,用于速释、延迟释放、调节释放、缓释、脉冲释放或控释应用。
本发明的化合物还可以以适合于经口或口含施用的形式,例如以溶液剂、凝胶剂、糖浆剂、漱口剂或混悬剂,或在使用前用水或其他合适的载剂构建的干粉末剂的形式存在,任选地与矫味剂和着色剂一起,用于人或兽用用途。也可使用固体组合物,例如片剂、胶囊剂、锭剂、软锭剂(pastille)、丸剂、大丸剂、粉末剂、糊剂、颗粒剂、弹丸剂或预混制剂。可根据本领域公知的方法制备用于经口使用的固体和液体组合物。这样的组合物还可包含一种或更多种可药用载体和赋形剂,其可以是固体或液体形式。
片剂可包含赋形剂,例如微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙和甘氨酸;崩解剂,例如淀粉(优选玉米、马铃薯或木薯淀粉)、羟基乙酸淀粉钠、交联羧甲基纤维素钠和某些配合物硅酸盐;以及制粒黏合剂,例如聚乙烯吡咯烷酮、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、蔗糖、明胶和阿拉伯胶。
另外,可包括润滑剂,例如硬脂酸镁、硬脂酸、山嵛酸甘油酯和滑石。
组合物可以以迅速释放或控释片剂、微粒剂、微型片剂、胶囊剂、小药囊剂和经口溶液剂或混悬剂或者用于制备它们的粉末剂的形式经口施用。除了本发明的泮托拉唑的新的固态形式作为活性物质外,经口制剂还可任选地包含多种标准药物载体和赋形剂,例如黏合剂、填充剂、缓冲剂、润滑剂、助流剂、染料、崩解剂、气味剂(odourant)、甜味剂、表面活性剂、脱模剂、抗黏剂和包衣剂。一些赋形剂在组合物中可能具有多种作用,例如既用作黏合剂又用作崩解剂。
用于经口组合物的可药用崩解剂的实例包括淀粉、预糊化淀粉、羟基乙酸淀粉钠、羧甲基纤维素钠、交联羧甲基纤维素钠、微晶纤维素、藻酸盐、树脂、表面活性剂、泡腾组合物、含水硅酸铝和交联聚乙烯吡咯烷酮。
用于经口组合物的可药用黏合剂的实例包括阿拉伯胶;纤维素衍生物,例如甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素或羟乙基纤维素;明胶、葡萄糖、右旋糖、木糖醇、聚甲基丙烯酸酯、聚乙烯吡咯烷酮、山梨糖醇、淀粉、预胶化淀粉、西黄蓍胶、黄原胶树脂、藻酸盐、硅酸铝镁、聚乙二醇或膨润土。
用于经口组合物的可药用填充剂的实例包括乳糖、脱水乳糖、乳糖一水合物、蔗糖、右旋糖、甘露醇、山梨糖醇、淀粉、纤维素(特别是微晶纤维素)、磷酸二氢钙或磷酸脱水钙、碳酸钙和硫酸钙。
可用于本发明的组合物中的可药用润滑剂的实例包括硬脂酸镁、滑石、聚乙二醇、环氧乙烷的聚合物、月桂基硫酸钠、月桂基硫酸镁、油酸钠、硬脂富马酸钠、和胶体二氧化硅。
用于经口组合物的合适的可药用气味剂的实例包括合成芳香剂(aroma)和天然芳香油,例如油、花、水果(例如,香蕉、苹果、酸樱桃、桃)及其组合的提取物,以及类似的芳香剂。它们的使用取决于许多因素,最重要的是对于将服用药物组合物的人群的感官可接受性。
用于经口组合物的合适的可药用染料的实例包括合成和天然染料,例如二氧化钛、β-胡萝卜素和葡萄柚皮提取物。
用于经口组合物的通常用于促进吞咽、改变释放特性、改善外观和/或掩盖组合物味道的可用的可药用包衣剂的实例包括羟丙基甲基纤维素、羟丙基纤维素和丙烯酸酯-甲基丙烯酸酯共聚物。
用于经口组合物的可药用甜味剂的实例包括阿斯巴甜、糖精、糖精钠、环拉酸钠(sodium cyclamate)、木糖醇、甘露醇、山梨糖醇、乳糖和蔗糖。
可药用缓冲剂的实例包括柠檬酸、柠檬酸钠、碳酸氢钠、磷酸氢二钠、氧化镁、碳酸钙和氢氧化镁。
可药用表面活性剂的实例包括月桂基硫酸钠和聚山梨酯。
相似类型的固体组合物也可用作明胶胶囊中的填充剂。在这方面,优选的赋形剂包括乳糖、淀粉、纤维素、牛乳糖或高分子量聚乙二醇。对于水性悬浮剂和/或酏剂,该药剂可与多种甜味剂或矫味剂,着色物质或染料,乳化剂和/或助悬剂以及稀释剂如水、乙醇、丙二醇和甘油及其组合结合。
本发明的化合物还可例如配制成含有例如用于人或兽用药物的常规栓剂基质的栓剂,或例如含有常规的阴道栓剂基质的阴道栓剂。
根据本发明的化合物可以以软膏剂、霜剂、凝胶剂、水凝胶剂、洗剂、溶液剂、洗发香波、粉末剂(包括喷雾剂或扑粉剂)、阴道栓剂、棉塞(tampon)、喷雾剂、浸剂(dip)、气雾剂、滴剂(例如眼耳滴剂或滴鼻剂)或浇泼剂(pour-on)的形式配制用于表面施用,用于人和兽用药物。
为了表面施用于皮肤,可将本发明的药剂配制为合适的软膏剂,其包含悬浮或溶解在例如与以下中的一种或更多种的混合物中的活性化合物:矿物油、液体矿脂、白矿脂、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蜡、脱水山梨糖醇单硬脂酸酯、聚乙二醇、液体石蜡、聚山梨酯60、鲸蜡酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苄醇和水。这样的组合物还可包含其他可药用赋形剂,例如聚合物、油、液体载体、表面活性剂、缓冲剂、防腐剂、稳定剂、抗氧化剂、保湿剂、润肤剂(emollient)、着色剂和气味剂。
适用于这样的表面组合物的可药用聚合物的实例包括丙烯酸类聚合物;纤维素衍生物,例如羧甲基纤维素钠、甲基纤维素或羟丙基纤维素;天然聚合物,例如藻酸盐、西黄蓍胶、果胶、黄原胶和胞嘧啶。
如此有用的合适的可药用油的实例包括矿物油、硅油、脂肪酸、醇和二醇。
合适的可药用液体载体的实例包括水、醇或二醇,例如乙醇、异丙醇、丙二醇、己二醇、甘油和聚乙二醇,或其混合物,其中伪多晶型物任选地溶解或分散在其中,任选地添加无毒的阴离子、阳离子或非离子表面活性剂,以及无机或有机缓冲剂。
可药用防腐剂的实例包括苯甲酸钠、抗坏血酸、对羟基苯甲酸的酯以及多种抗细菌和抗真菌剂,例如溶剂,例如乙醇、丙二醇、苄醇、氯丁醇、季铵盐和对羟基苯甲酸酯(例如对羟基苯甲酸甲酯、对羟基苯甲酸乙酯和对羟基苯甲酸丙酯)。
可药用稳定剂和抗氧化剂的实例包括乙二胺四乙酸(EDTA)、硫脲、生育酚和丁基羟基茴香醚。
可药用保湿剂的实例包括甘油、山梨糖醇、尿素和聚乙二醇。
可药用润肤剂的实例包括矿物油、肉豆蔻酸异丙酯和棕榈酸异丙酯。
化合物也可例如通过使用皮肤贴剂经皮肤(dermally)或经皮(transdermally)施用。
对于眼科用途,可将化合物配制成在等张的、pH经调节的无菌盐水中的微粉化悬浮剂,或者优选配制成在等张的、pH经调节的无菌盐水中的溶液剂,任选地与防腐剂例如苄基氯化铵组合。
如所指出的,本发明的化合物可鼻内或通过吸入施用,并且以干粉末吸入器或气雾剂喷雾剂形式从加压容器、泵、喷雾器(spray)或雾化器(nebulizer)中使用合适的推进剂,例如二氯二氟甲烷,三氯氟甲烷,二氯四氟乙烷,氢氟烷烃,例如1,1,1,2-四氟乙烷(HFA134AT)或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA)、二氧化碳或其他合适的气体来方便地递送。在加压气雾剂的情况下,剂量单位可通过提供阀门以递送计量的量来确定。加压容器、泵、喷雾器或雾化器可包含活性化合物的溶液或悬浮液,例如使用乙醇和推进剂的混合物作为溶剂,其可另外包含润滑剂,例如脱水山梨糖醇三油酸酯。
用于吸入器或吹入器的胶囊和药筒(例如,由明胶制成)可配制成包含化合物和合适的粉末基质例如乳糖或淀粉的粉末混合物。
对于通过吸入的表面施用,可通过雾化器递送根据本发明的化合物以用于人或兽用药物。
本发明的药物组合物可包含每体积0.01至99重量%的活性材料。对于表面施用,例如,该组合物通常包含0.01%至10%,更优选0.01%至1%的活性材料。
活性剂也可以脂质体递送系统的形式,例如小的单层囊泡、大的单层囊泡和多层囊泡施用。脂质体可由多种磷脂形成,例如胆固醇、硬脂胺或磷脂酰胆碱。
本发明的药物组合物或单位剂量形式可根据以上给出的指导原则,根据常规测试所定义的剂量和施用方案进行施用,以获得最佳活性,同时将对特定患者的毒性或副作用降至最低。然而,根据本文中给出的指导原则,治疗方案的这种微调是常规的。
本发明的活性剂的剂量可根据多种因素而变化,例如潜在的疾病状况、个体的状况、体重、性别和年龄以及施用方式。可通过本领域普通技术人员已知的经验方法,例如通过建立施用剂量和频率的模型并比较在模型的每个点处的一组实验单位或对象,来容易地确定治疗病症的有效量。待施用于患者的确切量将根据病症的状态和严重程度以及患者的身体状况而变化。任何症状或参数的可测量改善可由本领域技术人员确定或由患者报告给医师。
药剂的施用量可为约0.01至约25mg/kg/天,优选约0.1至约10mg/kg/天,最优选0.2至约5mg/kg/天。应当理解,本发明的药物制剂不必一定包含有效治疗该病症的药剂的全部量,因为可通过施用这种药物制剂的多个剂量来达到这种有效量。通常来说,“有效量”是指以临床相关的方式施用以改善、抑制或减轻对象的疾病或障碍或病症,或者疾病或障碍的症状的药物组合物的量。在对象中任何与临床相关的改善都被认为足以实现治疗。优选地,足以治疗的量是阻止感染的发生或者一种或更多种症状的量,或者是相对于未用本发明组合物治疗的对照对象,降低对象遭受或发生一种或更多种感染症状的严重性,或减少对象遭受或发生一种或更多种感染症状的时间长度的量。
在本发明的一个优选的实施方案中,将根据式I的化合物配制成胶囊剂或片剂,优选包含10至200mg的本发明的化合物,并且优选以10至300mg,优选20至150mg,最优选约50mg的总日剂量施用于患者。
用于肠胃外施用的药物组合物包含基于总药物组合物的100重量%的按重量计约0.01%至约100%的本发明的活性剂。
通常来说,经皮剂型包含相对于剂型100%总重量的按重量计约0.01%至约100%的活性剂。
药物组合物或单位剂量形式可以单一日剂量施用,或总日剂量可以分剂量施用。另外,可能需要共同施用或顺序施用另一种化合物来治疗该疾病。为此,将组合的活性成分配制成简单的剂量单位。
对于其中化合物处于单独剂量制剂中的联合治疗,可同时施用化合物,或者可以以交错的间隔施用每种化合物。另外的化合物也可以以特定的间隔施用。施用顺序取决于多种因素,包括患者的年龄、体重、性别和医疗状况;待治疗疾病的严重程度和病原学,施用途径,患者的肾和肝功能,患者的治疗史以及患者的响应性。可对施用顺序的确定进行微调,并且根据本文给出的指导原则,这种微调是常规的。
具体实施方式
合成
式I化合物,或者实际上式1a至1g的化合物,及其对映体、非对映体、N-氧化物和可药用盐,可通过下文概述的一般方法制备,所述方法构成本发明的另外的方面。
除文献中已知的、在实验部分例证的或本领域技术人员清楚的其他标准操作外,还可通过采用以下方案所示的反应来制备本发明的化合物。本文中未描述的原料可商购获得,或者可通过使用文献中描述的反应来制备,或者对于本领域技术人员是清楚的。提供以下实施例,以便可更全面地理解本发明,所述实施例仅是举例说明性的,并且不应解释为限制性的。
本领域技术人员将认识到,可期望使用用于制备根据式I的化合物的中间体的受保护的衍生物。可通过本领域已知的方法进行官能团的保护和脱保护(参见,例如,Greenand Wuts Protective Groups in Organic Synthesis.John Wiley and Sons,New York,1999)。
缩写PG描述了“保护基”,其在进行某些操作之前被引入反应性基团,并且随后被除去。用于保护反应性基团的PG的实例包括:乙酰基、三氟乙酰基、苯甲酰基、乙氧基羰基、N-叔丁氧基羰基(BOC)、N-苄氧基羰基(Cbz)、苄基、甲氧基苄基、2,4-二甲氧基苄基,并且对于氨基另外地酞酰基(phthalyl)(对于氨基-烷基氨基或亚氨基);N-甲氧基甲基(MOM)、N-苄氧基甲基(BOM)、N-(三甲基甲硅烷基)乙氧基甲基(SEM)、N-叔丁基-二甲基甲硅烷氧基甲基、N-叔丁基-二甲基甲硅烷基(TBDMS)、N-三异丙基甲硅烷基(TIPS)、N-苄基、N-4-甲氧基苄基(PMB)、N-三苯甲基(Tr)、N-叔丁氧基羰基(BOC)、N-苄氧基羰基(Cbz)或N-三甲基甲硅烷基乙基磺酰基(SES)(对于酰胺基);甲氧基、苄氧基、三甲基甲硅烷基(TMS)、乙酰基、苯甲酰基、叔丁基、三苯甲基、苄基或四氢吡喃基(THP)(对于羟基);或三甲基甲硅烷基(TMS)、甲基-乙基、叔丁基、苄基或四氢吡喃基(THP)(对于羧基)。
本发明化合物通常根据以下不同方案制备。在某些情况下,可例如通过操纵取代基来进一步修饰最终产物。这些操作可包括但不限于本领域技术人员通常已知的还原、氧化、烷基化、酰化和水解反应。在某些情况下,可改变进行上述反应方案的顺序,以促进反应或避免不期望的反应产物。提供以下实施例,以便可更充分地理解本发明。这些实施例仅是举例说明性的,不应以任何方式构成对本发明的限制。
如以下方案1中所示,可通过使用本领域技术人员公知的合并方法通过亲核芳族取代或作为替代地通过还原胺化反应将市售化合物1选择性地转化为3-(R2-氨基)-5-溴吡啶-2-甲腈(2)。进而将2与必要的二胺(3)缩合以获得R2-N-5-溴-吡啶-3-胺N-甲基-吡啶-3-胺的2-(4,5-二氢-1H-咪唑-2-基)-或2-(1,4,5,6-四氢嘧啶-2-基)衍生物(4)。在下一步中,化合物4随后通过反应物环化,得到相应的化合物5,其最终进行反应以直接产生R1取代的中间体,从而获得落入式1a或1e范围内的化合物。该最后的衍生化过程可使用标准方法来进行,例如如布赫瓦尔德反应、酰化反应、烷基化或可用于形成根据式1a和1e的化合物的目的的任何种类的N-衍生化反应,该过程是本领域技术人员公知的。相同的反应步骤可重新排列,提前或推迟合成中的每个步骤而没有任何限制,例如布赫瓦尔德反应可作为整个过程的最后一步进行,或者作为替代地作为第一步进行。
对于以下方案1,技术人员将理解,化合物4至6说明了与化合物3反应后,含nR6取代基的环可以是包含两个氮原子的五元或六元杂环的可能性。当整数m’的值等于1或2并提供基团-(C)m’-为单个亚甲基桥碳原子或顺序地为一对亚甲基桥碳原子时,这会发生,由此产生的杂环分别是咪唑啉或嘧啶衍生物。咪唑啉衍生物由式1a所示,并包含如表1中所示的化合物1至69,而嘧啶衍生物由式1e所示,并包含如表4中所示的化合物141至155。
方案1:根据式1a和1e的化合物的产生。
如以下方案2中所示,可通过使用本领域技术人员公知的合并方法,通过对相应的氨基或醛衍生物进行亲核芳族取代或作为替代地通过对其进行还原胺化,将市售化合物1转化为3-(R2-氨基)-5-卤代吡啶-2-羧酸甲酯(2)。在下一步中,化合物2随后通过反应物环化,得到相应的化合物3,将其与POCl3反应以获得式4至7的化合物。4进而与必需的酰肼衍生物环化,以获得经取代的3,4,6,8,13-五氮杂三环[7.4.0.02,6]十三-1(9),2,4,10,12-五烯-7-酮衍生物(5)。在最后一步中,具有卤素衍生物(X’基团)的化合物5最终进行反应直接产生R1取代的中间体,从而获得落入式1c范围内的化合物。该最后的衍生化过程可使用标准方法来进行,例如如布赫瓦尔德反应、芳族亲核反应、酰化反应、烷基化或本领域技术人员公知的可用于形成根据式1c的化合物6的目的的任何种类的N-衍生化反应。方案2还显示化合物7与必需的酰肼衍生物环化以获得经取代的2,4,5,7,10-五氮杂三环[7.4.0.03,7]十三-1(13),3,5,9,11-五烯-8-酮衍生物(8)。在最后一步中,具有卤素衍生物(X’基团)的化合物8最终进行反应以直接产生R1取代的中间体,从而获得落入式1f范围内的化合物9。该最后的衍生化过程可使用标准方法来进行,例如如布赫瓦尔德反应、芳族亲核反应、酰化反应、烷基化或本领域技术人员公知的可用于形成根据式1f的化合物的目的的任何种类的N-衍生化反应。相同的反应步骤可重新排列,提前或推迟合成中的每个步骤而没有任何限制,例如布赫瓦尔德反应可作为整个过程的最后一步进行,或者作为替代地作为第一步进行。
方案2:根据式1c和1f的化合物的产生。
如以下方案3中所示,可商购的化合物1可通过与反应物一起环化成4-氨基-6-卤代-1H-吡啶并[3,2-d]嘧啶-2-酮(2)。在下一步中,化合物2随后与试剂反应,得到相应的化合物3,将其与4环化,获得化合物5。5进而最终进行反应以直接产生R1取代的中间体,获得落入式1b范围内的化合物。该最后的衍生化过程可使用标准方法来进行,例如如布赫瓦尔德反应、芳族亲核反应、酰化反应、烷基化或本领域技术人员公知的可用于形成根据式1b的化合物的目的的任何种类的N-衍生化反应。相同的反应步骤可重新排列,提前或推迟合成中的每个步骤而没有任何限制,例如布赫瓦尔德反应可作为整个过程的最后一步进行,或者作为替代地作为第一步进行。
方案3:根据式1b的化合物的产生。
如以下方案4中所示,可将市售化合物1与异丙醇反应,得到5-溴-2-异丙氧基羰基-吡啶-3-羧酸(2)。在下一步中,化合物2随后与2-芳基乙酸甲酯反应,得到相应的化合物3,将其水解成4。4进而与酰肼反应,获得化合物5。在下一步中,5与POCl3反应,获得化合物6,化合物6与所需的酰肼衍生物反应,得到化合物7。使化合物7最终进行反应,直接产生R1取代的中间体,以获得落入式1d范围内的化合物。该最后的衍生化过程可使用标准方法来进行,例如如布赫瓦尔德反应、芳族亲核反应、酰化反应、烷基化或本领域技术人员公知的可用于形成根据式1d的化合物的目的的任何种类的N-衍生化反应。相同的反应步骤可重新排列,提前或推迟合成中的每个步骤而没有任何限制,例如布赫瓦尔德反应可作为整个过程的最后一步进行,或者作为替代地作为第一步进行。
方案4:根据式1d的化合物的产生。
如以下方案5中所示,可通过标准方法将可商购的化合物1反应生成R1取代的中间体2,所述标准方法例如如布赫瓦尔德反应、芳族亲核反应、酰化反应、烷基化或本领域技术人员公知的可用于形成式化合物2的目的的任何种类的N-衍生化反应。可根据Y’,通过标准方法,使得到的中间体2反应,该化合物可通过与三氯乙酰基异氰酸酯反应而环化为化合物4,所述标准方法例如如芳族亲核反应、还原胺化、布赫瓦尔德反应、或可用于获得对应化合物3的目的的任何种类的N-衍生化反应。化合物4进而与市售或适当合成的中间体5缩合,以获得经适当取代的3,6,8,13-四氮杂三环[7.4.0.02,6]十三-1(9),2,10,12-四烯-4,7-二酮衍生物6,其落入式1g范围内。相同的反应步骤可重新排列,提前或推迟合成中的每个步骤而没有任何限制,例如布赫瓦尔德反应可作为整个过程的最后一步进行,或者作为替代地作为第一步进行。
方案5:根据式1g的化合物的产生。
目前在本概述中未描述的其他化合物的合成在下面的本发明实验部分中有充分的文献记载。
在本领域公知的标准条件下,可将根据式I的化合物的游离碱,或者实际上是式1a至1g的化合物的游离碱、它们的非对映体或对映体转化为相应的可药用盐。例如,将游离碱溶于合适的有机溶剂,例如甲醇中,用例如1当量的马来酸或草酸、1或2当量的盐酸或甲磺酸处理,然后在真空下浓缩以提供相应的可药用盐。然后可通过从合适的有机溶剂或有机溶剂混合物,例如甲醇/乙醚中重结晶来纯化剩余物。
可通过本领域技术人员公知的简单氧化过程来合成根据式I的化合物的N-氧化物,或者实际上是式1a至1g的化合物的N-氧化物。
通式I化合物的制备
除非另有说明,否则下文描述的实施例的化合物的一种或更多种互变异构形式可原位制备和/或分离。下文描述的实施例的化合物的所有互变异构形式均应视为已公开。
通过以下实施例举例说明本发明,其中可使用以下缩写:
AcOH 乙酸
MeCN 乙腈
Aq. 水性
BOC 叔丁氧羰基
conc. 浓的
DCM 二氯甲烷
DCE 1,2-二氯乙烷
DIPEA N,N-二异丙基乙胺
DMAc N,N-二甲基乙酰胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EI 电子电离
ESI 电喷雾电离
EtOAc 乙酸乙酯
EtOH 乙醇
HCl 盐酸
HCOOH 甲酸
MeOH 甲醇
MS 质谱法
MW 分子量
NaOH 氢氧化钠
NH4OH 氢氧化铵(水中30%氨)
PE 石油醚
Rf 保留值(来自薄层色谱法)
RT或r.t. 室温
Rt 保留时间(来自HPLC)
THF 四氢呋喃
TEA 三乙胺
TFA 三氟乙酸
UPLC 超高效液相色谱法
UPLC-MS UPLC与质谱法联用
以下实施例举例说明了制备上述一些通式I化合物的方法。这些实施例仅是举例说明性的,并不意图限制本发明的范围。试剂和原料是本领域技术人员容易获得的。
实施例1
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-5(3H)-酮
和
实施例18
6-(4-甲氧基苄基)-8-(吗啉-4-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-5(3H)-酮
3-氟-5-吗啉代吡啶-2-甲腈(步骤1)
向微波小瓶中的1.04g3,5-二氟吡啶-2-甲腈(7.46mmol)在DMAC(5mL)中的溶液添加0.65mL吗啉(0.65g,7.46mmol)和2.08mL TEA(1.51g,14.92mmol)。将混合物在微波辐射下于100℃下搅拌30分钟。冷却至室温后,向混合物添加水,获得白色沉淀物。将其用水洗涤并干燥,获得1.3g作为白色固体的3-氟-5-吗啉代吡啶-2-甲腈(产率:84%)。
3-[(4-甲氧基苯基)甲基氨基]-5-吗啉代吡啶-2-甲腈(步骤2)
向0.5g 3-氟-5-吗啉代-吡啶-2-甲腈(2.41mmol)在DMAC(10mL)中的溶液添加1.89mL(4-甲氧基苯基)甲胺(1.98g,14.48mmol)和0.4mL的TEA(0.29g 2.89mmol)。将混合物在MW辐射下于150℃下搅拌1小时。冷却至室温后,将水添加至混合物。获得白色固体,将其用水洗涤并在真空下干燥,以获得550mg(产率70%)的3-[(4-甲氧基苯基)甲基氨基]-5-吗啉代吡啶-2-甲腈,将其不经进一步纯化即用于下一步。
2-(4-异丙基-4,5-二氢-1H-咪唑-2-基)-N-[(4-甲氧基苯基)甲基]-5-吗啉代吡
啶-3-胺(步骤3)
向微波小瓶中的300mg 3-[(4-甲氧基苯基)甲基氨基]-5-吗啉代吡啶-2-甲腈(0.92mmol)在5mL DMAC中的溶液添加486mg 3-甲基丁烷-1,2-二胺HCl(2.77mmol)和0.77mL TEA(561mg,5.55mmol)。将小瓶密封并将混合物在160℃下加热8小时。冷却至室温后,将混合物用EtOAc稀释,并将有机层用水、盐水洗涤,并经无水Na2SO4干燥,蒸发至干,以获得310mg作为黄色油状物的标题产物(81%),将其不经进一步纯化即用于下一步。
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-5(3H)-酮和6-(4-甲氧基苄基)-8-(吗啉-4-基)-2-(丙烷-2-基)-2,6-二
氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮(步骤4)
向在微波小瓶中的300mg 2-(4-异丙基-4,5-二氢-1H-咪唑-2-基)-N-[(4-甲氧基苯基)甲基]-5-吗啉代吡啶-3-胺(0.73mmol)在8mL乙腈中的溶液添加142mg羰基二咪唑(CDI)(0.88mmol)和18mg DMAP(0.15mmol)。将小瓶密封并在微波辐射下于150℃加热90分钟。添加1.2当量的CDI和0.2当量的DMAP,并将混合物在相同条件下再加热90分钟。将反应混合物倒入水中,用EtOAc萃取,经无水Na2SO4干燥。将溶剂蒸发至干,并将粗制品通过自动快速色谱法(Biotage Isolera-Dalton,SNAP25 Ultra柱),用CHCl3-MeOH 95/5洗脱来进行纯化,得到6-(4-甲氧基苄基)-8-(吗啉-4-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮(实施例18)
UPLC-MS[M+H]+=436.3
1H NMR(400MHz,METHANOL-d4)δppm 8.15(d,1H)7.18-7.32(m,2H)6.85-6.92(m,2H)6.74(d,1H)5.08-5.26(m,2H)4.11-4.20(m,1H)4.00-4.09(m,1H)3,75-3.82(m,5H)3.74(s,3H)3.16-3.26(m,4H)1.85-2.02(m,1H)1.05(d,3H)0.98(d,3H).。
通过Biotage Isolera-Dalton,SNAP10Ultra柱进行再纯化后得到了另一组收集的级分,用5%至10%MeOH的EtOAc-MeOH梯度洗脱,得到14mg作为无色油状物的位置异构体6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮(实施例1)(产率:4.4%)。
UPLC-MS[M+H]+=436.29
1H NMR(400MHz,METHANOL-d4)δppm8.23(d,1H),7.25(m,2H),6,92(m,2H),6.80(d,1H),5.25(AB四重峰,2H),4.54-4.69(m,1H),3.83-4.13(m,2H),3.80(m,4H),3.78(s,3H),3.25-3.30(m,4H),2.59-2.74(m,1H),1.00(d,3H),0.87(d,3H).
按照针对实施例1化合物所述的过程,但是在步骤2中用3,5-二甲氧基苄胺替代(4-甲氧基苯基)甲胺,然后根据需要在步骤3中用适当的1,2-二胺(从可得供应商处购买或通过文献公开的方法合成)替换3-甲基丁烷-1,2-二胺,来制备表1所示的示例性化合物2至9、22、35、43、44、46、47。所报道的产率参考最后一步。
实施例2
6-(3,5-二甲氧基苄基)-3-甲基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
和
实施例3
6-(3,5-二甲氧基苄基)-2-甲基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色固体的实施例2(11.3%)和实施例3(22%)。
实施例2:HPLC-MS[M+H]+=438.1,具有一些实施例3的污染
1H NMR(400MHz,氯仿-d)δppm 8.27-8.09(m,1H),6.54(d,1H),6.36(s,3H),5.31(d,3H),5.14(q,2H),4.72(s,1H),4.31(q,1H),3.80(t,5H),3.75(d,7H),3.22(dd,4H),1.52(dd,3H).
实施例3:HPLC-MS[M+H]+=438.1
1H NMR(400MHz,氯仿-d)δppm 8.22(d,1H),6.54(d,1H),6.46-630(m,3H),5.28-5.03(m,2H),4.63(q,1H),4.38(t,1H),3.80(q,5H),3.75(s,6H),3.26(t,4H),1.52(d,3H).
实施例4
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-
c]吡啶并[2,3-e]嘧啶-5(3H)-酮
和
实施例9
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)-2,6-二氢咪唑并[1,2-
c]吡啶并[2,3-e]嘧啶-5(3H)-酮
借助于Isolera One(Biotage),柱型SNAP50,使用EtOAC 100%至EtOAc∶MeOH 8∶2的梯度纯化反应粗制品,得到棕色粉末,然后将其在反相柱色谱,柱型SNAP60上使用NH4HCO3缓冲液:MeCN 9∶1至NH4HCO3缓冲液∶MeCN 3∶7的梯度进行纯化,得到淡黄色粉末。然后将样品从乙腈中结晶并过滤,得到实施例4(白色粉末,43.4%)。母液也作为位置异构体的1∶1混合物回收。借助于Isolera One Biotage,柱型SNAP25,使用100%EtOAc至EtOAc∶MeOH 8∶2的梯度进行进一步纯化,得到作为浅黄色粉末的实施例9。
实施例4:HPLC-MS[M+H]+=466.23
1H NMR(400MHz,氯仿-d)δppm 8.17(d,1H)6.58(d,1H)6.41(d,2H)6.34-6.39(m,1H)4.95-5.29(m,2H)4.16-4.34(m,1H)4.03-4.15(m,1H)3.80-3.86(m,5H)3.77(s,6H)3.14-3.23(m,4H)1.92-2.10(m,1H)0.95-1.20(m,6H)
实施例9:HPLC-MS[M+H]+=466.23
1H NMR(400MHz,氯仿-d)δppm 8.13(d,1H)6.57(d,1H)6.37-6.49(m,2H)6.36(dd,1H)4.83-5.36(m,2H)4.55(ddd,1H)3.90-4.18(m,2H)3.77-3.87(m,4H)3.76(s,6H)3.15-3.30(m,4H)2.52-2.82(m,1H)0.74-1.09(m,6H)
实施例5
6-(3,5-二甲氧基苄基)-2-乙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
和
实施例6
6-(3,5-二甲氧基苄基)-3-乙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到实施例5(19%)和实施例6(5%)。
实施例5:HPLC-MS[M+H]+=452.55
1H NMR(400MHz,氯仿-d)δppm 8.27(d,1H),6.56(d,1H),6.39(s,3H),5.29-5.05(m,2H),4.51(m,1H),4.36(t,1H),3.92(dd,1H),3.83(t,4H),3.78(s,6H),3.29(t,4H),2.10-1.92(m,1H),1.79(dt,1H),1.10(t,3H).
实施例6:HPLC-MS[M+H]+=452.1
实施例7
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]
嘧啶-5(3H)-酮
浅黄色固体(46%)。
HPLC-MS[M+H]+=424.37
1H NMR(400MHz,DMSO-d6)δppm 8.17(d,1H)6.79(d,1H)6.50(d,2H)6.39(t,1H)5.15(s,2H)3.86-4.10(m,4H)3.60-3.78(m,10H)3.22-3.28(m,4H)
实施例8
6-(3,5-二甲氧基苄基)-2,3-二甲基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-5(3H)-酮
通过制备型TLC,使用DCM中的MeOH(0至>5%)作为洗脱剂纯化。
产率:29.6%
HPLC-MS[M+H]+=452.6
1H NMR(300MHz,氯仿-d)δppm 8.13(d,1H),6.55(d,1H),6.37(m,3H),5.13(s,2H),4.65(dt,1H),4.53-4.40(m,1H),3.81(t,4H),3.75(s,7H),3.18(t,4H),1.45(d,3H),1.36(d,3H).
实施例22
b-(3,5-二甲氧基苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2- c]吡啶并[2,3-e]嘧啶-5(3H)-酮
和
实施例35
6-(3,5-二甲氧基苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-
c]吡啶并[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到实施例22(16%)和实施例35(11.7%)。
实施例22:HPLC-MS[M+H]+=480.24
实施例35:HPLC-MS[M+H]+=480.34
实施例43
2-环己基-6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶
并[2,3-e]嘧啶-5(3H)-酮
和
实施例44
3-环己基-6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶
并[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到实施例43(56%)和实施例44(8.7%)。
实施例43:HPLC-MS[M+H]+=506.41
实施例44:HPLC-MS[M+H]+=506.35
实施例46
6-(3,5-三甲氧基苄基)-8-(吗啉-4-基)-2-苯基-2,6-三氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
和
实施例47
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-3-苯基-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到实施例46(26.6%)和实施例47(2.8%)。
实施例46:HPLC-MS[M+H]+=500.38
实施例47:HPLC-MS[M+H]+=500.26
按照针对实施例1所述的过程,但是在步骤2中用4-氯苄基胺替代(4-甲氧基苯基)甲胺,并在需要时在步骤3中用适当的1,2-二胺(从可得供应商处购买或通过文献公开的方法合成)替换3-甲基丁烷-1,2-二胺,来制备表1中所示的实施例10至14、25、26、30、31、36、40、41、45、50、54、55、61至63。所报道的产率参考最后一步。
实施例10
6-(4-氯苄基)-2-环丙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-
e]嘧啶-5(3H)-酮
和
实施例12
6-(4-氯苄基)-3-环丙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-
e]嘧啶-5(3H)-酮
通过使用DCM中的MeOH(0至5%)的快速色谱法,然后通过制备型HPLC纯化粗制品,得到6.6%的实施例10和2%的实施例12。
实施例10:HPLC-MS[M+H]+=438.06
1H NMR(300MHz,氯仿-d)δppm 8.17(d,1H),7.38-7.31(m,2H),7.26-7.16(m,2H),6.46(d,1H),5.31-5.06(m,2H),4.31-4.16(m,1H),3.99-3.86(m,2H),3.87-3.80(m,4H),3.19(dd,4H),1.07(dd,1H),0.74-0.52(m,3H),0.45(q,1H).
实施例12:HPLC-MS[M+H]+=438.11
实施例11
6-(4-氯苄基)-2-(甲氧基甲基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
和
实施例13
6-(4-氯苄基)-3-(甲氧基甲基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
通过使用DCM中的MeOH(0至5%)的快速色谱法,然后通过制备型HPLC纯化粗制品,得到5%的实施例11和5%的实施例13。
实施例11:HPLC-MS[M+H]+=442.05
1H NMR(300MHz,氯仿-d)δppm 8.82(d,1H),7.37(d,1H),7.23-7.15(m,2H),6.90-6.81(m,2H),4.41(s,2H),3.95-3.84(m,4H),3.78(s,3H),3.73-3.63(m,1H),3.31-3.16(m,4H),1.57(d,6H).
实施例13:HPLC-MS[M+H]+=442.12
实施例14
6-(4-氯苄基)-8-(吗啉-4-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
和
实施例162
6-(4-氯苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
粗制品通过自动快速色谱法(Biotage Isolera-Dalton),SNAP25 Ultra柱,用等度CHCl3-MeOH 95/5洗脱来进行纯化。分离出富集在每个位置异构体中的两组级分。每组用SNAP10 Ultra柱,用5%至10%的EtOAc-MeOH梯度洗脱进行再纯化,得到作为浅黄色固体的实施例14(50%)和作为浅黄色固体的实施例162(3.8%)。
实施例14:
1H NMR(400MHz,DMSO-d6)δppm8.16(d,1H)7.32-7.45(m,4H)6.73(d,1H)5.12-5.33(m,2H)3.91-4.05(m,2H)3.71(t,4H)3.52-3.65(m,1H)3.24(dd,4H)1.65-1.86(m,1H)0.99(d,3H)0.92(d,3H)
UPLC-MS[M+H]+=440.24
实施例162:
UPLC-MS[M+H]+=440.28
1H NMR(400MHz,DMSO-d6)δppm 8.17(d,1H)7.38-7.45(m,2H)7.30-7.35(m,2H)6.76(d,1H)5.17-5.33(m,2H)435-446(m,1H)3.87-3.96(m,1H)3.77(dd,1H)3.70(t,4H)3.20-3.28(m,4H)2.53(br d,1H)0.89(d,3H)0.74(d,3H)
实施例25
6-(4-氯苄基)-2-环己基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-
e]嘧啶-5(3H)-酮
和
实施例26
6-(4-氯苄基)-3-环己基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-
e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为蜡状黄色固体的实施例25(83%)和实施例26(12%)。
实施例25:HPLC-MS[M+H]+=480.4
实施例26:HPLC-MS[M+H]+=480.4
实施例30
6-(4-氯苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
和
实施例31
6-(4-氯苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为蜡状黄色固体的实施例30(59%)和实施例31(15%)。
实施例30:HPLC-MS[M+H]+=454.46
实施例31:HPLC-MS[M+H]+=454.38
实施例36
6-(4-氯苄基)-8-(吗啉-4-基)-2-苯基-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]
嘧啶-5(3H)-酮
和
实施例45
6-(4-氯苄基)-8-(吗啉-4-基)-3-苯基-2,6-二氢咪唑并[[1,2-c]吡啶并[2,3-e]
嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色蜡状固体的实施例36和实施例45。
实施例36:HPLC-MS[M+H]+=474.3
实施例45:HPLC-MS[M+H]+=474.3
实施例40
6-(4-氯苄基)-8-(吗啉-4-基)-2’,3’,5’,6’-四氢螺[咪唑并[1,2-c]吡啶并[2,
3-e]嘧啶-2,4’-吡喃]-5(6H)-酮
和
实施例41
6-(4-氯苄基)-8-(吗啉-4-基)-2,2’,3’,5’,6,6’-六氢-5H-螺[咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-3,4’-吡喃]-5-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色蜡状固体的实施例40(53%)和实施例41(16.2%)。
实施例40:UPLC-MS[M+H]+=468.4
实施例41:UPLC-MS[M+H]+=468.4
实施例50
6-(4-氯苄基)-2-乙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]
嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色蜡状固体的实施例50(12.7%)。
实施例41:UPLC-MS[M+H]+=426.5
实施例54
6-(4-氯苄基)-8-(吗啉-4-基)-2-(吗啉-4-基羰基)-2,6-二氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-5(3H)-酮
和
实施例55
6-(4-氯苄基)-8-(吗啉-4-基)-3-(吗啉-4-基羰基)-2,6-二氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色蜡状固体的实施例54(1.75%)和55(1%)。
实施例54:UPLC-MS[M+H]+=511.32
实施例55:UPLC-MS[M+H]+=511.25
实施例61
6-(4-氯苄基)-2-(环己基甲基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色蜡状固体的实施例61(12%)。
实施例61:UPLC-MS[M+H]+=494.38
实施例62
6-(4-氯苄基)-2-(3-甲基丁基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
和
实施例63
6-(4-氯苄基)-3-(3-甲基丁基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
通过使用DCM中的MeOH(梯度为0至10%)作为洗脱剂的快速色谱法,随后进行制备型HPLC纯化,得到实施例62(25%)和实施例63(8.8%)。
化合物62:HPLC-MS[M+H]+=468.21
化合物63:HPLC-MS[M+H]+=468.28
按照针对实施例1所述的过程,但在步骤3中用适当的1,2-二胺(从可得供应商处购买或通过文献公开的方法合成)替代3-甲基丁烷-1,2-二胺,来制备表1中所示的实施例23、24、28、29、32至34、37、38、52、53、56、57、65、66、67。所报道的产率参考最后一步。
实施例23
2-环己基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
和
实施例24
3-环己基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色蜡状固体的实施例23(7.4%)和实施例24(2.4%)。
化合物23:HPLC-MS[M+H]+=476.48
化合物24:HPLC-MS[M+H]+=476.39
实施例28
6-(4-甲氧基苄基)-8-(吗啉-4-基)-2-苯基-2,6-二氢咪唑并[1,2-c]吡啶并[2,
3-e]嘧啶-5(3H)-酮
和
实施例29
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-苯基-2,6-二氢咪唑并[1,2-c]吡啶并[2,
3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色蜡状固体的实施例28(5.9%)和实施例29(5.1%)。
化合物28:HPLC-MS[M+H]+=470.46
化合物29:HPLC-MS[M+H]+=470.39
实施例32
2-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到实施例32(6.6%)。
HPLC-MS[M+H]+=450.48
1H NMR(300MHz,氯仿-d)δppm 8.16(d,1H),7.23-7.14(m,2H),6.93-6.83(m,2H),6.56(d,1H),5.28-5.01(m,2H),4.23-3.97(m,2H),3.90(dd,1H),3.85-3.74(m,7H),3.24-3.10(m,4H),1.03(s,9H).
实施例33
2-环丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H二)-酮
通过制备型HPLC纯化反应粗制品,得到实施例33(5.2%)。
HPLC-MS[M+H]+=448.13
1H NMR(300MHz,氯仿-d)δppm 8.14(d,1H),7.18(d,2H),6.93-6.82(m,2H),6.55(d,1H),5.24-5.04(m,2H),449-435(m,1H),4.20-4.07(m,1H),3.86-3.75(m,7H),3.71(dd,1H),3.24-3.12(m,4H),2.63-2.53(m,1H),2.20-1.85(m,6H).
实施例34
2-(2,2-二甲基丙基)-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-
c]吡啶并[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到实施例34(10.4%)
HPLC-MS[M+H]+=464.14
1H NMR(300MHz,氯仿-d)δppm 8.16(d,1H),7.24-7.18(m,2H),6.92-6.86(m,2H),6.57(d,1H),5.17(s,2H),4.47-4.36(m,1H),4.35-4.27(m,1H),3.86-3.79(m,7H),3.78-3.70(m,1H),3.24-3.16(m,4H),2.12(dd,1H),1.54(dd,1H),1.04(s,9H).
实施例37
6-(4-甲氧基苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-5(3H)-酮
和
实施例38
6-(4-甲氧基苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色蜡状固体的实施例37(66.6%)和实施例38(15.9%)。
化合物37:HPLC-MS[M+H]+=450.20
化合物38:HPLC-MS[M+H]+=450.38
实施例52
2-乙基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,
3-e]嘧啶-5(3H)-酮
和
实施例53
3-乙基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,
3-e]嘧啶-5(3H)-酮
通过制备型HPLC纯化反应粗制品,得到作为黄色蜡状固体的实施例52(26.6%)和实施例53(3%)。
化合物52:HPLC-MS[M+H]+=422.28
化合物53:HPLC-MS[M+H]+=422.36
实施例56
6-(4-甲氧基苄基)-8-(吗啉-4-基)-2-(2,2,2-三氟乙基)-2,6-二氢咪唑并[1,2-
c]吡啶并[2,3-e]嘧啶-5(3H)-酮
通过快速色谱法(DCM中的MeOH(梯度0至>10%)作为洗脱液),随后进行制备型HPLC,来纯化反应粗制品,得到实施例56(10.4%)。
HPLC-MS[M+H]+=476.14
1H NMR(300MHz,氯仿-d)δppm 8.14(s,1H),7.21-7.15(m,2H),6.91-6.81(m,2H),6.56(s,1H),5.21-5.07(m,2H),4.73-4.58(m,1H),4.38-4.27(m,1H),3.96-3.86(m,1H),3.84-3.76(m,7H),3.23-3.14(m,4H),3.00-2.87(m,1H),2.46-2.28(m,1H).
实施例57
2-(叔丁氧基甲基)-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]
吡啶并[2,3-e]嘧啶-5(3H)-酮
和
实施例67
3-(叔丁氧基甲基)-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]
吡啶并[2,3-e]嘧啶-5(3H)-酮
通过快速色谱法(DCM中的MeOH(梯度0至>10%)作为洗脱液),随后进行制备型HPLC,来纯化反应粗制品,得到实施例57(14.8%)和实施例67(3.5%)。
化合物57:HPLC-MS[M+H]+=480.39
1H NMR(300MHz,氯仿-d)δppm 8.13(d,1H),7.23-7.15(m,2H),6.90-6.83(m,2H),6.55(d,1H),5.25-5.07(m,2H),4.60-4.47(m,1H),4.22-4.11(m,1H),4.07-3.97(m,1H),3.86-3.76(m,7H),3.40-3.32(m,1H),3.21-3.14(m,4H),1.20(s,9H).
化合物67:HPLC-MS[M+H]+=480.26
实施例65
6-(4-甲氧基苄基)-2-(2-甲氧基乙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]
吡啶并[2,3-e]嘧啶-5(3H)-酮
和
实施例66
6-(4-甲氧基苄基)-3-(2-甲氧基乙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]
吡啶并[2,3-e]嘧啶-5(3H)-酮
通过快速色谱法(DCM中的MeOH(梯度0至>10%)作为洗脱液),随后进行制备型HPLC,来纯化反应粗制品,得到实施例65(16.6%)和实施例66(8.4%)。
化合物65:HPLC-MS[M+H]+=452.38
化合物66:HPLC-MS[M+H]+=452.27
实施例15
6-(4-氯苄基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-2-(丙烷-2-基)-2,6-二氢
咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
5-溴-2-(4-异丙基-4,5-二氢-1H-咪唑-2-基)吡啶-3-胺(步骤1)
在两个20mL密封的小瓶中装入溶于DMA(0.50mL)中的3-氨基-5-溴吡啶-2-甲腈(1.23g,6.18mmol)、3-甲基丁烷-1,2-二胺(1.262g,12.36mmol)和二硫化碳(0.093mL,1.545mmol)。将反应混合物在120℃下加热1小时,冷却至室温,用EtOAc吸收。用水洗涤有机溶剂两次,分离并经Na2SO4干燥,蒸发至干,得到粗制品,将其通过柱色谱法在硅胶上用PE/EtOAc 9/1纯化,得到标题实施例(1.2g,68.58%,纯度100%)。
8-溴-3-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮和
8-溴-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮(步骤2)
在20mL微波小瓶中,将溶于乙腈(10mL)中的5-溴-2-(4-异丙基-4,5-二氢-1H-咪唑-2-基)吡啶-3-胺(1.2g,4.24mmol)和羰基二咪唑(2.061g,12.713mmol)在微波小瓶中于100℃下加热2小时。形成沉淀物,将其在冷却至室温后过滤,用MeCN(4ml)在滤器上洗涤。用DCM(5ml)二次研磨后,合并母液,蒸发至干,用EtOAc萃取,用水洗涤,经硫酸钠干燥,并再次蒸发,用DCM研磨剩余物两次(3mL)。收集到的沉淀物为1.2g白色固体的8-溴-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮(91.59%产率)和0.16g来自上清液的异构体。
8-溴-6-(4-氯苄基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧
啶-5(3H)-酮(步骤3)
在搅拌下将8-溴-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮(700mg,2.26mmol)溶于10mL DMF中。添加1-(溴甲基)-4-氯苯(697.87mg,3.40mmol),将反应混合物搅拌5分钟,然后添加在1ml无水di DMF中的氢化钠(135.85mg,3.396mmol)。搅拌过夜后,将反应用水淬灭,用EtOAc萃取两次。EtOAc经硫酸钠干燥,过滤并蒸发至干,得到粗制品,将其通过柱色谱法在硅胶上用PE/EtOAc 7/3洗脱来进行纯化,得到630mg(64.15%产率)的标题化合物。
6-(4-氯苄基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-2-(丙烷-2-基)-2,6-二氢
咪唑并[1.2-c]吡啶并[2.3-e]嘧啶-5(3H)-酮(步骤4)
在2ml微波小瓶中,将步骤4的产物(50mg,0.115mmol)、碳酸铯(75.12mg,0.23mmol)和Xantphos(16.01mg,0.028mmol)溶于1,4-二氧六环(0.50mL)。向反应容器内鼓入氩气,然后添加2-氧杂-6-氮杂螺[3.3]庚烷草酸酯(24.93mg,0.087mmol),随后添加0.75mg Cs2CO3和Pd(OAc)2(4.14mg,0.018mmol)。将混合物在100℃下搅拌过夜,冷却并在PTFTE滤器上过滤,用MeOH洗涤。用EtOAc稀释滤液,用盐水洗涤,用Na2SO4干燥并蒸发至干,得到粗制品,将其通过制备型HPLC在H2O(+0.1%NH3)/ACN中纯化,得到标题产物(23mg,44.15%产率)。
HPLC-MS[M+H]+=452.12
如针对前述针对实施例15的化合物所报道的那样制备以下实施例,在最后一步中替代适当的胺:
实施例16
6-(4-氯苄基)-8-(4-甲氧基哌啶-1-基)-2-(丙烷-2-基)-2.6-二氢咪唑并[1,2-
c]吡啶并[2,3-e]嘧啶-5(3H)-酮
来自4-甲氧基哌啶。产率:22.4%。
HPLC-MS[M+H]+=468.16
实施例17
6-(4-氯苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-2-(丙烷-2-基)-2,6-二氢
咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
来自3-(甲氧基甲基)氮杂环丁烷。产率:33.52%。
HPLC-MS[M+H]+=454.32
实施例51
6-(4-氯苄基)-8-(4-羟基哌啶-1-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]
吡啶并[2,3-e]嘧啶-5(3H)-酮
来自4-羟基哌啶。产率:10.1%。
HPLC-MS[M+H]+=454.12
如针对实施例15所报道的那样制备以下实施例,在步骤3中替代适当的烷基化剂和在最后一步中替代适当的胺:
实施例19
6-(4-甲氧基苄基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-2-(丙烷-2-基)-2,6-
二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
来自2-氧杂-6-氮杂螺[3.3]庚烷草酸酯。产率:43.85%
HPLC-MS[M+H]+=448.46
实施例20
8-[4-(羟甲基)哌啶-1-基]-6-(4-甲氧基苄基)-2-(丙烷-2-基)-2,6-二氢咪唑并
[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
来自4-哌啶基甲醇。产率:10.58%。
HPLC-MS[M+H]+=464.41
实施例21
8-[4-(二甲基氨基)哌啶-1-基]-6-(4-甲氧基苄基)-2-(丙烷-2-基)-2,6-二氢咪
唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
来自N,N-二甲基哌啶-4-胺。产率:30.88%。
HPLC-MS[M+H]+=477.58
如针对实施例15所报道的那样制备以下实施例,在步骤1中替代二胺,在步骤3中替代适当的烷基化剂和在最后一步中替代适当的胺。
实施例27
2-乙基-6-(4-甲氧基苄基)-8-[(3R)-3-甲氧基吡咯烷-1-基]-2,6-二氢咪唑并
[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
来自[(3R)-3-甲氧基吡咯烷。产率:95%。
HPLC-MS[M+H]+=436.39
实施例39
2-乙基-6-(4-甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-2,6-二氢咪
唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
来自3-(甲氧基甲基)氮杂环丁烷。产率:36.8%。
HPLC-MS[M+H]+=436.38
如针对实施例15所报道的那样制备以下实施例,在步骤3中替代适当的烷基化剂和在最后一步中替代适当的胺。
实施例42
8-(4-氨基哌啶-1-基)-6-(3,5-二甲氧基苄基)-2-(丙烷-2-基)-2,6-二氢咪唑并
[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
来自哌啶-4-胺。产率:10.6%。
HPLC-MS[M+H]+=479.35
实施例49
6-(3,5-二甲氧基苄基)-2-(丙烷-2-基)-8-(四氢-2H-吡喃-4-基氨基)-2,6-二氢
咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
来自四氢吡喃-4-胺。产率:28.5%。
HPLC-MS[M+H]+=480.38
实施例48
6-(4-氯苄基-8-羟基-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧
啶-5(3H)-酮
在微波小瓶中,将8-溴-6-(4-氯苄基)-2-(丙烷-2-基)-2,6二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮(参见实施例15-步骤3)(50mg,0.116mmol)、铜(Z)-4-羟基戊-3-烯-2-酮(0.152mg,0.0006mmo1)、N,N’-双(4-羟基-2,6-二甲基-苯基)草酰胺(0.1893mg,0.0006mmol)和氢氧化锂水合物(10.158mg,0.242mmol)在DMSO(0.09ml)和水(0.03ml)中的混合物的溶液在80℃的沙浴中加热16小时。然后添加水和乙酸乙酯,分离两个液相,水层用乙酸乙酯(2×5ml)萃取。将粗制品通过反相柱色谱法,用70∶30开始至30∶70的NH4HCO3水(0.5%HCOOH)/乙腈梯度洗脱来纯化。收集到10mg作为白色粉末的实施例48。(产率=23%)
UPLC-MS[M+H]+=371.05
实施例58
6-(3,5-二甲氧基苄基)-5-氧代-2-(丙烷-2-基)-N-(四氢-2H-吡喃-4-基)-2,3, 5,6-四氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-8-甲酰胺在微波小瓶中,将8-溴-6-(3,5-二甲氧基苄基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮(按照针对实施例15-步骤3所述的过程制备,用1-(溴甲基)-4-(3,5-二甲氧基苯)替代1-(溴甲基)-4-氯苯)(35mg,0.076mmol)、羟基铯水合物(127.96mg,0.762mmol)、Xantphos(4.41mg,0.0076mmol、二乙酸钯(II)(0.428mg,0.002mmol)和四氢吡喃-4-胺(0.008mL,0.076mmol)在甲苯(0.45mL)、DMSO(0.200mL)和氯仿(0.018mL,0.229mmol)的混合物中的溶液于80℃的沙浴中加热16小时。然后添加水和乙酸乙酯,将两个液相分离,水层用乙酸乙酯(2×5ml)萃取。将粗制品通过反相柱色谱法,用70∶30开始至30∶70的梯度NH4HCO3水(0.1%NH3)/乙腈洗脱来纯化,收集到5.4mg作为白色粉末的实施例58的化合物。(产率=14%)
UPLC-MS[M+H]+=508.2
实施例59
6-(3,5-二甲氧基苄基)-5-氧代-2-(丙烷-2-基)-2,3,5,6-四氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-8-羧酸
在用反相柱色谱法纯化实施例58的过程中,分离出1.6mg作为白色粉末的实施例59的化合物(产率:4.4%)
UPLC-MS[M+H]+=425.29
实施例60
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基羰基)-2-(丙烷-2-基)-2,6-二氢咪唑并
[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
如实施例58所述制备实施例60,用吗啉替代四氢吡喃-4-胺。分离出3.8mg白色粉末。(产率:10%)
UPLC-MS[M+H]+=494.3
实施例64
6-(4-氯苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧
啶-2,5(3H,6H)-二酮
3-[(4-氯苄基)氨基]-5-(吗啉-4-基)吡啶-2-甲腈(步骤1)
按照针对实施例1-步骤2报道的过程制备,用4-氯苄胺替代4-甲氧基苄胺(产率:80%,白色固体)。
4-氨基-1-(4-氯苄基))-7-(吗啉-4-基)吡啶并[3,2-d]嘧啶-2(1H)-酮(步骤2)
在0℃,N2 atm下,向[(4-氯苄基氨基)-5-(吗啉-4-基)吡啶-2-甲腈(0.912mmol,300mg)在无水THF(10mL)中的搅拌溶液逐滴添加三氯乙酰基异氰酸酯(0.9124mmol,171.9mg,0,109mL)。将反应混合物在室温下搅拌,直到进行UPLC-MS,并且羰基中间体的形成完成(M=517)。在0℃下用过量的MeOH淬灭反应,并在减压下蒸发溶剂。将剩余物用7M氨的MeOH溶液(28mmol,4mL)冲洗,并搅拌过夜。过滤白色沉淀物,并用冷甲醇洗涤,得到作为白色固体被分离的标题实施例(0.538mmol,200mg)(产率:59%)。
6-(4-氯苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧
啶-2,5(3H,6H)-二酮(步骤3)
向2-溴-3,3-二甲基-丁酸(1.076mmol,209.8mg)在甲苯(3mL)中的溶液添加草酰氯(1.345mmol,170.7mg,0.11mL)和两滴DMF,将溶液在室温下搅拌3小时。将溶剂蒸发至干,并将剩余物溶于DMA(1mL)中,并添加至4-氨基-1-[(4-氯苯基)甲基]-7-吗啉代-吡啶并[3,2-d]嘧啶-2-酮(来自步骤2)(0.269mmol,100mg)和DIPEA(3.23mmol,371.9mg,0.493mL)的溶液,将反应混合物在室温下搅拌过夜,然后在120℃下加热3小时。然后将反应混合物倒入水中,用DCM萃取,经Na2SO4干燥,并将溶剂蒸发至干。粗制品通过制备型HPLC纯化,得到实施例64(产率:5.3%)。
HPLC-MS[M+H]+=468.1
实施例68
3-叔丁基-6-(4-氯苄基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-2,5
(3H,6H)-二酮
在实施例64的步骤3中,使用2-溴-4-甲基-戊酸替代2-溴-3,3-二甲基-丁酸进行反应。然后将反应混合物倒入水中,用EtOAc萃取,经Na2SO4干燥,并将溶剂蒸发至干。粗制品通过自动快速色谱法(Biotage Isolera-Dalton),SNAP10柱,用等度CHCl3/MeOH 95/5洗脱来进行纯化。分离出作为浅黄色固体的标题实施例。(产率:17%)
UPLC-MS[M+H]+=468.32
1H NMR(400MHz,DMSO-d6)δppm 8.42(m,1H)7.40(m,4H)6.82(m,1H)5.37(m,2H)424(m,1H)3.67-3.78(m,4H)3.41-3.51(m,4H)1.02(m,9H)
实施例69
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧
啶-2,5(3H,6H)-二酮
按照针对实施例64所述的过程,从实施例1的化合物-步骤2的化合物(3-[(4-甲氧基苯基)甲基氨基]-5-吗啉代-吡啶-2-甲腈)替代3-[(4-氯苄基)氨基]-5-(吗啉-4-基)吡啶-2-甲腈(实施例64-步骤1)开始,并在最后一步中使用2-溴-4-甲基-戊酸替代2-溴-3,3-二甲基丁酸,来制备标题化合物。
UPLC-MS[M+H]+=464.87
1H NMR(400MHz,DMSO-d6)δppm 8.41(m,1H)7.32(m,2H)6.85-6.93(m,3H)5.30(m,2H)4.26(m,1H)3.68-377(m,7H)3.41-3.49(m,4H)1.03(m,9H).
[M+1]+=464.38
实施例70
6-[(3,5-二甲氧基苯基)甲基]-2,3-二甲基-8-{[(氧杂环丁烷-3-基)甲基]氨基}
咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
4-氨基-7-溴-1H-吡啶并[3,2-d]嘧啶-2-酮(步骤1)
向0℃下的1g 3-氨基-5-溴吡啶-2-甲腈(5.05mmol)在15mL无水THF中的溶液在氮气氛下逐滴添加0.60mL 2,2,2-三氯乙酰基异氰酸酯(0.95g,5.05mmol)。将反应混合物在室温下搅拌。并由TLC进行监控以确保完成。在0℃下用MeOH淬灭反应,并在减压下蒸发溶剂。将剩余物用8mL的7M氨的MeOH溶液(56mmol)冲洗,并搅拌过夜。过滤白色沉淀物,用MeOH洗涤,并在60℃的烘箱中真空干燥,得到1.13g作为白色固体的所需产物(产率93%),将其无需进一步纯化即用于下一步。
1H NMR(400MHz,DMSO-d6)δppm 10.75(s,1H),8.43(s,1H),8.05(s,1H),7.94(s,1H),7.68(s,1H).
4-氨基-7-溴-1-[(3,5-二甲氧基苯基)甲基]吡啶并[3,2-d]嘧啶-2-酮(步骤2)
在N2 atm下向1g 4-氨基-7-溴-1H-吡啶并[3,2-d]嘧啶-2-酮(4.15mmol)在40mL无水DMF中的溶液添加182.52mg NaH 60%在油中的分散体(4.56mmol),将混合物在室温下搅拌30分钟。之后,添加1.15g的1-(溴甲基)-3,5-二甲氧基苯(4.98mmol),并将混合物在室温下搅拌过夜。过滤反应过程中形成的固体,并用少量的DMF和水洗涤。将粗制品用DCM研磨,并将悬浮液过滤,得到1.2g的作为浅黄色固体的所需产物(产率74%),将其无需进一步纯化即用于下一步。
8-溴-6-(3,5-二甲氧基苄基)-2,3-二甲基咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5
(6H)-酮(步骤3)
将700mg 4-氨基-7-溴-1-[(3,5-二甲氧基苯基)甲基]吡啶并[3,2-d]嘧啶-2-酮(1.79mmol)和0.38mL 3-溴丁-2-酮(540mg,3.58mmol,2当量)在4mL DMAc中的溶液在160℃的MW烘箱中搅拌45分钟。将反应混合物冷却至室温,倒入水中并用EtOAc萃取。将有机层用水洗涤,经无水Na2SO4干燥,将溶剂蒸发至干。所得粗制品通过自动快速色谱法(BiotageIsolera-Dalton,SNAP 25柱),用30%PE/EtOAc至100%EtOAc的梯度洗脱来进行纯化,以获得260mg作为浅黄色固体的所需产物(产率33%)。
6-[(3,5-二甲氧基苯基)甲基]-2,3-二甲基-8-{[(氧杂环丁烷-3-基)甲基]氨基}
咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮(步骤4)
在微波小瓶中,将120mg的8-溴-6-(3,5-二甲氧基苄基)-2,3-二甲基咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮(0.27mmol)和35.4mg氧杂环丁烷-3-基甲胺(0.41mmol)溶于4mL 1,4-二氧六环中。用N2吹扫溶液,并在5分钟后,添加12.15mg乙酸钯(II)(0.054mmol),62.65mg Xantphos(0.108mmol)和176.4mg碳酸铯(0.54mmol),并将混合物在150℃下的微波炉中搅拌1小时。将反应倒入水中并用EtOAc萃取。有机层经无水Na2SO4干燥,过滤并蒸发至干。粗制剩余物通过Biotage Isolera One仪器,柱型SNAP10,使用EtOAc100%至EtOAc∶MeOH 95∶5的梯度进行纯化,以获得100mg所需产物(产率82%)。
UPLC-MS[M+H]+=450.30
1H NMR(400MHz,氯仿-d)δppm 8.01(d,1H),6.53(d,1H),6.26-6.46(m,3H),5.35(s,2H),4.82(dd,2H),4.35(br s,1H),4.39(dd,2H),3.75(s,6H),3.28-3.46(m,2H),3.03-3.22(m,1H),2.68(s,3H),2.34(s,3H).
实施例71
2-(2-甲基丙基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
4-氨基-1H-吡啶并[3,2-d]嘧啶-2-酮(步骤1)
按照文献过程从3-氨基吡啶-2-甲腈开始合成4-氨基-1H-吡啶并[3,2-d]嘧啶-2-酮。
2-(2-甲基丙基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮(步骤2)
按照针对实施例70的步骤3中所述的过程,用1-溴-4-甲基-戊-2-酮替代3-溴丁-2-酮,制备标题实施例。
浅黄色固体(47%)
UPLC-MS[M+H]+=243.05
实施例72
6-[(4-甲基苯基)甲基]-2-(2-甲基丙基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5
(6H)-酮
按照针对实施例70步骤2中所述的过程,用1-(溴甲基)-4-甲基苯替代1-(溴甲基)-3,5-二甲氧基苯,来制备标题实施例。
浅黄色固体(41%)
UPLC-MS[M+H]+=347.16
实施例73
6-[(4-氯苯基)甲基]-2-(2-甲基丙基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)咪
唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
4-氨基-7-溴-1-[(4-氯苯基)甲基]吡啶并[3,2-d]嘧啶-2-酮(步骤1)
将NaH(60mg,1.2当量)和4-氨基-7-溴-1H-吡啶并[3,2-d]嘧啶-2-酮(实施例70-步骤1,300mg,1.0当量)放入干燥的Schlenk烧瓶中,并用DMF(8mL)稀释。将反应混合物在室温下搅拌30分钟(淡黄色浆液变成澄清的红色)。然后逐滴添加1-(溴甲基)-4-氯苯(333mg,1.3当量)在DMF(4mL)中的溶液,并将该反应在室温下搅拌30分钟,然后在80℃下搅拌3小时。使反应混合物冷却至室温,在30分钟后过滤。然后将水(50mL)添加至滤液,将其在室温下搅拌过夜。通过过滤收集固体,并用DCM(2×5mL)洗涤。
1H NMR(400MHz,DMSO-d6)δppm 8.48(s,1H),8.20(s,1H),8.10(s,1H),7.99(s,1H),7.37(m,4H).
8-溴-6-(4-氯苄基)-2-(2-甲基丙基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-
酮(步骤2)
向4-氨基-7-溴-1-[(4-氯苯基)甲基]吡啶并[3,2-d]嘧啶-2-酮(250mg,1当量)在DMA(4.5mL)中的溶液添加1-氯-4-甲基戊-2-酮(134.60μL,2当量)。将混合物在微波辐射下在150℃下搅拌75分钟。添加水,并将所得乳液状物用二氯甲烷萃取。合并的有机萃取物用快速色谱法纯化。
6-[(4-氯苯基)甲基]-2-(2-甲基丙基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)咪
唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮(步骤3)
将8-溴-6-(4-氯苄基)-2-(2-甲基丙基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮(60mg,1当量)、Xantphos(9.3mg,0.12当量)、碳酸铯(88mg,2当量)和2-氧杂-6-氮杂螺[3.3]庚烷(13.3mg,1当量)在1,4-二氧六环(1mL)中的溶液在声波浴中脱气,并在装有隔板的反应器中用氩气吹扫。然后添加乙酸钯,并将反应混合物在90℃下搅拌过夜。在减压下除去溶剂,并将粗制品通过快速色谱法纯化。将合并的级分在减压下干燥,并将所得的剩余物通过结晶(二乙醚/二氯甲烷)纯化,以获得所需的产物(48mg,产率76.9%)。
HPLC-MS[M+H]+=463.9
1H NMR(400MHz,氯仿-d)δppm 7.88(d,1H),7.54(d,1H),7.36(d,2H),7.22(d,2H),6.28(d,1H),5.44(s,2H),4.86(s,4H),4.11(s,4H),2.64(dd,2H),2.23(dq,1H),1.01(d,6H).
实施例70-替代过程
6-[(3,5-二甲氧基苯基)甲基]-2,3-二甲基-8-{[(氧杂环丁烷-3-基)甲基]氨基}
咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例73所述的过程,但是在步骤1中用1-(溴甲基)-3,5-二甲氧基苯替代1-(溴甲基)-4-氯苯,在步骤2中用3-溴丁-2-酮替代1-氯-4-甲基戊-2-酮,并在步骤3中用氧杂环丁烷-3-基甲胺替代2-氧杂-6-氮杂螺[3.3]庚烷,来制备表2中所示的实施例70(产率60%)。
UPLC-MS[M+H]+=450.39
1H NMR(400MHz,DMSO-d6)δppm 7.95(d,1H)6.61-6.71(m,2H)6.48(d,2H)6.40-6.45(m,1H)5.34(s,2H)4.60(dd,2H)4.24(t,2H)3.70(s,6H)3.35(dd,2H)2.96-3.12(m,1H)2.58(s,3H)2.21(s,3H)
实施例74
6-[(3,5-二甲氧基苯基)甲基]-2-(2-甲基丙基)-8-(吗啉-4-基)咪唑并[1,2-c]
吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例73中所述的过程,但是在步骤1中用1-(溴甲基)-3,5-二甲氧基苯替代1-(溴甲基)-4-氯苯并在步骤3中用吗啉替代2-氧杂-6-氮杂螺[3.3]庚烷,来制备表2中所示的实施例74(产率49%)。
UPLC-MS[M+H]+=478.30
1H NMR(400MHz,氯仿-d)δppm 8.35(d,1H)7.57(s,1H)6.89(d,1H)6.41-6.48(m,2H)633-6.41(m,1H)5.43(s,2H)3.81-3.93(m,4H)3.76(s,6H)3.14-3.27(m,4H)2.67(d,2H)2.24(dquin,1H)1.02(d,6H)
实施例75
6-[(4-氯-2,6-二氟苯基)甲基]-2-(2-甲基丙基)-8-(吗啉-4-基)咪唑并[1,2-c]
吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例73所述的过程,但是在步骤1中用2-(溴甲基)-5-氯-1,3-二氟苯替代1-(溴甲基)-4-氯苯并在步骤3中用吗啉替代2-氧杂-6-氮杂螺[3.3]庚烷,来制备表2中所示的实施例75(产率28%)。
HPLC-MS[M+H]+=4879
1H NMR(400MHz,氯仿-d)δppm 8.32(d,1H),7.53(s,1H),6.96(m,2H),6.87(d,1H),5.59(s,2H),3.89(dd,4H),3.26(dd,4H),2.62(d,2H),2.27-2.12(m,1H),0.98(d,6H).
实施例76和77
6-[(3,5-二甲氧基苯基)甲基]-2-乙基-3-甲基-8-{[(氧杂环丁烷-3-基)甲基]氨
基}咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
和
6-[(3,5-二甲氧基苯基)甲基]-3-乙基-2-甲基-8-{[(氧杂环丁烷-3-基)甲基]氨
基}咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例70所述的过程,但是在步骤3中用2-溴戊-3-酮替代3-溴丁-2-酮,来制备表2中所示的实施例76和77(产率33%)。
制备型HPLC纯化得到7.2mg实施例76和5.2mg实施例77。
实施例76
HPLC-MS[M+H]+=464.7
1H NMR(400MHz,氯仿-d)δppm 8.02(d,1H),6.53(d,1H),6.39(s,3H),5.35(s,2H),4.91-4.74(m,2H),4.40(t,2H),3.77(s,6H),3.41(d,2H),3.17-3.08(m,1H),2.78-2.65(m,5H),1.33(t,3H).
实施例77
HPLC-MS[M+H]+=464.7
NMR:1H NMR(400MHz,氯仿-d)δppm 8.04(d,1H),6.55(d,1H),6.39(s,3H),5.37(s,2H),4.91-4.77(m,2H),4.41(t,2H),3.77(s,6H),3.43(d,2H),3.13(m,3H),2.37(s,3H),1.30(t,3H).
实施例78
6-(4-甲氧基苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并b2,3-e]嘧啶-5(6H)-酮
按照针对实施例73所述的过程,但是在步骤2中用1-(溴甲基)-4-甲氧基苯替代1-(溴甲基)-4-氯苯并在步骤3中用吗啉替代2-氧杂-6-氮杂螺[3.3]庚烷,来制备表2中所示的实施例78(产率67%)。
UPLC-MS[M+H]+=448.40
1H NMR(400MHz,氯仿-d)δppm 8.36(d,1H)7.58(s,1H)7.23(d,2H)6.85-6.97(m,3H)5.45(s,2H)3.84-3.92(m,4H)3.81(s,3H)3.16-3.27(m,4H)2.69(d,2H)2.24(dquin,1H)1.02(d,6H).
实施例79
6-(3,5-二甲氧基苄基)-3-甲基-8-(吗啉-4-基)-2-(丙烷-2-基)咪唑并[1,2-c]
吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例70所述的过程,但是在步骤3中用2-溴-4-甲基戊-3-酮替代3-溴丁-2-酮,并在步骤4中用吗啉替代2-氧杂-6-氮杂螺[3.3]庚烷,来制备表2中所示的实施例79(产率56%)。
HPLC-MS[M+H]+=477.9
1H NMR(400MHz,氯仿-d)δppm 8.30(d,1H),6.80(d,1H),6.41-6.34(m,3H),5.34(s,2H),3.86-3.80(m,4H),3.74(s,5H),3.15(dd,4H),3.13-3.03(m,1H),2.70(d,3H),1.37(d,6H).
实施例80
6-(3,5-二甲氧基苄基)-8-[4-(羟乙酰基)哌嗪-1-基]-2-(2-甲基丙基)咪唑并
[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例73中所述的过程,但在步骤1中用1-(溴甲基)-4-氯苯替代1-(溴甲基)-3,5-二甲氧基苯并在步骤3中用2-羟基-1-哌嗪-1-基乙酮替代2-氧杂-6-氮杂螺[3.3]庚烷,来制备表2中所示的实施例80(产率16%)
HPLC-MS[M+H]+=535.2
1H NMR(400MHz,氯仿-d)δppm 8.35(d,1H),7.58(s,1H),6.91(d,1H),6.40(s,3H),5.44(s,2H),4.23(s,2H),3.84(t,2H),3.77(s,6H),3.54(s,1H),3.46(t,2H),3.28(dt,4H),2.70-2.62(m,2H),2.23(dt,1H),1.01(d,6H).
实施例81
6-(3,5-二甲氧基苄基)-2,3-二甲基-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)咪唑
并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例70所述的过程,但是在步骤4中用2-氧杂-6-氮杂螺[3.3]庚烷替代氧杂环丁烷-3-基甲胺,来制备表2所示的实施例81(产率27.5%)。
HPLC-MS[M+H]+=462.1
1H NMR(400MHz,氯仿-d)δppm 8.13(s,1H),7.80(s,1H),6.36(s,2H),6.31(d,J=2.1Hz,1H),5.31(s,2H),4.83(s,4H),4.08(s,4H),3.75(s,6H),2.66(s,3H),2.33(s,3H).
实施例82
6-(3,5-二甲氧基苄基)-2,3-二甲基-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-
e]嘧啶-5(6H)-酮
按照针对实施例70所述的过程,但是在步骤4中用吗啉替代氧杂环丁烷-3-基甲胺,来制备表2中所示的实施例82(产率16.6%)。
HPLC-MS[M+H]+=450.1
1H NMR(400MHz,氯仿-d)δppm 8.30(d,1H),6.82(d,1H),6.39(q,3H),5.37(8,2H),3,90-3.83(m,4H),3.76(s,6H),3.24-3.16(m,4H),2.70(d,3H),2.37(d,3H).
实施例83
6-(3,5-二甲氧基苄基)-3-甲基-8-[(氧杂环丁烷-3-基甲基)氨基]-2-(丙烷-2-
基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例70所述的过程,但是在步骤3中用2-溴-4-甲基-戊-3-酮替代3-溴丁-2-酮,来制备表2中所示的实施例83(产率19.7%)。
HPLC-MS[M+H]+=478.6
1H NMR(400MHz,氯仿-d)δppm 8.15(s,1H),6.50(s,1H),6.37(s,3H),5.34(s,2H),4.82(dd,2H),4.39(t,2H),3.76(s,6H),3.39(d,2H),3.21-3.08(m,3H),2.70(s,3H),1.40(d,6H).
实施例84
8-(4-乙酰基哌嗪-1-基)-6-(3,5-二甲氧基苄基)-3-甲基-2-(丙烷-2-基)咪b并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例70所述的过程,但是在步骤3中用2-溴-4-甲基戊-3-酮替代3-溴丁-2-酮,并在步骤4中用1-哌嗪-1-基乙酮替代氧杂环丁烷-3-基甲胺,来制备表2中所示的实施例84(产率49%)。
HPLC-MS[M+H]+=519.2
1H NMR(400MHz,氯仿-d)δppm 8.34(d,1H),6.82(d,1H),6.39(s,3H),5.37(s,2H),3.77(m,8H),3.64(t,2H),3.30(d,2H),3.18(t,2H),3.16-3.10(m,1H),2.73(s,3H),2.16(s,3H),1.41(d,6H).
实施例85
6-(3,5-二甲氧基苄基)-8-(4-甲氧基哌啶-1-基)-2,3-二甲基咪唑并[1,2-c]吡 啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例70所述的过程,但在步骤4中用4-甲氧基哌啶替代氧杂环丁烷-3-基甲胺,来制备表2所示的实施例85。
HPLC-MS[M+H]+=478.2
1H NMR(400MHz,氯仿-d),δppm 8.36(s,1H),6.81(s,1H),6.43-6.36(m,3H),5.36(s,2H),3.77(s,6H),3.57-3.40(m,5H),3.39(m,3H),3.13(m,2H),2.70(s,3H),2.43(s,3H),1.93(m,2H).
实施例86
5-(3,5-二甲氧基苄基)-8,9-二甲基-3-(吗啉-4-基)咪唑并[1,2-c]蝶啶-6(5H)-
酮
3-氯-5-吗啉代吡嗪-2-甲腈(步骤1)
向在1ml无水THF中的吗啉(12.5mg,0.144mmol)和DIPEA(27.9mg,0.216mmol)的混合物添加两次3,5-二氯吡嗪-2-甲腈(24.9mg,0.144mmol)。将反应在室温下搅拌2小时。在减压下除去溶剂,并将剩余物悬浮在乙酸乙酯中。有机层用1M HCl溶液、碳酸氢钠饱和水溶液和盐水洗涤。有机相经Na2SO4干燥并真空浓缩。将粗制产物无需进一步纯化即用于下一步。
3-[(3,5-二甲氧基苯基)甲基氨基]-5-吗啉代吡嗪-2-甲腈(步骤2)
将3-氯-5-吗啉代吡嗪-2-甲腈(31mg,0.138mmol)、DIPEA(21.4mg,0.166mmol)和(3,5-二甲氧基苯基)甲胺(1.2当量)在1,4-二氧六环(1ml)中的溶液在100℃下搅拌过夜。在减压下除去溶剂,并将剩余物悬浮在乙酸乙酯中。有机层用水和盐水洗涤。有机相经Na2SO4干燥并真空浓缩。将粗制产物无需进一步纯化即用于下一步。
4-氨基-1-[(3,5-二甲氧基苯基)甲基]-7-吗啉代蝶呤-2-酮(步骤3)
向3-[(3,5-二甲氧基苯基)甲基氨基]-5-吗啉代吡嗪-2-甲腈(22mg,0.142mmol)在无水THF(1ml)中的冰冷却溶液逐滴添加三氯乙酰基异氰酸酯(1.5当量)。使反应混合物升温至室温,并继续搅拌直至观察到底物完全转化(TLC,己烷中的40%乙酸乙酯)。将混合物冷却,小心地添加甲醇(1ml),并将所得混合物搅拌30分钟。在减压下除去溶剂,并将所得剩余物用7.7M NH3的甲醇溶液(2ml)稀释,并在室温下搅拌过夜。过滤出沉淀出的灰白色固体,用冰冷的甲醇洗涤并在减压下干燥。(产率12%)
5-(3,5-二甲氧基苄基)-8,9-二甲基-3-(吗啉-4-基)咪唑并[1,2-c]蝶啶-6(5H)-
酮(步骤4)
向4-氨基-1-[(3,5-二甲氧基苯基)甲基]-7-吗啉代蝶啶-2-酮(50mg,1当量)在DMA(0.5mL)中的溶液添加3-溴丁-2-酮(26.7μL 2当量)。将混合物在微波辐射下在150℃下搅拌75分钟。添加水,并将所得乳液状物用二氯甲烷萃取。将合并的有机萃取物在减压下干燥,并且通过制备型TLC分离所需产物(产率20%)。
HPLC-MS[M+H]+=451.1
1H NMR(400MHz,氯仿-d)δppm 8.07(s,1H),6.51(d,2H),6.35(d,1H),5.45(s,2H),3.84-3.79(m,4H),3.74(s,6H),3.71-366(m,4H),2.65(s,3H),2.32(s,3H).
实施例87
6-(3,5-二甲氧基苄基)-8-(4-甲氧基哌啶-1-基)-3-甲基-2-(丙烷-2-基)咪唑并
[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例70所述的过程,但是在步骤3中用2-溴-4-甲基戊-3-酮替代3-溴丁-2-酮,并在步骤4中用4-甲氧基哌啶替代氧杂环丁烷-3-基甲胺,制备表2中所示的实施例87(产率31%)。
HPLC-MS[M+H]+=506.2
1 HNMR(400MHz,氯仿-d)δppm 8.33(d,1H),6.84(d,1H),6.45-6.34(m,3H),5.36(s,2H),3.76(s,6H),3.53-3.41(m,3H),3.39(s,3H),3.18-3.04(m,3H),2.72(s,3H),1.94(t,2H),1.76-1.64(m,2H),1.39(d,6H).
实施例88
6-(3,5-二甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-甲基-2-(丙
烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例70所述的过程,但在步骤3中用2-溴-4-甲基-戊-3-酮替代3-溴丁-2-酮,并在步骤4中用3(甲氧基甲基)氮杂环丁烷替代氧杂环丁烷-3-基甲胺,来制备表2中所示的实施例88(产率16%)。
HPLC-MS[M+H]+=492.2
1H NMR(400MHz,氯仿-d)δppm 7.84(d,1H),6.38(s,3H),6.30(d,1H),5.32(s,2H),3.99(t,2H),3.85-3.66(m,8H),360(d,2H),3.41(s,3H),3.13-2.97(m,2H),2.70(s,3H),1.39(d,6H).
实施例89
6-(4-甲氧基苄基)-3-甲基-8-(吗啉-4-基)-2-(丙烷-2-基)咪唑并[1,2-c]吡啶
并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例73所述的过程,但在步骤1中用1-(溴甲基)-4-甲氧基苯替代1-(溴甲基)-4-氯苯,在步骤2中用2-溴-4-甲基戊-3-酮替代1-氯-4-甲基-戊-2-酮,在步骤4中用吗啉替代2-氧杂-6-氮杂螺[3.3]庚烷,来制备表2中所示的实施例89(产率21%)。
UPLC-MS[M+H]+=448.32
1H NMR(400MHz,氯仿-d)δppm 8.35(br d,1H)7.17-7.25(m,2H)6.87-6.98(m,2H)6.82(d,1H)5.39(s,2H)3.83-3.94(m,4H)3.81(s,3H)3.20(dd,4H)3.10-3.17(m,1H)2.74(s,3H)1.42(d,6H).
实施例90
6-(4-氯苄基)-3-甲基-8-(吗啉-4-基)-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,
3-e]嘧啶-5(6H)-酮
按照针对实施例73中所述的过程,但是在步骤2中用2-溴-4-甲基-戊-3-酮替代1-氯-4-甲基-戊-2-酮,并在步骤4中用吗啉替代2-氧杂-6-氮杂螺[3.3]庚烷,来制备表2中所示的实施例90(产率49.6%)。
HPLC-MS[M+H]+=452.5
1H NMR(400MHz,氯仿-d)δppm 8.32(d,1H),7.33(d,2H),7.21(d,2H),6.69(d,1H),5.39(s,2H),3.90-3.81(m,4H),3.22-3.13(m,4H),3.13-3.02(m,1H),2.71(s,3H),1.39(d,6H).
实施例91
6-(4-氯苄基)-3-甲基-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-2-(丙烷-2-基)咪
唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例73中所述的过程,但是在步骤2中用2-溴-4-甲基戊-3-酮替代1-氯-4-甲基戊-2-酮,来制备表2中所示的实施例91(产率24%)。
HPLC-MS[M+H]+=464.5
1H NMR(400MHz,氯仿-d)δppm 7.85(d,1H),7.35(d,2H),7.21(d,2H),6.22(d,1H),5.38(s,2H),486(s,4H),4.09(s,4H),3.10(m,1H),2.70(s,3H),1.39(d,6H).
实施例92
6-(4-甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-甲基-2-(丙烷-2-
基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例73中所述的过程,但是在步骤2中用2-溴-4-甲基戊-3-酮替代1-氯-4-甲基戊-2-酮,并在步骤4中用3-(甲氧基甲基)氮杂环丁烷替代2-氧杂-6氮杂螺[3.3]庚烷,来制备表2中所示的实施例92(产率5%)
UPLC-MS[M+H]+=462.27
1H NMR(400MHz,氯仿-d)□7.85(d,1H)7.21(d,2H)6.79-7.00(m,2H)6.26-6.42(m,1H)5.34(s,2H)4.00(t,2H)3.80(s,3H)3.69-3.78(m,2H)3.61(d,2H)3.41(s,3H)2.95-3.20(m,2H)2.72(s,3H)1.40(d,6H)
实施例93
6-(4-甲氧基苄基)-3-甲基-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-2-(丙烷-2-
基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例73中所述的过程,但是在步骤1中用1-(溴甲基)-4-甲氧基苯替代1-(溴甲基)-4-氯苯,并在步骤2中用2-溴-4-甲基戊-3-酮替代1-氯-4-甲基戊-2-酮,来制备表2中所示的实施例93(产率45%)。
UPLC-MS[M+H]+=460.38
1H NMR(400MHz,DMSO-d6)□7.76(d,1H)7.25-7.38(m,2H)6.86-6.94(m,2H)6.62(d,1H)5.36(s,2H)4.72(s,4H)4.11(s,4H)3.72(s,3H)3.05(spt,1H)2.78(s,1H)2.61(s,3H)1.24(d,5H)
实施例94
6-(4-氯苄基)-8-[(4-羟基哌啶-1-基)羰基]-3-甲基-2-(丙烷-2-基)咪唑并[1,
2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮
按照针对实施例73所述的过程直至步骤2,但用2-溴-4-甲基戊-3-酮替代1-氯-4-甲基戊-2-酮,来制备表2中所示的实施例94。步骤4如下所述进行:
6-(4-氯苄基)-8-[(4-羟基哌啶-1-基)羰基]-3-甲基-2-(丙烷-2-基)咪唑并[1,
2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮(步骤4)
反应在两室烧瓶中进行。将8-溴-6-(4-氯苄基)-3-甲基-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮(50mg,0.112mmol)、哌啶4-醇(13.6mg,0.135mmol)、Xantphos(3.2mg,0.006mmol)和碳酸铯(109.6mg,0.337mmol)引入室A中并在氩气氛下用甲苯(1ml)稀释。将甲磺酰氯(77mg,0.673mmol)和甲酸(31mg,0.673mmol)放入室B,并在氩气氛下用甲苯(0.6ml)稀释。将烧瓶抽空,并用3个氩气循环回填。将乙酸钯(1.3mg,0.006mmol)添加至室A,并将烧瓶密封。将TEA(136mg,1.346mmol)在甲苯中的溶液注入腔室B中。发生剧烈反应。将混合物在室温下搅拌2分钟,然后在100℃下加热过夜。通过pTLC(5%甲醇/二氯甲烷)分离所需产物。(产率39.7%)。
HPLC-MS[M+H]+=494.8
1H NMR(300MHz,氯仿-d)δppm 8.60(d,1H),7.50(d,1H),7.35-7.29(m,2H),7.19(d,2H),5.44(s,2H),4.20-3.89(m,3H),3.55-3.38(m,2H),3.18-3.02(m,2H),2.74(s,3H),1.80-1.55(m,4H),1.38(d,6H).
实施例95
6-(4-氯苄基)-N-(2-羟基乙基)-3-甲基-5-氧代-2-(丙烷-2-基)-5,6-二氢咪唑
并[1,2-c]吡啶并[2,3-e]嘧啶-8-甲酰胺。
按照针对实施例94中所述的过程,但是在步骤4中用2-氨基乙醇替代哌啶-4-醇,来制备表2中所示的实施例95。(产率13%)
HPLC-MS[M+H]+=454.7
1H NMR(300MHz,氯仿-d)δppm 8.86(s,1H),8.12(s,1H),7.32(d,2H),7.25(d,2H),5.45(s,2H),3.86(s,2H),3.66(s,2H),3.20-3.04(m,1H),2.76(s,3H),1.35(d,6H).
实施例96
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,
3-c]嘧啶-5(6H)-酮
5-溴-3-[(4-甲氧基苯基)甲基氨基]吡啶-2-羧酸甲酯(步骤1)
向3-氟-5-溴吡啶-2-羧酸甲酯(3.0g,12.82mmol)和(4-甲氧基苯基)甲胺(2.286g,2.17mL,16.66mmol)在60ml乙腈中的溶液添加乙基二异丙胺(3.313g,4.39mL,25.64mmol),并将混合物在回流下搅拌4小时。冷却至室温后,在真空下除去乙腈。将粗制品溶于乙酸乙酯。有机溶液用水和盐水洗涤,经Na2SO4干燥,过滤并蒸发至干。收集到4.33g作为白色粉末的5-溴-3-[(4-甲氧基苯基)甲基氨基]吡啶-2-羧酸甲酯,将其无需进一步纯化即用于下一步。
7-溴-1-[(4-甲氧基苯基)甲基]吡啶并[3,2-d]嘧啶-2,4-二酮(步骤2)
向5-溴-3-[(4-甲氧基苯基)甲基氨基]吡啶-2-羧酸甲酯在35ml DCM中的搅拌溶液添加2,2,2-三氯乙酰基异氰酸酯(7.12mmol,0.85m1,1.34g)。将反应在室温下搅拌18小时。然后蒸发溶剂并添加甲醇钠(11.8g,12.4ml,54.4mmol)。将悬浮液在60℃下加热1小时。冷却至室温后,向混合物添加水和冰乙酸直至完全溶解(pH=4至5)。用二氯甲烷萃取水层(3次),有机相经Na2SO4干燥,过滤并蒸发。收集到1.96g 7-溴-1-[(4-甲氧基苯基)甲基]吡啶并[3,2-d]嘧啶-2,4-二酮,将其无需进一步纯化即用于下一步。
7-溴-4-氯-1-[(4-甲氧基苯基)甲基]吡啶并[3,2-d]嘧啶-2-酮(步骤3)
在氮气氛下,将7-溴-1-[(4-甲氧基苯基)甲基]吡啶并[3,2-d]嘧啶-2,4-二酮(0.475g,1.311mmol)和二异丙基乙胺(0.508g,0.673mL,3.93mmol)在POCl3(16.090g,9.63mL,104.9mmol)中的溶液在50℃下搅拌3小时。冷却至室温后,除去溶剂,并将剩余物用1,4-二氧六环稀释,并将混合物蒸发(3次)。收集500mg作为粗制深色油状物的7-溴-4-氯-1-[(4-甲氧基苯基)甲基]吡啶并[3,2-d]嘧啶-2-酮,将其无需进一步纯化即用于下一步。
8-溴-3-叔丁基-6-(4-甲氧基苄基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5
(6H)-酮(步骤4)
将7-溴-4-氯-1-[(4-甲氧基苯基)甲基]吡啶并[3,2-d]嘧啶-2-酮(2.89g,7.593mmol)和2,2-二甲基丙酰肼(1.764g,15.19mmol)在40ml 1,4-二氧六环中的溶液于90℃下搅拌2小时。然后向其中添加水和乙酸乙酯。分离两相,有机层经Na2SO4干燥,过滤并蒸发至干。通过Biotage Isolera One,柱型SNAP50,使用石油醚∶乙酸乙酯=1∶1至石油醚∶乙酸乙酯=1∶9的梯度,来纯化粗制品。收集到1.1g作为浅黄色粉末的所需产物。
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,
3-c]嘧啶-5(6H)-酮(步骤5)
在微波小瓶中,将8-溴-3-叔丁基-6-(4-甲氧基苄基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮(155mg,0.35mmol)和吗啉(45.80mg,45.8μl,0.5257mmol)在1,4-二氧六环(2ml)中的溶液用氮气吹扫;5分钟后,添加乙酸钯(II)(15.73mg,0.07mmol)、xantphos(81.11mg,0.140mmol)和碳酸铯(228.4mg,0.70mmol),并将混合物在沙浴中于80℃下加热4小时。冷却至室温后,添加水和乙酸乙酯,分离两个液相,并将水层用乙酸乙酯萃取(2次)。合并的有机相经Na2SO4干燥,过滤并蒸发。通过Biotage Isolera One,柱型SNAP25,使用乙酸乙酯100%至乙酸乙酯∶甲醇9∶1的梯度来纯化粗制剩余物。收集的级分通过反相柱色谱法,用碳酸氢铵水溶液缓冲液∶乙腈8∶2至1∶1的梯度洗脱来进一步纯化。收集到15mg作为白色粉末的3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮。
UPLC-MS[M+H]+=449.26
1H NMR(400MHz,DMSO-d6)δppm 8.38(d,1H),7.34(m,2H),7.08(d,1H),6.90(m,2H),545(s,2H),3.73-3.79(m,4H),3.72(s,3H),3.31-3.34(m,4H),1.58(s,9H).
实施例96-替代过程
3-[(4-甲氧基苯基)甲基氨基]-5-吗啉代吡啶-2-甲酰胺(步骤1)
向冰浴中冷却的3-[(4-甲氧基苯基)甲基氨基]-5-吗啉代吡啶-2-甲腈(实施例1,步骤2,46.24mmol,15g)在DMSO(400mL)中的溶液添加1M氢氧化钠溶液(27.74mL),随后添加过氧化氢(30%至35%)(55.49mmol,5.67mL),并将混合物在室温下搅拌3小时。然后添加水和EtOAc,分离两相,水层用EtOAc萃取,合并的有机层经Na2SO4干燥,过滤并蒸发至干。将粗制品从乙腈中结晶,得到作为褐色固体被分离的3-[(4-甲氧基苯基)甲基氨基]-5-吗啉代吡啶-2-甲酰胺(12g)。产率:75%。
1-[(4-甲氧基苯基)甲基]-7-吗啉代吡啶并[3,2-d]嘧啶-2,4-二酮(步骤2)
在氮气氛下,向3-[(4-甲氧基苯基)甲基氨基]-5-吗啉代吡啶-2-甲酰胺(7.6mmol,2.6g)在无水THF(30mL)中的溶液添加氢化钠(7.6mmol,0.30g),将反应溶液在室温下搅拌15分钟。然后将混合物冷却至0至4℃,并逐滴添加氯甲酸乙酯(38mmol,3.6mL)。将反应混合物在回流下加热9小时。将混合物冷却至0℃并添加60%氢化钠(1.5g),将反应物在回流下再加热6小时。然后将混合物冷却至0至4℃,缓慢添加水并将pH调节为约8至9。过滤沉淀物以得到1-[(4-甲氧基苯基)甲基]-7-吗啉代-吡啶并[3,2-d]嘧啶-2,4-二酮(4.89mmol,1.8g),将其无需进一步纯化即用于下一步。产率:64%
替代制备:1-[(4-甲氧基苯基)甲基]-7-吗啉代吡啶并[3,2-d]嘧啶-2,4-二酮(步 骤2)该中间体也可通过与吗啉的布赫瓦尔德反应由7-溴-1-[(4-甲氧基苯基)甲基]吡啶并[3,2-d]嘧啶-2,4-二酮(实施例96主过程的步骤3)制备,如主过程步骤5所述。
4-氯-1-[(4-4-甲氧基苯基)甲基]-7-吗啉代-吡啶并[3,2-d]嘧啶-2-酮(步骤3)
向1-[(4-甲氧基苯基)甲基]-7-吗啉代吡啶并[3,2-d]嘧啶-2,4-二酮(2.24mmol,834mg)在乙基二异丙胺(1.15mL)中的悬浮液添加POCl3(10mL)并将所得混合物在50℃下搅拌20分钟并冷却至室温。蒸发液体,用二氧六环冲洗并蒸发,得到4-氯-1-[(4-4-甲氧基苯基)甲基]-7-吗啉代-吡啶并[3,2-d]嘧啶-2-酮,将其无需进一步纯化即用于下一步。
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,
3-c]嘧啶-5(6H)-酮(步骤4)
向4-氯-1-[(4-甲氧基苯基)甲基]-7-吗啉代-吡啶并[3,2-d]嘧啶-2-酮(0.87g,2.224mmol)在二氧六环(15mL)中的溶液添加2-甲基丙酰肼(0.4543g,4.448mmol),并将反应混合物在80℃下搅拌4小时,冷却至室温,倒入水中并用EtOAc萃取。有机相用水洗涤,经Na2SO4干燥并将溶剂蒸发至干,得到粗制品,将其通过自动快速色谱法,用10∶0至8∶2的EtOAc∶MeOH梯度洗脱来纯化,得到实施例97,mg 335产率34%。
UPLC-MS[M+H]+=449.05
按照针对以上实施例96-替代过程所报道的过程,从1-[(4-甲氧基苯基)甲基]-7-吗啉代吡啶并[3,2-d]嘧啶-2,4-二酮或1-[(4-氯苯基)甲基]-7-吗啉代吡啶并[3,2-d]嘧啶-2,4-二酮(类似制备)开始并在步骤4中使用适当的酰肼(从可得供应商处购买或通过文献公开的方法合成)替代新戊酰肼,来制备实施例97至100、102至105、108。
实施例97
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-e][1,2,4]三唑
并[4,3-c]嘧啶-5(6H)-酮
来自2-甲基丙酰肼。
HPLC-MS[M+H]+=507.10
1H NMR(300MHz,氯仿-d)δppm 8.37(d,1H),7.22(d,2H),6.91(d,2H),6.83(d,1H),5.38(s,2H),4.10-4.00(m,1H),3.88(dd,4H),3.82(s,3H),3.29-3.19(m,4H),1.56-1.52(m,6H).
实施例98
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-[(四氢-2H-吡喃-4-基氧基)甲基]吡啶并
[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮
来自2-(四氢-2H-吡喃-4-基氧基)乙酰肼。
HPLC-MS[M+H]+=507.36
1H NMR(300MHz,氯仿-d)δppm 8.38(d,1H),7.23(d,2H),6.95-6.88(m,2H),6.85(d,1H),5.40(s,2H),5.23(s,2H),3.98(dt,2H),3.96-3.82(m,5H),3.82(s,3H),3.56-3.41(m,2H),3.26(dd,4H),2.06-1.93(m,2H),1,79-1,64(m,2H).
实施例99
6-(4-氯苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-e][1,2,4]三唑并[4,
3-c]嘧啶-5(6H)-酮
来自2-甲基丙酰肼。
HPLC-MS[M+H]+=439.05
1H NMR(300MHz,氯仿-d)δppm 8.36(d,1H),7.40-7.31(m,2H),7.20(d,2H),6.68(d,1H),5.39(s,2H),3.99(m,1H),3.90-3.79(m,4H),3.26-3.14(m,4H),1.53(d,6H).
实施例100
6-(4-氯苄基)-8-(吗啉-4-基)-3-(吡啶-3-基甲基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮
来自3-吡啶乙酰肼。
HPLC-MS[M+H]+=488.02
实施例102
6-(4-氯苄基)-3-(1-甲基环丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并
[4,3-c]嘧啶-5(6H)-酮
来自1-甲基环丙烷甲酰肼。
HPLC-MS[M+H]+=451.07
1H NMR(300MHz,氯仿-d)δppm 8.35(d,1H),7.39-7.32(m,2H),7.23-7.17(m,2H),6.68(d,1H),5.41(s,2H),3,91-3.81(m,4H),3.25-3.16(m,4H),1.38-1.25(m,5H),0.98-0.91(m,2H).
实施例103
2-[6-(4-氯苄基)-8-(吗啉-4-基)-5-氧代-5,6-二氢吡啶并[2,3-e][1,2,4]三唑
并[4,3-c]嘧啶-3-基]-N-(丙烷-2-基)乙酰胺
来自3-肼基-3-氧代-N-(丙烷-2-基)丙酰胺。
HPLC-MS[M+H]+=496.1
1H NMR(300MHz,氯仿-d)δppm 8.39-8.35(m,1H),7.35(d,2H),7.20(d,2H),6.69(d,1H),6.30(brs,1H),5.37(s,2H),4.35(s,2H),4.15-4.06(m,1H),3.86(t,4H),3.23(t,4H),1.17(d,6H).
实施例104
6-(4-甲氧基苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑
并[4,3-c]嘧啶-5(6H)-酮
来自3-甲基丁酰肼。
HPLC-MS[M+H]+=449.26
实施例105
6-(4-氯苄基)-3-[(2-羟基吡啶-3-基)甲基]-8-(吗啉-4-基)吡啶并[2,3-e][1,
2,4]三唑并[4,3-c]嘧啶-5(6H)-酮
来自3-(2-羟基吡啶基)乙酰肼。
HPLC-MS[M+H]+=504.00
1H NMR(300MHz,氯仿-d)δppm 12.00(br,1H),8.38(d,1H),7.46(d,J=6,6Hz,1H),7.37-7.28(m,3H),7.26-7.20(m,2H),6.74(d,1H),6.20(t,1H),5.50(s,2H),4.26(s,2H),3.88-3.82(m,4H),3.28-3.21(m,4H).
实施例108
6-(4-氯苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并
[4,3-c]嘧啶-5(6H)-酮
来自3-甲基丁酰肼。
HPLC-MS[M+H]+=453.87
实施例101
6-(3,5-二甲氧基苄基)-3-甲基-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并
[4,3-c]嘧啶-5(6H)-酮
如实施例96标准过程所述,在步骤1中使用3,5-二甲氧基苯基甲胺替代(4-甲氧基苯基)甲胺,并在步骤4中使用乙酰肼替代2,2-二甲基丙酰肼,来进行制备。
HPLC-MS[M+H]+=[M+H]+=437.28
1H NMR(400MHz,氯仿-d)δppm 8.37(d,1H),6.88(d,1H),6.41(d,2H),6.37(t,1H),5.46(s,2H),3.90-3.81(m,4H),3.74(s,6H),3.31-3.21(m,4H),2.65(s,3H).
实施例106
6-(4-氯苄基)-3-[(2-甲基吡啶-3-基)甲基]-8-(吗啉-4-基)吡啶并[2,3-e][1,
2,4]三唑并[4,3-c]嘧啶-5(6H)-酮
向如上针对类似物所述制备的4-氯-1-[(4-氯苯基)甲基]-7-吗啉吡喃并[3,2-d]嘧啶-2-酮(0.608mmol,237mg)在二氧六环(5mL)中的溶液添加2-(2-甲基-3-吡啶基)乙酰肼(0.67mmol,88mg),并将反应混合物在室温下搅拌1小时,倒入水中,并用EtOAc萃取。用水洗涤有机相,经Na2SO4干燥,并将溶剂蒸发至干。将剩余物溶于THF(5mL)中,并添加Burgess试剂(0.217g,1.5当量),并将反应混合物在室温下搅拌过夜,倒入水中并用EtOAc萃取。用水洗涤有机相,经Na2SO4干燥,并将溶剂蒸发至干,得到粗制品。粗制品通过自动快速色谱法(Biotage-Isolera Dalton),以10∶0至8∶2的EtOAc-MeOH梯度洗脱和通过SNAP30-C18柱,以8∶2至2∶8的H2O-ACN梯度洗脱来纯化,得到6-(4-氯苄基)-3-[(2-甲基吡啶-3-基)甲基]-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮,mg 41。产率14%。
HPLC-MS[M+H]+=502.10
1H NMR(300MHz,氯仿-d)δppm 8.40(dd,1H),8.36(d,1H),7.47(d,1H),7.39-7.31(m,2H),7.14(d,2H),7.06(dd,1H),6.66(d,1H),5.33(s,2H),4.74(s,2H),3.85(dd,4H),3.21(dd,4H),2.71(s,3H).
通过实施例106中所述的相同过程,用适当的酰肼替代2-(2-甲基-3-吡啶基)乙酰肼,来制备以下实施例107、109、110。
实施例107
6-(4-氯苄基)-3-(1-乙基-1H-吡唑-5-基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,
4]三唑并[4,3-c]嘧啶-5(6H)-酮
来自2-乙基吡唑-3-甲酰肼。
HPLC-MS[M+H]+=491.10
1H NMR(300MHz,氯仿-d)δppm 8.38(d,1H),7.53(d,1H),7.37-7.29(m,2H),7.20(d,2H),6.92(d,1H),6.69(d,1H),5.40(s,2H),4.32(q,2H),3.91-3.80(m,4H),3.25-3.19(m,4H),1.57(t,3H).
实施例109
6-(4-氯苄基)-3-(1-乙基-1H-吡唑-3-基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,
4]三唑并[4,3-c]嘧啶-5(6H)-酮
来自1-乙基吡唑-3-甲酰肼。
HPLC-MS[M+H]+=491.12
实施例110
HPLC-MS[M+H]+=492.05
实施例111
3-叔丁基-6-(4-氯苄基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]
哒嗪
5-溴-2-异丙氧基羰基吡啶-3-羧酸(步骤1)
在室温下将3-溴呋喃并[3,4-b]吡啶-5,7-二酮(15.2g,66.67mmol)在150ml异丙醇中的悬浮液搅拌过夜。获得澄清的棕色溶液。除去溶剂至干,并将粗制品通过柱色谱法,用二氯甲烷∶甲醇=10∶1洗脱进行纯化。获得13.7g所需的实施例(产率:71%)。
5-溴-3-[2-(4-氯苯基)-3-甲氧基-3-氧代-丙酰基]吡啶-2-羧酸异丙酯(步骤2)
向5-溴-2-异丙氧基羰基吡啶-3-羧酸(1g,3.5mmol)在无水DMF(10ml)中的溶液添加碳二咪唑(732mg,4.5mmol),并将反应混合物在50℃下搅拌过夜。冷却至室温后,添加2-(4-氯苯基)乙酸甲酯(628mg,3.8mmol),将混合物冷却至-40℃,并分四次添加NaH(487mg,4.5mmol,60%油悬浮液)。将反应混合物在-25℃下搅拌1小时,在0℃下搅拌1小时,在室温下搅拌2小时直至反应完成。将混合物用75ml水淬灭并用2M HCl中和。用乙酸乙酯(3×200ml)萃取水层。有机相用水和盐水洗涤,经Na2SO4干燥,过滤并在真空下浓缩。获得2g所需产物(产率66%)。
5-溴-3-[2-(4-氯苯基)乙酰基]吡啶-2-羧酸(步骤3)
向5-溴-3-[2-(4-氯苯基)-3-甲氧基-3-氧代-丙酰基]吡啶-2-羧酸异丙酯(1.5g,3.45mmol)在二氧六环(75ml)中的溶液添加6M HCl(8ml),并将混合物在80℃下搅拌2天。将混合物在真空下浓缩并用乙酸钠中和。用乙酸乙酯(3×100ml)萃取水相,有机层经MgSO4干燥,过滤并真空蒸发至干。获得906mg的所需实施例(产率74%)。
3-溴-5-[(4-氯苯基)甲基]-7H-吡啶并[2,3-d]哒嗪-8-酮(步骤4)
向5-溴-3-[2-(4-(氯苯基)乙酰基]吡啶-2-羧酸(906mg,2.7mmol)在20ml乙醇中的溶液添加酰肼一水合物(203mg,4.1mmol)。将混合物在60℃下搅拌24小时。蒸发乙醇,并将粗制品用水稀释,并用乙酸乙酯(3×100ml)萃取。有机层用盐水洗涤,经无水MgSO4干燥,过滤并蒸发至干。将粗制品通过硅胶柱色谱法,用0∶100至100∶0的乙酸乙酯/己烷梯度洗脱进行纯化。获得350mg所需产物(产率37%)。
3-溴-8-氯-5-[(4-氯苯基)甲基]吡啶并[2,3-d]哒嗪(步骤5)
将3-溴-5-[(4-氯苯基)甲基]-7H-吡啶并[2,3-d]哒嗪-8-酮(760mg,2.17mmol)和乙基二异丙胺(840.5mg,1.11ml,6.50mmol)与POCl3(26.590g,15.9ml,173.4mmol)一起放置在干燥烧瓶中。将混合物在50℃下搅拌3小时。冷却至室温后,除去溶剂,并将剩余物用1,4-二氧六环稀释,并将混合物蒸发(重复3次)。得到2.5g作为深色油状物的所需产物,将其无需进一步纯化即用于下一步。
8-溴-3-叔丁基-6-(4-氯苄)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪(步骤6)
(实施例112)
将3-溴-8-氯-5-[(4-氯苯基)甲基]吡啶并[2,3-d]哒嗪(760mg,2.06mmol)和2,2-二甲基丙酰肼(717.7mg,6.18mmol)在1,4-二氧六环(20ml)中的溶液在60℃下搅拌2小时,然后在室温下搅拌过夜。真空除去溶剂,添加水和乙酸乙酯。分离有机层,经无水Na2SO4干燥,过滤并蒸发至干。将获得的粗制品通过Biotage Isolera One,柱型SNAP50,用石油醚:乙酸乙酯1∶1至乙酸乙酯100%的梯度洗脱来进行纯化。收集到560mg作为橙色粉末的实施例136(产率:63%)
UPLC-MS[M+H]+=430.16-432.23
1H NMR(400MHz,DMSO-d6)δppm 9.29(d,1H)8.98(d,1H)7.42(s,4H)4.65(s,2H)1.43(s,9H)
3-叔丁基-6-(4-氯苄基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]
哒嗪(步骤7)
在微波小瓶中将8-溴-3-叔丁基-6-(4-氯苄基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪(50mg,0.116mmol)和吗啉(15.17mg,0.17mmol)在1,4-二氧六环(2ml)中的溶液用N2吹扫;5分钟后,添加乙酸钯(II)(5.212mg,0.023mmol)、xantphos(26.87mg,0.0464mmol)和碳酸铯(75.65mg,0.232mmol),并将混合物在80℃的沙浴中加热2小时。然后添加水和乙酸乙酯,分离两个液相,水层用乙酸乙酯(2×25ml)萃取。有机相经无水Na2SO4干燥,过滤并蒸发至干。粗制剩余物通过Biotage Isolera One,柱型SNAP10,使用乙酸乙酯-甲醇100∶0至乙酸乙酯-甲醇80∶20的梯度进行纯化。收集级分,得到24mg作为黄色粉末的所需产物,将其在反相柱色谱上,使用NH4HCO3缓冲液-MeCN从7∶3开始至NH4HCO3缓冲液-MeCN 3∶7的梯度再次纯化。收集到11mg作为黄色粉末的实施例137。(产率:21%)。
UPLC-MS[M+H]+=437.28
1H NMR(400MHz,氯仿-d)δppm 8.88(d,1H),7.32-7.39(m,3H),7.23(d,2H),4.46(s,2H),3.89-3.98(m,4H),3.27-3.36(m,4H),1.62(s,9H).
按照针对实施例111所述的过程,但是在步骤2中用2-(4-甲基苯基)乙酸甲酯替代2-(4-氯苯基)乙酸甲酯并在步骤6中用2-环己基乙酰肼或乙酰肼或2-甲基丙酰肼(通过文献公开的方法合成或从可得供应商处购买)替换2,2-二甲基丙酰肼,在步骤7中用适当的胺(从可得供应商处购买)替代吗啉,来制备实施例113至115、117、137(表3)。
实施例113
N-(2-甲氧基乙基)-3-甲基-6-(4-甲基苄基)吡啶并[2,3-d][1,2,4]三唑并[4,3-
b]哒嗪-8-胺
黄色固体。产率:8%。
UPLC-MS[M+H]+=440.28
1H NMR(400MHz,氯仿-d)δppm 8.73-8.57(m,1H),7.21-7.03(m,5H),4.42(s,2H),3.59(t,2H),3.38(d,3H),3.28(t,2H),2.84(s,3H),2.31(s,3H).
实施例114
3-甲基-6-(4-甲基苄基)-N-(氧杂环丁烷-3-基甲基)吡啶并[2,3-d][1,2,4]三唑
并[4,3-b]哒嗪-8-胺
严率:10%。
UPLC-MS[M+H]+=375.25
1H NMR(400MHz,甲醇-d4)δppm 8.52(d,1H),7.46-6.85(m,5H),4.79(dd,2H),4.53(s,2H),4.42(t,2H),3.45(d,2H),3.13(m,1H),2.81(s,3H),2.33(s,3H).
实施例115
6-(4-甲基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-d][1,2,4]三唑并
[4,3-b]哒嗪
产率:4%。
UPLC-MS[M+H]+=403.46
1H NMR(400MHz,氯仿-d)δppm 8.83(s,1H),7.40(d,1H),7.16(q,J=8.2Hz,4H),4.45(s,2H),4.03-3.80(m,4H),3.71(dt,1H),3.35-3.14(m,4H),2.34(s,3H),1.60(d,6H).
实施例117
6-(4-甲基苄基)-8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d]
[1,2,4]三唑并[4,3-b]哒嗪
产率:6%。
UPLC-MS[M+H]+=459.1
按照实施例111所述的过程,但是在步骤2中用2-(3,5-二甲氧基苯基)乙酸甲酯替代2-(4-氯苯基)乙酸甲酯,并在步骤6中用适当的酰肼(从可得供应商处购买或通过文献公开的方法合成)替换2,2-二甲基丙酰肼,来制备表3中所示的实施例116和118至121。在步骤7中,在可能的情况下用适当的胺(从可得供应商处购买)替代吗啉。所报道的产率参考最后一步。
实施例116:
6-(3,5-二甲氧基苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]
三唑并[4,3-b]哒嗪
产率:5%。
UPLC-MS[M+H]+=463.2
实施例118
6-(3,5-二甲氧基苄基)-N-(2-甲氧基乙基)-3-(2-甲基丙基)吡啶并[2,3-d][1,
2,4]三唑并[4,3-b]哒嗪-8-胺
产率:5%。
UPLC-MS[M+H]+=451.3
实施例119
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-3-[(丙烷-2-基氧基)甲基]吡啶并[2,3-
d][1,2,4]三唑并[4,3-b]哒嗪
产率:18%。
UPLC-MS[M+H]+=479.2
实施例120
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-3-(丙-1-烯-2-基)吡啶并[2,3-d][1,2,
4]三唑并[4,3-b]哒嗪
产率:17%。
UPLC-MS[M+H]+=447.2
1H NMR(400MHz,氯仿-d)δppm 8.88(d,1H),746(d,1H),6.65(s,1H),6.44(d,2H),6.38(t,1H),5.71-5.63(m,1H),4.44(s,2H),4.01-3.86(m,4H),3.76(s,6H),3.39-3.22(m,4H),2.51(s,3H).
实施例121
6-(3,5-二甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-(2-甲基丙基)
吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪
产率:9%。
UPLC-MS[M+H]+=477.2
按照针对实施例111所述的过程,但是在步骤2中用2-(4-甲氧基苯基)乙酸甲酯替代2-(4-氯苯基)乙酸甲酯,并在步骤6中用适当的酰肼(通过文献中公开的方法合成或从现有的供应商处购买)替换2,2-二甲基丙酰肼,来制备表3中所示的实施例122至125、130。在步骤7中,在可能的情况下,用适当的胺(从现有的供应商处购买)替代吗啉。所报道的产率参考最后一步。
实施例122
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-d][1,2,4]三唑
并[4,3-b]哒嗪
产率:10%。
UPLC-MS[M+H]+=419.15
1H NMR(300MHz,氯仿-d)δppm 8.82(d,1H),7.37(d,1H),7.23-7.15(m,2H),6.90-6.81(m,2H),4.41(s,2H),3.95-3.84(m,4H),3.78(s,3H),3.73-3.63(m,1H),3.31-3.16(m,4H),1.57(d,6H).
实施例123:
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并[4,
3-b]哒嗪
产率:31%。
UPLC-MS[M+H]+=433.08
实施例124
6-(4-甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-(2-甲基丙基)吡啶
并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪
产率:30%。
UPLC-MS[M+H]+=447.17
1H NMR(300MHz,氯仿-d)δppm 8.82(d,1H),7.39(d,1H),7.18(d,2H),6.86(d,2H),4.40(s,2H),3.96-3.83(m,4H),3.78(s,3H),3.33-3.19(m,4H),1.63(s,9H).
实施例125
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d]
[1,2,4]三唑并[4,3-b]哒嗪
产率:7%。
UPLC-MS[M+H]+=475.14
实施例130:
6-(4-甲氧基苄基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-3-(四氢-2H-吡喃-4-
基甲基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪
产率:6%。
UPLC-MS[M+H]+=487.11
1H NMR(300MHz,氯仿-d)δppm 8.33(d,1H),7.20-7.14(m,2H),6.92(d,1H),6.89-6.83(m,2H),4.87(s,4H),4.37(s,2H),4.17(s,4H),3.94(d,2H),3.78(s,3H),3.46-332(m,2H),3.16(d,2H),2.34-2.23(m,1H),1.75-1,43(m,4H).
实施例137
3-(环己基甲基)-6-(4-甲基苄基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并
[4,3-b]哒嗪
产率:26%。
UPLC-MS[M+H]+=457.10
1H NMR(400MHz,氯仿-d)δppm 8.83(d,1H),7.40(d,1H),7.16(q,4H),4.44(s,2H),3.97-3.84(m,4H),3.32-3.22(m,4H),3.14(d,2H),2.34(s,3H),2.06(ddd,1H),1.74(m,6H),1.23-1.07(m,4H)
实施例134的化合物是通过实施例125的快速色谱法纯化得到的副产物。
实施例134
(4-甲氧基苯基)[8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d]
[1,2,4]三唑并[4,3-b]哒嗪-6-基]甲酮
产率:4%。
UPLC-MS[M+H]+=489.23
按照针对实施例111所述的过程,但是在步骤6中用适当的酰肼(从可得供应商处购买或通过文献所公开的方法合成)替代2,2-二甲基丙酰肼,来制备表3中所示的实施例126至129、132和133、138、140。在步骤7中,在可能的情况下,用适当的胺(从可得供应商处购买)替代吗啉。所报道的产率参考最后一步。
实施例126
6-(4-氯苄基)-8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d][1,
2,4]三唑并[4,3-b]哒嗪
产率:17%
UPLC-MS[M+H]+=479.08
1H NMR(300MHz,氯仿-d)δppm 8.85(d,1H),736-7.28(m,3H),7.20(d,2H),4.45(s,2H),4.02-3.83(m,6H),3.45-3.32(m,2H),3.32-3.23(m,4H),3.15(d,2H),2.36-2.21(m,1H),1.75-1.61(m,2H),1.57-1.39(m,2H).
实施例127
6-(4-氯苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-d][1,2,4]三唑并[4,
3-b]哒嗪
白色粉末。产率:18%。
UPLC-MS[M+H]+=423.08
实施例128:
6-(4-氯苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-(2-甲基丙基)吡啶并
[2,3-d][1,2,4]三唑并[4,3-b]哒嗪
产率:16%。
UPLC-MS[M+H]+=451.12
实施例129
6-(4-氯苄基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-3-(四氢-2H-吡喃-4-基甲
基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪
白色粉末。产率:2%。
UPLC-MS[M+H]+=491.1
1H NMR(300MHz,氯仿-d)δppm 8.45-8.32(m,1H),7.36-7.29(m,2H),7.21-7.15(m,2H),6.83(d,1H),4.87(s,4H),4.41(s,2H),4.20(s,4H),4.01-3.91(m,2H),3.41-3.32(m,2H),3.13(d,2H),2.28-2.18(m,1H),1.70-1.60(m,2H),1.57-1.43(m,2H).
实施例132
6-(4-氯苄基)-8-(吗啉-4-基)-3-[1-(四氢-2H-吡喃-4-基)乙基]吡啶并[2,3-d]
[1,2,4]三唑并[4,3-b]哒嗪
产率:6%。
UpLC-MS[M+H]+=493.13
1H NMR(300MHz,氯仿-d)δppm 8.85(d,1H),7.37-7.29(m,3H),7.24-7.16(m,2H),4.44(s,2H),4.05-3.97(m,1H),3.94-3.82(m,5H),3.44-3.21(m,7H),2.21-2.11(m,1H),1.87-1.75(m,1H),1.49(d,3H),1,41(dt,3H).
实施例133:
6-(4-氯苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并
[4,3-b]哒嗪
产率:7%。
UPLC-MS[M+H]+=437.15
1H NMR(300MHz,氯仿-d)δppm 8.85(d,1H),7.34-7.28(m,3H),7.23-7.17(m,2H),4.44(s,2H),3.95-3.86(m,4H),3.29-3.22(m,4H),3.09(d,2H),2.45-2.27(m,1H),1.03(d,6H).
实施例138:
{1-[3-叔丁基-6-(4-氯苄基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪-8-基]
哌啶-4-基}氨基甲酸叔丁酯
黄色粉末。产率:49%。
UPLC-MS[M+H]+=55027
1H NMR(400MHz,DMSO-d6)δppm 8.96(d,1H)7.75(d,1H)7.42(d,3H)688(br d,1H)4.60(s,2H)3.93-4.13(m,3H)3.53(s,1H)2.96-3.15(m,2H)1.81-1.95(m,2H)1.43(d,20H)
实施例140:
1-[3-叔丁基-6-(4-氯苄基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪-8-基]哌
啶-4-醇
白色粉末。产率:3%。
UPLC-MS[M+H]+=451.24
1H NMR(400MHz,氯仿-d)8.88(m,1H)7-32-7.39(m,2H)7.19-7.27(m,2H)4.45(m,2H)4.08-4.20(m,1H)4.03(m,1H)3.60-3.74(m,2H)3.20(m,2H)2.07(m,1H)1.65-1.79(m,5H)1.61(m,8H)
实施例131
(4-氯苯基){8-(吗啉-4-基)-3-[2-(四氢-2H-吡喃-4-基)乙基]吡啶并[2,3-d]
[1,2,4]三唑并[4,3-b]哒嗪-6-基}甲酮
和
实施例135
(4-氯苯基){8-(吗啉-4-基)-3-[2-(四氢-2H-吡喃-4-基)乙基]吡啶并[2,3-d]
[1,2,4]三唑并[4,3-b]哒嗪-6-基}甲醇
上述化合物(表3)是在按照针对实施例111所述的过程,但是在步骤6中用3-四氢吡喃-4-基丙酰肼(通过文献公开的方法合成)替代2,2-二甲基丙酰肼来尝试合成6-(4-氯苄基)-8-(吗啉-4-基)-3-[2-(四氢-2H-吡喃-4-基)乙基]吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪的过程中,作为副产物被分离出来的。
实施例131
产率:7%。
UPLC-MS[M+H]+=507.11
1H NMR(300MHz,氯仿-d)δppm δ8.95(d,1H),8.02-7.96(m,2H),7.70(d,1H),7.56-7.51(m,2H),3.98-3.84(m,6H),3.45-3.24(m,6H),3.20-3.09(m,2H),1.95-1.77(m,2H),1.69-1.29(m,5H).
实施例135
产率:3%。
UPLC-MS[M+H]+=509.09
实施例136
3-(环己基甲基)-6-[(4-甲基苯基)甲基]吡啶并[2,3-d][1,2,4]三唑并[4,3-b]
哒嗪
按照针对实施例112所述的过程,但在步骤1中用呋喃并[3,4-b]吡啶-5,7-二酮替代3-溴呋喃并[3,4-b]吡啶-5,7-二酮,在步骤2中用2-(4-氯苯基)乙酸甲酯替代2-(4-甲基苯基)乙酸甲酯,并在步骤6中用适当的酰肼(通过文献公开的方法合成)替换2,2-二甲基丙酰肼,来制备该化合物。产率:27%。
UPLC-MS[M+H]+=372.4
实施例139:
1-[3-叔丁基-6-(4-氯苄基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪-8-基]哌
啶-4-胺
向实施例138(60mg,0.109mmol)在CHCl3(1mL)中的冰浴冷却的溶液添加三氟乙酸(2.181mmol,248.7mg,0.168mL),并将所得混合物在室温下搅拌2天。然后,在减压下除去氯仿和过量的TFA。添加2N NaOH溶液和DCM,分离两相,水层用DCM萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤并蒸发。收集到39mg作为黄色粉末的实施例139的化合物(产率:79%)。
UPLC-MS[M+H]+=450.25
1H NMR(400MHz,DMSO-d6)δppm 8.96(d,1H)7.73(d,1H)7.33-7.49(m,4H)4.60(s,2H)3.90-4.05(m,2H)2.96-3.11(m,2H)2.77-2.91(m,1H)1.69-1.88(m,4H)1.44(s,9H)1.19-1.36(m,2H)
实施例147
5-(3,5-二甲氧基苄基)-9,9-二甲基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并
[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮
5-溴-2-(5,5-二甲基-4,6-二氢-1H-嘧啶-2-基)吡啶-3-胺(步骤1)
将3-氨基-5-溴-吡啶-2-甲腈(500mg,2.52mmol)、2,2-二甲基丙-1,3-二胺(774mg,7.57mmol)和DMAc(5ml)放入微波小瓶中。将小瓶密封并将反应在沙浴中在160℃下加热并搅拌过夜。将反应冷却至室温,添加水,获得沉淀的固体。过滤浅黄色固体,用水洗涤,并在60℃的烘箱中在真空下干燥,得到700mg所需产物(产率98%),将其无需进一步纯化即用于下一步。
3-溴-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮
(步骤2,实施例142)
将5-溴-2-(5,5-二甲基-4,6-二氢-1H-嘧啶-2-基)吡啶-3-胺(700mg,2.47mmol)溶于15mL乙腈中。添加羰基二咪唑(481mg,2.96mmol)后,将所得的混合物在80℃下加热过夜。将反应在室温冷却。获得固体沉淀物,过滤并用乙腈洗涤。分离作为淡黄色固体的粗制产物(700mg,产率91%),将其无需进一步纯化即用于下一步。
HPLC-MS[M+H]+=310.08.
3-溴-5-(3,5-二甲氧基苄基)-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧
啶并[1,2-c]嘧啶-6-酮(步骤3,实施例146)
在氮气氛下,向3-溴-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-]嘧啶-6-酮(150mg,0.485mml)在5mL无水DMF中的溶液添加NaH 60%(23.287mg,0.5822mmol),并将混合物在室温下搅拌30分钟。然后,添加1-(溴甲基)-3,5-二甲氧基苯(123.33mg,0.534mmol),并将混合物在室温下搅拌过夜。将获得的沉淀物过滤并用小部分的DMF洗涤。向滤液添加水,获得所得的固体。将粗制产物与DCM一起研磨,将悬浮液过滤,得到120mg作为浅黄色固体的所需产物(产率54%),将其无需纯化即用于下一步。
HPLC-MS[M+H]+=460.58
5-(3,5-二甲氧基苄基)-9,9-二甲基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并
[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮(步骤4)
向微波小瓶中添加用N2吹扫的3-溴-5-(3,5-二甲氧基苄基)-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮(120mg,0.2613mmol)和吗啉(34.14mg,0.3919mmol)在3ml 1,4-二氧六环中的溶液,5分钟后,添加乙酸钯(II)(11.73mg,0.052mmol)、XantPhos(60.47mg,0.10mmol)和碳酸铯(170mg,0.52mmol)。将混合物在微波炉中于150℃下搅拌2小时,冷却至室温,倒入水中并用EtOAc萃取。有机层用水洗涤,经无水Na2SO4干燥,蒸发溶剂,得到粗制品,将其通过自动快速色谱法(Isolera,SNAP10),用5%至20%的EtOAc/MeOH-NH3梯度洗脱,来进行纯化。分离出作为浅黄色固体的所需产物(70mg)。(产率57%)。
UPLC-MS[M+H]+=466.32
1H NMR(400MHz,DMSO-d6)δppm 8.22(d,1H),6.85(d,1H),6.49(d,2H),6.40(dd,1H),5.25(s,2H),3.70-3.76(m,4H),3.70(s,6H),3.62(s,2H),3.30-3.34(m,4H),3.27(s,2H),1.01(s,6H).
表4中所示的以下实施例141、144至146和148至155的化合物以如下所述的类似方式制备:
实施例141
9,9-二甲基-5-[(4-甲基苯基)甲基]-3-{[(氧杂环丁烷-3-基)甲基]氨基}-5,8,
9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮
3-溴-9,9-二甲基-5-(4-甲基苄基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并
[1,2-c]嘧啶-6-酮(步骤1)
使用1-(溴甲基)-4-甲基苯替代1-(溴甲基)-3,5-二甲氧基苯(实施例147-步骤3)合成作为实施例146的化合物的标题实施例,得到标题实施例。
9,9-二甲基-5-[(4-甲基苯基)甲基]-3-{[(氧杂环丁烷-3-基)甲基]氨基}-5,8,
9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮(步骤2)
按照针对实施例147的化合物所述的过程,用适当的胺(从可得供应商处购买)替换吗啉,来制备标题实施例。产率11%。
1H NMR(400MHz,氯仿-d)δppm 7.97(d,1H),7.13(s,4H),6.28(d,1H),520(s,2H),4.76(dd,2H),4.34(t,2H),3.66(s,2H),3.43(s,2H),3.33(dd,2H),3.08(q,1H),2.32(s,3H),1.06(s,6H).
HPLC-MS[M+H]+=491.9
实施例144
5-(3,5-二甲氧基苄基)-3-[(2-羟基乙基)氨基]-9,9-二甲基-5,8,9,10-四氢-
6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮
如针对步骤147的化合物所述,在步骤4中使用乙醇胺替代吗啉,合成标题实施例。产率4%。
HPLC-MS[M+H]+=439.9
1H NMR(400MHz,氯仿-d)δppm 7.88(s,1H),6.41-6.32(m,4H),5.16(s,2H),3.75(s,9H),3.65(s,2H),3.43(s,2H),3.20(q,2H),1.06(s,6H).
实施例148
3-溴-5-(4-氯苄基)-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,
2-c]嘧啶-6-酮
如针对实施例146的化合物所述,使用1-氯-4-(氯甲基)苯替代1-(溴甲基)-3,5-二甲氧基苯(实施例147-步骤3)合成标题实施例。产率4%。
HPLC-MS[M+H]+=434.91
按照针对实施例147-步骤4的化合物所述的过程,从实施例148的化合物开始,并用适当的胺(从可得供应商处购买)替换吗啉,来制备表4所示的实施例143和149。
实施例143
5-(4-氯苄基)-3-[(2-羟基乙基)氨基]-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并
[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮
产率11%。
1H NMR(400MHz,氯仿-d)δppm 8.17(d,1H),7.84(s,1H),7.31(d,2H),7.26(d,2H),6.31(d,1H),5.29(s,2H),3.88(m,2H),3.70(s,2H),3.49(s,2H),3.15(m,3H),1.16(s,6H).
[M+H]+=413.9
实施例149
5-(4-氯苄基)-3-[3-(甲氧基甲基)氮杂环丁烷-1-基]-9,9-二甲基-5,8,9,10-四
氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮
产率32%。
1H NMR(400MHz,DMSO-d6)δppm 7.62(d,1H)7.38-7.47(m,2H)7.28-7.36(m,2H)6.26(d,1H)5.24(s,2H)3.94(t,2H)3.64(dd,2H)3.56(s,2H)3.50(d,2H)3.27(s,3H)3.22-3.26(m,2H)2.89-3.01(m,1H)0.98(s,6H)
HPLC-MS[M+H]+=455.56
实施例145
5-(3,5-二甲氧基苄基)-9-甲基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,
3-e]嘧啶并[1,2-c]嘧啶-6-酮
3-溴-9-甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮(步骤
1)。
按照针对实施例142的化合物所述的过程,在步骤1-实施例147中,用适当的二胺(从可得供应商处购买)替换2,2-二甲基丙-1,3-二胺,来制备标题实施例。
3-溴-5-(3,5-二甲氧基苄基)-9-甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并
[1,2-c]嘧啶-6-酮(步骤2)
使用1-(溴甲基)甲苯替代1-(溴甲基)-3,5-二甲氧基苯(实施例147-步骤3),如实施例146合成标题实施例。
5-(3,5-二甲氧基苄基)-9-甲基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,
3-e]嘧啶并[1,2-c]嘧啶-6-酮
如实施例147-步骤4合成标题实施例。
1H NMR(400MHz,氯仿-d)δppm 8.15(d,1H),655(d,1H),6.36(dd,3H),5.33-4.97(m,2H),4.48-4.22(m,1H),4.00-3.85(m,1H),3.80(t,4H),3.75(s,6H),3.30-3.21(m,2H),3.15(t,4H),2.06(d,1H),1.10(d,3H).
产率15%。
HPLC-MS[M+H]+=452.5
按照针对实施例1的化合物所述的过程,从如实施例1-步骤2中所述制备的3-[(3,5-二甲氧基苯基)甲基氨基]-5-吗啉代吡啶-2-甲腈开始,用3,5-二甲氧基苄基氯替代4-甲氧基苄基氯,并在步骤3中用适当的1,3-二胺替代3-甲基丁烷-1,2-二胺,来制备实施例150和151。通过制备型HPLC的纯化得到。
实施例150
5-(3,5-二甲氧基苄基)-10-乙基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,
3-e]嘧啶并[1,2-c]嘧啶-6-酮
产率4%。
HPLC-MS[M+H]+=512.5
实施例151
5-(3,5-二甲氧基苄基)-8-乙基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,
3-e]嘧啶并[1,2-c]嘧啶-6-酮
产率27%。
HPLC-MS[M+H]+=512.2
按照针对实施例1的化合物所述的过程,在步骤3中用适当的1,3-二胺替代3-甲基丁烷-1,2-二胺,来制备实施例152和153。通过制备型HPLC纯化得到:
实施例152
10-乙基-5-(4-甲氧基苄基)-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]
嘧啶并[1,2-c]嘧啶-6-酮
产率17%。
HPLC-MS[M+H]+=482.4
实施例153
8-乙基-5-(4-甲氧基苄基)-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]
嘧啶并[1,2-c]嘧啶-6-酮
产率4%。
HPLC-MS[M+H]+=482.7
按照针对实施例1的化合物所述的过程,从如实施例1-步骤2所述制备的3-[(4-氯苯基)甲基氨基]-5-吗啉代吡啶-2-甲腈开始,用3,5-二甲氧基苄基氯替代4-氯苄基氯,并在步骤3中用适当的1,3-二胺替代3-甲基丁烷-1,2-二胺,来制备实施例154和155。通过制备型HPLC纯化得到:
实施例154
5-(4-氯苄基)-10-乙基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶
并[1,2-c]嘧啶-6-酮
产率6%。
HPLC-MS[M+H]+=487.4
实施例155
5-(4-氯苄基)-8-乙基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶
并[1,2-c]嘧啶-6-酮
产率4%
HPLC-MS[M+H]+=487.4
实施例156
6-(4-甲氧基苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑
并[1,5-c]嘧啶-5(6H)-酮
在实施例104的步骤6的柱色谱法纯化过程中,标题化合物也作为白色粉末被分离。产率:2%。
UPLC-MS[M+H]+=44934
实施例157
2-叔丁基-6-(4-甲氧基苄基)-84吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-
c]嘧啶-5(6H)-酮
在实施例96的化合物的步骤6的柱色谱法纯化过程中,标题化合物也作为白色粉末被分离(产率7%)。
UPLC-MS[M+H]+=449.26
1H NMR(400MHz.DMSO-d6)δppm 8.44(d,1H)7.34(d,2H)7.12(d,1H)689(d,2H)5.51(s,2H)373-3.80(m,4H)3.72(s,3H)3.32-3.40(m,4H)1.44(s,9H)
实施例158
6-(4-氯苄基)-9-甲氧基-3-(四氢-2H-吡喃-4-基甲基)嘧啶并[4,5-e][1,2,4]三
唑并[4,3-c]嘧啶-5(6H)-酮
5-氨基-2-甲基硫烷基-嘧啶-4-羧酸甲酯(步骤1)
在0℃下向5-氨基-2-甲基硫烷基嘧啶-4-羧酸(10.80mmol,2g)在二氯甲烷(100mL)和甲醇(20mL)的混合物中的溶液添加4-二甲基氨基吡啶(8.6393mmol,1.056g),随后添加(3-二甲基氨基丙基)乙基碳二亚胺.HCl(19.44mmol,3.73g),并将混合物在0℃下搅拌90分钟,然后在室温下搅拌过夜。有机层用水洗涤两次,用饱和NaHCO3溶液洗涤两次,用盐水洗涤一次,然后经硫酸钠干燥。将粗制品通过硅胶柱色谱法,用从20∶80开始至70∶30的乙酸乙酯/石油醚梯度洗脱,来进行纯化。获得1.5g作为黄色粉末的所需产物(产率:70%)。
5-[(4-氯苯基)甲基氨基]-2-甲基硫烷基-嘧啶-4-羧酸甲酯(步骤2)
向5-氨基-2-甲基硫烷基-嘧啶-4-羧酸甲酯(3.76mmol,750mg)、4-氯苯甲醛(7.5290mmol,1058.3mg)和乙酸(7.53mmol,0.431mL,452.1mg)在二氯甲烷(50mL)中的混合物分批添加三乙酰氧基硼氢化钠(11.293mmol,2393.5mg),并将所得混合物在室温下搅拌2天,每天添加1当量的还原剂。然后将反应用水淬灭,分离两相,并用DCM萃取水层。合并的有机相经Na2SO4干燥,过滤并蒸发。将粗制品通过硅胶柱色谱法,用从0∶100开始至40∶60的乙酸乙酯/石油醚梯度洗脱来进行纯化。获得1.19g作为黄色油状物的所需产物(产率:97%)。
5-[(4-氯苯基)甲基]-2-甲氧基-嘧啶并[5,4-d]嘧啶-6,8-二酮(步骤3)
向5-[(4-氯苯基)甲基氨基]-2-甲基硫烷基嘧啶-4-羧酸甲酯(3.68mmol,1.19g)在DCM中的搅拌溶液添加2,2,2-三氯乙酰基异氰酸酯(4.01mmol,0.477mL,0.755g)并将反应在室温下搅拌过夜。然后蒸发溶剂并添加甲醇钠(36.8mmol,8.40mL,7.94g,25质量%),并将悬浮液在60℃下加热1小时。冷却至室温后,添加乙酸直至pH=4至5,然后添加水和DCM,分离两相,并将水层用DCM萃取(3次)。合并的有机层经Na2SO4干燥,过滤并蒸发。收集黄色粉末,将其悬浮在乙醚中,过滤,得到670mg作为浅黄色粉末的所需产物(57%)。
4-氯-1-[(4-氯苯基)甲基]-6-甲氧基-嘧啶并[5,4-d]嘧啶-2-酮(步骤4)
在氮气氛下,将5-[(4-氯苯基)甲基]-2-甲氧基-嘧啶并[5,4-d]嘧啶-6,8-二酮(4.67mmol,1490mg)和乙基二异丙胺(14.03mmol,2.40mL,1813mg)在POCl3(374.0mmol,34.3mL,57350mg)中的溶液在50℃下搅拌3小时。冷却至室温后,除去溶剂,并将剩余物用1,4-二氧六环稀释,并将混合物蒸发(重复3次)。收集到1550mg的作为深色油状物的所需粗制产物,将其无需进一步纯化即用于下一步。(98%)
6-(4-氯苄基)-9-甲氧基-3-(四氢-2H-吡喃-4-基甲基)嘧啶并[4,5-e][1,2,4]三
唑并[4,3-c]嘧啶-5(6H)-酮(步骤5)
将4-氯-1-[(4-氯苯基)甲基]-6-甲氧基嘧啶并[5,4-d]嘧啶-2-酮(0.468mmol,158mg)和2-四氢吡喃-4-基乙酰肼(0.47mmol,74mg)(通过文献公开的方法合成)在1,4-二氧六环(5mL,100质量%)中的溶液在室温下搅拌30分钟。然后将混合物在回流下加热1小时。在室温下冷却后,添加水和EtOAc,并分离两相。然后将水相用EtOAc萃取,并将合并的有机相经Na2SO4干燥,过滤并蒸发。将粗制品通过硅胶柱色谱法,用0∶100开始至10∶90的甲醇/乙酸乙酯梯度洗脱来进行纯化。获得40mg作为黄色粉末的所需产物。产率:19%。
UPLC-MS[M+H]+=441.16
1H NMR(400MHz.DMSO-d6)δppm 8.76(s,1H)745-7.54(m,2H)737-7.43(m,2H)5.49(s,2H)4.01(s,3H)385(br dd,2H)330(br dd,2H)3.21-3.27(m,2H)2.18(ttd,1H)1.65(brdd,2H)1.29-1.44(m,2H)
按照实施例1中所述的过程,在步骤2中用(4-氯苯基)甲胺(从可得供应商处购买)替代(4-甲氧基苯基)甲胺,并在步骤3中用4,4,4-三氟丁烷-1,2-二胺(从可得供应商处购买)替换3-甲基丁烷-1,2-二胺HCl,来制备表5中所示的实施例159至160。所报道的产率参考最后一步。
实施例159
6-(4-氯苄基)-8-吗啉代-2-(2,2,2-三氟乙基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
和
实施例160
6-(4-氯苄基)-8-吗啉代-3-(2,2,2-三氟乙基)-2,6-二氢咪唑并[1,2-c]吡啶并
[2,3-e]嘧啶-5(3H)-酮
首先洗脱:实施例159。黄色黏性固体(产率35%)。
UPLC-MS[M+H]+=480.14
1H NMR(400MHz,乙腈-d3+TFA)δppm 8.36(br d,1H),7.32-745(m,4H),6.62(d,1H),5.35(s,2H),4.85(m,1H),4.63(t,1H),4.23(m,1H),3.73-3.83(m,4H),3.46-3.55(m,4H),2.78-2.97(m,2H)
第二洗脱:实施例160:黄色黏性固体(产率25%)
UPLC-MS[M+H]+=480.14
1H NMR(400MHz,乙腈-d3)δppm 8.35(d,1H),7.34-7.45(m,4H),6.61(d,1H),5.27(s,1H),5.25-5.39(m,1H),5.11-5.19(m,1H),4.39(t,1H),4.11(m,1H),3.73-3.81(m,4H),3.43-3.54(m,4H),3.15-3.29(m,1H),2.81-3.01(m,1H).
实施例161
6-(3,5-二甲氧基苄基)-2,2-二甲基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡
啶并[2,3-e]嘧啶-5(3H)-酮
按照针对实施例1的化合物所述的过程,但是在步骤2中用3,5-二甲氧基苄胺替代(4-甲氧基苯基)甲胺,并在步骤3中用适当的2-甲基丙烯-1,2-二胺(从可得供应商处购买或通过文献公开的方法合成)替换3-甲基丁烷-1,2-二胺,来进行制备。
黄色固体(51.8%)。
HPLC-MS[M+H]+=452.70
1HNMR(400MHz,氯仿-d)δppm 8,12(d,1H),6.55(d,1H),6.37(dd,3H),5.12(s,2H),3.85-3.76(m,6H),3.75(s,6H),3.19-3.12(m,4H),1.46(s,6H),1.26(d,9H),0.92-0.80(m,4H).
如针对先前实施例64所报道的,使用适当的苄基卤化物、α-溴代羧酸和胺(均从可得供应商处购买或通过文献公开的方法合成),来合成实施例163至165。
实施例163
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-
e]嘧啶-2,5(3H,6H)-二酮
黄色固体。产率:36.78%。
1H NMR(400MHz,DMSO-d6)δppm 8.46(d,1H)7.40(s,4H)6.83(d,1H)5.42-5.52(m,1H)5.25-5.38(m,1H)4.41(d,1H)3.72(t,4H)3.39-3.56(m,4H)2.76(m,1H)1.16(d,3H)0.78(d,3H)
UPLC-MS[M+H]+=451.21
实施例164
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-
e]嘧啶-2,5(3H,6H)-二酮
淡黄色固体。
1H NMR(400MHz,DMSO-d6)δppm 8.45(d,1H)7.23-7.36(m,2H)6.85-6.94(m,3H)5.23-5.43(m,2H)4.43(d,1H)3.68-376(m,7H)3.39-3.53(m,4H)2.78(m,1H)1.17(d,3H)0.78(d,3H)
实施例165
3-叔丁基-8-(二乙基氨基)-6-(4-甲氧基苄基)咪唑并[1,2-c]吡啶并[2,3-e]嘧
啶-2,5(3H,6H)-二酮
淡黄色固体
1H NMR(400MHz,DMSO-d6)δppm 8.18(d,1H)7.31(d,2H)6.86-6.98(m,2H)6.47(d,1H)5.18-541(m,2H)4.24(s,1H)3.71(s,3H)338-358(m,4H)1.04(s,9H)1.01(t,6H)
按照针对化合物158所述的过程,但是在步骤5中用适当的酰肼(从可得供应商处购买)替代2-四氢吡喃-4-基乙酰肼,来制备表5中所示的实施例166和168的化合物。所报道的产率参考最后一步。
实施例166
6-(4-氯苄基)-9-甲氧基-3-(1-甲基环丙基)嘧啶并[4,5-e][1,2,4]三唑并[4,3-
c]嘧啶-5(6H)-酮
浅棕色粉末。产率:4%。
UPLC-MS[M+H]+=397.17
1H NMR(400MHz,氯仿-d)δppm 8.60(s,1H)7.34-7.45(m,2H)7.21-7.31(m,2H)5.47(s,2H)4.17(s,3H)1.62(s,3H)1.32-1.40(m,2H)0.98-1.07(m,2H)
实施例168
3-叔丁基-6-(4-氯苄基)-9-甲氧基嘧啶并[4,5-e][1,2,4]三唑并[4,3-c]嘧啶-5
(6H)-酮
黄色粉末。产率:29%
UPLC-MS[M+H]+=399.15
1H NMR(400MHz,DMSO-d6)δppm 8.76(s,1H)7.45-7.51(m,2H)7.37-7.43(m,2H)5.51(s,2H)4.01(s,3H)1.59(s,9H)
按照针对化合物158所述的过程,但是在步骤2中用4-甲氧基苯甲醛替代4-氯苯甲醛,并在步骤5中用适当的酰肼(从可得供应商处购买)替换2-四氢吡喃-4-基乙酰肼,来制备表5中所示的实施例167和169。所报道的产率参考最后一步。
实施例167
3-叔丁基-9-甲氧基-6-(4-甲氧基苄基)嘧啶并[4,5-e][1,2,4]三唑并[4,3-c]嘧
啶-5(6H)-酮
黄色粉末。产率:17%。
UPLC-MS[M+H]+=395.18
1H NMR(400MHz,DMSO-d6)δppm 8.81(s,1H)7.37(d,2H)6.83-6.96(m,2H)5.45(s,2H)4.00(s,3H)3.73(s,3H)1.60(s,9H)
实施例169
9-甲氧基-6-(4-甲氧基苄基)-3-(1-甲基环丙基)嘧啶并[4,5-e][1,2,4]三唑并
[4,3-c]嘧啶-5(6H)-酮
黄色粉末。产率:42%。
UPLC-MS[M+H]+=393.21
1H NMR(400MHz,DMSO-d6)δppm 8.79(s,1H)7.39(d,2H)6.86-6.98(m,2H)5.45(s,2H)3.99(s,3H)3.73(s,3H)1.52(s,3H)1.18-1.28(m,2H)0.80-0.95(m,2H)
按照针对化合物158所述的过程,但是在步骤2中用4-甲氧基苯甲醛替代4-氯苯甲醛,来制备表5中所示的实施例170。所报道的产率参考最后一步。
实施例170
9-甲氧基-6-(4-甲氧基苄基)-3-(四氢-2H-吡喃-4-基甲基)嘧啶并[4,5-e][1,2,
4]三唑并[4,3-c]嘧啶-5(6H)-酮
黄色粉末。产率:27%。
UPLC-MS[M+H]+=437.19
1H NMR(400MHz,DMSO-d6)δppm 8.80(s,1H)7.38(d,2H)6.82-6.98(m,2H)5.43(s,2H)4.00(s,3H)3.85(br dd,2H)3.73(s,3H)3.29(br d,2H)3.25(d,2H)2.12-2.26(m,1H)1.65(br dd,2H)1.28-1.43(m,2H)
实施例172
6-(4-氯苄基)-2-(1-甲基环丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并
[1,5-c]嘧啶-5(6H)-酮
在实施例102的化合物的步骤6的柱色谱法纯化中,还分离了实施例172的化合物。
橙色粉末。产率11%。
UPLC-MS[M+H]+=451.25
1H NMR(400MHz,DMSO-d6)δppm 7.69(d,1H)739(s,4H)7,09(d,1H)5.29(s,2H)3.74-3.86(m,4H)3.34-3.44(m,4H)1.40(s,3H)1.08-1.17(m,2H)1.04(s,2H)
实施例173
3-叔丁基-6-[(5-氯吡啶-2-基)甲基]-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三
唑并[4,3-c]嘧啶-5(6H)-酮
按照针对实施例96的化合物所述的过程,在步骤2中用(5-氯-2-吡啶基)甲胺(从可得供应商处购买)替代(4-甲氧基苯基)甲胺,来制备如表5所示的实施例173。所报道的产率参考最后一步。
黄色固体的。产率:7%。
UPLC-MS[M+H]+=454.21
1H NMR(400MHz,氯仿-d)δppm 8.54(d,1H)8.38(d,1H)7.72(dd,1H)7.44(d,1H)7.33(d,1H)5.51(s,2H)3.88-3.96(m,4H)3.30-3.41(m,4H)1.69(s,9H)
实施例174
6-(4-甲氧基苄基)-3-(1-甲基环丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三
唑并[4,3-c]嘧啶-5(6H)-酮
按照针对实施例96的化合物所述的过程,在步骤6中用1-甲基环丙烷甲酰肼(从可得供应商处购买)替代2,2-二甲基丙酰肼,来制备表5中所示的实施例174。所报道的产率参考最后一步。
黄色固体。产率:5%。
UPLC-MS[M+H]+=447.22
1H NMR(400MHz,氯仿-d)δppm8,35(d,1H)7.23(d,2H)6.88-6.96(m,2H)6.83(d,1H)5.41(s,2H)3.84-3.92(m,4H)3.82(s,3H)3.20-3.28(m,4H)1.62(s,3H)1.30-1.39(m,2H)0.95-1.03(m,2H)
实施例177
3-叔丁基-8-(4-羟基哌啶-1-基)-6-(4-甲氧基苄基)吡啶并[2,3-e][1,2,4]三唑
并[4,3-c]嘧啶-5(6H)-酮
按照针对实施例96的化合物(替代合成)所述的过程,用哌啶-4-醇(从可得供应商处购买)替代吗啉,来制备表5中所示的实施例177。所报道的产率参考最后一步。
黄色粉末。产率:2%。
UPLC-MS[M+H]+=463.26
1H NMR(400MHz,氯仿-d)δppm 8.40(d,1H)7.28(s,1H)6.90-6.93(m,1H)6.85-6.90(m,2H)5.49(s,2H)4.00(tt,1H)3.77-3.84(m,4H)3.57-3.72(m,3H)3.11-3.26(m,2H)1.90-204(m,3H)1.66(ddd,5H)1.57(s,10H)
在实施例177的步骤5的柱色谱法纯化中,还分离了实施例175和实施例176的化合物。
实施例175
2-叔丁基-8-(4-羟基哌啶-1-基)-6-(4-甲氧基苄基)吡啶并[2,3-e][1,2,4]三唑
并[4,3-c]嘧啶-5(6H)-酮
黄色粉末。产率:7%。
UPLC-MS[M+H]+=463.32
1H NMR(400MHz,氯仿-d)δppm 8.41(d,1H)7.27(d,2H)6.93(d,1H)6.85-6.91(m,2H)5.49(s,2H)4.00(tt,1H)3.75-3.83(m,3H)3.58-3.70(m,2H)3.100-3.24(m,2H)1.91-2.06(m,2H)1.60-1.73(m,3H)1.51-1.60(m,10H)
实施例176
8-氨基-3-叔丁基-6-(4-甲氧基苄基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧
啶-5(6H)-酮
黄色粉末。产率:7%。
UPLC-MS[M+H]+=379.26
1H NMR(400MHz,DMSO-d6)δppm 7.98(d,1H)7.28(d,2H)686-6.98(m,3H)6.78(d,1H)6.20(s,2H)5.27(s,2H)3.73(s,4H)1.49-1.64(m,11H)
按照针对实施例96的替代合成中所述的过程(在最后步骤中通过Buchwald),在步骤1中用(4-氯苯基)甲胺(从可得供应商处购买)替换(4-甲氧基苯基)甲胺,在步骤4中用2-甲基丙酰肼(从可得供应商处购买)替换2,2-二甲基丙酰肼,在步骤5中用吗啉替代哌啶-4-醇(从可得供应商处购买),来制备表5中所示的实施例171。所报道的产率参考最后一步。
实施例171
6-(4-氯苄基)-8-(4-羟基哌啶-1-基)-3-(丙烷-2-基)吡啶并[2,3-e][1,2,4]三
唑并[4,3-c]嘧啶-5(6H)-酮
黄色粉末。产率:2%。
UPLC-MS[M+H]+=453.31
1H NMR(400MHz,氯仿-d)δppm 8.42(d,1H)7.32-7.39(m,2H)7.24-7.28(m,2H)6.77(d,1H)5.53(s,2H)4.01(m,1H)3.57-3.69(m,2H)3.37(spt,1H)3.18(ddd,2H)1.90-2.04(m,2H)1.61-1.71(m,2H)1.51(d,6H)
实施例178
9-叔丁基-5-(4-氯苄基)-3-(吗啉-4-基)[1,2,4]三唑并[1’,5’:1,6]嘧啶并[5,
4-c]哒嗪-6(5H)-酮
6-氯-4-((4-氯苄基)氨基)哒嗪-3-羧酸甲酯(步骤1)
在室温下将(4-氯苯基)甲胺(1.95mL,15.94mmol)和DIPEA(2.78mL,15.94mmol)添加至4,6-二氯哒嗪-3-羧酸甲酯(3.0g,14.49mmol)在MeCN(48.3mL,0.925mol)中的搅拌溶液。搅拌1小时后,通过过滤分离形成的沉淀物。将该粉末与含有少量DMF的Et2O一起研磨,得到作为灰白色粉末的标题化合物(3.8g,产率:84%)。
6-氯-4-((4-氯苄基)氨基)哒嗪-3-甲酰胺(步骤2)
在室温下,用7N氨的MeOH溶液(71.3mL)处理6-氯-4-[(4-氯苯基)甲基氨基]哒嗪-3-羧酸甲酯(3.8g,12.17mmol)。将反应在50℃下搅拌1小时。真空除去挥发物,得到作为白色固体的标题化合物(2.9g,产率:80%)。
3-氯-5-(4-氯苄基)嘧啶并[5,4-c]哒嗪-6,8(5H,7H)-二酮(步骤3)
在室温下用在矿物油中的氢化钠60%分散体(0.807g,20.19mmol)和CDI(3.3g,20.19mmol)处理6-氯-4-((4-氯苄基)氨基)哒嗪-3-甲酰胺(2.0g,6.73mmol)在DMF(67.0mL)中的搅拌溶液。将反应混合物在室温下搅拌1小时。除去溶剂,试图用少量DMSO溶解粗制物质以进行反相纯化,形成沉淀物并通过过滤分离,在与MeCN一起研磨后得到第一量的所需产物(630mg)。滤液(30克)用C18柱,并用1/1H2O/MeCN洗脱来进行纯化,得到第二量的所需产物(580mg)。合并的级分得到作为白色固体的标题化合物(1.2克,产率:55%)。
3-(叔丁基)-8-氯-6-(4-氯苄基)-[1,2,4]三唑并[4’,3’:1,6]嘧啶并[5,4-c]哒
嗪-5(6H)-酮(步骤4)
在室温下将DIPEA(1.1mL,6.7mmol)逐滴添加至3-氯-5-[(4-氯苯基)甲基]嘧啶并[5,4-c]哒嗪-6,8-二酮(545.mg,1.69mmol)在磷酰氯(30.0mL)中的搅拌悬浮液。将反应混合物在80℃下加热3小时,通过UPLC监测(用MeOH淬灭,观察到Cl中间体的形成为甲氧基类似物ES+=337)。冷却后,蒸发挥发物,并将所得剩余物溶于1,4-二氧六环(30.7mL)中,并添加2,2-二甲基丙酰肼(293.88mg,2.53mmol)。在50℃下继续搅拌30分钟,通过UPLC监测开放中间体的形成(ES+=421),然后在在回流下获得三唑的闭环。冷却后,将混合物用饱和NaHCO3溶液处理,并用EtOAc萃取。有机相用盐水洗涤,经Na2SO4干燥,过滤后得到剩余物,将其通过RP色谱法纯化,得到标题化合物(160mg,产率:23%)。
9-叔丁基-5-(4-氯苄基)-3-(吗啉-4-基)[1,2,4]三唑并[1’,5’:1,6]嘧啶并[5,
4-c]哒嗪-6(5H)-酮(步骤5)
将3-(叔丁基)-8-氯-6-(4-氯苄基)-[1,2,4]三唑并[4’,3’:1,6]嘧啶并[5,4-c]哒嗪-5(6H)-酮(80mg,0.20mmol)、Xantphos(27.45mg,0.050mmol)、碳酸二铯(131mg,0.40mmol)溶于脱气的1,4-二氧六环(2mL)中。然后添加吗啉(27μL,0.30mmol)和Pd(OAc)2(7mg,0.03mmol)。将混合物在100℃下搅拌1小时,冷却后,将反应物通过SolkaFloc过滤并除去溶剂。将粗制品通过RP柱色谱法,以8∶2开始至1∶1的水+0.1%TFA/ACN+0.1%TFA梯度洗脱来进行纯化。获得作为浅黄色固体的标题化合物(4mg,产率:5%)。
UPLC-MS[M+H]+=454.31
1H NMR(400MHz,DMSO-d6)δppm 7.35-7.47(m,4H),6.80(s,1H),5.48(s,2H),3.49-3.76(m,8H),1.44(s,9H).
光诱导镍催化胺化反应的一般过程
在装有磁性和PTFE/硅氧烷隔板的小瓶中装入适当的氯或溴中间体(见下文,1.0当量)、胺(1.5当量)、DABCO(1.8当量)和4,4’-二-叔丁基-2,2’-联吡啶)双[3,5-二氟-2-[5-三氟甲基-2-吡啶基-kN)苯基-kC]六氟磷酸铱(III)(0.020当量),随后装入DMA和DMA中的氯化镍(2+)-1,2-二甲氧基乙烷(1∶2∶1)(0.050当量)(总计0.25M)。将混合物严格脱气(首先将样品瓶用氮气填充,在-78℃下冷却,然后在真空下脱气,用氮气回填,并温热至室温,3个循环),然后将小瓶用封口膜带密封。对小瓶进行365nm LED照射(距34W蓝色LED灯2cm的距离)。照射时的内部温度为约55℃(无风扇冷却)。2至4小时后,将反应用EtOAc稀释,并顺序地用水和盐水洗涤。有机相经Na2SO4干燥,过滤并除去溶剂后得到剩余物,其通过色谱法或RP-HPLC纯化。
实施例179
8-(4-氨基哌啶-1-基)-3-叔丁基-6-(4-氯苄基)[1,2,4]三唑并[4’,3’:1,6]嘧啶
并[5,4-c]哒嗪-5(6H)-酮
根据针对化合物178所述的过程,但在步骤5中按照光诱导镍催化胺化反应的一般过程,使用3-(叔丁基)-8-氯-6-(4-氯苄基)-[1,2,4]三唑并[4’,3’:1,6]嘧啶并[5,4-c]哒嗪-5(6H)-酮(70mg,0.17mmol)和N-(4-哌啶基)氨基甲酸酯(52mg,0.26mmol)来制备表5中所示的实施例179。用DCM/TFA(9/1)处理2小时并除去溶剂后,将所得剩余物通过RP-HPLC纯化,得到标题化合物。
浅黄色固体。产率:12%。
UPLC-MS[M+H]+=467.49
1H NMR(400MHz,DMSO-d6)δppm 7.78-791(m,3H),7.37-7.48(m,4H),6.79(s,1H),5.45(s,2H),4.45-4.56(m,2H),3.06(br t,2H),1.98(br d,2H),1.55(s,9H),1.37-1.52(m,3H)
实施例180
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)[1,2,4]三唑并[4’,3’:1,6]嘧啶并
[5,4-c]哒嗪-5(6H)-酮
按照实施例178中所述的过程,在步骤1中用(4-甲氧基苯基)甲胺(从可得供应商处购买)替换(4-氯苯基)甲胺,并对于最后一步,进行光诱导镍催化胺化反应,如实施例180所述,用吗啉替代4-氨基哌啶,来制备表5中所示的实施例181的化合物。所报道的产率参考最后一步。
浅棕色固体。产率:21%。
UPLC-MS[M+H]+=450.41
1H NMR(400MHz,DMSO-d6)δppm7.36(brd,2H),6.91-7.01(m,1H),6.87(brd,2H),5.40(s,2H),3.71-3.85(m,4H),3.70(s,7H),1.55(s,9H)
按照针对实施例96的替代合成中所述的过程(在最后步骤中通过Buchwald),在步骤1中用适当的胺(按照公开的文献方法合成或从可得供应商处购买)替换(4-甲氧基苯基)甲胺,并且如果需要的话在最后一步中进行光诱导镍催化胺化反应时,用适当的胺(从可得供应商处购买)替代吗啉,来制备表5中所示的实施例181至185。所报道的产率参考最后一步。
实施例181
4-[3-叔丁基-6-(4-氯苄基-5-氧代-5,6-二氢吡啶并[2,3-e][1,2,4]三唑并[4,
3-c]嘧啶-8-基]哌嗪-1-羧酸叔丁酯(步骤1)
根据用于光诱导镍催化胺化反应的一般过程使用8-溴-3-(叔丁基)-6-(4-氯苄基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮(80.0mg,0.180mmol)和哌嗪-1-羧酸叔丁酯(50.03mg,0.270mmol)来制备该化合物。粗制物通过RP柱色谱法,用从8∶2开始至1∶1的水+0.1%TFA/ACN+0.1%TFA梯度洗脱来进行纯化,得到标题化合物(35mg,35%产率)。
3-(叔丁基)-6-(4-氯苄基)-8-(哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-
c]嘧啶-5(6H)-酮(步骤2)
在0℃下将TFA(0.1mL)添加至4-(3-(叔丁基)-6-(4-氯苄基)-5-氧代-5,6-二氢吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-8-基)哌嗪-1-羧酸叔丁酯(35.mg,0.060mmol)在DCM(0.900mL)中的搅拌溶液。将反应在室温下升温,并搅拌2小时。真空除去挥发物,并将粗制品通过RP柱色谱法,以从8∶2开始至1∶1的水+0.1%TFA/ACN+0.1%TFA梯度洗脱来进行纯化,得到作为浅棕色粉末的标题化合物(19mg,产率:66%)。
UPLC-MS[M+H]+=452.46
1H NMR(400MHz,DMSO-d6+TFA)δppm 8.91(br s,2H),8.49(br s,1H),7.42(s,2H),7.39(s,2H),7.08(br s,1H),5.55(br s,2H),3.50-3.58(m,4H),3.24(br s,4H),1.55(brs,9H)
实施例182
2-(叔丁基)-6-(4-氯苄基)-8-(哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-
c]嘧啶-5(6H)-酮
在通过柱色谱法纯化实施例181的化合物的最后的步骤中,实施例182的化合物也作为白色粉末被分离(16mg,产率:31%)。
UPLC-MS[M+H]+=452.31
1H NMR(400MHz,DMSO-d6)δppm 8.78(br s,2H),8.49(d,1H),7.36-7.45(m,4H),7.10(d,1H),5.57(s,2H),3.55-3.70(m,4H),3.15-334(m,4H),1.43(s,9H).
实施例183
3-(叔丁基)-6-(4-氯苄基)-8-(3-甲氧基吡咯烷-1-基)吡啶并[2,3-e][1,2,4]三
唑并[4,3-c]嘧啶-5(6H)-酮
根据用于光诱导镍催化胺化反应的一般过程使用8-溴-3-(叔丁基)-6-(4-氯苄基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮(70.mg,0.160mmol)和3-甲氧基吡咯烷(23.77mg,0.240mmol)制备该化合物。将粗制品通过RP柱色谱法,以从8∶2开始至1∶1的水+0.1%TFA/ACN+0.1%TFA梯度洗脱来进行纯化,得到作为浅黄色固体的标题化合物(13.8mg,产率19%)
UPLC-MS[M+H]+=467.42
1H NMR(400MHz,DMSO-d6)δppm 8.19(d,1H),7.37-7.53(m,4H),5.57(s,2H),4.12(br s,1H),3.50(br s,3H),3.32-3.44(m,1H),3.26(s,3H),1.98-2.22(m,2H),1.57(s,9H)
实施例184
3-(叔丁基)-6-(4-氯苄基)-8-((四氢-2H-吡喃-4-基)氨基)吡啶并[2,3-e][1,2,
4]三唑并[4,3-c]嘧啶-5(6H)-酮
根据用于光诱导镍催化胺化反应的一般过程,使用8-溴-3-(叔丁基)-6-(4-氯苄基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮(20mg,0.04mmol)和四氢吡喃-4-胺(7μL,0.07mmol),来制备标题化合物。将粗制品通过RP柱色谱法,以从8∶2开始至1∶1的水+0.1%TFA/ACN+0.1%TFA梯度洗脱来进行纯化,得到作为浅黄色固体的标题化合物(4mg,产率:15%)
UPLC-MS[M+H]+=467.20
1H NMR(400MHz,DMSO-d6)δppm 8.09-8.26(m,1H),735-7.55(m,4H),6.59(d,1H),5.54(s,2H),3.83(brd,2H),3.53-3.69(m,1H),3.24-3.45(m,2H),1.52-1.66(m,11H),1.12-1.42(m,2H).
实施例185
3-叔丁基-6-[(5-甲基噻吩-2-基)甲基]-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]
三唑并[4,3-c]嘧啶-5(6H)-酮
根据用于光诱导镍催化胺化反应的一般过程,使用8-溴-3-(叔丁基)-6-((5-甲基噻吩-2-基)甲基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮478-100(60mg,0.132mmol)作为原料,来制备标题化合物。将粗制品通过RP柱色谱法,以从8∶2开始至4∶6的水+0.1%TFA/ACN+0.1%TFA梯度洗脱来进行纯化,得到作为浅黄色固体的标题化合物(19mg,产率:32%)
UPLC-MS[M+H]+=439.19
1H NMR(400MHz,DMSO-d6)δppm 8.42(d,1H),7.36(d,1H),7.10(d,1H),6.66(m,1H),5.60(s,2H),3.70-3.88(m,4H),3.37-3.48(m,4H),2.35(s,3H),1.57(s,9H).
按照针对实施例96的替代合成中所述的过程(在最后步骤中通过Buchwald),在步骤1中用(4-氯苯基)甲胺(从可得供应商处购买)替换(4-甲氧基苯基)甲胺,在步骤4中用适当的酰肼(按照公开的文献程序合成或从可得供应商处购买)替换2,2-二甲基丙酰肼,在步骤5中用适当的胺替换吗啉,来制备表5中所示的实施例186至188。所报道的产率参考最后一步。
实施例186
6-(4-氯苄基)-8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-e][1,
2,4]三唑并[4,3-c]嘧啶-5(6H)-酮
浅黄色固体。产率:15%。
UPLC-MS[M+H]+=495.20
1H NMR(400MHz,DMSO-d6)δppm 8.47(d,1H)7.51-7.59(m,2H)7.41-7.50(m,2H)7.07(d,1H)5.56(s,2H)3.93(dd,2H)3.77-3.86(m,4H)3.33-348(m,6H)3.26(d,2H)2.19-2.34(m,1H)1.69-1.80(m,2H)1.34-1.50(m,2H)
实施例187
8-(4-乙酰基哌嗪-1-基)-6-(4-氯苄基)-3-(丙烷-2-基)吡啶并[2,3-e][1,2,4]
三唑并[4,3-c]嘧啶-5(6H)-酮
浅黄色固体。产率:9%。
UPLC-MS[M+H]+=480.24
1H NMR(400MHz,DMSO-d6)δppm 845(d,1 H)7.35-750(m,4H)703(d,1H)5.57(s,2H)3.52-3.65(m,4H)334-3.48(m,4H)3.18(spt,1H)2.05(s,3H)1.38(d,6H)
实施例188
6-(4-氯苄基)-8-(吗啉-4-基)-3-[(四氢-2H-吡喃-4-基氧基)甲基]吡啶并[2,3-
e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮
浅黄色固体。产率19%。
UPLC-MS[M+H]+=511.21
1H NMR(400MHz,DMSO-d6)δppm 8.41(d,1H)7.31-7.50(m,4H)7.01(d,1H)5.50(s,2H)5.08(s,2H)3.76-3.90(m,3H)3.69-3.75(m,4H)3.25-3.42(m,6H)1.82-1.98(m,2H)1.39-1.57(m,2H)
实施例189
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[3,4-e][1,2,4]三唑并[4,
3-c]嘧啶-5(6H)-酮
6-氯-4-[(4-甲氧基苯基)甲基氨基]吡啶-3-甲腈(步骤1)
向4,6-二氯吡啶-3-甲腈(5.78mmol,1000mg)在MeCN(20mL)中的溶液添加(4-甲氧基苯基)甲胺(8.68mmol,1189.4mg,1.13mL),并将混合物在65℃下搅拌12小时,形成白色沉淀物。在室温下冷却后,添加水和EtAcO,分离两相,有机层用水和盐水洗涤,经Na2SO4干燥,过滤并蒸发。将粗制品通过硅胶柱色谱法,用从0∶100开始至30∶70的乙酸乙酯/石油醚梯度洗脱,来进行纯化。获得513mg作为白色粉末的所需产物(产率32%)。
4-[(4-甲氧基苯基]甲基氨基]-6-吗啉代-吡啶-3-甲腈(步骤2)
向MW小瓶中的6-氯-4-[(4-甲氧基苯基)甲基氨基]吡啶-3-甲腈(1.87mmol,513mg)在NMP(10mL)中的溶液添加吗啉(2.81mmol,244.9mg,0.245mL),并将混合物在微波辐射下于130℃下搅拌2小时(1小时后添加1当量的吗啉)。在室温下冷却后,添加水和EtOAc,并分离两相。然后将水相用EtOAc萃取,并将合并的有机相经Na2SO4干燥,过滤并蒸发。将粗制品通过硅胶柱色谱法,用从20∶80开始至50∶50的乙酸乙酯/石油醚梯度洗脱来进行纯化。获得500mg作为白色粉末的所需产物(产率82%)。
4-/(4-甲氧基苯基)甲基氨基]-6-吗啉代-吡啶-3-甲酰胺(步骤3)
向4-[(4-甲氧基苯基)甲基氨基]-6-吗啉代-吡啶-3-甲腈(0.669mmol,217mg)在DMSO(5mL)中的冰浴中冷却的溶液添加氢氧化钠溶液(0.401mmol,0.4014mL,1mol/L),随后添加30%过氧化氢溶液(0.803mmol,0.082mL,91.01mg),并将混合物在室温下搅拌2小时。然后添加水和EtOAc,分离两相,水层用EtOAc萃取(3次),合并的有机层经Na2SO4干燥,过滤并蒸发。收集到190mg作为灰白色粉末的所需产物,将其无需进一步纯化即用于下一步(产率82%)。
1-[(4-甲氧基苯基)甲基]-7-吗啉代-吡啶并[4,3-d]嘧啶-2,4-二酮(步骤4)
向4-[(4-甲氧基苯基)甲基氨基]-6-吗啉代-吡啶-3-甲酰胺(0.730mmol,250mg)在DMF(10mL,100质量%)中的溶液添加氢化钠(4.381mmol,175.2mg,60质量%),随后添加二(咪唑-1-基)甲酮(4.381mmol,710.4mg),并将混合物在室温下搅拌过夜。添加乙酸直至pH=3至4,然后添加水并形成白色沉淀物。过滤后,收集到220mg作为白色粉末的所需产物(产率=81%)。
4-氯-1-[(4-甲氧基苯基)甲基]-7-吗啉代吡啶并[4,3-d]嘧啶-2-酮(步骤5)
在氮气氛下将1-[(4-甲氧基苯基)甲基]-7-吗啉代-吡啶并[4,3-d]嘧啶-2,4-二酮(0.271mmol,100mg)悬浮在乙基二异丙胺(0.814mmol,0.139mL,105.2mg)中并逐滴添加POCl3(38mmol,3.49mL,5827mg),并将混合物在50℃下搅拌1小时。将混合物冷却至室温,将POCl3在减压下蒸发并将剩余物用1,4-二氧六环洗涤(3次)。收集到104mg作为粗制品的所需产物(深色油状物),将其无需进一步纯化即用于下一步(产率99%)。
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[3,4-e][1,2,4]三唑并[4,
3-c]嘧啶-5(6H)-酮(步骤6)
将4-氯-1-[(4-甲氧基苯基)甲基]-7-吗啉代-吡啶并[4,3-d]嘧啶-2-酮(0.269mmol,104mg)和2,2-二甲基丙酰肼(0.403mmol,47mg)在1,4二氧六环(3ml)中的溶液在室温下搅拌30分钟。然后将混合物在回流下加热2小时。在室温下冷却后,添加水和EtOAc,并分离两相。用EtOAc萃取水相,并将合并的有机相经Na2SO4干燥,过滤并蒸发。将粗制剩余物溶于无水四氢呋喃(5mL,100质量%)中,并添加Burgess试剂(0.864mmol,0.206g),并将混合物在室温下搅拌过夜,用EtOAc萃取水相,并将合并的有机相经Na2SO4干燥,过滤并蒸发。将粗制品通过硅胶柱色谱法,用从50∶50开始至100∶0的乙酸乙酯/石油醚梯度洗脱来进行纯化。获得20mg的实施例189。
白色粉末。产率:16%。
UPLC-MS[M+H]+=449.15
1H NMR(400MHz,DMSO-d6)δppm 8.94(s,1H)7.34(d,2H)6.86-6.96(m,2H)6.54(s,1H)5.41(s,2H)3.72(s,3H)3.64-3.71(m,4H)3.50-3.58(m,4H)1.55(s,9H)
按照针对化合物189所述的过程,但是在步骤6中用1-甲基环丙烷甲酰肼(从可得供应商处购买)替代2-2-二甲基丙酰肼,来制备表5中所示的实施例190。
实施例190
6-(4-甲氧基苄基)-3-(1-甲基环丙基)-8-(吗啉-4-基)吡啶并[3,4-e][1,2,4]三
唑并[4,3-c]嘧啶-5(6H)-酮
浅黄色粉末。产率:25%。
UPLC-MS[M+H]+=447.29
1H NMR(400MHz,DMSO-d6)δppm 8.90(s,1H)7.37(d,2H)6.85-6.94(m,2H)6.52(s,1H)5.40(s,2H)3.72(s,3H)3.63-3.70(m,4H)3.49-3.56(m,4H)1.48(s,3H)1,14-1.19(m,2H)0.79-0.87(m,2H)
按照针对化合物180所述的过程,但是在步骤1中用(4-氯苯基)甲胺(从可得供应商处购买)替代(4-甲氧基苯基)甲胺,来制备表5中所示的实施例191。
实施例191
3-叔丁基-6-(4-氯苄基)-8-(吗啉-4-基)[1,2,4]三唑并[4’,3’:1,6]嘧啶并[5,
4-c]哒嗪-5(6H)-酮
按照针对实施例189中的化合物所述的过程,在步骤1中用(4-氯苯基)甲胺(从可得供应商处购买)替换(4-甲氧基苯基)甲胺,来制备表5中所示的实施例192。
实施例192
3-叔丁基-6-(4-氯苄基)-8-(吗啉-4-基)吡啶并[3,4-e][1,2,4]三唑并[4,3-c]
嘧啶-5(6H)-酮
浅黄色粉末。产率:23%。
UPLC-MS[M+H]+=452.95
按照实施例1中所述的过程,在步骤2中用(3,5-二甲氧基苯基)甲胺(从可得供应商处购买)替换(4-甲氧基苯基)甲胺,并在步骤3中用4,4-二甲基戊烷1,2-二胺(从可得供应商处购买)替代3-甲基丁烷-1,2-二胺HCl,来制备表5中所示的实施例193至194。所报道的产率参考最后一步。
实施例193
6-(3,5-二甲氧基苄基)-2-(2,2--二甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并
[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
和
实施例194
6-(3,5-二甲氧基苄基)-3-(2,2-二甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并
[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮
首先洗脱:实施例194。灰白色固体(产率:25%)。
UPLC-MS[M+H]+=494.28
1H NMR(400MHz,乙腈-d3)δppm 8.11(s,1H),6.64(s,1H),6.48(s,2H),6.40(br s,1H),5.13(br s,2H),4.25-436(m,1H),4.08-4.23(m,1H),3.75(s,10H),3.53(br t,1H),3.13-3.25(m,4H),1.83(m,1H),1.53(m,1H),1.05(s,9H).
第二洗脱:实施例195。浅黄色固体(产率:13%)。
1H NMR(400MHz,乙腈-d3+TFA)δppm 9.63(brs,22H),8.33(d,1H),6.59-6.68(m,1H),6.43-6.50(m,3H),5.15-5.39(m,2H),4.83-5.01(m,1H),4.24-4.40(m,1H),3.84-3.99(m,1H),3.74-3.80(m,10H),3.43-3.52(m,4H),2.13-2.38(m,1H),1.97(m,5H),1.62-1.85(m,1H),1.05(s,9H).
生物测定:钙荧光测量
已将用于人嘌呤能P2X3受体的测定适配于使用FLEXSTATION作为阅读器和光蛋白作为发光读数的内部筛选仪器。该测定包括重组共表达人P2rx3受体的CHO-K1细胞和Ca2+敏感性光蛋白。将细胞维持在DMEM F-12(1∶1)混合物(LONZA目录编号BE04-687F/U1)中,该混合物补充有9mL的100mM丙酮酸钠(LONZA目录编号BE13-115E)、29mL的7.5%碳酸氢钠(LONZA目录号:BE17-613E)、5.5mL 1M Hepes(LONZA目录号BE17-737E)、5mL 100×青霉素/链霉素(LONZA目录号DE17-602E)和50mL胎牛血清(Sigma目录号F7524)、1mg/mL G418(Sigma目录号G8168)和5μg/ml嘌呤霉素(Sigma目录号P9620)。标准增殖条件包括每周两次在P75烧瓶中接种,回收约20x106个细胞,相当于约80%的汇合。将细胞以40000个细胞/孔的密度接种到黑壁透明底部96孔板中的蒂罗德缓冲液(标准蒂罗德缓冲液:内部溶液,130mM NaCl,5mM KCl,2mM CaCl2、5mM NaHCO3、1mM MgCl2,20mM HEPES,pH 7.4)。24小时后,将培养基用200μL/孔的蒂罗德缓冲液中的腔肠素(腔肠素(Coelenterazine):来自BIOSYNTH(目录号C-7001)。在DMSO和谷胱甘肽中制备10mM储备液,并在-20℃下储存)替换。将板在37℃下孵育4小时,然后注入10μL/孔的蒂罗德缓冲液中的25×浓度的测试化合物。4分钟后,进行第二次注入50μL/孔的蒂罗德缓冲液中的5×α,β-Met-ATP(α,β-Met-ATP:来自Tocris(目录号3209),以100mM溶解在水中,并在-20℃下等分储存),并通过FLEXSTATIONIII(Molecular Devices)记录发射的发光信号。所测试的化合物显示出对人P2X3受体的1nM至10μM的拮抗作用。实施例96和实施例102分别显示出20.7和25.5nM的抑制。
以对根据本发明制备的某些目的化合物的IC50(nM)表示的人P2X3受体的选定拮抗剂在下表6至9中示出。
表6:对于本发明的选定化合物的人P2X3受体拮抗剂活性。
表7:对于本发明的选定化合物的人P2X3受体拮抗剂活性。
表8:对于本发明的选定化合物的人P2X3受体拮抗剂活性。
表9:对于本发明的选定化合物的人P2X3受体拮抗剂活性。
统计分析。
使用软件Prism4.0(Graphpad,San Diego,CA)通过非线性回归分析来确定测试的化合物对克隆的P2X3受体的抑制曲线。该程序估计了IC50值和伪希尔斜率系数(pseudo-Hill slope coefficient)。
Claims (15)
1.根据式I的化合物或者其对映体、非对映体、N-氧化物或可药用盐或组合:
其中:
每个A独立地表示选自C、N、S或O的原子;
X和Y选自C和N原子,其中单元X-Y分别表示N-C基团或C=N基团;
每个R1独立地表示氢、卤素原子,或任选取代的羟基、羰基、羧基、氨基、酰胺基、C1-C6烷基或C1-C6烷氧基,任选取代的单环、双环或三环C6-C14芳基,或包含1至5个选自N、O或S的杂原子的任选取代的单环、双环或三环的C1-C13杂环基;
R2不存在,或者表示氢,或任选取代的C1-C6烷基、C1-C6烷氧基、C4-C14芳基烷基、C4-C14杂芳基烷基、C3-C7环烷基,单环、双环或三环C6-C14芳基,或者包含1至5个选自N、O或S的杂原子的单环、双环或三环C1-C13杂环基;
基团R3和R4,或者作为替代地基团R3和R5彼此连接以形成五元或六元杂环,所述杂环包含选自N、O和S的2至3个杂原子,任选地被一个或更多个基团nR6取代,前提是剩余的不与基团R3连接以形成杂环的R4或R5不存在,或是独立地选自N、O或S的直接与含X-Y环双键键合的原子;
每个R6独立地表示氢,选自F、Cl、Br或I的卤素原子,或任选取代的羰基、氧代、C1-C6烷基、C1-C6烷氧基或C3-C7环烷基,任选取代的单环、双环或三环C6-C14芳基,或包含1至5个选自N、O或S的杂原子的任选取代的单环、双环或三环C1-C13杂环基团,或者作为替代地,两个R6基团彼此连接以形成式-(Zp)-的基团,其中p为3至5的整数,并且每个Z独立地表示氧原子或任选取代的亚甲基,前提是没有两个相邻的Y部分表示氧原子;并且
n是独立地选自0至3的整数。
2.根据权利要求1所述的化合物,其中所述任选的取代基独立地选自卤素原子、C1-C6烷基、C1-C6烷氧基、羟基、巯基、硝基、氰基、氧代、卤代(C1-C6)烷基、卤代(C1-C6)烷氧基、C1-C6烷硫基、C1-C6烷基磺酰基、C1-C6烷基羰基、氨基磺酰基、C1-C6烷基氨基磺酰基、二(C1-C6)烷基氨基磺酰基、(C1-C6)烷氧基羰基和(C1-C6)烷基羰基(C1-C6)烷基,以及选自式-NR*R*、-C(=O)-NR*R*、-D、-O-D、-C(=O)-D、-(CH2)q-D、-NR**-D、-C(=O)-NR**-D、-NR**C(=O)-D和-O-C(=O)-D的基团,其中每个R*独立地表示氢原子或C1-C6烷基、C1-C6烷氧基、C1-C6烷基羰基、苯基或苄基,R**表示氢原子或C1-C6烷基,q为1至6的整数,并且D表示苯基或包含1至3个选自N、O和S的杂原子的C1-C8杂环基,C1-C6环烷基,每个基团D还任选地被1至3个独立地选自卤素、羟基、氰基、硝基和C1-C6烷基的基团取代,优选其中所述任选的取代基选自卤素原子和C1-C6烷基。
3.根据权利要求1或权利要求2所述的化合物,其中基团X-Y表示N-C基团,基团R3和R4彼此连接以形成包含2至3个氮杂原子的五元或六元杂环,其任选地被一个或更多个nR6基团取代,并且R5为羰基。
4.根据权利要求1或权利要求2所述的化合物,其中基团X-Y表示N-C基团,基团R3和R5彼此连接以形成包含2至3个氮杂原子的五元杂环,其任选地被一个或更多个基团nR6取代,并且R4为羰基。
5.根据权利要求1或权利要求2所述的化合物,其中基团X-Y表示C=N基团,基团R3和R4彼此连接以形成包含2至3个氮杂原子的五元或六元杂环,其任选地被一个或更多个基团nR6取代,并且R5不存在。
6.根据任意前述权利要求所述的化合物,其中R1选自包含以下的组:H、Br、羟基、羧基、甲氧基、甲氧基乙基氨基、2-羟基乙基氨基、叔丁氧基羰基氨基、2-羟基乙基氨基羰基,任选取代的氮杂环丁烷基、吗啉基、氧杂环丁烷基、哌嗪基、哌啶基、吡喃基或吡咯烷基部分、或其衍生物,或任选取代的包含1至5个选自N、O或S的杂原子的螺稠合的双环或三环C1-C13杂环基。
7.根据权利要求6所述的化合物,其中R1选自包含以下的组:2-氧杂-6-氮杂螺[3.3]庚烷-6-基、3-甲氧基甲基氮杂环丁烷-1-基、3-甲氧基吡咯烷-1-基、4-乙酰基哌嗪-1-基、4-氨基哌啶-1-基、4-羟基哌啶-1-基、4-羟基哌啶-1-基-羰基、4-甲氧基哌啶-1-基、4-吗啉基、二甲基氨基哌啶-1-基、羟甲基哌啶-1-基、吗啉-4-基羰基、四氢-2H-吡喃-4-基氨基或四氢-2H-吡喃-4-基氨基羰基。
8.根据任意前述权利要求所述的化合物,其中R2是氢原子或任选取代的苄基或其衍生物。
9.根据权利要求8所述的化合物,其中R2是氢原子,或选自包含以下的组:3,5-二甲氧基苄基、4-甲氧基苄基、4-甲基苄基、4-氯苄基或4-氯-2,6-二氟苄基。
10.根据任意前述权利要求所述的化合物,其中R6选自包含以下的组:苯基、(1-苯基)乙基、1-乙基-1H-吡唑-3-基、1-乙基-1H-吡唑-5-基、(四氢-2H-吡喃-4-基)甲基、(四氢-2H-吡喃-4-基氧基)甲基、(四氢-2H-吡喃-4-基)乙基、3,5-二甲基-1,2唑-4-基、2-羟基吡啶-3-基、2-甲基吡啶-3-基、吗啉-4-基-羰基、吡啶-3-基-甲基、氧代、甲基、乙基、异丙基、叔丁基、甲基丙基、2,2-二甲基丙基、3-甲基丁基、2,2,2-三氟乙基、甲氧基甲基、甲氧基乙基、(丙烷-2-基氧基)甲基、叔丁氧基甲基、丙-1-烯-2-基、丙烷-2-基-乙酰胺、环丙基、环丁基、环己基、1-甲基环丙基。
11.根据权利要求1所述的化合物,其中-(Zp)-表示选自以下的基团:-O-(CH2)2-O-、-O-(CH2)3-O-、-O-(CH2)2-、-O-(CH2)3-、-CH2-O-CH2-或-(CH2)2-O-(CH2)2。
13.根据权利要求1所述的化合物,所述化合物选自:
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-3-甲基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-2-甲基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-2-乙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-3-乙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-2,3-二甲基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-2-环丙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-2-(甲氧基甲基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-3-环丙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-3-(甲氧基甲基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(4-甲氧基哌啶-1-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-甲氧基苄基)-8-(吗啉-4-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-甲氧基苄基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
8-[4-(羟甲基)哌啶-1-基]-6-(4-甲氧基苄基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
8-[4-(二甲基氨基)哌啶-1-基]-6-(4-甲氧基苄基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
2-环己基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
3-环己基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-2-环己基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-3-环己基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
2-乙基-6-(4-甲氧基苄基)-8-[(3r)-3-甲氧基吡咯烷-1-基]-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-甲氧基苄基)-8-(吗啉-4-基)-2-苯基-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-苯基-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
2-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
2-环丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
2-(2,2-二甲基丙基)-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-2-苯基-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-甲氧基苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-甲氧基苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
2-乙基-6-(4-甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-2’,3’,5’,6’-四氢螺[咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-2,4’-吡喃]-5(6H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-2,2’,3’,5’,6,6’-六氢-5h-螺[咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-3,4’-吡喃]-5-酮;
8-(4-氨基哌啶-1-基)-6-(3,5-二甲氧基苄基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
2-环己基-6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
3-环己基-6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-3-苯基-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-2-苯基-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-3-苯基-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-羟基-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-2-(丙烷-2-基)-8-(四氢-2H-吡喃-4-基氨基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-2-乙基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(4-羟基哌啶-1-基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
2-乙基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
3-乙基-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-2-(吗啉-4-基羰基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-3-(吗啉-4-基羰基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-甲氧基苄基)-8-(吗啉-4-基)-2-(2,2,2-三氟乙基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
2-(叔丁氧基甲基)-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-5-氧代-2-(丙烷-2-基)-n-(四氢-2H-吡喃-4-基)-2,3,5,6-四氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-8-甲酰胺;
6-(3,5-二甲氧基苄基)-5-氧代-2-(丙烷-2-基)-2,3,5,6-四氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-8-羧酸;
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基羰基)-2-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-2-(环己基甲基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-2-(3-甲基丁基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-3-(3-甲基丁基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-2,5(3H,6H)-二酮;
6-(4-甲氧基苄基)-2-(2-甲氧基乙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-甲氧基苄基)-3-(2-甲氧基乙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
3-(叔丁氧基甲基)-6-(4-甲氧基苄基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
3-叔丁基-6-(4-氯苄基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-2,5(3H,6H)-二酮;
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-2,5(3H,6H)-二酮;
6-(3,5-二甲氧基苄基)-2,3-二甲基-8-{[(氧杂环丁烷-3-基)甲基]氨基}咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
2-(2-甲基丙基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-甲基苄基)-2-(2-甲基丙基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-氯苄基)-2-(2-甲基丙基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-氯-2,6-二氟苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-2-乙基-3-甲基-8-{[(氧杂环丁烷-3-基)甲基]氨基}咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-3-乙基-2-甲基-8-{[(氧杂环丁烷-3-基)甲基]氨基}咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-甲氧基苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-3-甲基-8-(吗啉-4-基)-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-8-[4-(羟基乙酰基)哌嗪-1-基]-2-(2-甲基丙基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-2,3-二甲基-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-2,3-二甲基-8-(吗啉-4-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-3-甲基-8-[(氧杂环丁烷-3-基甲基)氨基]-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
8-(4-乙酰基哌嗪-1-基)-6-(3,5-二甲氧基苄基)-3-甲基-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-8-(4-甲氧基哌啶-1-基)-2,3-二甲基咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
5-(3,5-二甲氧基苄基)-8,9-二甲基-3-(吗啉-4-基)咪唑并[1,2-c]蝶啶-6(5h)-酮;
6-(3,5-二甲氧基苄基)-8-(4-甲氧基哌啶-1-基)-3-甲基-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-甲基-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-甲氧基苄基)-3-甲基-8-(吗啉-4-基)-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-氯苄基)-3-甲基-8-(吗啉-4-基)-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-氯苄基)-3-甲基-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-甲基-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-甲氧基苄基)-3-甲基-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-氯苄基)-8-[(4-羟基哌啶-1-基)羰基]-3-甲基-2-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(6H)-酮;
6-(4-氯苄基)-n-(2-羟基乙基)-3-甲基-5-氧代-2-(丙烷-2-基)-5,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-8-甲酰胺;
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-[(四氢-2H-吡喃-4-基氧基)甲基]吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-3-(吡啶-3-基甲基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-3-甲基-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-3-(1-甲基环丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
2-[6-(4-氯苄基)-8-(吗啉-4-基)-5-氧代-5,6-二氢吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-3-基]-n-(丙烷-2-基)乙酰胺;
6-(4-甲氧基苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-3-[(2-羟基吡啶-3-基)甲基]-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-3-[(2-甲基吡啶-3-基)甲基]-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-3-(1-乙基-1h-吡唑-5-基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-3-(1-乙基-1h-吡唑-3-基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
3-叔丁基-6-(4-氯苄基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
8-溴-3-叔丁基-6-(4-氯苄基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
n-(2-甲氧基乙基)-3-甲基-6-(4-甲基苄基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪-8-胺;
3-甲基-6-(4-甲基苄基)-n-(氧杂环丁烷-3-基甲基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪-8-胺;
6-(4-甲基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(3,5-二甲氧基苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-甲基苄基)-8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(3,5-二甲氧基苄基)-n-(2-甲氧基乙基)-3-(2-甲基丙基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪-8胺;
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-3-[(丙烷-2-基氧基)甲基]吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(3,5-二甲氧基苄基)-8-(吗啉-4-基)-3-(丙-1-烯-2-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(3,5-二甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-(2-甲基丙基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-甲氧基苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-(2-甲基丙基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-氯苄基)-8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-氯苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-氯苄基)-8-[3-(甲氧基甲基)氮杂环丁烷-1-基]-3-(2-甲基丙基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-氯苄基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-甲氧基苄基)-8-(2-氧杂-6-氮杂螺[3.3]庚烷-6-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
(4-氯苯基){8-(吗啉-4-基)-3-[2-(四氢-2H-吡喃-4-基)乙基]吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪-6-基}甲酮;
6-(4-氯苄基)-8-(吗啉-4-基)-3-[1-(四氢-2H-吡喃-4-基)乙基]吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
6-(4-氯苄基)-3-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
(4-甲氧基苯基)[8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪-6-基]甲酮;
(4-氯苯基){8-(吗啉-4-基)-3-[2-(四氢-2H-吡喃-4-基)乙基]吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪-6-基}甲醇;
3-(环己基甲基)-6-(4-甲基苄基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
3-(环己基甲基)-6-(4-甲基苄基)-8-(吗啉-4-基)吡啶并[2,3-d][1,2,4]三唑并[4,3-b]哒嗪;
n-[1-[5-叔丁基-8-(4-氯苄基)-3,4,6,7,13-五氮杂三环[7.4.0.02,6]十三-1(9),2,4,7,10,12-六烯-11-基]-4-哌啶基]氨基甲酸叔丁酯;
1-[5-叔丁基-8-(4-氯苄基)-3,4,6,7,13-五氮杂三环[7.4.0.02,6]十三-1(9),2,4,7,10,12-六烯-11-基]哌啶-4-胺;
1-[5-叔丁基-8-(4-氯苄基)-3,4,6,7,13-五氮杂三环[7.4.0.02,6]十三-1(9),2,4,7,10,12-六烯-11-基]哌啶-4-醇;
9,9-二甲基-5-(4-甲基苄基)-3-{[(氧杂环丁烷-3-基)甲基]氨基}-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
3-溴-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
5-(4-氯苄基)-3-[(2-羟基乙基)氨基]-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
5-(3,5-二甲氧基苄基)-3-[(2-羟基乙基)氨基]-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
5-(3,5-二甲氧基苄基)-9-甲基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
3-溴-5-(3,5-二甲氧基苄基)-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
5-(3,5-二甲氧基苄基)-9,9-二甲基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
3-溴-5-(4-氯苄基)-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
5-(4-氯苄基)-3-[3-(甲氧基甲基)氮杂环丁烷-1-基]-9,9-二甲基-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
5-(3,5-二甲氧基苄基)-10-乙基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
5-(3,5-二甲氧基苄基)-8-乙基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
10-乙基-5-(4-甲氧基苄基)-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
8-乙基-5-(4-甲氧基苄基)-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
5-(4-氯苄基)-10-乙基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
5-(4-氯苄基)-8-乙基-3-(吗啉-4-基)-5,8,9,10-四氢-6H-吡啶并[2,3-e]嘧啶并[1,2-c]嘧啶-6-酮;
6-(4-甲氧基苄基)-2-(2-甲基丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-c]嘧啶-5(6H)-酮;
2-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-9-甲氧基-3-(四氢-2H-吡喃-4-基甲基)嘧啶并[4,5-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-8-吗啉代-2-(2,2,2-三氟乙基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-吗啉代-3-(2,2,2-三氟乙基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(3,5-二甲氧基苄基)-2,2-二甲基-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-2,5(3H,6H)-二酮;
6-(4-甲氧基苄基)-8-(吗啉-4-基)-3-(丙烷-2-基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-2,5(3H,6H)-二酮;
3-叔丁基-8-(二乙基氨基)-6-(4-甲氧基苄基)咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-2,5(3H,6H)-二酮;
6-(4-氯苄基)-9-甲氧基-3-(1-甲基环丙基)嘧啶并[4,5-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
3-叔丁基-9-甲氧基-6-(4-甲氧基苄基)嘧啶并[4,5-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
3-叔丁基-6-(4-氯苄基)-9-甲氧基嘧啶并[4,5-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
9-甲氧基-6-(4-甲氧基苄基)-3-(1-甲基环丙基)嘧啶并[4,5-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
9-甲氧基-6-(4-甲氧基苄基)-3-(四氢-2H-吡喃-4-基甲基)嘧啶并[4,5-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-8-(4-羟基哌啶-1-基)-3-(丙烷-2-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-2-(1-甲基环丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-c]嘧啶-5(6H)-酮;
3-叔丁基-6-[(5-氯吡啶-2-基)甲基]-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-甲氧基苄基)-3-(1-甲基环丙基)-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
2-叔丁基-8-(4-羟基哌啶-1-基)-6-(4-甲氧基苄基)吡啶并[2,3-e][1,2,4]三唑并[1,5-c]嘧啶-5(6H)-酮;
8-氨基-3-叔丁基-6-(4-甲氧基苄基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
3-叔丁基-8-(4-羟基哌啶-1-基)-6-(4-甲氧基苄基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
9-叔丁基-5-(4-氯苄基)-3-(吗啉-4-基)[1,2,4]三唑并[1’,5’:1,6]嘧啶并[5,4-c]哒嗪-6(5h)-酮;
8-(4-氨基哌啶-1-基)-3-叔丁基-6-(4-氯苄基)[1,2,4]三唑并[4’,3’:1,6]嘧啶并[5,4-c]哒嗪-5(6H)-酮;
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)[1,2,4]三唑并[4’,3’:1,6]嘧啶并[5,4-c]哒嗪-5(6H)-酮;
3-叔丁基-6-(4-氯苄基)-8-(哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
2-叔丁基-6-(4-氯苄基)-8-(哌嗪-1-基)吡啶并[2,3-e][1,2,4]三唑并[1,5-c]嘧啶-5(6H)-酮;
3-(叔丁基)-6-(4-氯苄基)-8-(3-甲氧基吡咯烷-1-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
3-叔丁基-6-(4-氯苄基)-8-(四氢-2H-吡喃-4-基氨基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
3-叔丁基-6-[(5-甲基噻吩-2-基)甲基]-8-(吗啉-4-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-3-(四氢-2H-吡喃-4-基甲基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
8-(4-乙酰基哌嗪-1-基)-6-(4-氯苄基)-3-(丙烷-2-基)吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-氯苄基)-8-(吗啉-4-基)-3-[(四氢-2H-吡喃-4-基氧基)甲基]吡啶并[2,3-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
3-叔丁基-6-(4-甲氧基苄基)-8-(吗啉-4-基)吡啶并[3,4-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(4-甲氧基苄基)-3-(1-甲基环丙基)-8-(吗啉-4-基)吡啶并[3,4-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
3-叔丁基-6-(4-氯苄基)-8-(吗啉-4-基)[1,2,4]三唑并[4’,3’:1,6]嘧啶并[5,4-c]哒嗪-5(6H)-酮;
3-叔丁基-6-(4-氯苄基)-8-(吗啉-4-基)吡啶并[3,4-e][1,2,4]三唑并[4,3-c]嘧啶-5(6H)-酮;
6-(3,5-二甲氧基苄基)-2-(2,2-二甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮;以及
6-(3,5-二甲氧基苄基)-3-(2,2-二甲基丙基)-8-(吗啉-4-基)-2,6-二氢咪唑并[1,2-c]吡啶并[2,3-e]嘧啶-5(3H)-酮。
14.药物组合物,其包含根据权利要求1至12中任一项所述的化合物以及可药用载体或稀释剂。
15.化合物,其用于治疗或预防疼痛、慢性疼痛和癌性疼痛,对镇痛剂的成瘾和耐受,选自哮喘、咳嗽、COPD和难治性慢性咳嗽的呼吸系统病症和功能障碍、选自膀胱过度活动症、尿失禁、膀胱疼痛综合征、排尿困难和子宫内膜异位症的泌尿生殖系统疾病,与偏头痛和瘙痒相关的选自肠易激综合征(IBS)和灼口综合征(BMS)的心血管病症,以P2X3和P2X2/3参与为特征的内脏器官疾病和病症,所述治疗或预防包括向需要治疗的对象施用有效量的根据权利要求14所述的药物组合物。
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WO2022175514A1 (en) | 2021-02-22 | 2022-08-25 | Bayer Aktiengesellschaft | N-(pyridin-2-yl)-acetamides as p2x3 inhibitors |
CN114516826A (zh) * | 2022-02-21 | 2022-05-20 | 八叶草健康产业研究院(厦门)有限公司 | 一种褪黑素的制备方法 |
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