CN107406426B - 作为rock抑制剂的环状脲类 - Google Patents
作为rock抑制剂的环状脲类 Download PDFInfo
- Publication number
- CN107406426B CN107406426B CN201680012270.1A CN201680012270A CN107406426B CN 107406426 B CN107406426 B CN 107406426B CN 201680012270 A CN201680012270 A CN 201680012270A CN 107406426 B CN107406426 B CN 107406426B
- Authority
- CN
- China
- Prior art keywords
- pyrazol
- phenyl
- imidazolidin
- methoxybenzyl
- pyridin
- 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.)
- Active
Links
- -1 Cyclic ureas Chemical class 0.000 title claims description 134
- 239000011435 rock Substances 0.000 title abstract description 40
- 239000003112 inhibitor Substances 0.000 title abstract description 12
- 235000013877 carbamide Nutrition 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 158
- 150000003839 salts Chemical class 0.000 claims abstract description 63
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 210000002460 smooth muscle Anatomy 0.000 claims abstract description 5
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 4
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 190
- 229910052731 fluorine Inorganic materials 0.000 claims description 153
- 229910052801 chlorine Inorganic materials 0.000 claims description 151
- 229910052794 bromium Inorganic materials 0.000 claims description 147
- 125000000217 alkyl group Chemical group 0.000 claims description 118
- 229910052739 hydrogen Inorganic materials 0.000 claims description 108
- 238000011282 treatment Methods 0.000 claims description 43
- 238000006467 substitution reaction Methods 0.000 claims description 33
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 201000010099 disease Diseases 0.000 claims description 26
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 18
- 230000000694 effects Effects 0.000 claims description 16
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 13
- 239000003937 drug carrier Substances 0.000 claims description 12
- 206010020772 Hypertension Diseases 0.000 claims description 9
- 108010041788 rho-Associated Kinases Proteins 0.000 claims description 9
- 102000000568 rho-Associated Kinases Human genes 0.000 claims description 9
- 208000006011 Stroke Diseases 0.000 claims description 8
- YFLOLCNMBKTBQE-UHFFFAOYSA-N 4-(hydroxymethyl)-1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1CO)CC1=CC(=CC=C1)OC)=O YFLOLCNMBKTBQE-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- KHWUOEFJPTYZGZ-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[(3-fluorophenyl)methyl]imidazol-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(C=C1)CC1=CC(=CC=C1)F)=O KHWUOEFJPTYZGZ-UHFFFAOYSA-N 0.000 claims description 6
- VUHMKNHUHMYLFV-UHFFFAOYSA-N 4-(2-hydroxypropan-2-yl)-3-[(3-methoxyphenyl)methyl]-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)C(C)(C)O)CC1=CC(=CC=C1)OC)=O VUHMKNHUHMYLFV-UHFFFAOYSA-N 0.000 claims description 6
- NDCFPYSZIBBKFT-UHFFFAOYSA-N 4-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)CO)CC1=CC(=CC=C1)OC)=O NDCFPYSZIBBKFT-UHFFFAOYSA-N 0.000 claims description 6
- NNBQSRWXJWCBRZ-OAHLLOKOSA-N 1-[(1R)-1-(3-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O NNBQSRWXJWCBRZ-OAHLLOKOSA-N 0.000 claims description 5
- MNXTVUMNYVTDPV-UHFFFAOYSA-N 1-[2-methoxy-1-(3-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(COC)C1=CC(=CC=C1)OC)=O MNXTVUMNYVTDPV-UHFFFAOYSA-N 0.000 claims description 5
- LGSYJKNZJDHFDF-UHFFFAOYSA-N 5-(hydroxymethyl)-1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-2,4-dione Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1=O)CO)CC1=CC(=CC=C1)OC)=O LGSYJKNZJDHFDF-UHFFFAOYSA-N 0.000 claims description 5
- 206010019280 Heart failures Diseases 0.000 claims description 5
- CZICJUUKDCDBET-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound COC1=CC(=NC=C1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O CZICJUUKDCDBET-UHFFFAOYSA-N 0.000 claims description 4
- AYQLRXTWBJMVHE-UHFFFAOYSA-N 1-[2-hydroxy-1-(3-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(CO)C1=CC(=CC=C1)OC)=O AYQLRXTWBJMVHE-UHFFFAOYSA-N 0.000 claims description 4
- OHGHOAABSRQUAT-UHFFFAOYSA-N 3-[(3-methoxyphenyl)methyl]-4,4-dimethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)(C)C)CC1=CC(=CC=C1)OC)=O OHGHOAABSRQUAT-UHFFFAOYSA-N 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 230000001594 aberrant effect Effects 0.000 claims description 4
- JDVUMNUUUJSWKP-INIZCTEOSA-N (4S)-3-[(4-fluoro-3-methoxyphenyl)methyl]-4-(hydroxymethyl)-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N([C@@H](C1)CO)CC1=CC(=C(C=C1)F)OC)=O JDVUMNUUUJSWKP-INIZCTEOSA-N 0.000 claims description 3
- FRCVRNZDCPEEQG-UHFFFAOYSA-N 1-[(2-fluoro-3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=C(C(=CC=C1)OC)F)=O FRCVRNZDCPEEQG-UHFFFAOYSA-N 0.000 claims description 3
- HHWDCAKVSSSKCZ-UHFFFAOYSA-N 1-[(2-fluoro-5-methoxyphenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=C1)OC HHWDCAKVSSSKCZ-UHFFFAOYSA-N 0.000 claims description 3
- HYEOCFWCWKJHQY-MRXNPFEDSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(1R)-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O HYEOCFWCWKJHQY-MRXNPFEDSA-N 0.000 claims description 3
- OEZPGBYRQQBYMV-UHFFFAOYSA-N 2-(3-methoxyphenyl)-N-methyl-2-[2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-1-yl]propanamide Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(C(=O)NC)(C)C1=CC(=CC=C1)OC)=O OEZPGBYRQQBYMV-UHFFFAOYSA-N 0.000 claims description 3
- YANQUJBGDOPLFF-UHFFFAOYSA-N 4-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]-1-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound OCC1N(C(N(C1)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O)CC1=CC(=CC=C1)OC YANQUJBGDOPLFF-UHFFFAOYSA-N 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 3
- FZUXLJASNZTFSZ-MRXNPFEDSA-N (4R)-1-(4-bromophenyl)-4-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N([C@H](C1)CO)CC1=CC(=CC=C1)OC)=O FZUXLJASNZTFSZ-MRXNPFEDSA-N 0.000 claims description 2
- NDCFPYSZIBBKFT-LJQANCHMSA-N (4R)-4-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N([C@H](C1)CO)CC1=CC(=CC=C1)OC)=O NDCFPYSZIBBKFT-LJQANCHMSA-N 0.000 claims description 2
- COGKCVIZDSDFHI-UHFFFAOYSA-N 1-(2-phenylethyl)-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CCC1=CC=CC=C1)=O COGKCVIZDSDFHI-UHFFFAOYSA-N 0.000 claims description 2
- XTEIMRMVNBUQSJ-OAHLLOKOSA-N 1-[(1R)-1-(3-methoxyphenyl)ethyl]-3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=C1)C=1C=NNC=1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O XTEIMRMVNBUQSJ-OAHLLOKOSA-N 0.000 claims description 2
- KQMNRLFJZUFDTR-OAHLLOKOSA-N 1-[(1R)-1-(3-methoxyphenyl)ethyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O KQMNRLFJZUFDTR-OAHLLOKOSA-N 0.000 claims description 2
- LXEYNVHQNOXMQK-UHFFFAOYSA-N 1-[(2,6-difluorophenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C(=CC=C1)F LXEYNVHQNOXMQK-UHFFFAOYSA-N 0.000 claims description 2
- JVEFMTIWWVNIRU-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-4-carboxylic acid Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1C(=O)O)CC1=CC(=CC=C1)F)=O JVEFMTIWWVNIRU-UHFFFAOYSA-N 0.000 claims description 2
- HFJHECSDPULPIU-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=C(C=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 HFJHECSDPULPIU-UHFFFAOYSA-N 0.000 claims description 2
- MUKLZKCIRDTYCM-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-4-(hydroxymethyl)-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1CO)CC1=CC(=CC=C1)F)=O MUKLZKCIRDTYCM-UHFFFAOYSA-N 0.000 claims description 2
- IWXDJTRBIGVMEG-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-4-carboxylic acid Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1C(=O)O)CC1=CC(=CC=C1)OC)=O IWXDJTRBIGVMEG-UHFFFAOYSA-N 0.000 claims description 2
- CZOOOQPOAOPIDL-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]imidazol-2-one Chemical compound N1C=CC=2C1=NC=CC=2C1=CC=C(C=C1)N1C(N(C=C1)CC1=CC(=CC=C1)OC)=O CZOOOQPOAOPIDL-UHFFFAOYSA-N 0.000 claims description 2
- QISMYKJVOCVFLG-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]imidazolidin-2-one Chemical compound N1C=CC=2C1=NC=CC=2C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O QISMYKJVOCVFLG-UHFFFAOYSA-N 0.000 claims description 2
- XAQWJBMIHYQAMU-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]imidazolidin-2-one Chemical compound N1=CN=C(C2=C1NC=C2)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O XAQWJBMIHYQAMU-UHFFFAOYSA-N 0.000 claims description 2
- GMTPXBSFZHPKIJ-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound COC1=CC=CC(CN2C(NCC2)=O)=C1 GMTPXBSFZHPKIJ-UHFFFAOYSA-N 0.000 claims description 2
- VVEHBLSVDUDEBQ-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)-2-(methylamino)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(CNC)C1=CC(=CC=C1)OC)=O VVEHBLSVDUDEBQ-UHFFFAOYSA-N 0.000 claims description 2
- OELXHHPUYDQIOD-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)ethyl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl]imidazol-2-one Chemical compound N1C=CC=2C1=NC=CC=2C1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OC)=O OELXHHPUYDQIOD-UHFFFAOYSA-N 0.000 claims description 2
- YUFVWTLQOPZHKP-UHFFFAOYSA-N 1-[1-hydroxy-2-(3-methoxyphenyl)propan-2-yl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(CO)(C)C1=CC(=CC=C1)OC)=O YUFVWTLQOPZHKP-UHFFFAOYSA-N 0.000 claims description 2
- WJASCAQGZUNIRX-UHFFFAOYSA-N 1-[2-(2-fluorophenyl)ethyl]-3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=C(CCN2C(N(CC2)C2=C(C=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 WJASCAQGZUNIRX-UHFFFAOYSA-N 0.000 claims description 2
- LWPSWPKLURSGJK-UHFFFAOYSA-N 1-[2-(2-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CCC1=C(C=CC=C1)OC)=O LWPSWPKLURSGJK-UHFFFAOYSA-N 0.000 claims description 2
- XGCROCOIBGNQTI-UHFFFAOYSA-N 1-[2-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=CC=C(CCN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C1 XGCROCOIBGNQTI-UHFFFAOYSA-N 0.000 claims description 2
- PSWXAEMYQXFGRU-UHFFFAOYSA-N 1-[2-hydroxy-1-(3-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)C(CO)C1=CC(=CC=C1)OC)=O PSWXAEMYQXFGRU-UHFFFAOYSA-N 0.000 claims description 2
- IEOVIHKCZAPBIR-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(2-fluorophenyl)methyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=C(C=CC=C1)F)=O IEOVIHKCZAPBIR-UHFFFAOYSA-N 0.000 claims description 2
- CSPKLCFKIURJPC-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-fluorophenyl)methyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC=C1)F)=O CSPKLCFKIURJPC-UHFFFAOYSA-N 0.000 claims description 2
- ZMXBRPWXVIXAAF-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O ZMXBRPWXVIXAAF-UHFFFAOYSA-N 0.000 claims description 2
- WYJMOUGDPGZMCS-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[2-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CCC1=CC(=CC=C1)OC)=O WYJMOUGDPGZMCS-UHFFFAOYSA-N 0.000 claims description 2
- HEJCJVHXTDWFJO-UHFFFAOYSA-N 1-[3-hydroxy-1-(3-methoxyphenyl)-3-methylbutyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound OC(CC(C1=CC(=CC=C1)OC)N1C(N(CC1)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O)(C)C HEJCJVHXTDWFJO-UHFFFAOYSA-N 0.000 claims description 2
- WZBRLPCQUOXSNO-UHFFFAOYSA-N 1-[3-hydroxy-1-(3-methoxyphenyl)propyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound OCCC(C1=CC(=CC=C1)OC)N1C(N(CC1)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O WZBRLPCQUOXSNO-UHFFFAOYSA-N 0.000 claims description 2
- FNAYFJWFINCCCN-UHFFFAOYSA-N 1-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]-3-[[2-(1H-pyrazol-4-yl)phenyl]methyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 FNAYFJWFINCCCN-UHFFFAOYSA-N 0.000 claims description 2
- PYALLCMXWCFOCX-UHFFFAOYSA-N 1-[4-(2-aminopyridin-4-yl)phenyl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound NC1=NC=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O PYALLCMXWCFOCX-UHFFFAOYSA-N 0.000 claims description 2
- NXMVPMHQRPARFQ-UHFFFAOYSA-N 1-[4-(2-aminopyrimidin-4-yl)phenyl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound NC1=NC=CC(=N1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O NXMVPMHQRPARFQ-UHFFFAOYSA-N 0.000 claims description 2
- DHLBIEDLHLUPOQ-UHFFFAOYSA-N 1-[4-(2-fluoropyridin-4-yl)phenyl]-3-[1-(3-methoxyphenyl)ethyl]imidazol-2-one Chemical compound FC1=NC=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OC)=O DHLBIEDLHLUPOQ-UHFFFAOYSA-N 0.000 claims description 2
- UFARZHULZNJGDE-UHFFFAOYSA-N 1-benzyl-3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound C(C1=CC=CC=C1)N1C(N(CC1)C1=C(C=C(C=C1)C=1C=NNC=1)OC)=O UFARZHULZNJGDE-UHFFFAOYSA-N 0.000 claims description 2
- CZCPSFBOZOSXND-UHFFFAOYSA-N 1-benzyl-3-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound C(C1=CC=CC=C1)N1C(N(CC1)C1=CC(=C(C=C1)C=1C=NNC=1)CC)=O CZCPSFBOZOSXND-UHFFFAOYSA-N 0.000 claims description 2
- FLXJPPGGLXLDJM-UHFFFAOYSA-N 1-benzyl-4-(hydroxymethyl)-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1CO)CC1=CC=CC=C1)=O FLXJPPGGLXLDJM-UHFFFAOYSA-N 0.000 claims description 2
- VKQVMEOGLGJQSF-UHFFFAOYSA-N 2-(3-methoxyphenyl)-2-[2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-1-yl]acetic acid Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(C(=O)O)C1=CC(=CC=C1)OC)=O VKQVMEOGLGJQSF-UHFFFAOYSA-N 0.000 claims description 2
- WWUAAPGMDKZRPZ-UHFFFAOYSA-N 3-(3-methoxyphenyl)-3-[3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]-2-oxoimidazolidin-1-yl]propanoic acid Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)C(CC(=O)O)C1=CC(=CC=C1)OC)=O WWUAAPGMDKZRPZ-UHFFFAOYSA-N 0.000 claims description 2
- NRXLNOGWWFSOTE-UHFFFAOYSA-N 3-[(3-fluorophenyl)methyl]-2-oxo-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-4-carboxylic acid Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)C(=O)O)CC1=CC(=CC=C1)F)=O NRXLNOGWWFSOTE-UHFFFAOYSA-N 0.000 claims description 2
- PYXRSVHHYDHINP-UHFFFAOYSA-N 3-benzyl-1-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidine-2,4-dione Chemical compound C(C1=CC=CC=C1)N1C(N(CC1=O)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O PYXRSVHHYDHINP-UHFFFAOYSA-N 0.000 claims description 2
- PJNUHHGFVZSTRI-UHFFFAOYSA-N 3-benzyl-4-(hydroxymethyl)-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)CO)CC1=CC=CC=C1)=O PJNUHHGFVZSTRI-UHFFFAOYSA-N 0.000 claims description 2
- RCPLGAPSWVOJNE-UHFFFAOYSA-N ethyl 1-[(3-methoxyphenyl)methyl]-2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-4-carboxylate Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1C(=O)OCC)CC1=CC(=CC=C1)OC)=O RCPLGAPSWVOJNE-UHFFFAOYSA-N 0.000 claims description 2
- NRFKMJQVWJLUDU-UHFFFAOYSA-N ethyl 1-benzyl-2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-4-carboxylate Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1C(=O)OCC)CC1=CC=CC=C1)=O NRFKMJQVWJLUDU-UHFFFAOYSA-N 0.000 claims description 2
- UPIBKDSLZYCEGT-UHFFFAOYSA-N methyl 1-[(3-fluorophenyl)methyl]-2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-4-carboxylate Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1C(=O)OC)CC1=CC(=CC=C1)F)=O UPIBKDSLZYCEGT-UHFFFAOYSA-N 0.000 claims description 2
- WBYNBMUJYKEWCB-UHFFFAOYSA-N methyl 3-(3-methoxyphenyl)-3-[3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]-2-oxoimidazolidin-1-yl]propanoate Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)C(CC(=O)OC)C1=CC(=CC=C1)OC)=O WBYNBMUJYKEWCB-UHFFFAOYSA-N 0.000 claims description 2
- HPWRFOIQNZCVTC-UHFFFAOYSA-N 1-(1-phenylethyl)-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC=CC=C1)=O HPWRFOIQNZCVTC-UHFFFAOYSA-N 0.000 claims 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 2
- DZGIQDUKBMVTQU-UHFFFAOYSA-N 1-(2-phenylethyl)-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CCC1=CC=CC=C1)=O DZGIQDUKBMVTQU-UHFFFAOYSA-N 0.000 claims 2
- CNIFQLLZVBPGPN-UHFFFAOYSA-N 1-[(2-fluoro-3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C(=CC=C1)OC)F)=O CNIFQLLZVBPGPN-UHFFFAOYSA-N 0.000 claims 2
- UAAWBEDGPSQWEM-UHFFFAOYSA-N 1-[(2-fluoro-5-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C=CC(=C1)OC)F)=O UAAWBEDGPSQWEM-UHFFFAOYSA-N 0.000 claims 2
- WHHKKWFOEPHZMI-UHFFFAOYSA-N 1-[(2-fluoro-5-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=C(C=CC(=C1)OC)F)=O WHHKKWFOEPHZMI-UHFFFAOYSA-N 0.000 claims 2
- QHRZEOOKVYIBBH-UHFFFAOYSA-N 1-[(3-fluoro-4-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=C(C=C1)OC)F)=O QHRZEOOKVYIBBH-UHFFFAOYSA-N 0.000 claims 2
- WZQGRNJPDPOKNW-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=CC(=CC(=C1)OC)F)=O WZQGRNJPDPOKNW-UHFFFAOYSA-N 0.000 claims 2
- PVAAZFIDEYLRTK-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=CC(=CC=C1)OC)=O PVAAZFIDEYLRTK-UHFFFAOYSA-N 0.000 claims 2
- FGOMTLHXSYOFBY-UHFFFAOYSA-N 1-[(5-fluoro-2-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=C(C=CC(=C1)F)OC)=O FGOMTLHXSYOFBY-UHFFFAOYSA-N 0.000 claims 2
- HUAWURIGFIUMJJ-UHFFFAOYSA-N 1-[2-(2-fluorophenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CCC1=C(C=CC=C1)F)=O HUAWURIGFIUMJJ-UHFFFAOYSA-N 0.000 claims 2
- PXWSQGAXTWXIHP-UHFFFAOYSA-N 1-[2-hydroxy-1-(3-methoxyphenyl)ethyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)C(CO)C1=CC(=CC=C1)OC)=O PXWSQGAXTWXIHP-UHFFFAOYSA-N 0.000 claims 2
- UMBCSUSMUZUHPC-UHFFFAOYSA-N 1-[[3-(difluoromethoxy)phenyl]methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=CC(=CC=C1)OC(F)F)=O UMBCSUSMUZUHPC-UHFFFAOYSA-N 0.000 claims 2
- VBZGDFFATKAMSR-UHFFFAOYSA-N COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1=O)C(C)C1=CC=CC=C1)=O Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1=O)C(C)C1=CC=CC=C1)=O VBZGDFFATKAMSR-UHFFFAOYSA-N 0.000 claims 2
- PKWYICKWRQFDOZ-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)C(C)C1=CC=CC=C1)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)C(C)C1=CC=CC=C1)=O PKWYICKWRQFDOZ-UHFFFAOYSA-N 0.000 claims 2
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 claims 2
- HITDVUZMMZFWIT-LJQANCHMSA-N (4R)-1-[4-(3-fluoropyridin-4-yl)phenyl]-4-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound FC=1C=NC=CC=1C1=CC=C(C=C1)N1C(N([C@H](C1)CO)CC1=CC(=CC=C1)OC)=O HITDVUZMMZFWIT-LJQANCHMSA-N 0.000 claims 1
- HKTDEKDMGUYETF-QGZVFWFLSA-N (4R)-3-[(3-fluoro-5-methoxyphenyl)methyl]-4-(hydroxymethyl)-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N([C@H](C1)CO)CC1=CC(=CC(=C1)OC)F)=O HKTDEKDMGUYETF-QGZVFWFLSA-N 0.000 claims 1
- VNGVLAQSSDJZIK-GOSISDBHSA-N (4R)-3-[(4-fluoro-3-methoxyphenyl)methyl]-4-(hydroxymethyl)-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N([C@H](C1)CO)CC1=CC(=C(C=C1)F)OC)=O VNGVLAQSSDJZIK-GOSISDBHSA-N 0.000 claims 1
- ONIRGNARSHJPAJ-QGZVFWFLSA-N (4R)-4-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N([C@H](C1)CO)CC1=CC(=CC=C1)OC)=O ONIRGNARSHJPAJ-QGZVFWFLSA-N 0.000 claims 1
- ORWSOLWVQJKYQB-YQYDADCPSA-N (4R)-4-(hydroxymethyl)-3-[1-(3-methoxyphenyl)ethyl]-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N([C@H](C1)CO)C(C)C1=CC(=CC=C1)OC)=O ORWSOLWVQJKYQB-YQYDADCPSA-N 0.000 claims 1
- KEHRNOGEWQSDPN-IBGZPJMESA-N (4S)-3-[(3-fluoro-5-methoxyphenyl)methyl]-4-(hydroxymethyl)-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N([C@@H](C1)CO)CC1=CC(=CC(=C1)OC)F)=O KEHRNOGEWQSDPN-IBGZPJMESA-N 0.000 claims 1
- HKTDEKDMGUYETF-KRWDZBQOSA-N (4S)-3-[(3-fluoro-5-methoxyphenyl)methyl]-4-(hydroxymethyl)-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N([C@@H](C1)CO)CC1=CC(=CC(=C1)OC)F)=O HKTDEKDMGUYETF-KRWDZBQOSA-N 0.000 claims 1
- VNGVLAQSSDJZIK-SFHVURJKSA-N (4S)-3-[(4-fluoro-3-methoxyphenyl)methyl]-4-(hydroxymethyl)-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N([C@@H](C1)CO)CC1=CC(=C(C=C1)F)OC)=O VNGVLAQSSDJZIK-SFHVURJKSA-N 0.000 claims 1
- ZHAYAQHLCWVMRU-QFIPXVFZSA-N (4S)-3-[[3-(cyclopropylmethoxy)phenyl]methyl]-4-(hydroxymethyl)-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N([C@@H](C1)CO)CC1=CC(=CC=C1)OCC1CC1)=O ZHAYAQHLCWVMRU-QFIPXVFZSA-N 0.000 claims 1
- ONIRGNARSHJPAJ-KRWDZBQOSA-N (4S)-4-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N([C@@H](C1)CO)CC1=CC(=CC=C1)OC)=O ONIRGNARSHJPAJ-KRWDZBQOSA-N 0.000 claims 1
- OOJAPPVMNDCAMR-UHFFFAOYSA-N 1-(cyclohexylmethyl)-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1CCCCC1)=O OOJAPPVMNDCAMR-UHFFFAOYSA-N 0.000 claims 1
- WINDAOBCTURSTE-UHFFFAOYSA-N 1-(cyclohexylmethyl)-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound C1(CCCCC1)CN1C(N(C=C1)C1=NC(=C(C=C1)C=1C=NNC=1)OC)=O WINDAOBCTURSTE-UHFFFAOYSA-N 0.000 claims 1
- CQOQJWCXZCWPPB-UHFFFAOYSA-N 1-(cyclohexylmethyl)-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CCCCC1)CN1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)OC)=O CQOQJWCXZCWPPB-UHFFFAOYSA-N 0.000 claims 1
- NNBQSRWXJWCBRZ-HNNXBMFYSA-N 1-[(1S)-1-(3-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)[C@@H](C)C1=CC(=CC=C1)OC)=O NNBQSRWXJWCBRZ-HNNXBMFYSA-N 0.000 claims 1
- HYPWMNDIIYGDPX-UHFFFAOYSA-N 1-[(2,3-difluorophenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C(=CC=C1)F)F)=O HYPWMNDIIYGDPX-UHFFFAOYSA-N 0.000 claims 1
- XRFQKDJRWIYRKT-UHFFFAOYSA-N 1-[(2,3-difluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC1=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1F XRFQKDJRWIYRKT-UHFFFAOYSA-N 0.000 claims 1
- ROOFBKFPRRQUDJ-UHFFFAOYSA-N 1-[(2,3-difluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1F ROOFBKFPRRQUDJ-UHFFFAOYSA-N 0.000 claims 1
- FWASGDAYXFUIMC-UHFFFAOYSA-N 1-[(2,4-difluorophenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C=C(C=C1)F)F)=O FWASGDAYXFUIMC-UHFFFAOYSA-N 0.000 claims 1
- JTYPFGZNTUDBAS-UHFFFAOYSA-N 1-[(2,4-difluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC1=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC(=C1)F JTYPFGZNTUDBAS-UHFFFAOYSA-N 0.000 claims 1
- FRQCCKUXYLQPEL-UHFFFAOYSA-N 1-[(2,4-difluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC(=C1)F FRQCCKUXYLQPEL-UHFFFAOYSA-N 0.000 claims 1
- FBYNPXJKRJXINQ-UHFFFAOYSA-N 1-[(2,5-difluorophenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C=CC(=C1)F)F)=O FBYNPXJKRJXINQ-UHFFFAOYSA-N 0.000 claims 1
- HEPVZAYWZLXFSV-UHFFFAOYSA-N 1-[(2,5-difluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC1=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=C1)F HEPVZAYWZLXFSV-UHFFFAOYSA-N 0.000 claims 1
- BTGDNEDYDYAYBU-UHFFFAOYSA-N 1-[(2,5-difluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=C1)F BTGDNEDYDYAYBU-UHFFFAOYSA-N 0.000 claims 1
- LRUDVDHHWYYDRX-UHFFFAOYSA-N 1-[(2,6-difluorophenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C=CC=C1F)F)=O LRUDVDHHWYYDRX-UHFFFAOYSA-N 0.000 claims 1
- FIZCHIYMDUPZAW-UHFFFAOYSA-N 1-[(2-fluoro-3-methoxyphenyl)methyl]-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)F)=O)C=CC=C1OC FIZCHIYMDUPZAW-UHFFFAOYSA-N 0.000 claims 1
- PRORMYUHVUBEEW-UHFFFAOYSA-N 1-[(2-fluoro-3-methoxyphenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=C(C(=CC=C1)OC)F)=O PRORMYUHVUBEEW-UHFFFAOYSA-N 0.000 claims 1
- PMHKVUJEOYZEIC-UHFFFAOYSA-N 1-[(2-fluoro-3-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1OC PMHKVUJEOYZEIC-UHFFFAOYSA-N 0.000 claims 1
- KYVZOEFABARCDI-UHFFFAOYSA-N 1-[(2-fluoro-5-methoxyphenyl)methyl]-3-(3-methoxy-4-pyridin-4-ylphenyl)imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=CC(=C(C=C2)C2=CC=NC=C2)OC)=O)C=C(C=C1)OC KYVZOEFABARCDI-UHFFFAOYSA-N 0.000 claims 1
- XSSVWBLLNSFRDZ-UHFFFAOYSA-N 1-[(2-fluoro-5-methoxyphenyl)methyl]-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=C(C=CC(=C1)OC)F)=O XSSVWBLLNSFRDZ-UHFFFAOYSA-N 0.000 claims 1
- PXSNOJBFVLEQTQ-UHFFFAOYSA-N 1-[(2-fluoro-5-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC1=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=C1)OC PXSNOJBFVLEQTQ-UHFFFAOYSA-N 0.000 claims 1
- KOLWVOIPQMBYNT-UHFFFAOYSA-N 1-[(2-fluoro-5-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=C1)OC KOLWVOIPQMBYNT-UHFFFAOYSA-N 0.000 claims 1
- NUHDTXKXQYGFFC-UHFFFAOYSA-N 1-[(2-fluoro-6-methoxyphenyl)methyl]-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=C(C=CC=C1OC)F)=O NUHDTXKXQYGFFC-UHFFFAOYSA-N 0.000 claims 1
- WHILMPNEXFHWDL-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-3-(4-pyridin-4-ylphenyl)imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=CC=C(C=C2)C2=CC=NC=C2)=O)C=CC=C1 WHILMPNEXFHWDL-UHFFFAOYSA-N 0.000 claims 1
- JGCLONHGVAZFHQ-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C=CC=C1)F)=O JGCLONHGVAZFHQ-UHFFFAOYSA-N 0.000 claims 1
- RYQGAUNAYHHYNY-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 RYQGAUNAYHHYNY-UHFFFAOYSA-N 0.000 claims 1
- PJMMKDFXNMRSDA-UHFFFAOYSA-N 1-[(3,4-dichlorophenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=C(C=C1)Cl)Cl)=O PJMMKDFXNMRSDA-UHFFFAOYSA-N 0.000 claims 1
- FVEJGNAYTMNDIG-UHFFFAOYSA-N 1-[(3,4-difluorophenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=C(C=C1)F)F)=O FVEJGNAYTMNDIG-UHFFFAOYSA-N 0.000 claims 1
- DUQJMBHMYOTDRY-UHFFFAOYSA-N 1-[(3,5-difluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=N1)N1CCN(CC2=CC(F)=CC(F)=C2)C1=O)C1=CNN=C1 DUQJMBHMYOTDRY-UHFFFAOYSA-N 0.000 claims 1
- VZYGDEKCCQNFFH-UHFFFAOYSA-N 1-[(3,5-dimethylphenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=CC(=C1)C)C)=O VZYGDEKCCQNFFH-UHFFFAOYSA-N 0.000 claims 1
- YWPDZHJWAFIZOI-UHFFFAOYSA-N 1-[(3-chlorophenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=CC=C1)Cl)=O YWPDZHJWAFIZOI-UHFFFAOYSA-N 0.000 claims 1
- KYAVNIAFAXVLLC-UHFFFAOYSA-N 1-[(3-chlorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound ClC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 KYAVNIAFAXVLLC-UHFFFAOYSA-N 0.000 claims 1
- LFVOZZZKXZKZQK-UHFFFAOYSA-N 1-[(3-fluoro-2-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C(=CC=C1)F)OC)=O LFVOZZZKXZKZQK-UHFFFAOYSA-N 0.000 claims 1
- MVSTYPQXWZPZIH-UHFFFAOYSA-N 1-[(3-fluoro-2-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=C(C(=CC=C1)F)OC)=O MVSTYPQXWZPZIH-UHFFFAOYSA-N 0.000 claims 1
- ISFYHWIUXVEIDU-UHFFFAOYSA-N 1-[(3-fluoro-2-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC=1C(=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1)OC ISFYHWIUXVEIDU-UHFFFAOYSA-N 0.000 claims 1
- KNTQYCWTZUZKOG-UHFFFAOYSA-N 1-[(3-fluoro-2-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C(=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1)OC KNTQYCWTZUZKOG-UHFFFAOYSA-N 0.000 claims 1
- WEWKGPXKGWTNGZ-UHFFFAOYSA-N 1-[(3-fluoro-2-methylphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C(=CC=C1)F)C)=O WEWKGPXKGWTNGZ-UHFFFAOYSA-N 0.000 claims 1
- XOYGTWRWIMFDIK-UHFFFAOYSA-N 1-[(3-fluoro-2-methylphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC=1C(=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1)C XOYGTWRWIMFDIK-UHFFFAOYSA-N 0.000 claims 1
- IJUQFSVSJMBDRO-UHFFFAOYSA-N 1-[(3-fluoro-2-methylphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C(=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1)C IJUQFSVSJMBDRO-UHFFFAOYSA-N 0.000 claims 1
- WIVCEILENVRQEB-UHFFFAOYSA-N 1-[(3-fluoro-4-methoxyphenyl)methyl]-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=C(C=C1)OC)F)=O WIVCEILENVRQEB-UHFFFAOYSA-N 0.000 claims 1
- UULLNFKMISESDA-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O UULLNFKMISESDA-UHFFFAOYSA-N 0.000 claims 1
- KOSNAHJQYVHNFX-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound FC=1C=C(CN2C(N(C=C2)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=1)OC KOSNAHJQYVHNFX-UHFFFAOYSA-N 0.000 claims 1
- DAUHKVGLUNGRIR-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)C)=O)C=C(C=1)OC DAUHKVGLUNGRIR-UHFFFAOYSA-N 0.000 claims 1
- KKLCFOZFNXJUAP-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=C(C=C(C=C1)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O)C(F)(F)F KKLCFOZFNXJUAP-UHFFFAOYSA-N 0.000 claims 1
- COXTUVDTHDCUAR-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O COXTUVDTHDCUAR-UHFFFAOYSA-N 0.000 claims 1
- QBNOBLTUSCCPTN-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[4-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=NC=C(C(=C2)OC)C=2C=NNC=2)=O)C=C(C=1)OC QBNOBLTUSCCPTN-UHFFFAOYSA-N 0.000 claims 1
- OUSWJZHPFCRKFA-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[4-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=NC=C(C(=C2)C)C=2C=NNC=2)=O)C=C(C=1)OC OUSWJZHPFCRKFA-UHFFFAOYSA-N 0.000 claims 1
- HIZZQSCVIKVGQP-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C=C1)CC1=CC(=CC(=C1)OC)F)=O HIZZQSCVIKVGQP-UHFFFAOYSA-N 0.000 claims 1
- SANBOOKSKCBVLK-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O SANBOOKSKCBVLK-UHFFFAOYSA-N 0.000 claims 1
- RSSXASDRFVQZQB-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[6-(1H-pyrazol-4-yl)pyridin-3-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=N1)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O RSSXASDRFVQZQB-UHFFFAOYSA-N 0.000 claims 1
- BLYCRBAFBBNWHG-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[6-(methylamino)-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)NC)=O)C=C(C=1)OC BLYCRBAFBBNWHG-UHFFFAOYSA-N 0.000 claims 1
- NLSIFEDVOQAGRW-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC=1C=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=1)OC NLSIFEDVOQAGRW-UHFFFAOYSA-N 0.000 claims 1
- ARIVIPBDPHKXNV-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=1)OC ARIVIPBDPHKXNV-UHFFFAOYSA-N 0.000 claims 1
- NNQRYXQKMXVBTA-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC=1C=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)C)=O)C=C(C=1)OC NNQRYXQKMXVBTA-UHFFFAOYSA-N 0.000 claims 1
- QRQMUJMQZGJHDU-UHFFFAOYSA-N 1-[(3-fluoro-5-methoxyphenyl)methyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)C)=O)C=C(C=1)OC QRQMUJMQZGJHDU-UHFFFAOYSA-N 0.000 claims 1
- GJSLVUTVODVNLG-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-(3-methoxy-4-pyridin-4-ylphenyl)imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=CC(=C(C=C2)C2=CC=NC=C2)OC)=O)C=CC=1 GJSLVUTVODVNLG-UHFFFAOYSA-N 0.000 claims 1
- DXTFBQOPYBDWDF-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-(4-pyridin-4-ylphenyl)imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)C2=CC=NC=C2)=O)C=CC=1 DXTFBQOPYBDWDF-UHFFFAOYSA-N 0.000 claims 1
- DRIARACRVPLVMH-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=CC(=CC=C1)F)=O DRIARACRVPLVMH-UHFFFAOYSA-N 0.000 claims 1
- CSSXRPHJVGXJPK-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)F)=O CSSXRPHJVGXJPK-UHFFFAOYSA-N 0.000 claims 1
- KLZWGRXNEOWSFZ-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC=1C=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 KLZWGRXNEOWSFZ-UHFFFAOYSA-N 0.000 claims 1
- GNOSHWUXHSSDJW-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 GNOSHWUXHSSDJW-UHFFFAOYSA-N 0.000 claims 1
- ZBZJWXCLTYCVTE-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C=C1)CC1=CC(=CC=C1)OC)=O ZBZJWXCLTYCVTE-UHFFFAOYSA-N 0.000 claims 1
- WRPIFYNLTYYKHX-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=C(C=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)C(F)(F)F WRPIFYNLTYYKHX-UHFFFAOYSA-N 0.000 claims 1
- LUEHBCSODCQQPA-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC1=CC=CC(CN2CCN(C2=O)C2=CC=C(C=C2)C2=CNN=C2)=C1 LUEHBCSODCQQPA-UHFFFAOYSA-N 0.000 claims 1
- VTZZUNMGLFWIOY-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound COC=1C=C(CN2C(N(CC2)C2=NC=C(C(=C2)C)C=2C=NNC=2)=O)C=CC=1 VTZZUNMGLFWIOY-UHFFFAOYSA-N 0.000 claims 1
- POMWMMRXPFRLPQ-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C=C1)CC1=CC(=CC=C1)OC)=O POMWMMRXPFRLPQ-UHFFFAOYSA-N 0.000 claims 1
- DPJMYBYZHLENNM-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O DPJMYBYZHLENNM-UHFFFAOYSA-N 0.000 claims 1
- SRRYCHZSNRYFBH-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[6-(1H-pyrazol-4-yl)pyridin-3-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=N1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O SRRYCHZSNRYFBH-UHFFFAOYSA-N 0.000 claims 1
- KASBRRFZXKYVCX-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[6-(methylamino)-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound COC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)NC)=O)C=CC=1 KASBRRFZXKYVCX-UHFFFAOYSA-N 0.000 claims 1
- GAQLJRDVVWYLQO-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound COC1=C(C=CC(=N1)N1C(N(C=C1)CC1=CC(=CC=C1)OC)=O)C=1C=NNC=1 GAQLJRDVVWYLQO-UHFFFAOYSA-N 0.000 claims 1
- NMALFYWVIROLGU-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=N1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)C=1C=NNC=1 NMALFYWVIROLGU-UHFFFAOYSA-N 0.000 claims 1
- FPOYGULALOMRBW-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound COC=1C=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)C)=O)C=CC=1 FPOYGULALOMRBW-UHFFFAOYSA-N 0.000 claims 1
- PAOXHKIRVXMJBR-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound COC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)C)=O)C=CC=1 PAOXHKIRVXMJBR-UHFFFAOYSA-N 0.000 claims 1
- MZMZECZZNSTCBX-UHFFFAOYSA-N 1-[(3-methylphenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=CC=C1)C)=O MZMZECZZNSTCBX-UHFFFAOYSA-N 0.000 claims 1
- LHMLLRBRDPMMIB-UHFFFAOYSA-N 1-[(4-fluoro-2-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C=C(C=C1)F)OC)=O LHMLLRBRDPMMIB-UHFFFAOYSA-N 0.000 claims 1
- FEIMTRUQBVDOFN-UHFFFAOYSA-N 1-[(4-fluoro-2-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC1=CC(=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C1)OC FEIMTRUQBVDOFN-UHFFFAOYSA-N 0.000 claims 1
- FCGPUHFYBLBYSA-UHFFFAOYSA-N 1-[(4-fluoro-2-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=CC(=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C1)OC FCGPUHFYBLBYSA-UHFFFAOYSA-N 0.000 claims 1
- HRPWAZWSUXJJMA-UHFFFAOYSA-N 1-[(4-fluoro-2-methylphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C=C(C=C1)F)C)=O HRPWAZWSUXJJMA-UHFFFAOYSA-N 0.000 claims 1
- DPBINJZIRZCKFM-UHFFFAOYSA-N 1-[(4-fluoro-2-methylphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC1=CC(=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C1)C DPBINJZIRZCKFM-UHFFFAOYSA-N 0.000 claims 1
- YKHHLPYCYDZLGF-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=C(C=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)F)=O)C=C1)OC YKHHLPYCYDZLGF-UHFFFAOYSA-N 0.000 claims 1
- APOKYONLRLHYFK-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC1=C(C=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)C)=O)C=C1)OC APOKYONLRLHYFK-UHFFFAOYSA-N 0.000 claims 1
- FOIBMLMZGXWGOI-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)-3-(trifluoromethyl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=C(C=C(C=C1)N1C(N(CC1)CC1=CC(=C(C=C1)F)OC)=O)C(F)(F)F FOIBMLMZGXWGOI-UHFFFAOYSA-N 0.000 claims 1
- BSZMSNCCDYOECH-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=CC(=C(C=C1)F)OC)=O BSZMSNCCDYOECH-UHFFFAOYSA-N 0.000 claims 1
- ZROOVBQOVZTDAO-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=C(C=C1)F)OC)=O ZROOVBQOVZTDAO-UHFFFAOYSA-N 0.000 claims 1
- MBXPIYGVPPNQIM-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C=C1)CC1=CC(=C(C=C1)F)OC)=O MBXPIYGVPPNQIM-UHFFFAOYSA-N 0.000 claims 1
- CCDWNCDVUFGMEP-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[6-(1H-pyrazol-4-yl)pyridin-3-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=N1)N1C(N(CC1)CC1=CC(=C(C=C1)F)OC)=O CCDWNCDVUFGMEP-UHFFFAOYSA-N 0.000 claims 1
- OFTVVDSMUWCXPK-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[6-(methylamino)-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)NC)=O)C=C1)OC OFTVVDSMUWCXPK-UHFFFAOYSA-N 0.000 claims 1
- MWZUUUZSTSCZIL-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC1=C(C=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C1)OC MWZUUUZSTSCZIL-UHFFFAOYSA-N 0.000 claims 1
- ZHTMEVFWWFSICG-UHFFFAOYSA-N 1-[(4-fluoro-3-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C1)OC ZHTMEVFWWFSICG-UHFFFAOYSA-N 0.000 claims 1
- MXJQZDZJJVAITJ-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=CC=C(C=C1)F)=O MXJQZDZJJVAITJ-UHFFFAOYSA-N 0.000 claims 1
- ANZSXWTVEFKFKO-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC=C(C=C1)F)=O ANZSXWTVEFKFKO-UHFFFAOYSA-N 0.000 claims 1
- WAIDPWQCGYJTTR-UHFFFAOYSA-N 1-[(5-fluoro-2-methoxyphenyl)methyl]-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound FC=1C=CC(=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)F)=O)C=1)OC WAIDPWQCGYJTTR-UHFFFAOYSA-N 0.000 claims 1
- AXBJKOJSKSODPW-UHFFFAOYSA-N 1-[(5-fluoro-2-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC=1C=CC(=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=1)OC AXBJKOJSKSODPW-UHFFFAOYSA-N 0.000 claims 1
- GWVHHDKTVKONKQ-UHFFFAOYSA-N 1-[(5-fluoro-2-methoxyphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=CC(=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=1)OC GWVHHDKTVKONKQ-UHFFFAOYSA-N 0.000 claims 1
- CPMDUUNJUNFUML-UHFFFAOYSA-N 1-[(5-fluoro-2-methylphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=C(C=CC(=C1)F)C)=O CPMDUUNJUNFUML-UHFFFAOYSA-N 0.000 claims 1
- JWTKSAAKGXDNNG-UHFFFAOYSA-N 1-[(5-fluoro-2-methylphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC=1C=CC(=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=1)C JWTKSAAKGXDNNG-UHFFFAOYSA-N 0.000 claims 1
- UBJYUGVHVLBYCH-UHFFFAOYSA-N 1-[(5-fluoro-2-methylphenyl)methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=CC(=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=1)C UBJYUGVHVLBYCH-UHFFFAOYSA-N 0.000 claims 1
- FIYRRAPSWMGXGG-UHFFFAOYSA-N 1-[1-(3-ethoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OCC)=O FIYRRAPSWMGXGG-UHFFFAOYSA-N 0.000 claims 1
- JLPOZDSQONUNAQ-UHFFFAOYSA-N 1-[1-(3-ethoxyphenyl)ethyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OCC)=O JLPOZDSQONUNAQ-UHFFFAOYSA-N 0.000 claims 1
- JKNHJHMLYGQCGY-UHFFFAOYSA-N 1-[1-(3-ethoxyphenyl)ethyl]-3-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound C(C)OC=1C=C(C=CC=1)C(C)N1C(N(C=C1)C1=NC(=C(C=C1)C=1C=NNC=1)CC)=O JKNHJHMLYGQCGY-UHFFFAOYSA-N 0.000 claims 1
- XJCBJKBIXSHBFC-UHFFFAOYSA-N 1-[1-(3-ethoxyphenyl)ethyl]-3-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C(C)OC=1C=C(C=CC=1)C(C)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)CC)=O XJCBJKBIXSHBFC-UHFFFAOYSA-N 0.000 claims 1
- UWZPVGZSXWWHQR-UHFFFAOYSA-N 1-[1-(3-fluoro-5-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC(=CC(=C1)OC)F)=O UWZPVGZSXWWHQR-UHFFFAOYSA-N 0.000 claims 1
- ZGABLCSZOPXNHR-UHFFFAOYSA-N 1-[1-(3-fluoro-5-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(C)C1=CC(=CC(=C1)OC)F)=O ZGABLCSZOPXNHR-UHFFFAOYSA-N 0.000 claims 1
- VPJIBVUKHAHSPP-UHFFFAOYSA-N 1-[1-(3-fluoro-5-methoxyphenyl)ethyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C=C1)C(C)C1=CC(=CC(=C1)OC)F)=O VPJIBVUKHAHSPP-UHFFFAOYSA-N 0.000 claims 1
- AQSYOJTVFKWJRT-UHFFFAOYSA-N 1-[1-(3-fluoro-5-methoxyphenyl)ethyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC=1C=C(C=C(C=1)OC)C(C)N1C(N(C=C1)C1=NC(=C(C=C1)C=1C=NNC=1)OC)=O AQSYOJTVFKWJRT-UHFFFAOYSA-N 0.000 claims 1
- FURHOUDWVFHJIM-UHFFFAOYSA-N 1-[1-(3-fluoro-5-methoxyphenyl)ethyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=C(C=C(C=1)OC)C(C)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)OC)=O FURHOUDWVFHJIM-UHFFFAOYSA-N 0.000 claims 1
- YXTZYEZUROOQND-UHFFFAOYSA-N 1-[1-(3-fluoro-5-methoxyphenyl)ethyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=C(C=C(C=1)OC)C(C)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)C)=O YXTZYEZUROOQND-UHFFFAOYSA-N 0.000 claims 1
- UUGAWHBEXTYAET-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)ethyl]-3-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC=1C=C(C=CC=1)C(C)N1C(N(CC1)C1=CC(=C(C=C1)C=1C=NNC=1)C)=O UUGAWHBEXTYAET-UHFFFAOYSA-N 0.000 claims 1
- AOKSQIBKSMJTTA-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)ethyl]-3-[4-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound COC=1C=C(C=CC=1)C(C)N1C(N(CC1)C1=NC=C(C(=C1)C)C=1C=NNC=1)=O AOKSQIBKSMJTTA-UHFFFAOYSA-N 0.000 claims 1
- IPRGATQJQMSIOI-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)ethyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OC)=O IPRGATQJQMSIOI-UHFFFAOYSA-N 0.000 claims 1
- GHJIWXKAPIKJAK-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)ethyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)C(C)C1=CC(=CC=C1)OC)=O GHJIWXKAPIKJAK-UHFFFAOYSA-N 0.000 claims 1
- BEZHZXICNQEZSA-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)ethyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound COC1=C(C=CC(=N1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OC)=O)C=1C=NNC=1 BEZHZXICNQEZSA-UHFFFAOYSA-N 0.000 claims 1
- OGJQLPDMSCHLRU-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)ethyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=N1)N1C(N(CC1)C(C)C1=CC(=CC=C1)OC)=O)C=1C=NNC=1 OGJQLPDMSCHLRU-UHFFFAOYSA-N 0.000 claims 1
- LTLVHNKPJGFFKW-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)ethyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound COC=1C=C(C=CC=1)C(C)N1C(N(C=C1)C1=NC(=C(C=C1)C=1C=NNC=1)C)=O LTLVHNKPJGFFKW-UHFFFAOYSA-N 0.000 claims 1
- RSSUGRSZNGFZTD-UHFFFAOYSA-N 1-[1-(3-methoxyphenyl)ethyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound COC=1C=C(C=CC=1)C(C)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)C)=O RSSUGRSZNGFZTD-UHFFFAOYSA-N 0.000 claims 1
- OZBCHFMNNNZSJL-UHFFFAOYSA-N 1-[1-(4-fluoro-3-methoxyphenyl)ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC(=C(C=C1)F)OC)=O OZBCHFMNNNZSJL-UHFFFAOYSA-N 0.000 claims 1
- KJQDOWULSHQMJQ-UHFFFAOYSA-N 1-[1-(4-fluoro-3-methoxyphenyl)ethyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC1=C(C=C(C=C1)C(C)N1C(N(C=C1)C1=NC(=C(C=C1)C=1C=NNC=1)OC)=O)OC KJQDOWULSHQMJQ-UHFFFAOYSA-N 0.000 claims 1
- MQUWUKWYCNRPDJ-UHFFFAOYSA-N 1-[1-(4-fluoro-3-methoxyphenyl)ethyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(C=C(C=C1)C(C)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)OC)=O)OC MQUWUKWYCNRPDJ-UHFFFAOYSA-N 0.000 claims 1
- QYGQRCFCMYAKSN-UHFFFAOYSA-N 1-[1-(4-fluoro-3-methoxyphenyl)ethyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(C=C(C=C1)C(C)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)C)=O)OC QYGQRCFCMYAKSN-UHFFFAOYSA-N 0.000 claims 1
- RQMBWHQGOXRSGZ-UHFFFAOYSA-N 1-[1-[3-(cyclopropylmethoxy)phenyl]ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OCC1CC1)=O RQMBWHQGOXRSGZ-UHFFFAOYSA-N 0.000 claims 1
- RWHYBFYLYCCRRZ-UHFFFAOYSA-N 1-[1-[3-(cyclopropylmethoxy)phenyl]ethyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(C)C1=CC(=CC=C1)OCC1CC1)=O RWHYBFYLYCCRRZ-UHFFFAOYSA-N 0.000 claims 1
- PGXCARIRBGVSAU-UHFFFAOYSA-N 1-[1-[3-(cyclopropylmethoxy)phenyl]ethyl]-3-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound C1(CC1)COC=1C=C(C=CC=1)C(C)N1C(N(C=C1)C1=NC(=C(C=C1)C=1C=NNC=1)CC)=O PGXCARIRBGVSAU-UHFFFAOYSA-N 0.000 claims 1
- WFYBYSUZNXFRRT-UHFFFAOYSA-N 1-[1-[3-(cyclopropylmethoxy)phenyl]ethyl]-3-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(C=CC=1)C(C)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)CC)=O WFYBYSUZNXFRRT-UHFFFAOYSA-N 0.000 claims 1
- HBXXAWOBUUXAFN-UHFFFAOYSA-N 1-[1-[3-(cyclopropylmethoxy)phenyl]ethyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(C=CC=1)C(C)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)OC)=O HBXXAWOBUUXAFN-UHFFFAOYSA-N 0.000 claims 1
- ZGEGYKFYSQTPBJ-UHFFFAOYSA-N 1-[1-[3-(cyclopropylmethoxy)phenyl]ethyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(C=CC=1)C(C)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)C)=O ZGEGYKFYSQTPBJ-UHFFFAOYSA-N 0.000 claims 1
- HZTZOTGHZLVSRP-UHFFFAOYSA-N 1-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-fluoro-5-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound FC1=C(C=C(C(=C1)C=1C=NNC=1)F)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O HZTZOTGHZLVSRP-UHFFFAOYSA-N 0.000 claims 1
- OOYWWGDEHFPAIF-UHFFFAOYSA-N 1-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound FC1=C(C=C(C(=C1)C=1C=NNC=1)F)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O OOYWWGDEHFPAIF-UHFFFAOYSA-N 0.000 claims 1
- IBGZVGIPHKLAJH-UHFFFAOYSA-N 1-[2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl]-3-[(4-fluoro-3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound FC1=C(C=C(C(=C1)C=1C=NNC=1)F)N1C(N(CC1)CC1=CC(=C(C=C1)F)OC)=O IBGZVGIPHKLAJH-UHFFFAOYSA-N 0.000 claims 1
- PIBHIIWRJHFPLC-UHFFFAOYSA-N 1-[2-hydroxy-1-(3-methoxyphenyl)ethyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound OCC(C1=CC(=CC=C1)OC)N1C(N(C=C1)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O PIBHIIWRJHFPLC-UHFFFAOYSA-N 0.000 claims 1
- XKJWGAMYWUKBPI-UHFFFAOYSA-N 1-[2-hydroxy-1-(3-methoxyphenyl)ethyl]-3-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound OCC(C1=CC(=CC=C1)OC)N1C(N(CC1)C1=CC(=C(C=C1)C=1C=NNC=1)C)=O XKJWGAMYWUKBPI-UHFFFAOYSA-N 0.000 claims 1
- LHUDZKTYUZRUCG-UHFFFAOYSA-N 1-[2-hydroxy-1-(3-methoxyphenyl)ethyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound OCC(C1=CC(=CC=C1)OC)N1C(N(CC1)C1=NC(=C(C=C1)C=1C=NNC=1)C)=O LHUDZKTYUZRUCG-UHFFFAOYSA-N 0.000 claims 1
- AZCIOFVDGFKNNV-UHFFFAOYSA-N 1-[3-cyclopropyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-fluoro-5-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C1(CC1)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O AZCIOFVDGFKNNV-UHFFFAOYSA-N 0.000 claims 1
- JGBHDQDNQSCJLL-UHFFFAOYSA-N 1-[3-cyclopropyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C1(CC1)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O JGBHDQDNQSCJLL-UHFFFAOYSA-N 0.000 claims 1
- QRPRDOOKZHTHGC-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-fluoro-5-methoxyphenyl)methyl]-4,4-dimethylimidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C(C1)(C)C)CC1=CC(=CC(=C1)OC)F)=O QRPRDOOKZHTHGC-UHFFFAOYSA-N 0.000 claims 1
- USHOKNGVPBTRGH-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-fluoro-5-methoxyphenyl)methyl]imidazol-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C=C1)CC1=CC(=CC(=C1)OC)F)=O USHOKNGVPBTRGH-UHFFFAOYSA-N 0.000 claims 1
- FBSFMWMWJQGVMY-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-fluoro-5-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O FBSFMWMWJQGVMY-UHFFFAOYSA-N 0.000 claims 1
- ARJSOFSUDJUKBP-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-methoxyphenyl)methyl]-4,4-dimethylimidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C(C1)(C)C)CC1=CC(=CC=C1)OC)=O ARJSOFSUDJUKBP-UHFFFAOYSA-N 0.000 claims 1
- HEYQMVLGYOCVEE-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(3-methoxyphenyl)methyl]imidazol-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C=C1)CC1=CC(=CC=C1)OC)=O HEYQMVLGYOCVEE-UHFFFAOYSA-N 0.000 claims 1
- FDJDTSFDOUONOF-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(4-fluoro-3-methoxyphenyl)methyl]imidazol-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C=C1)CC1=CC(=C(C=C1)F)OC)=O FDJDTSFDOUONOF-UHFFFAOYSA-N 0.000 claims 1
- KFVHCOGKDQKGLC-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[(4-fluoro-3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=C(C=C1)F)OC)=O KFVHCOGKDQKGLC-UHFFFAOYSA-N 0.000 claims 1
- JCYHHCZFLFQRPI-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[1-(3-methoxyphenyl)ethyl]imidazol-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OC)=O JCYHHCZFLFQRPI-UHFFFAOYSA-N 0.000 claims 1
- HTXGHHDKFIWTHF-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[2-hydroxy-1-(3-methoxyphenyl)ethyl]imidazol-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C=C1)C(CO)C1=CC(=CC=C1)OC)=O HTXGHHDKFIWTHF-UHFFFAOYSA-N 0.000 claims 1
- PIZYAMUJPXKHLD-UHFFFAOYSA-N 1-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]-3-[2-hydroxy-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C(C)C=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)C(CO)C1=CC(=CC=C1)OC)=O PIZYAMUJPXKHLD-UHFFFAOYSA-N 0.000 claims 1
- QFKAVLUZEIMTPB-UHFFFAOYSA-N 1-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]-3-[2-hydroxy-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound FC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)C(CO)C1=CC(=CC=C1)OC)=O QFKAVLUZEIMTPB-UHFFFAOYSA-N 0.000 claims 1
- BZNLVNWDORLPIK-UHFFFAOYSA-N 1-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]-3-[[3-(2-methylpropoxy)phenyl]methyl]imidazolidin-2-one Chemical compound FC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC=C1)OCC(C)C)=O BZNLVNWDORLPIK-UHFFFAOYSA-N 0.000 claims 1
- QPJGTJZIINTWSG-UHFFFAOYSA-N 1-[4-(1H-pyrazol-4-yl)phenyl]-3-(pyridin-3-ylmethyl)imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC=1C=NC=CC=1)=O QPJGTJZIINTWSG-UHFFFAOYSA-N 0.000 claims 1
- ZPPQBMCQBKSOCD-UHFFFAOYSA-N 1-[4-(2-aminopyrimidin-4-yl)phenyl]-3-[1-(3-methoxyphenyl)ethyl]imidazol-2-one Chemical compound NC1=NC=CC(=N1)C1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OC)=O ZPPQBMCQBKSOCD-UHFFFAOYSA-N 0.000 claims 1
- YOLIBMBZJPGZPJ-UHFFFAOYSA-N 1-[4-(3-fluoropyridin-4-yl)phenyl]-3-[1-(3-methoxyphenyl)ethyl]imidazol-2-one Chemical compound FC=1C=NC=CC=1C1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OC)=O YOLIBMBZJPGZPJ-UHFFFAOYSA-N 0.000 claims 1
- CGQMARBJJFEVLS-UHFFFAOYSA-N 1-[4-ethoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)OC1=CC(=NC=C1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O CGQMARBJJFEVLS-UHFFFAOYSA-N 0.000 claims 1
- DENKDPMCJMIQLP-UHFFFAOYSA-N 1-[4-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(3-fluoro-5-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)C1=CC(=NC=C1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O DENKDPMCJMIQLP-UHFFFAOYSA-N 0.000 claims 1
- ZQVOSLRZDNCIMU-UHFFFAOYSA-N 1-[4-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)C1=CC(=NC=C1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O ZQVOSLRZDNCIMU-UHFFFAOYSA-N 0.000 claims 1
- ZEBHGBWWNBTVEZ-UHFFFAOYSA-N 1-[4-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(4-fluoro-3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)C1=CC(=NC=C1C=1C=NNC=1)N1C(N(CC1)CC1=CC(=C(C=C1)F)OC)=O ZEBHGBWWNBTVEZ-UHFFFAOYSA-N 0.000 claims 1
- WRKHPKGZNAVRHV-UHFFFAOYSA-N 1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-(pyridin-2-ylmethyl)imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=NC=CC=C1)=O WRKHPKGZNAVRHV-UHFFFAOYSA-N 0.000 claims 1
- ZCTPNICMHMVPRE-UHFFFAOYSA-N 1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-(pyridin-3-ylmethyl)imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC=1C=NC=CC=1)=O ZCTPNICMHMVPRE-UHFFFAOYSA-N 0.000 claims 1
- OQURQGWIMIQLES-UHFFFAOYSA-N 1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[[3-(trifluoromethyl)phenyl]methyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=CC=C1)C(F)(F)F)=O OQURQGWIMIQLES-UHFFFAOYSA-N 0.000 claims 1
- HPPHRWFBNGGKBZ-UHFFFAOYSA-N 1-[5-(2-fluoropyridin-4-yl)-6-methoxypyridin-2-yl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound FC1=NC=CC(=C1)C=1C(=NC(=CC=1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)OC HPPHRWFBNGGKBZ-UHFFFAOYSA-N 0.000 claims 1
- KUGVYROMWMFUNT-UHFFFAOYSA-N 1-[5-(3-fluoropyridin-4-yl)-6-methoxypyridin-2-yl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound FC=1C=NC=CC=1C=1C(=NC(=CC=1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)OC KUGVYROMWMFUNT-UHFFFAOYSA-N 0.000 claims 1
- YIUUZSJFNZGRLO-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(3-fluoro-5-methoxyphenyl)methyl]imidazol-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(C=C1)CC1=CC(=CC(=C1)OC)F)=O)C=1C=NNC=1 YIUUZSJFNZGRLO-UHFFFAOYSA-N 0.000 claims 1
- VYMUTPBFKZYSOK-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(3-fluoro-5-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(CC1)CC1=CC(=CC(=C1)OC)F)=O)C=1C=NNC=1 VYMUTPBFKZYSOK-UHFFFAOYSA-N 0.000 claims 1
- CDQPNKMBLFADLR-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(3-methoxyphenyl)methyl]imidazol-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(C=C1)CC1=CC(=CC=C1)OC)=O)C=1C=NNC=1 CDQPNKMBLFADLR-UHFFFAOYSA-N 0.000 claims 1
- GNOXBBFMRULTSI-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)C=1C=NNC=1 GNOXBBFMRULTSI-UHFFFAOYSA-N 0.000 claims 1
- MQLXAFHIFWRELE-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(4-fluoro-3-methoxyphenyl)methyl]imidazol-2-one Chemical compound CCC1=C(C=CC(=N1)N1C=CN(CC2=CC(OC)=C(F)C=C2)C1=O)C1=CNN=C1 MQLXAFHIFWRELE-UHFFFAOYSA-N 0.000 claims 1
- OMVUEBVXVPXIKT-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(4-fluoro-3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(CC1)CC1=CC(=C(C=C1)F)OC)=O)C=1C=NNC=1 OMVUEBVXVPXIKT-UHFFFAOYSA-N 0.000 claims 1
- ZAJYVSJQBUCHRN-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[1-(3-fluoro-5-methoxyphenyl)ethyl]imidazol-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(C=C1)C(C)C1=CC(=CC(=C1)OC)F)=O)C=1C=NNC=1 ZAJYVSJQBUCHRN-UHFFFAOYSA-N 0.000 claims 1
- TZGFXFJEONKMRV-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[1-(3-fluoro-5-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(CC1)C(C)C1=CC(=CC(=C1)OC)F)=O)C=1C=NNC=1 TZGFXFJEONKMRV-UHFFFAOYSA-N 0.000 claims 1
- KWAJIWGPEJHWEK-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[1-(3-methoxyphenyl)ethyl]imidazol-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OC)=O)C=1C=NNC=1 KWAJIWGPEJHWEK-UHFFFAOYSA-N 0.000 claims 1
- KAXADGLPKOQTSL-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(CC1)C(C)C1=CC(=CC=C1)OC)=O)C=1C=NNC=1 KAXADGLPKOQTSL-UHFFFAOYSA-N 0.000 claims 1
- NUZCQRYEYWCOAA-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[1-(4-fluoro-3-methoxyphenyl)ethyl]imidazol-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(C=C1)C(C)C1=CC(=C(C=C1)F)OC)=O)C=1C=NNC=1 NUZCQRYEYWCOAA-UHFFFAOYSA-N 0.000 claims 1
- VLHCVFIWLCINHC-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[1-(4-fluoro-3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(CC1)C(C)C1=CC(=C(C=C1)F)OC)=O)C=1C=NNC=1 VLHCVFIWLCINHC-UHFFFAOYSA-N 0.000 claims 1
- KPHODYIEDYMMMY-UHFFFAOYSA-N 1-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[2-hydroxy-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound C(C)C1=C(C=CC(=N1)N1C(N(CC1)C(CO)C1=CC(=CC=C1)OC)=O)C=1C=NNC=1 KPHODYIEDYMMMY-UHFFFAOYSA-N 0.000 claims 1
- ZXKDAFANNWMICV-UHFFFAOYSA-N 1-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-(oxolan-2-ylmethyl)imidazol-2-one Chemical compound COC1=C(C=CC(=N1)N1C(N(C=C1)CC1OCCC1)=O)C=1C=NNC=1 ZXKDAFANNWMICV-UHFFFAOYSA-N 0.000 claims 1
- KLISNVABZUKOLD-UHFFFAOYSA-N 1-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-(oxolan-2-ylmethyl)imidazolidin-2-one Chemical compound COC1=C(C=CC(=N1)N1C(N(CC1)CC1OCCC1)=O)C=1C=NNC=1 KLISNVABZUKOLD-UHFFFAOYSA-N 0.000 claims 1
- WKZWXFAYVGZWEH-UHFFFAOYSA-N 1-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-(pyridin-3-ylmethyl)imidazol-2-one Chemical compound COC1=C(C=CC(=N1)N1C(N(C=C1)CC=1C=NC=CC=1)=O)C=1C=NNC=1 WKZWXFAYVGZWEH-UHFFFAOYSA-N 0.000 claims 1
- YIHAYFWHZLPFJQ-UHFFFAOYSA-N 1-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-(pyridin-3-ylmethyl)imidazolidin-2-one Chemical compound COC1=C(C=CC(=N1)N1CCN(CC2=CC=CN=C2)C1=O)C1=CNN=C1 YIHAYFWHZLPFJQ-UHFFFAOYSA-N 0.000 claims 1
- BYINPRSFSRXWQD-UHFFFAOYSA-N 1-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(3-methylphenyl)methyl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=N1)N1C(N(CC1)CC1=CC(=CC=C1)C)=O)C=1C=NNC=1 BYINPRSFSRXWQD-UHFFFAOYSA-N 0.000 claims 1
- VFVXEMAGDYBBKY-UHFFFAOYSA-N 1-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]-3-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=N1)N1CCN(CC2=NOC(C)=N2)C1=O)C1=CNN=C1 VFVXEMAGDYBBKY-UHFFFAOYSA-N 0.000 claims 1
- QLNKRYAWKCADAZ-UHFFFAOYSA-N 1-[6-methoxy-5-(5-methyl-1H-pyrazol-4-yl)pyridin-2-yl]-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=N1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)C=1C=NNC=1C QLNKRYAWKCADAZ-UHFFFAOYSA-N 0.000 claims 1
- GZJGIYUSMPZCTG-UHFFFAOYSA-N 1-[[3-(2-methylpropoxy)phenyl]methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=CC=C1)OCC(C)C)=O GZJGIYUSMPZCTG-UHFFFAOYSA-N 0.000 claims 1
- QVJWDQUPBQCNEN-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)-4-fluorophenyl]methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1F QVJWDQUPBQCNEN-UHFFFAOYSA-N 0.000 claims 1
- INOZBOKFKARLNN-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)-4-fluorophenyl]methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1F INOZBOKFKARLNN-UHFFFAOYSA-N 0.000 claims 1
- SYCJZAZMEYXHNE-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)-4-fluorophenyl]methyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)C)=O)C=CC=1F SYCJZAZMEYXHNE-UHFFFAOYSA-N 0.000 claims 1
- VXUZVVAAFCZBNJ-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)-5-fluorophenyl]methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C=C1)CC1=CC(=CC(=C1)F)OCC1CC1)=O VXUZVVAAFCZBNJ-UHFFFAOYSA-N 0.000 claims 1
- SSOKPDQQFFCXNL-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)-5-fluorophenyl]methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=1)F SSOKPDQQFFCXNL-UHFFFAOYSA-N 0.000 claims 1
- JATVGAXBXSJMRS-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)-5-fluorophenyl]methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=1)F JATVGAXBXSJMRS-UHFFFAOYSA-N 0.000 claims 1
- CKNTZDZUFLAZPJ-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]imidazol-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(C=C2)C2=CC(=C(C=C2)C=2C=NNC=2)CC)=O)C=CC=1 CKNTZDZUFLAZPJ-UHFFFAOYSA-N 0.000 claims 1
- SZSOXERFPBHJRS-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[3-ethyl-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)CC)=O)C=CC=1 SZSOXERFPBHJRS-UHFFFAOYSA-N 0.000 claims 1
- VWCVUZJDCBTPNM-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[3-methyl-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(CC2)C2=CC(=C(C=C2)C=2C=NNC=2)C)=O)C=CC=1 VWCVUZJDCBTPNM-UHFFFAOYSA-N 0.000 claims 1
- MRXOWUBIGKOLHF-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C=C1)CC1=CC(=CC=C1)OCC1CC1)=O MRXOWUBIGKOLHF-UHFFFAOYSA-N 0.000 claims 1
- GVGGVWIDECSBET-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC1=CC(=CC=C1)OCC1CC1)=O GVGGVWIDECSBET-UHFFFAOYSA-N 0.000 claims 1
- SKZIUUGKERTQSP-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[6-(1H-pyrazol-4-yl)pyridin-3-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=N1)N1C(N(CC1)CC1=CC(=CC=C1)OCC1CC1)=O SKZIUUGKERTQSP-UHFFFAOYSA-N 0.000 claims 1
- OPDADVHAMPACNV-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[6-(methylamino)-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)NC)=O)C=CC=1 OPDADVHAMPACNV-UHFFFAOYSA-N 0.000 claims 1
- VECOITNPLZSYDK-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[6-ethyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)CC)=O)C=CC=1 VECOITNPLZSYDK-UHFFFAOYSA-N 0.000 claims 1
- MAISDVRONQUZJX-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 MAISDVRONQUZJX-UHFFFAOYSA-N 0.000 claims 1
- SRSPVYHLEUVKDA-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 SRSPVYHLEUVKDA-UHFFFAOYSA-N 0.000 claims 1
- RURSLGSQQKJFLR-UHFFFAOYSA-N 1-[[3-(cyclopropylmethoxy)phenyl]methyl]-3-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound C1(CC1)COC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)C)=O)C=CC=1 RURSLGSQQKJFLR-UHFFFAOYSA-N 0.000 claims 1
- GICZLZPQMWMPAU-UHFFFAOYSA-N 1-[[3-(difluoromethoxy)phenyl]methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-2-one Chemical compound FC(OC=1C=C(CN2C(N(C=C2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1)F GICZLZPQMWMPAU-UHFFFAOYSA-N 0.000 claims 1
- QWNCOGPCRQEEGS-UHFFFAOYSA-N 1-[[3-(difluoromethoxy)phenyl]methyl]-3-[6-methoxy-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC(OC=1C=C(CN2C(N(CC2)C2=NC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1)F QWNCOGPCRQEEGS-UHFFFAOYSA-N 0.000 claims 1
- GLHKINUSSNXCEJ-UHFFFAOYSA-N 1-benzyl-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC=CC=C1)=O GLHKINUSSNXCEJ-UHFFFAOYSA-N 0.000 claims 1
- GWHBHYJCQPVLQY-UHFFFAOYSA-N 2-(3-methoxyphenyl)-2-[2-oxo-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazol-1-yl]acetic acid Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C=C1)C(C(=O)O)C1=CC(=CC=C1)OC)=O GWHBHYJCQPVLQY-UHFFFAOYSA-N 0.000 claims 1
- PJTPUKDFAQRJSX-UHFFFAOYSA-N 2-(3-methoxyphenyl)-2-[3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]-2-oxoimidazol-1-yl]acetic acid Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C=C1)C(C(=O)O)C1=CC(=CC=C1)OC)=O PJTPUKDFAQRJSX-UHFFFAOYSA-N 0.000 claims 1
- DWGMMBWSXHQZLU-UHFFFAOYSA-N 2-(3-methoxyphenyl)-N-methyl-2-[2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-1-yl]acetamide Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(C(=O)NC)C1=CC(=CC=C1)OC)=O DWGMMBWSXHQZLU-UHFFFAOYSA-N 0.000 claims 1
- JPNIWGYXLKQUSB-UHFFFAOYSA-N 3-[(2-fluoro-3-methoxyphenyl)methyl]-4,4-dimethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)(C)C)CC1=C(C(=CC=C1)OC)F)=O JPNIWGYXLKQUSB-UHFFFAOYSA-N 0.000 claims 1
- HWLVVOHQJUDIDK-UHFFFAOYSA-N 3-[(3-fluoro-4-methoxyphenyl)methyl]-4,4-dimethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)(C)C)CC1=CC(=C(C=C1)OC)F)=O HWLVVOHQJUDIDK-UHFFFAOYSA-N 0.000 claims 1
- YKJVADKRDRRLCJ-UHFFFAOYSA-N 3-[(3-fluoro-5-methoxyphenyl)methyl]-4,4-dimethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)(C)C)CC1=CC(=CC(=C1)OC)F)=O YKJVADKRDRRLCJ-UHFFFAOYSA-N 0.000 claims 1
- LMMGPWWFABVPBM-UHFFFAOYSA-N 3-[(3-fluoro-5-methoxyphenyl)methyl]-4,4-dimethyl-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C(C1)(C)C)CC1=CC(=CC(=C1)OC)F)=O LMMGPWWFABVPBM-UHFFFAOYSA-N 0.000 claims 1
- XVLVXNBCRFLRHI-UHFFFAOYSA-N 3-[(3-fluoro-5-methoxyphenyl)methyl]-4,4-dimethyl-1-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC=1C=C(CN2C(N(CC2(C)C)C2=NC(=C(C=C2)C=2C=NNC=2)C)=O)C=C(C=1)OC XVLVXNBCRFLRHI-UHFFFAOYSA-N 0.000 claims 1
- AILGMGSJPKCLAX-UHFFFAOYSA-N 3-[(3-fluorophenyl)methyl]-4,4-dimethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)(C)C)CC1=CC(=CC=C1)F)=O AILGMGSJPKCLAX-UHFFFAOYSA-N 0.000 claims 1
- GHMNBUSOQCANNI-UHFFFAOYSA-N 3-[(3-methoxyphenyl)methyl]-4,4-dimethyl-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C(C1)(C)C)CC1=CC(=CC=C1)OC)=O GHMNBUSOQCANNI-UHFFFAOYSA-N 0.000 claims 1
- MZKXSFOPKXDXGS-UHFFFAOYSA-N 3-[(4-fluoro-3-methoxyphenyl)methyl]-4,4-dimethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)(C)C)CC1=CC(=C(C=C1)F)OC)=O MZKXSFOPKXDXGS-UHFFFAOYSA-N 0.000 claims 1
- VYCRNUWUEYCGQP-UHFFFAOYSA-N 3-[(4-fluoro-3-methoxyphenyl)methyl]-4,4-dimethyl-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C(C1)(C)C)CC1=CC(=C(C=C1)F)OC)=O VYCRNUWUEYCGQP-UHFFFAOYSA-N 0.000 claims 1
- UGWQIZIEKFKUFJ-UHFFFAOYSA-N 3-[(4-fluoro-3-methoxyphenyl)methyl]-4,4-dimethyl-1-[6-methyl-5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound FC1=C(C=C(CN2C(N(CC2(C)C)C2=NC(=C(C=C2)C=2C=NNC=2)C)=O)C=C1)OC UGWQIZIEKFKUFJ-UHFFFAOYSA-N 0.000 claims 1
- WTDKCDOXKVVVJX-UHFFFAOYSA-N 3-[1-(3-methoxyphenyl)ethyl]-4,4-dimethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)(C)C)C(C)C1=CC(=CC=C1)OC)=O WTDKCDOXKVVVJX-UHFFFAOYSA-N 0.000 claims 1
- UDAAXBHKZOOBBP-UHFFFAOYSA-N 3-[[2-oxo-3-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-1-yl]methyl]benzoic acid Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC=1C=C(C(=O)O)C=CC=1)=O UDAAXBHKZOOBBP-UHFFFAOYSA-N 0.000 claims 1
- RWPQJFHPCWCKJF-UHFFFAOYSA-N 3-[[3-(cyclopropylmethoxy)phenyl]methyl]-4,4-dimethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)(C)C)CC1=CC(=CC=C1)OCC1CC1)=O RWPQJFHPCWCKJF-UHFFFAOYSA-N 0.000 claims 1
- LGVRFSGALGSEIE-UHFFFAOYSA-N 3-[[3-(cyclopropylmethoxy)phenyl]methyl]-4,4-dimethyl-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(C(C1)(C)C)CC1=CC(=CC=C1)OCC1CC1)=O LGVRFSGALGSEIE-UHFFFAOYSA-N 0.000 claims 1
- MQEFGZIWUKKTHK-UHFFFAOYSA-N 3-[[3-(cyclopropylmethoxy)phenyl]methyl]-4-ethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)CC)CC1=CC(=CC=C1)OCC1CC1)=O MQEFGZIWUKKTHK-UHFFFAOYSA-N 0.000 claims 1
- NULRZNZAGSRFJK-UHFFFAOYSA-N 3-[[3-(difluoromethoxy)phenyl]methyl]-4,4-dimethyl-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)(C)C)CC1=CC(=CC=C1)OC(F)F)=O NULRZNZAGSRFJK-UHFFFAOYSA-N 0.000 claims 1
- FIFVMMVRGAQOFY-UHFFFAOYSA-N 4-ethyl-3-[(3-fluoro-5-methoxyphenyl)methyl]-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)CC)CC1=CC(=CC(=C1)OC)F)=O FIFVMMVRGAQOFY-UHFFFAOYSA-N 0.000 claims 1
- IBZABVXSSWTYHW-UHFFFAOYSA-N 4-ethyl-3-[(3-methoxyphenyl)methyl]-1-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)CC)CC1=CC(=CC=C1)OC)=O IBZABVXSSWTYHW-UHFFFAOYSA-N 0.000 claims 1
- PIYBVBQIXZEJQS-UHFFFAOYSA-N 5-[3-[(3-fluoro-5-methoxyphenyl)methyl]-2-oxoimidazolidin-1-yl]-2-(1H-pyrazol-4-yl)benzonitrile Chemical compound FC=1C=C(CN2C(N(CC2)C=2C=CC(=C(C#N)C=2)C=2C=NNC=2)=O)C=C(C=1)OC PIYBVBQIXZEJQS-UHFFFAOYSA-N 0.000 claims 1
- FUBVWUJQYCYNGQ-UHFFFAOYSA-N 5-[3-[(3-methoxyphenyl)methyl]-2-oxoimidazolidin-1-yl]-2-(1H-pyrazol-4-yl)benzonitrile Chemical compound COC=1C=C(CN2C(N(CC2)C=2C=CC(=C(C#N)C=2)C=2C=NNC=2)=O)C=CC=1 FUBVWUJQYCYNGQ-UHFFFAOYSA-N 0.000 claims 1
- XMQFYTZLMHQWLG-UHFFFAOYSA-N 5-[3-[(4-fluoro-3-methoxyphenyl)methyl]-2-oxoimidazolidin-1-yl]-2-(1H-pyrazol-4-yl)benzonitrile Chemical compound FC1=C(C=C(CN2C(N(CC2)C=2C=CC(=C(C#N)C=2)C=2C=NNC=2)=O)C=C1)OC XMQFYTZLMHQWLG-UHFFFAOYSA-N 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- RJJUWVXZUSZOOK-UHFFFAOYSA-N C(C1=CC=CC=C1)N1C(N(C(C1)=O)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O Chemical compound C(C1=CC=CC=C1)N1C(N(C(C1)=O)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O RJJUWVXZUSZOOK-UHFFFAOYSA-N 0.000 claims 1
- NWOKTQUAVVFQNI-UHFFFAOYSA-N C(C1=CC=CC=C1)N1C(N(CC1)C1=CC=C(C=C1)C1=C(C=NC=C1)F)=O Chemical compound C(C1=CC=CC=C1)N1C(N(CC1)C1=CC=C(C=C1)C1=C(C=NC=C1)F)=O NWOKTQUAVVFQNI-UHFFFAOYSA-N 0.000 claims 1
- RTKZHYVPYLRXHY-UHFFFAOYSA-N C(C1=CC=CC=C1)N1C(N(CC1)C1=CC=C(C=C1)C=1C=NOC=1)=O Chemical compound C(C1=CC=CC=C1)N1C(N(CC1)C1=CC=C(C=C1)C=1C=NOC=1)=O RTKZHYVPYLRXHY-UHFFFAOYSA-N 0.000 claims 1
- MFHJVZODKDNIPC-UHFFFAOYSA-N COC1=C(C=CC(=N1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)C1=C2C(=NC=C1)NC=C2 Chemical compound COC1=C(C=CC(=N1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)C1=C2C(=NC=C1)NC=C2 MFHJVZODKDNIPC-UHFFFAOYSA-N 0.000 claims 1
- AANOSYAGYWFVJQ-UHFFFAOYSA-N COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C(C1)=O)C(C)C1=CC=CC=C1)=O Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C(C1)=O)C(C)C1=CC=CC=C1)=O AANOSYAGYWFVJQ-UHFFFAOYSA-N 0.000 claims 1
- DIVZYZVWUCSASA-UHFFFAOYSA-N COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C(C1)=O)CC1=CC(=CC=C1)OC)=O Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C(C1)=O)CC1=CC(=CC=C1)OC)=O DIVZYZVWUCSASA-UHFFFAOYSA-N 0.000 claims 1
- OOYSZADHOOSSGT-UHFFFAOYSA-N COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C(C1)=O)CCC1=CC=CC=C1)=O Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(C(C1)=O)CCC1=CC=CC=C1)=O OOYSZADHOOSSGT-UHFFFAOYSA-N 0.000 claims 1
- QVAOPSGGIVVUTD-UHFFFAOYSA-N COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1=O)CC1=CC(=CC=C1)OC)=O Chemical compound COC=1C=C(C=CC=1C=1C=NNC=1)N1C(N(CC1=O)CC1=CC(=CC=C1)OC)=O QVAOPSGGIVVUTD-UHFFFAOYSA-N 0.000 claims 1
- OJIWLBVGLUIDCK-UHFFFAOYSA-N ClC1=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 Chemical compound ClC1=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 OJIWLBVGLUIDCK-UHFFFAOYSA-N 0.000 claims 1
- PDOJYKVEVSDUKX-UHFFFAOYSA-N ClC1=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 Chemical compound ClC1=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 PDOJYKVEVSDUKX-UHFFFAOYSA-N 0.000 claims 1
- GLJAWEUIMYLPTH-UHFFFAOYSA-N FC1=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=C1)F Chemical compound FC1=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=C1)F GLJAWEUIMYLPTH-UHFFFAOYSA-N 0.000 claims 1
- SYRBFDNYKFQIHJ-UHFFFAOYSA-N FC1=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 Chemical compound FC1=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 SYRBFDNYKFQIHJ-UHFFFAOYSA-N 0.000 claims 1
- XKGBONCQUGIHBX-UHFFFAOYSA-N FC1=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C(=CC=C1)F Chemical compound FC1=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C(=CC=C1)F XKGBONCQUGIHBX-UHFFFAOYSA-N 0.000 claims 1
- TULKAWMIQDRSHO-UHFFFAOYSA-N FC1=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 Chemical compound FC1=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=C1 TULKAWMIQDRSHO-UHFFFAOYSA-N 0.000 claims 1
- HFYYBVNYVLKNCN-UHFFFAOYSA-N FC1=NC=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O Chemical compound FC1=NC=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O HFYYBVNYVLKNCN-UHFFFAOYSA-N 0.000 claims 1
- VRECNGUKLBADFI-UHFFFAOYSA-N FC=1C=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=1)OC Chemical compound FC=1C=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=1)OC VRECNGUKLBADFI-UHFFFAOYSA-N 0.000 claims 1
- FBFUXWVYNWFOLW-UHFFFAOYSA-N FC=1C=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 Chemical compound FC=1C=C(CN2C(N(C(C2)=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 FBFUXWVYNWFOLW-UHFFFAOYSA-N 0.000 claims 1
- OJBAKHOJOJSOGQ-UHFFFAOYSA-N FC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)C2=C(C=NC=C2)F)=O)C=CC=1 Chemical compound FC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)C2=C(C=NC=C2)F)=O)C=CC=1 OJBAKHOJOJSOGQ-UHFFFAOYSA-N 0.000 claims 1
- WQIDVGDWQVGKSN-UHFFFAOYSA-N FC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)C2=CC(=NC=C2)F)=O)C=CC=1 Chemical compound FC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)C2=CC(=NC=C2)F)=O)C=CC=1 WQIDVGDWQVGKSN-UHFFFAOYSA-N 0.000 claims 1
- POCQZGFGFDXJLJ-UHFFFAOYSA-N FC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)C=2C=NOC=2)=O)C=CC=1 Chemical compound FC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)C=2C=NOC=2)=O)C=CC=1 POCQZGFGFDXJLJ-UHFFFAOYSA-N 0.000 claims 1
- PYKPTUIASRJGNS-UHFFFAOYSA-N FC=1C=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=1)OC Chemical compound FC=1C=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=C(C=1)OC PYKPTUIASRJGNS-UHFFFAOYSA-N 0.000 claims 1
- NGYALHIYPDRCCU-UHFFFAOYSA-N FC=1C=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 Chemical compound FC=1C=C(CN2C(N(CC2=O)C2=CC(=C(C=C2)C=2C=NNC=2)OC)=O)C=CC=1 NGYALHIYPDRCCU-UHFFFAOYSA-N 0.000 claims 1
- HVRSNIBQBODECE-UHFFFAOYSA-N FC=1C=NC=CC=1C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O Chemical compound FC=1C=NC=CC=1C1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O HVRSNIBQBODECE-UHFFFAOYSA-N 0.000 claims 1
- LCPNTBPUHUVFEW-UHFFFAOYSA-N FC=1C=NC=CC=1C1=CC=C(C=C1)N1C(N(CC1)CCC1=CC=CC=C1)=O Chemical compound FC=1C=NC=CC=1C1=CC=C(C=C1)N1C(N(CC1)CCC1=CC=CC=C1)=O LCPNTBPUHUVFEW-UHFFFAOYSA-N 0.000 claims 1
- QDWIKWFQICUGPY-UHFFFAOYSA-N N-methyl-2-[2-oxo-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidin-1-yl]-2-phenylacetamide Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1)C(C(=O)NC)C1=CC=CC=C1)=O QDWIKWFQICUGPY-UHFFFAOYSA-N 0.000 claims 1
- JZPXACJBGMIIAP-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)C(C)C1=CC=CC=C1)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)C(C)C1=CC=CC=C1)=O JZPXACJBGMIIAP-UHFFFAOYSA-N 0.000 claims 1
- OICJVZCDCUNDTF-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=C(C=CC(=C1)F)F)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=C(C=CC(=C1)F)F)=O OICJVZCDCUNDTF-UHFFFAOYSA-N 0.000 claims 1
- RONMLWTXMFBDMQ-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=C(C=CC=C1)Cl)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=C(C=CC=C1)Cl)=O RONMLWTXMFBDMQ-UHFFFAOYSA-N 0.000 claims 1
- BBYUHHHBXXMLCB-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=C(C=CC=C1F)F)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=C(C=CC=C1F)F)=O BBYUHHHBXXMLCB-UHFFFAOYSA-N 0.000 claims 1
- JVANJRJQPWUSCH-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=CC(=CC(=C1)OC)F)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=CC(=CC(=C1)OC)F)=O JVANJRJQPWUSCH-UHFFFAOYSA-N 0.000 claims 1
- STMXCQHNUFADNM-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=CC(=CC=C1)F)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=CC(=CC=C1)F)=O STMXCQHNUFADNM-UHFFFAOYSA-N 0.000 claims 1
- VTNZEVNZXQNTJB-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=CC(=CC=C1)OC)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=CC(=CC=C1)OC)=O VTNZEVNZXQNTJB-UHFFFAOYSA-N 0.000 claims 1
- SFAVEGXTGQMZFC-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=CC=CC=C1)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CC1=CC=CC=C1)=O SFAVEGXTGQMZFC-UHFFFAOYSA-N 0.000 claims 1
- RYIHZDJDDMZTBE-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CCC1=CC=CC=C1)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(C(C1)=O)CCC1=CC=CC=C1)=O RYIHZDJDDMZTBE-UHFFFAOYSA-N 0.000 claims 1
- LYLWZIQMTKDSDM-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=C(C=CC(=C1)F)F)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=C(C=CC(=C1)F)F)=O LYLWZIQMTKDSDM-UHFFFAOYSA-N 0.000 claims 1
- OFVKBEHPAZJLPA-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=C(C=CC=C1)Cl)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=C(C=CC=C1)Cl)=O OFVKBEHPAZJLPA-UHFFFAOYSA-N 0.000 claims 1
- BXENCNDVDOHADE-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=C(C=CC=C1)F)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=C(C=CC=C1)F)=O BXENCNDVDOHADE-UHFFFAOYSA-N 0.000 claims 1
- VNQUJGXEEJCIGC-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC(=CC(=C1)OC)F)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC(=CC(=C1)OC)F)=O VNQUJGXEEJCIGC-UHFFFAOYSA-N 0.000 claims 1
- RCPRYXBEYMCQHV-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC(=CC=C1)F)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC(=CC=C1)F)=O RCPRYXBEYMCQHV-UHFFFAOYSA-N 0.000 claims 1
- HAFXQTPECXYINQ-UHFFFAOYSA-N N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC=CC=C1)=O Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC=CC=C1)=O HAFXQTPECXYINQ-UHFFFAOYSA-N 0.000 claims 1
- MITQOMCHNIVHSX-UHFFFAOYSA-N N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC=1C=C(C#N)C=CC=1)=O Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N(CC1)CC=1C=C(C#N)C=CC=1)=O MITQOMCHNIVHSX-UHFFFAOYSA-N 0.000 claims 1
- 208000012902 Nervous system disease Diseases 0.000 claims 1
- 208000025966 Neurological disease Diseases 0.000 claims 1
- 208000031481 Pathologic Constriction Diseases 0.000 claims 1
- 208000018262 Peripheral vascular disease Diseases 0.000 claims 1
- 206010047163 Vasospasm Diseases 0.000 claims 1
- 208000026106 cerebrovascular disease Diseases 0.000 claims 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 230000000771 oncological effect Effects 0.000 claims 1
- 208000037804 stenosis Diseases 0.000 claims 1
- 230000036262 stenosis Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 88
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 4
- 230000001363 autoimmune Effects 0.000 abstract 1
- 230000007171 neuropathology Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 344
- 239000000203 mixture Substances 0.000 description 216
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 203
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 202
- 239000011541 reaction mixture Substances 0.000 description 173
- 239000007787 solid Substances 0.000 description 154
- 239000000243 solution Substances 0.000 description 147
- 235000019439 ethyl acetate Nutrition 0.000 description 139
- 239000000460 chlorine Substances 0.000 description 137
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 118
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 106
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 102
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 85
- 229910052757 nitrogen Inorganic materials 0.000 description 83
- 238000002360 preparation method Methods 0.000 description 83
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 80
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 76
- 239000012267 brine Substances 0.000 description 73
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 73
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
- 150000003254 radicals Chemical class 0.000 description 71
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 68
- 239000002904 solvent Substances 0.000 description 68
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 64
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 56
- 235000002639 sodium chloride Nutrition 0.000 description 55
- 239000000543 intermediate Substances 0.000 description 50
- 125000004433 nitrogen atom Chemical group N* 0.000 description 50
- 238000006243 chemical reaction Methods 0.000 description 47
- 238000003818 flash chromatography Methods 0.000 description 46
- 229910000027 potassium carbonate Inorganic materials 0.000 description 45
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 45
- 239000012043 crude product Substances 0.000 description 44
- 238000002953 preparative HPLC Methods 0.000 description 42
- 125000003118 aryl group Chemical group 0.000 description 41
- 239000011734 sodium Substances 0.000 description 41
- 229910052938 sodium sulfate Inorganic materials 0.000 description 40
- 239000000706 filtrate Substances 0.000 description 39
- 239000012044 organic layer Substances 0.000 description 38
- 229910000104 sodium hydride Inorganic materials 0.000 description 38
- 239000012453 solvate Substances 0.000 description 38
- 239000000047 product Substances 0.000 description 37
- 125000001072 heteroaryl group Chemical group 0.000 description 35
- 239000000651 prodrug Substances 0.000 description 35
- 125000000753 cycloalkyl group Chemical group 0.000 description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 34
- 229940002612 prodrug Drugs 0.000 description 34
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- IPISOFJLWYBCAV-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate Chemical compound C1=NN(C(=O)OC(C)(C)C)C=C1B1OC(C)(C)C(C)(C)O1 IPISOFJLWYBCAV-UHFFFAOYSA-N 0.000 description 32
- 239000007832 Na2SO4 Substances 0.000 description 30
- 239000012391 XPhos Pd G2 Substances 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 28
- 238000010828 elution Methods 0.000 description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 26
- 238000000746 purification Methods 0.000 description 24
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 23
- 239000012071 phase Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000006184 cosolvent Substances 0.000 description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 21
- 239000003208 petroleum Substances 0.000 description 21
- 238000004808 supercritical fluid chromatography Methods 0.000 description 21
- 125000006706 (C3-C6) carbocyclyl group Chemical group 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 238000001914 filtration Methods 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 125000001424 substituent group Chemical group 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- 239000002245 particle Substances 0.000 description 14
- 150000001412 amines Chemical class 0.000 description 13
- 229910052717 sulfur Inorganic materials 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 229910052796 boron Inorganic materials 0.000 description 12
- 239000002775 capsule Substances 0.000 description 12
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 12
- 125000004429 atom Chemical group 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical class ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 239000012948 isocyanate Substances 0.000 description 9
- 150000002513 isocyanates Chemical class 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000012312 sodium hydride Substances 0.000 description 9
- PHRJTGPFEAUEBC-UHFFFAOYSA-N 1-fluoro-3-(isocyanatomethyl)benzene Chemical compound FC1=CC=CC(CN=C=O)=C1 PHRJTGPFEAUEBC-UHFFFAOYSA-N 0.000 description 8
- SIOHQNFGXFYSHG-UHFFFAOYSA-N 2-[3-(4-bromophenyl)-2-oxoimidazolidin-1-yl]-2-(3-methoxyphenyl)acetic acid Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(C(=O)O)C1=CC(=CC=C1)OC)=O SIOHQNFGXFYSHG-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
- NMMPMZWIIQCZBA-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylethanamine Chemical compound [Pd+]Cl.NCCC1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 NMMPMZWIIQCZBA-UHFFFAOYSA-M 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 239000002480 mineral oil Substances 0.000 description 8
- 235000010446 mineral oil Nutrition 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 238000001665 trituration Methods 0.000 description 8
- ZKSOJQDNSNJIQW-UHFFFAOYSA-N 1-(bromomethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(CBr)=C1 ZKSOJQDNSNJIQW-UHFFFAOYSA-N 0.000 description 7
- CZQIJQFTRGDODI-UHFFFAOYSA-N 1-bromo-4-isocyanatobenzene Chemical compound BrC1=CC=C(N=C=O)C=C1 CZQIJQFTRGDODI-UHFFFAOYSA-N 0.000 description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 7
- 239000005695 Ammonium acetate Substances 0.000 description 7
- 101100356682 Caenorhabditis elegans rho-1 gene Proteins 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 101150111584 RHOA gene Proteins 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 235000019257 ammonium acetate Nutrition 0.000 description 7
- 229940043376 ammonium acetate Drugs 0.000 description 7
- 239000004202 carbamide Substances 0.000 description 7
- OENICUBCLXKLJQ-UHFFFAOYSA-N ethyl 2,3-dibromopropanoate Chemical compound CCOC(=O)C(Br)CBr OENICUBCLXKLJQ-UHFFFAOYSA-N 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 125000002950 monocyclic group Chemical group 0.000 description 7
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 229940124597 therapeutic agent Drugs 0.000 description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 7
- WVJLYSAXAFISSC-UHFFFAOYSA-N 2-fluoro-5-methoxy-n-methylaniline Chemical compound CNC1=CC(OC)=CC=C1F WVJLYSAXAFISSC-UHFFFAOYSA-N 0.000 description 6
- XYNBYRIOJLMJDM-UHFFFAOYSA-N 3-(4-bromophenyl)-1h-imidazol-2-one Chemical compound C1=CC(Br)=CC=C1N1C(=O)NC=C1 XYNBYRIOJLMJDM-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000006069 Suzuki reaction reaction Methods 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 239000012039 electrophile Substances 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- PUBVIAHPSLGSFN-UHFFFAOYSA-N phenyl n-(5-bromopyridin-2-yl)carbamate Chemical compound N1=CC(Br)=CC=C1NC(=O)OC1=CC=CC=C1 PUBVIAHPSLGSFN-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 6
- QWGAJMDRYUIPIT-UHFFFAOYSA-N 1-(isocyanatomethyl)-3-methoxybenzene Chemical group COC1=CC=CC(CN=C=O)=C1 QWGAJMDRYUIPIT-UHFFFAOYSA-N 0.000 description 5
- BCMYXYHEMGPZJN-UHFFFAOYSA-N 1-chloro-2-isocyanatoethane Chemical compound ClCCN=C=O BCMYXYHEMGPZJN-UHFFFAOYSA-N 0.000 description 5
- FHYDHJXZZQCXOX-UHFFFAOYSA-N 3-fluoro-n-methylaniline Chemical group CNC1=CC=CC(F)=C1 FHYDHJXZZQCXOX-UHFFFAOYSA-N 0.000 description 5
- VAFZZUKCXFHFMN-UHFFFAOYSA-N BrC1=CC=C(C=C1)NC(=O)NCC(OC)OC Chemical compound BrC1=CC=C(C=C1)NC(=O)NCC(OC)OC VAFZZUKCXFHFMN-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000001041 indolyl group Chemical group 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 125000003373 pyrazinyl group Chemical group 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000004434 sulfur atom Chemical group 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 5
- CJWGCBRQAHCVHW-SSDOTTSWSA-N (1r)-1-(3-methoxyphenyl)ethanamine Chemical compound COC1=CC=CC([C@@H](C)N)=C1 CJWGCBRQAHCVHW-SSDOTTSWSA-N 0.000 description 4
- SERVOTWJOQLFFE-QMMMGPOBSA-N (5S)-3-(4-bromophenyl)-5-(hydroxymethyl)imidazolidine-2,4-dione Chemical compound BrC1=CC=C(C=C1)N1C(N[C@H](C1=O)CO)=O SERVOTWJOQLFFE-QMMMGPOBSA-N 0.000 description 4
- MQGOIONIWRZMDB-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[1-(3-methoxyphenyl)ethyl]imidazol-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(C=C1)C(C)C1=CC(=CC=C1)OC)=O MQGOIONIWRZMDB-UHFFFAOYSA-N 0.000 description 4
- BSSSIZYVYOYHRG-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[2-hydroxy-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(CO)C1=CC(=CC=C1)OC)=O BSSSIZYVYOYHRG-UHFFFAOYSA-N 0.000 description 4
- IQYIOVFMXOWYEQ-UHFFFAOYSA-N 1-(4-bromophenyl)imidazolidin-2-one Chemical compound C1=CC(Br)=CC=C1N1C(=O)NCC1 IQYIOVFMXOWYEQ-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- GLDACSZMLWTLKU-UHFFFAOYSA-N 2-[3-(4-bromophenyl)-2-oxoimidazolidin-1-yl]-2-(3-methoxyphenyl)propanoic acid Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(C(=O)O)(C)C1=CC(=CC=C1)OC)=O GLDACSZMLWTLKU-UHFFFAOYSA-N 0.000 description 4
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 4
- QGQSOHAZQJREQX-UHFFFAOYSA-N 3-(4-bromophenyl)-1-[(3-methoxyphenyl)methyl]-2-oxoimidazolidine-4-carboxylic acid Chemical compound COC1=CC=CC(CN2CC(N(C2=O)C2=CC=C(Br)C=C2)C(O)=O)=C1 QGQSOHAZQJREQX-UHFFFAOYSA-N 0.000 description 4
- VCYCTWDKBKJCME-UHFFFAOYSA-N 3-(4-bromophenyl)-4-(hydroxymethyl)-1-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1CO)CC1=CC(=CC=C1)OC)=O VCYCTWDKBKJCME-UHFFFAOYSA-N 0.000 description 4
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 4
- CRIXOEJNMCGMFU-UHFFFAOYSA-N BrC1=CC=C(C=C1)NC(=O)NC(CO)(C)C Chemical compound BrC1=CC=C(C=C1)NC(=O)NC(CO)(C)C CRIXOEJNMCGMFU-UHFFFAOYSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 208000010228 Erectile Dysfunction Diseases 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 4
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000007872 degassing Methods 0.000 description 4
- 229910052805 deuterium Inorganic materials 0.000 description 4
- XQTDJCPVBBMKQC-UHFFFAOYSA-N ethyl 3-(4-bromophenyl)-1-[(3-methoxyphenyl)methyl]-2-oxoimidazolidine-4-carboxylate Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1C(=O)OCC)CC1=CC(=CC=C1)OC)=O XQTDJCPVBBMKQC-UHFFFAOYSA-N 0.000 description 4
- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical compound C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 description 4
- 229960002435 fasudil Drugs 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 125000004438 haloalkoxy group Chemical group 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 201000001881 impotence Diseases 0.000 description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000000842 isoxazolyl group Chemical group 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 125000002971 oxazolyl group Chemical group 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000010926 purge Methods 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulphite Substances [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 125000003831 tetrazolyl group Chemical group 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- 125000004306 triazinyl group Chemical group 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- 235000019798 tripotassium phosphate Nutrition 0.000 description 4
- HPNFVYCKGVTLQR-FQEVSTJZSA-N (4S)-1-(5-bromopyridin-2-yl)-3-[(4-fluoro-3-methoxyphenyl)methyl]-4-(phenylmethoxymethyl)imidazolidin-2-one Chemical compound C(C1=CC=CC=C1)OC[C@H]1N(C(N(C1)C1=NC=C(C=C1)Br)=O)CC1=CC(=C(C=C1)F)OC HPNFVYCKGVTLQR-FQEVSTJZSA-N 0.000 description 3
- NUSSSWUWRFNZSF-AWEZNQCLSA-N (4S)-1-(5-bromopyridin-2-yl)-4-(phenylmethoxymethyl)imidazolidin-2-one Chemical compound C(C1=CC=CC=C1)OC[C@H]1NC(N(C1)C1=NC=C(C=C1)Br)=O NUSSSWUWRFNZSF-AWEZNQCLSA-N 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- MCZOJSVFRSKRIT-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[(3-methoxyphenyl)methyl]-4,4-dimethylimidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(C(C1)(C)C)CC1=CC(=CC=C1)OC)=O MCZOJSVFRSKRIT-UHFFFAOYSA-N 0.000 description 3
- NKSKBHOFUFHTQW-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[1-(3-methoxyphenyl)-2-(methylamino)ethyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(CNC)C1=CC(=CC=C1)OC)=O NKSKBHOFUFHTQW-UHFFFAOYSA-N 0.000 description 3
- NDRRAZCFEDJIKV-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[2-hydroxy-1-(3-methoxyphenyl)ethyl]imidazol-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(C=C1)C(CO)C1=CC(=CC=C1)OC)=O NDRRAZCFEDJIKV-UHFFFAOYSA-N 0.000 description 3
- XOAWAEJRZAUCBQ-UHFFFAOYSA-N 1-(4-bromophenyl)-4,4-dimethylimidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(NC(C1)(C)C)=O XOAWAEJRZAUCBQ-UHFFFAOYSA-N 0.000 description 3
- HZGFMAINEPFALC-UHFFFAOYSA-N 1-(5-bromo-4-fluoropyridin-2-yl)-3-(2-chloroethyl)urea Chemical compound BrC=1C(=CC(=NC=1)NC(=O)NCCCl)F HZGFMAINEPFALC-UHFFFAOYSA-N 0.000 description 3
- MLBLLDLHRJCOIB-UHFFFAOYSA-N 1-(5-bromo-4-fluoropyridin-2-yl)imidazolidin-2-one Chemical compound BrC=1C(=CC(=NC=1)N1C(NCC1)=O)F MLBLLDLHRJCOIB-UHFFFAOYSA-N 0.000 description 3
- IFFLMCZOEDRKAW-UHFFFAOYSA-N 1-(5-bromo-4-methoxypyridin-2-yl)-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC=1C(=CC(=NC=1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)OC IFFLMCZOEDRKAW-UHFFFAOYSA-N 0.000 description 3
- NMJLMTJOGLHZFG-UHFFFAOYSA-N 1-(5-bromo-6-methoxypyridin-2-yl)-3-(2-chloroethyl)urea Chemical compound BrC=1C=CC(=NC=1OC)NC(=O)NCCCl NMJLMTJOGLHZFG-UHFFFAOYSA-N 0.000 description 3
- AJVYTJKQVYHHFD-UHFFFAOYSA-N 1-(5-bromo-6-methoxypyridin-2-yl)-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC=1C=CC(=NC=1OC)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O AJVYTJKQVYHHFD-UHFFFAOYSA-N 0.000 description 3
- QXPLHQMBJXUDBM-UHFFFAOYSA-N 1-(5-bromo-6-methoxypyridin-2-yl)imidazolidin-2-one Chemical compound BrC=1C=CC(=NC=1OC)N1C(NCC1)=O QXPLHQMBJXUDBM-UHFFFAOYSA-N 0.000 description 3
- CKPQCRZJUMIZSZ-UHFFFAOYSA-N 1-(5-bromopyridin-2-yl)-3-(2,2-dimethoxyethyl)urea Chemical compound BrC=1C=CC(=NC=1)NC(=O)NCC(OC)OC CKPQCRZJUMIZSZ-UHFFFAOYSA-N 0.000 description 3
- IRPQETWLVOSUFU-AWEZNQCLSA-N 1-(5-bromopyridin-2-yl)-3-[(2S)-1-hydroxy-3-phenylmethoxypropan-2-yl]urea Chemical compound C(C1=CC=CC=C1)OC[C@H](CO)NC(=O)NC1=NC=C(C=C1)Br IRPQETWLVOSUFU-AWEZNQCLSA-N 0.000 description 3
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- NWSPYGGFNRLOII-UHFFFAOYSA-N 2-[3-(4-bromophenyl)-2-oxoimidazolidin-1-yl]-2-(3-methoxyphenyl)-N-methylacetamide Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(C(=O)NC)C1=CC(=CC=C1)OC)=O NWSPYGGFNRLOII-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- LKJYNYKTZLTHJN-UHFFFAOYSA-N 3-cyclopropylaniline Chemical compound NC1=CC=CC(C2CC2)=C1 LKJYNYKTZLTHJN-UHFFFAOYSA-N 0.000 description 3
- TVOJIBGZFYMWDT-UHFFFAOYSA-N 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole Chemical compound O1C(C)(C)C(C)(C)OB1C1=CNN=C1 TVOJIBGZFYMWDT-UHFFFAOYSA-N 0.000 description 3
- IDDDVXIUIXWAGJ-DDSAHXNVSA-N 4-[(1r)-1-aminoethyl]-n-pyridin-4-ylcyclohexane-1-carboxamide;dihydrochloride Chemical compound Cl.Cl.C1CC([C@H](N)C)CCC1C(=O)NC1=CC=NC=C1 IDDDVXIUIXWAGJ-DDSAHXNVSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 206010003225 Arteriospasm coronary Diseases 0.000 description 3
- IXMVSHLVCSJCQJ-CQSZACIVSA-N BrC1=CC=C(C=C1)NC(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)CO Chemical compound BrC1=CC=C(C=C1)NC(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)CO IXMVSHLVCSJCQJ-CQSZACIVSA-N 0.000 description 3
- WNVUVURFLAMTNE-UHFFFAOYSA-N COC=1C=C(C=CC=1)C(C)N1C(N(C=C1)C1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O Chemical compound COC=1C=C(C=CC=1)C(C)N1C(N(C=C1)C1=CC=C(C=C1)B1OC(C(O1)(C)C)(C)C)=O WNVUVURFLAMTNE-UHFFFAOYSA-N 0.000 description 3
- 208000003890 Coronary Vasospasm Diseases 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- 208000010412 Glaucoma Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 101000669921 Homo sapiens Rho-associated protein kinase 2 Proteins 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Substances BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 201000011634 coronary artery vasospasm Diseases 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 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 description 3
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- XXBNIZMWCZGAQO-JTQLQIEISA-N ethyl (2S)-2-[(4-bromophenyl)carbamoylamino]-3-hydroxypropanoate Chemical compound BrC1=CC=C(C=C1)NC(N[C@H](C(=O)OCC)CO)=O XXBNIZMWCZGAQO-JTQLQIEISA-N 0.000 description 3
- GKCXXDSWWDWUHS-BYPYZUCNSA-N ethyl (2s)-2-amino-3-hydroxypropanoate Chemical compound CCOC(=O)[C@@H](N)CO GKCXXDSWWDWUHS-BYPYZUCNSA-N 0.000 description 3
- RNCZPRFKCVSQFD-UHFFFAOYSA-N ethyl 1-(4-bromophenyl)-3-[(3-methoxyphenyl)methyl]-2-oxoimidazolidine-4-carboxylate Chemical compound BrC1=CC=C(C=C1)N1C(N(C(C1)C(=O)OCC)CC1=CC(=CC=C1)OC)=O RNCZPRFKCVSQFD-UHFFFAOYSA-N 0.000 description 3
- FBUCEIBCUAHNFD-UHFFFAOYSA-N ethyl 2-bromo-3-(4-bromoanilino)propanoate Chemical compound BrC(C(=O)OCC)CNC1=CC=C(C=C1)Br FBUCEIBCUAHNFD-UHFFFAOYSA-N 0.000 description 3
- PDFLNJUJXGLBPQ-UHFFFAOYSA-N ethyl 3-[(4-bromophenyl)carbamoyl-[(3-methoxyphenyl)methyl]amino]-2-chloropropanoate Chemical compound BrC1=CC=C(C=C1)NC(N(CC1=CC(=CC=C1)OC)CC(C(=O)OCC)Cl)=O PDFLNJUJXGLBPQ-UHFFFAOYSA-N 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000007306 functionalization reaction Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 208000019622 heart disease Diseases 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 208000001286 intracranial vasospasm Diseases 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 3
- 150000002576 ketones Chemical group 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 3
- PSYWPDSYDAKOJA-UHFFFAOYSA-N methyl 2-[3-(4-bromophenyl)-2-oxoimidazolidin-1-yl]-2-(3-methoxyphenyl)acetate Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(C(=O)OC)C1=CC(=CC=C1)OC)=O PSYWPDSYDAKOJA-UHFFFAOYSA-N 0.000 description 3
- YWMCHHGKDMGQPQ-UHFFFAOYSA-N methyl 2-bromo-2-(3-methoxyphenyl)acetate Chemical compound COC(=O)C(Br)C1=CC=CC(OC)=C1 YWMCHHGKDMGQPQ-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 description 3
- 239000000123 paper Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 3
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- CWPBIJUKARSYKD-UHFFFAOYSA-N tert-butyl N-(4-bromo-3-cyclopropylphenyl)carbamate Chemical compound BrC1=C(C=C(C=C1)NC(OC(C)(C)C)=O)C1CC1 CWPBIJUKARSYKD-UHFFFAOYSA-N 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- AAZCFOYBTCRVEJ-YUMQZZPRSA-N (2S,5S)-2,5-diethylphospholane Chemical compound CC[C@H]1CC[C@H](CC)P1 AAZCFOYBTCRVEJ-YUMQZZPRSA-N 0.000 description 2
- CWRWOJOKTRDGBA-QHCPKHFHSA-N (4S)-3-[(4-fluoro-3-methoxyphenyl)methyl]-4-(phenylmethoxymethyl)-1-[5-(1H-pyrazol-4-yl)pyridin-2-yl]imidazolidin-2-one Chemical compound N1N=CC(=C1)C=1C=CC(=NC=1)N1C(N([C@@H](C1)COCC1=CC=CC=C1)CC1=CC(=C(C=C1)F)OC)=O CWRWOJOKTRDGBA-QHCPKHFHSA-N 0.000 description 2
- KEVZSEIFNDIJIH-INIZCTEOSA-N (5S)-3-(4-bromophenyl)-5-(hydroxymethyl)-1-[(3-methoxyphenyl)methyl]imidazolidine-2,4-dione Chemical compound BrC1=CC=C(C=C1)N1C(N([C@H](C1=O)CO)CC1=CC(=CC=C1)OC)=O KEVZSEIFNDIJIH-INIZCTEOSA-N 0.000 description 2
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 2
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N (trimethylsilyl)diazomethane Substances C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- TZFCICDGDYSTCO-CYBMUJFWSA-N 1-(4-bromophenyl)-1-(2-chloroethyl)-3-[(1R)-1-(3-methoxyphenyl)ethyl]urea Chemical compound BrC1=CC=C(C=C1)N(C(=O)N[C@H](C)C1=CC(=CC=C1)OC)CCCl TZFCICDGDYSTCO-CYBMUJFWSA-N 0.000 description 2
- WEBSBVNASIARDC-UHFFFAOYSA-N 1-(4-bromophenyl)-3-(2-chloroethyl)urea Chemical compound ClCCNC(=O)NC1=CC=C(Br)C=C1 WEBSBVNASIARDC-UHFFFAOYSA-N 0.000 description 2
- RDDYFVDFDWOHSP-UHFFFAOYSA-N 1-(4-bromophenyl)-4-(2-hydroxypropan-2-yl)-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(C(C1)C(C)(C)O)CC1=CC(=CC=C1)OC)=O RDDYFVDFDWOHSP-UHFFFAOYSA-N 0.000 description 2
- UZPHQWVNBDGGCU-UHFFFAOYSA-N 1-(5-bromo-4-methylpyridin-2-yl)-3-(2-chloroethyl)urea Chemical compound BrC=1C(=CC(=NC=1)NC(=O)NCCCl)C UZPHQWVNBDGGCU-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- OOFVDIINTYBOKP-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[2-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC1=CC=CC(CN2CCN(C2=O)C2=C(OC)C=C(C=C2)C2=CNN=C2)=C1 OOFVDIINTYBOKP-UHFFFAOYSA-N 0.000 description 2
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 2
- 125000005955 1H-indazolyl group Chemical group 0.000 description 2
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
- RZELRWJJAXTINL-UHFFFAOYSA-N 2-[3-(4-bromophenyl)-2-oxoimidazolidin-1-yl]-2-(3-methoxyphenyl)-N-methylpropanamide Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(C(=O)NC)(C)C1=CC(=CC=C1)OC)=O RZELRWJJAXTINL-UHFFFAOYSA-N 0.000 description 2
- HBWXWGQFMNTOIZ-UHFFFAOYSA-N 2-[3-(4-bromophenyl)-2-oxoimidazolidin-1-yl]-N-ethyl-2-(3-methoxyphenyl)acetamide Chemical compound CCNC(=O)C(N1CCN(C1=O)C1=CC=C(Br)C=C1)C1=CC(OC)=CC=C1 HBWXWGQFMNTOIZ-UHFFFAOYSA-N 0.000 description 2
- LDVAIJZDACHGML-UHFFFAOYSA-N 2-fluoro-n-methylaniline Chemical compound CNC1=CC=CC=C1F LDVAIJZDACHGML-UHFFFAOYSA-N 0.000 description 2
- HACRKYQRZABURO-UHFFFAOYSA-N 2-phenylethyl isocyanate Chemical compound O=C=NCCC1=CC=CC=C1 HACRKYQRZABURO-UHFFFAOYSA-N 0.000 description 2
- KEVZSEIFNDIJIH-UHFFFAOYSA-N 3-(4-bromophenyl)-5-(hydroxymethyl)-1-[(3-methoxyphenyl)methyl]imidazolidine-2,4-dione Chemical compound BrC1=CC=C(C=C1)N1C(N(C(C1=O)CO)CC1=CC(=CC=C1)OC)=O KEVZSEIFNDIJIH-UHFFFAOYSA-N 0.000 description 2
- XJEJLZQJTWXQAB-UHFFFAOYSA-N 3-(5-bromopyridin-2-yl)-1H-imidazol-2-one Chemical compound BrC=1C=CC(=NC=1)N1C(NC=C1)=O XJEJLZQJTWXQAB-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- WRFYIYOXJWKONR-UHFFFAOYSA-N 4-bromo-2-methoxyaniline Chemical compound COC1=CC(Br)=CC=C1N WRFYIYOXJWKONR-UHFFFAOYSA-N 0.000 description 2
- UVDWSNIVPGNZFL-UHFFFAOYSA-N 4-bromo-3-cyclopropylaniline Chemical compound NC1=CC=C(Br)C(C2CC2)=C1 UVDWSNIVPGNZFL-UHFFFAOYSA-N 0.000 description 2
- RUTNWXBHRAIQSP-UHFFFAOYSA-N 4-bromo-3-methoxyaniline Chemical compound COC1=CC(N)=CC=C1Br RUTNWXBHRAIQSP-UHFFFAOYSA-N 0.000 description 2
- NTZTWGPSRYUWFM-UHFFFAOYSA-N 4-bromo-N-(2-chloroethyl)-3-methoxyaniline Chemical compound BrC1=C(C=C(NCCCl)C=C1)OC NTZTWGPSRYUWFM-UHFFFAOYSA-N 0.000 description 2
- XIXFJFPXOWYEJY-UHFFFAOYSA-N 4-bromo-n-(2-chloroethyl)aniline Chemical compound ClCCNC1=CC=C(Br)C=C1 XIXFJFPXOWYEJY-UHFFFAOYSA-N 0.000 description 2
- ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical class OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 description 2
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- UMYTZPUJKKRUDX-CYBMUJFWSA-N BrC1=CC=C(C=C1)N1C(N[C@H](C1)CO[Si](C)(C)C(C)(C)C)=O Chemical compound BrC1=CC=C(C=C1)N1C(N[C@H](C1)CO[Si](C)(C)C(C)(C)C)=O UMYTZPUJKKRUDX-CYBMUJFWSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- 201000000057 Coronary Stenosis Diseases 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- 238000010640 amide synthesis reaction Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 2
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 125000004452 carbocyclyl group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 230000035874 hyperreactivity Effects 0.000 description 2
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- YDNLNVZZTACNJX-UHFFFAOYSA-N isocyanatomethylbenzene Chemical compound O=C=NCC1=CC=CC=C1 YDNLNVZZTACNJX-UHFFFAOYSA-N 0.000 description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 2
- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- IBIKHMZPHNKTHM-RDTXWAMCSA-N merck compound 25 Chemical compound C1C[C@@H](C(O)=O)[C@H](O)CN1C(C1=C(F)C=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C1CC1 IBIKHMZPHNKTHM-RDTXWAMCSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000008692 neointimal formation Effects 0.000 description 2
- LYRFLYHAGKPMFH-UHFFFAOYSA-N octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(N)=O LYRFLYHAGKPMFH-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000003182 parenteral nutrition solution Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 238000009117 preventive therapy Methods 0.000 description 2
- 230000009862 primary prevention Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 230000009863 secondary prevention Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 230000016160 smooth muscle contraction Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 150000003413 spiro compounds Chemical class 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- NSNJTAGQKCBELZ-UHFFFAOYSA-N tert-butyl 4-[4-[5-(hydroxymethyl)-3-[(3-methoxyphenyl)methyl]-2-oxoimidazolidin-1-yl]phenyl]pyrazole-1-carboxylate Chemical compound OCC1CN(C(N1C1=CC=C(C=C1)C=1C=NN(C=1)C(=O)OC(C)(C)C)=O)CC1=CC(=CC=C1)OC NSNJTAGQKCBELZ-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- XFQNWPYGEGCIMF-HCUGAJCMSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].[Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 XFQNWPYGEGCIMF-HCUGAJCMSA-N 0.000 description 1
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical group NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- BJWHQBTUHVIRJJ-PPHPATTJSA-N (2s)-2-amino-3-phenylmethoxypropan-1-ol;hydrochloride Chemical compound Cl.OC[C@H](N)COCC1=CC=CC=C1 BJWHQBTUHVIRJJ-PPHPATTJSA-N 0.000 description 1
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical group NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 1
- CUKWUWBLQQDQAC-VEQWQPCFSA-N (3s)-3-amino-4-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s,3s)-1-[[(2s)-1-[(2s)-2-[[(1s)-1-carboxyethyl]carbamoyl]pyrrolidin-1-yl]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-methyl-1-ox Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 CUKWUWBLQQDQAC-VEQWQPCFSA-N 0.000 description 1
- SQBOSZXDOHQFAA-SEVDZJIVSA-N (4r,5r,6r,7r)-1,3-dibenzyl-5,6-dihydroxy-4,7-bis(phenoxymethyl)-1,3-diazepan-2-one Chemical compound C([C@@H]1[C@@H](O)[C@@H]([C@H](N(CC=2C=CC=CC=2)C(=O)N1CC=1C=CC=CC=1)COC=1C=CC=CC=1)O)OC1=CC=CC=C1 SQBOSZXDOHQFAA-SEVDZJIVSA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- NCWDBNBNYVVARF-UHFFFAOYSA-N 1,3,2-dioxaborolane Chemical compound B1OCCO1 NCWDBNBNYVVARF-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 1
- YGBWEVLCLQXBKI-UHFFFAOYSA-N 1-(1-bromoethyl)-3-methoxybenzene Chemical compound COC1=CC=CC(C(C)Br)=C1 YGBWEVLCLQXBKI-UHFFFAOYSA-N 0.000 description 1
- UIIJKBSUGZNVQN-UHFFFAOYSA-N 1-(2-bromoethyl)-2-methoxybenzene Chemical compound COC1=CC=CC=C1CCBr UIIJKBSUGZNVQN-UHFFFAOYSA-N 0.000 description 1
- DGGRDUPQQAZJQY-UHFFFAOYSA-N 1-(4-bromo-2-methoxyphenyl)-1-(2-chloroethyl)-3-[(3-fluorophenyl)methyl]urea Chemical compound BrC1=CC(=C(C=C1)N(C(=O)NCC1=CC(=CC=C1)F)CCCl)OC DGGRDUPQQAZJQY-UHFFFAOYSA-N 0.000 description 1
- NNNYSDGVSDTRHQ-UHFFFAOYSA-N 1-(4-bromo-2-methoxyphenyl)-3-[(3-fluorophenyl)methyl]imidazolidin-2-one Chemical compound BrC1=CC(=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)F)=O)OC NNNYSDGVSDTRHQ-UHFFFAOYSA-N 0.000 description 1
- ZFRQKSSARXFRCG-UHFFFAOYSA-N 1-(4-bromo-3-ethylphenyl)-1-(2-chloroethyl)-3-[(3-methoxyphenyl)methyl]urea Chemical compound BrC1=C(C=C(C=C1)N(C(=O)NCC1=CC(=CC=C1)OC)CCCl)CC ZFRQKSSARXFRCG-UHFFFAOYSA-N 0.000 description 1
- AEQLCUFHTKMUCJ-UHFFFAOYSA-N 1-(4-bromo-3-ethylphenyl)-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O)CC AEQLCUFHTKMUCJ-UHFFFAOYSA-N 0.000 description 1
- RXXLOHMFXXJWHV-CYBMUJFWSA-N 1-(4-bromo-3-methoxyphenyl)-1-(2-chloroethyl)-3-[(1R)-1-(3-methoxyphenyl)ethyl]urea Chemical compound BrC1=C(C=C(C=C1)N(C(=O)N[C@H](C)C1=CC(=CC=C1)OC)CCCl)OC RXXLOHMFXXJWHV-CYBMUJFWSA-N 0.000 description 1
- BFXUJCLRNMNMDW-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)-1-(2-chloroethyl)-3-[(2-fluoro-5-methoxyphenyl)methyl]urea Chemical compound BrC1=C(C=C(C=C1)N(C(=O)NCC1=C(C=CC(=C1)OC)F)CCCl)OC BFXUJCLRNMNMDW-UHFFFAOYSA-N 0.000 description 1
- IZPRJISEQYKMHD-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)-1-(2-chloroethyl)-3-[(3-fluorophenyl)methyl]urea Chemical compound BrC1=C(C=C(C=C1)N(C(=O)NCC1=CC(=CC=C1)F)CCCl)OC IZPRJISEQYKMHD-UHFFFAOYSA-N 0.000 description 1
- TYPKFBQSXUKNHA-CYBMUJFWSA-N 1-(4-bromo-3-methoxyphenyl)-3-[(1R)-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O)OC TYPKFBQSXUKNHA-CYBMUJFWSA-N 0.000 description 1
- XSVLKZQXPUILGI-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)-3-[(2-fluoro-5-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)CC1=C(C=CC(=C1)OC)F)=O)OC XSVLKZQXPUILGI-UHFFFAOYSA-N 0.000 description 1
- OUGWHKSVLQVDCC-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)-3-[3-hydroxy-1-(3-methoxyphenyl)-3-methylbutyl]imidazolidin-2-one Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)C(CC(C)(C)O)C1=CC(=CC=C1)OC)=O)OC OUGWHKSVLQVDCC-UHFFFAOYSA-N 0.000 description 1
- OOUCBNBSUFSKRS-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)-3-[3-hydroxy-1-(3-methoxyphenyl)propyl]imidazolidin-2-one Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)C(CCO)C1=CC(=CC=C1)OC)=O)OC OOUCBNBSUFSKRS-UHFFFAOYSA-N 0.000 description 1
- PFKFBFMSSQETNP-UHFFFAOYSA-N 1-(4-bromo-3-methoxyphenyl)imidazolidine-2,4-dione Chemical compound C1=C(Br)C(OC)=CC(N2C(NC(=O)C2)=O)=C1 PFKFBFMSSQETNP-UHFFFAOYSA-N 0.000 description 1
- ZAJXQINKXUAWJJ-UHFFFAOYSA-N 1-(4-bromophenyl)-1-(2-chloroethyl)-3-(2-phenylethyl)urea Chemical compound BrC1=CC=C(C=C1)N(C(=O)NCCC1=CC=CC=C1)CCCl ZAJXQINKXUAWJJ-UHFFFAOYSA-N 0.000 description 1
- PWNKYCIDSZTIOF-UHFFFAOYSA-N 1-(4-bromophenyl)-3-(2-phenylethyl)imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)CCC1=CC=CC=C1)=O PWNKYCIDSZTIOF-UHFFFAOYSA-N 0.000 description 1
- PVYONXVJSUIHAF-CYBMUJFWSA-N 1-(4-bromophenyl)-3-[(1R)-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)[C@H](C)C1=CC(=CC=C1)OC)=O PVYONXVJSUIHAF-CYBMUJFWSA-N 0.000 description 1
- PXKIBFIJNCCZEX-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[(2-fluoro-3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)CC1=C(C(=CC=C1)OC)F)=O PXKIBFIJNCCZEX-UHFFFAOYSA-N 0.000 description 1
- WRXPWZKUFYCYKU-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[(3-methoxyphenyl)methyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)CC1=CC(=CC=C1)OC)=O WRXPWZKUFYCYKU-UHFFFAOYSA-N 0.000 description 1
- ZZKPVYCYRCLTTI-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[1-hydroxy-2-(3-methoxyphenyl)propan-2-yl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(CO)(C)C1=CC(=CC=C1)OC)=O ZZKPVYCYRCLTTI-UHFFFAOYSA-N 0.000 description 1
- QMJUROHCICDVFF-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[2-(2-methoxyphenyl)ethyl]imidazol-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(C=C1)CCC1=C(C=CC=C1)OC)=O QMJUROHCICDVFF-UHFFFAOYSA-N 0.000 description 1
- WGZLOQZMQMXWOJ-UHFFFAOYSA-N 1-(4-bromophenyl)-3-[2-methoxy-1-(3-methoxyphenyl)ethyl]imidazolidin-2-one Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(COC)C1=CC(=CC=C1)OC)=O WGZLOQZMQMXWOJ-UHFFFAOYSA-N 0.000 description 1
- AFJSFTQVPPXCRQ-UHFFFAOYSA-N 1-(bromomethyl)-2-fluoro-3-methoxybenzene Chemical compound COC1=CC=CC(CBr)=C1F AFJSFTQVPPXCRQ-UHFFFAOYSA-N 0.000 description 1
- SCBZBMXPJYMXRC-UHFFFAOYSA-N 1-(bromomethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(CBr)=C1 SCBZBMXPJYMXRC-UHFFFAOYSA-N 0.000 description 1
- FRAKDSWLOARUNH-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=C1)N1CCN(CC2=C(F)C=CC=C2)C1=O)C1=CNN=C1 FRAKDSWLOARUNH-UHFFFAOYSA-N 0.000 description 1
- WGEUAXKQYVSRHY-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=C1)N1CCN(CC2=CC(F)=CC=C2)C1=O)C1=CNN=C1 WGEUAXKQYVSRHY-UHFFFAOYSA-N 0.000 description 1
- RKCCODFZRAFCMG-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC1=CC=CC(CN2CCN(C2=O)C2=CC(OC)=C(C=C2)C2=CNN=C2)=C1 RKCCODFZRAFCMG-UHFFFAOYSA-N 0.000 description 1
- BMEJPAZHWTWBKT-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-3-[4-(1H-pyrazol-4-yl)phenyl]imidazolidine-2,4-dione Chemical compound N1N=CC(=C1)C1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC(=CC=C1)OC)=O BMEJPAZHWTWBKT-UHFFFAOYSA-N 0.000 description 1
- BNAOBLINABTTSO-UHFFFAOYSA-N 1-benzyl-3-(4-bromophenyl)-4-(hydroxymethyl)imidazolidin-2-one Chemical compound C(C1=CC=CC=C1)N1C(N(C(C1)CO)C1=CC=C(C=C1)Br)=O BNAOBLINABTTSO-UHFFFAOYSA-N 0.000 description 1
- LPXPDXVUMPDTEP-UHFFFAOYSA-N 1-benzyl-3-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound COC1=C(C=CC(=C1)N1CCN(CC2=CC=CC=C2)C1=O)C1=CNN=C1 LPXPDXVUMPDTEP-UHFFFAOYSA-N 0.000 description 1
- URHPTYWRULWLGI-UHFFFAOYSA-N 1-bromo-2,4-diisocyanatobenzene Chemical compound BrC1=CC=C(N=C=O)C=C1N=C=O URHPTYWRULWLGI-UHFFFAOYSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- FDCHHLBMDMJXGM-UHFFFAOYSA-N 1-fluoro-4-(2-isocyanatoethyl)benzene Chemical compound FC1=CC=C(CCN=C=O)C=C1 FDCHHLBMDMJXGM-UHFFFAOYSA-N 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- FYRGAOZTXCHMGK-UHFFFAOYSA-N 2,6-difluoro-n-methylaniline Chemical group CNC1=C(F)C=CC=C1F FYRGAOZTXCHMGK-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- 125000005273 2-acetoxybenzoic acid group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- PCLMNCBIXQQRMB-UHFFFAOYSA-N 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NC(F)=C1 PCLMNCBIXQQRMB-UHFFFAOYSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 1
- VSCBATMPTLKTOV-UHFFFAOYSA-N 2-tert-butylimino-n,n-diethyl-1,3-dimethyl-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C VSCBATMPTLKTOV-UHFFFAOYSA-N 0.000 description 1
- CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- LRSUMZGSORKIJR-UHFFFAOYSA-N 3-(4-bromophenyl)-1-[(3-methoxyphenyl)methyl]imidazolidine-2,4-dione Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1=O)CC1=CC(=CC=C1)OC)=O LRSUMZGSORKIJR-UHFFFAOYSA-N 0.000 description 1
- FPFDMHRKTCRRBC-UHFFFAOYSA-N 3-(4-bromophenyl)imidazolidine-2,4-dione Chemical compound C1=CC(Br)=CC=C1N1C(=O)NCC1=O FPFDMHRKTCRRBC-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- OWOQDSHISJTONB-UHFFFAOYSA-N 3-[3-(4-bromo-3-methoxyphenyl)-2-oxoimidazolidin-1-yl]-3-(3-methoxyphenyl)propanoic acid Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)C(CC(=O)O)C1=CC(=CC=C1)OC)=O)OC OWOQDSHISJTONB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- BNXVBSPMYKOITQ-UHFFFAOYSA-N 3-benzyl-1-(4-bromo-3-methoxyphenyl)imidazolidine-2,4-dione Chemical compound C(C1=CC=CC=C1)N1C(N(CC1=O)C1=CC(=C(C=C1)Br)OC)=O BNXVBSPMYKOITQ-UHFFFAOYSA-N 0.000 description 1
- NDWIDQDXARXUKA-UHFFFAOYSA-N 3-benzyl-4-(hydroxymethyl)-1-[3-methoxy-4-(1H-pyrazol-4-yl)phenyl]imidazolidin-2-one Chemical compound C(C1=CC=CC=C1)N1C(N(CC1CO)C1=CC(=C(C=C1)C=1C=NNC=1)OC)=O NDWIDQDXARXUKA-UHFFFAOYSA-N 0.000 description 1
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- MLFGHAHGSVFKMI-UHFFFAOYSA-N 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=NC=C1F MLFGHAHGSVFKMI-UHFFFAOYSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- XRLJROQMXLOJFO-UHFFFAOYSA-N 4-(bromomethyl)-1-fluoro-2-methoxybenzene Chemical compound COC1=CC(CBr)=CC=C1F XRLJROQMXLOJFO-UHFFFAOYSA-N 0.000 description 1
- KWQNNOZROOJVJB-UHFFFAOYSA-N 4-bromo-3-ethylaniline Chemical compound CCC1=CC(N)=CC=C1Br KWQNNOZROOJVJB-UHFFFAOYSA-N 0.000 description 1
- MAQAEXGARJHNTD-UHFFFAOYSA-N 4-bromo-N-(2-chloroethyl)-2-methoxyaniline Chemical compound BrC1=CC(=C(NCCCl)C=C1)OC MAQAEXGARJHNTD-UHFFFAOYSA-N 0.000 description 1
- VXOFSWLIUSBFDH-UHFFFAOYSA-N 4-bromo-N-(2-chloroethyl)-3-ethylaniline Chemical compound BrC1=C(C=C(NCCCl)C=C1)CC VXOFSWLIUSBFDH-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-IDEBNGHGSA-N 4-bromoaniline Chemical group N[13C]1=[13CH][13CH]=[13C](Br)[13CH]=[13CH]1 WDFQBORIUYODSI-IDEBNGHGSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- RQMWVVBHJMUJNZ-UHFFFAOYSA-N 4-chloropyridin-2-amine Chemical compound NC1=CC(Cl)=CC=N1 RQMWVVBHJMUJNZ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003119 4-methyl-3-pentenyl group Chemical group [H]\C(=C(/C([H])([H])[H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001054 5 membered carbocyclic group Chemical group 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- FLDSMVTWEZKONL-AWEZNQCLSA-N 5,5-dimethyl-N-[(3S)-5-methyl-4-oxo-2,3-dihydro-1,5-benzoxazepin-3-yl]-1,4,7,8-tetrahydrooxepino[4,5-c]pyrazole-3-carboxamide Chemical compound CC1(CC2=C(NN=C2C(=O)N[C@@H]2C(N(C3=C(OC2)C=CC=C3)C)=O)CCO1)C FLDSMVTWEZKONL-AWEZNQCLSA-N 0.000 description 1
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 description 1
- GGHBRLQYBZMEPV-UHFFFAOYSA-N 5-bromo-4-fluoropyridin-2-amine Chemical compound NC1=CC(F)=C(Br)C=N1 GGHBRLQYBZMEPV-UHFFFAOYSA-N 0.000 description 1
- JDNCMHOKWINDKI-UHFFFAOYSA-N 5-bromo-4-methylpyridin-2-amine Chemical compound CC1=CC(N)=NC=C1Br JDNCMHOKWINDKI-UHFFFAOYSA-N 0.000 description 1
- STTFWVSVDMLUCF-UHFFFAOYSA-N 5-bromo-6-methoxypyridin-2-amine Chemical compound COC1=NC(N)=CC=C1Br STTFWVSVDMLUCF-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- 125000004008 6 membered carbocyclic group Chemical group 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 102100023818 ADP-ribosylation factor 3 Human genes 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 229910015844 BCl3 Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- KAEYSBNPPDKJSI-OAQYLSRUSA-N BrC1=CC=C(C=C1)N1C(N([C@H](C1)CO[Si](C)(C)C(C)(C)C)CC1=CC(=CC=C1)OC)=O Chemical compound BrC1=CC=C(C=C1)N1C(N([C@H](C1)CO[Si](C)(C)C(C)(C)C)CC1=CC(=CC=C1)OC)=O KAEYSBNPPDKJSI-OAQYLSRUSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- VUWBMXNMKRWSEI-UHFFFAOYSA-N C1(CCCCC1)P(C1=C(C=CC=C1)C1=C(C=C(C=C1C(C)C)C(C)C)C(C)C)C1CCCCC1.[Cl] Chemical group C1(CCCCC1)P(C1=C(C=CC=C1)C1=C(C=C(C=C1C(C)C)C(C)C)C(C)C)C1CCCCC1.[Cl] VUWBMXNMKRWSEI-UHFFFAOYSA-N 0.000 description 1
- ZCRFNXVZYIQDHL-UHFFFAOYSA-N C1=CC=C2CO[IH]C2=C1 Chemical compound C1=CC=C2CO[IH]C2=C1 ZCRFNXVZYIQDHL-UHFFFAOYSA-N 0.000 description 1
- VNBXBHYGOAGGOG-UHFFFAOYSA-N COC=1C=C(CN2C(N(C=C2)C2=CC=C(C=C2)B2OC(C(O2)(C)C)(C)C)=O)C=CC=1 Chemical compound COC=1C=C(CN2C(N(C=C2)C2=CC=C(C=C2)B2OC(C(O2)(C)C)(C)C)=O)C=CC=1 VNBXBHYGOAGGOG-UHFFFAOYSA-N 0.000 description 1
- BNQQJIRZGZUKEJ-UHFFFAOYSA-N COC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)B2OC(C(O2)(C)C)(C)C)=O)C=CC=1 Chemical compound COC=1C=C(CN2C(N(CC2)C2=CC=C(C=C2)B2OC(C(O2)(C)C)(C)C)=O)C=CC=1 BNQQJIRZGZUKEJ-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Substances CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 101100022323 Drosophila melanogaster Marf gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 101000684275 Homo sapiens ADP-ribosylation factor 3 Proteins 0.000 description 1
- 101001000061 Homo sapiens Protein phosphatase 1 regulatory subunit 12A Proteins 0.000 description 1
- 101001130437 Homo sapiens Ras-related protein Rap-2b Proteins 0.000 description 1
- 101000669917 Homo sapiens Rho-associated protein kinase 1 Proteins 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920001410 Microfiber Polymers 0.000 description 1
- 108010037801 Myosin-Light-Chain Phosphatase Proteins 0.000 description 1
- 102000011131 Myosin-Light-Chain Phosphatase Human genes 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 229910003204 NH2 Inorganic materials 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 1
- 102100036547 Protein phosphatase 1 regulatory subunit 12A Human genes 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000002200 Respiratory Hypersensitivity Diseases 0.000 description 1
- 102100039313 Rho-associated protein kinase 1 Human genes 0.000 description 1
- 102100027609 Rho-related GTP-binding protein RhoD Human genes 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000050488 Urotensin II Human genes 0.000 description 1
- 108010018369 Urotensin II Proteins 0.000 description 1
- 206010047295 Ventricular hypertrophy Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- WGOBPPNNYVSJTE-HSZRJFAPSA-N [(2r)-1-diphenylphosphanylpropan-2-yl]-diphenylphosphane Chemical compound C([C@@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)C1=CC=CC=C1 WGOBPPNNYVSJTE-HSZRJFAPSA-N 0.000 description 1
- CKUAXEQHGKSLHN-UHFFFAOYSA-N [C].[N] Chemical group [C].[N] CKUAXEQHGKSLHN-UHFFFAOYSA-N 0.000 description 1
- HMHFSBLPBQMMCO-UHFFFAOYSA-N [Rh].C1=CCCC=CCC1.C1=CC=CC=C1 Chemical compound [Rh].C1=CCCC=CCC1.C1=CC=CC=C1 HMHFSBLPBQMMCO-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 208000037883 airway inflammation Diseases 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- FCDPQMAOJARMTG-UHFFFAOYSA-L benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphane Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-L 0.000 description 1
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 239000011111 cardboard Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- ARQRPTNYUOLOGH-UHFFFAOYSA-N chcl3 chloroform Chemical compound ClC(Cl)Cl.ClC(Cl)Cl ARQRPTNYUOLOGH-UHFFFAOYSA-N 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000035605 chemotaxis Effects 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(II) acetate Substances [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- XSYZCZPCBXYQTE-UHFFFAOYSA-N cyclodecylcyclodecane Chemical compound C1CCCCCCCCC1C1CCCCCCCCC1 XSYZCZPCBXYQTE-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 230000021953 cytokinesis Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 229960004486 desoxycorticosterone acetate Drugs 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- MUJOVVKDDICVMS-UHFFFAOYSA-N diazaphosphinine Chemical compound C1=CN=NP=C1 MUJOVVKDDICVMS-UHFFFAOYSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 102000038379 digestive enzymes Human genes 0.000 description 1
- 108091007734 digestive enzymes Proteins 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- DYTUEMCDMKQUGA-UHFFFAOYSA-N ethyl 1-(4-bromophenyl)-3-[(3-fluorophenyl)methyl]-2-oxoimidazolidine-4-carboxylate Chemical compound BrC1=CC=C(C=C1)N1C(N(C(C1)C(=O)OCC)CC1=CC(=CC=C1)F)=O DYTUEMCDMKQUGA-UHFFFAOYSA-N 0.000 description 1
- JWTXPITXBAPBLU-UHFFFAOYSA-N ethyl 1-[(3-methoxyphenyl)methyl]aziridine-2-carboxylate Chemical compound COC=1C=C(CN2C(C2)C(=O)OCC)C=CC=1 JWTXPITXBAPBLU-UHFFFAOYSA-N 0.000 description 1
- QEULPJZBADJNAU-UHFFFAOYSA-N ethyl 1-benzyl-3-(4-bromophenyl)-2-oxoimidazolidine-4-carboxylate Chemical compound C(C1=CC=CC=C1)N1C(N(C(C1)C(=O)OCC)C1=CC=C(C=C1)Br)=O QEULPJZBADJNAU-UHFFFAOYSA-N 0.000 description 1
- KTCGWJMDEAMXBP-UHFFFAOYSA-N ethyl 2-(4-bromo-3-methoxyanilino)acetate Chemical compound CCOC(=O)CNC1=CC=C(Br)C(OC)=C1 KTCGWJMDEAMXBP-UHFFFAOYSA-N 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- HFIJJDZJYSFOIM-UHFFFAOYSA-N ethyl 2-chloro-3-[(3-fluorophenyl)methylamino]propanoate Chemical compound ClC(C(=O)OCC)CNCC1=CC(=CC=C1)F HFIJJDZJYSFOIM-UHFFFAOYSA-N 0.000 description 1
- WAFOXBLHEIRCAP-UHFFFAOYSA-N ethyl 2-chloro-3-[(3-methoxyphenyl)methylamino]propanoate Chemical compound ClC(C(=O)OCC)CNCC1=CC(=CC=C1)OC WAFOXBLHEIRCAP-UHFFFAOYSA-N 0.000 description 1
- AMLWQSYZUFWMJI-UHFFFAOYSA-N ethyl 3-(benzylamino)-2-chloropropanoate Chemical compound C(C1=CC=CC=C1)NCC(C(=O)OCC)Cl AMLWQSYZUFWMJI-UHFFFAOYSA-N 0.000 description 1
- OJGRWMKNEOUTSP-UHFFFAOYSA-N ethyl 3-[(4-bromophenyl)carbamoyl-[(3-fluorophenyl)methyl]amino]-2-chloropropanoate Chemical compound BrC1=CC=C(C=C1)NC(N(CC1=CC(=CC=C1)F)CC(C(=O)OCC)Cl)=O OJGRWMKNEOUTSP-UHFFFAOYSA-N 0.000 description 1
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000004047 hyperresponsiveness Effects 0.000 description 1
- 238000013299 hypertensive rat model Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- PVPRFDHZRBRHAN-UHFFFAOYSA-N methyl 2-[3-(4-bromophenyl)-2-oxoimidazolidin-1-yl]-2-(3-methoxyphenyl)propanoate Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1)C(C(=O)OC)(C)C1=CC(=CC=C1)OC)=O PVPRFDHZRBRHAN-UHFFFAOYSA-N 0.000 description 1
- TYYPCXSXKVPRQJ-UHFFFAOYSA-N methyl 3-(4-bromophenyl)-1-[(3-fluorophenyl)methyl]-2-oxoimidazolidine-4-carboxylate Chemical compound BrC1=CC=C(C=C1)N1C(N(CC1C(=O)OC)CC1=CC(=CC=C1)F)=O TYYPCXSXKVPRQJ-UHFFFAOYSA-N 0.000 description 1
- SCQXGTAVEQAZKX-UHFFFAOYSA-N methyl 3-[3-(4-bromo-3-methoxyphenyl)-2-oxoimidazolidin-1-yl]-3-(3-methoxyphenyl)propanoate Chemical compound BrC1=C(C=C(C=C1)N1C(N(CC1)C(CC(=O)OC)C1=CC(=CC=C1)OC)=O)OC SCQXGTAVEQAZKX-UHFFFAOYSA-N 0.000 description 1
- NZHBIDSURCFQBE-UHFFFAOYSA-N methyl 3-[[(4-bromo-3-methoxyphenyl)-(2-chloroethyl)carbamoyl]amino]-3-(3-methoxyphenyl)propanoate Chemical compound BrC1=C(C=C(C=C1)N(C(NC(CC(=O)OC)C1=CC(=CC=C1)OC)=O)CCCl)OC NZHBIDSURCFQBE-UHFFFAOYSA-N 0.000 description 1
- DOYKYXMRPXMHLZ-UHFFFAOYSA-N methyl 3-amino-3-(3-methoxyphenyl)propanoate Chemical group COC(=O)CC(N)C1=CC=CC(OC)=C1 DOYKYXMRPXMHLZ-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 239000003658 microfiber Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- RCSBCWXPGSPJNF-UHFFFAOYSA-N n-[4-[5-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3,4-oxadiazol-2-yl]butyl]-4-(1,8-naphthyridin-2-yl)butanamide Chemical compound C1=C(Cl)C(OC(F)(F)F)=CC=C1C(O1)=NN=C1CCCCNC(=O)CCCC1=CC=C(C=CC=N2)C2=N1 RCSBCWXPGSPJNF-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000007971 neurological deficit Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 125000005327 perimidinyl group Chemical group N1C(=NC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 208000030613 peripheral artery disease Diseases 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- XNQULTQRGBXLIA-UHFFFAOYSA-O phosphonic anhydride Chemical compound O[P+](O)=O XNQULTQRGBXLIA-UHFFFAOYSA-O 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 125000004585 polycyclic heterocycle group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012041 precatalyst Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 239000011674 pyridoxal Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 229940037312 stearamide Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YQRMLCCOGRDYLW-UHFFFAOYSA-N tert-butyl 4-[2-methoxy-4-[3-[3-methoxy-1-(3-methoxyphenyl)-3-oxopropyl]-2-oxoimidazolidin-1-yl]phenyl]pyrazole-1-carboxylate Chemical compound COC1=C(C=CC(=C1)N1C(N(CC1)C(CC(=O)OC)C1=CC(=CC=C1)OC)=O)C=1C=NN(C=1)C(=O)OC(C)(C)C YQRMLCCOGRDYLW-UHFFFAOYSA-N 0.000 description 1
- BFRDYMOJBOOXNG-UHFFFAOYSA-N tert-butyl 4-[4-(3-benzyl-5-ethoxycarbonyl-2-oxoimidazolidin-1-yl)phenyl]pyrazole-1-carboxylate Chemical compound C(C1=CC=CC=C1)N1C(N(C(C1)C(=O)OCC)C1=CC=C(C=C1)C=1C=NN(C=1)C(=O)OC(C)(C)C)=O BFRDYMOJBOOXNG-UHFFFAOYSA-N 0.000 description 1
- SIJXZJOHGFLPSZ-UHFFFAOYSA-N tert-butyl 4-[4-[4-ethoxycarbonyl-3-[(3-methoxyphenyl)methyl]-2-oxoimidazolidin-1-yl]phenyl]pyrazole-1-carboxylate Chemical compound C(C)OC(=O)C1N(C(N(C1)C1=CC=C(C=C1)C=1C=NN(C=1)C(=O)OC(C)(C)C)=O)CC1=CC(=CC=C1)OC SIJXZJOHGFLPSZ-UHFFFAOYSA-N 0.000 description 1
- KIGIRYPHYKALIK-UHFFFAOYSA-N tert-butyl N-(3-cyclopropylphenyl)carbamate Chemical compound C1(CC1)C=1C=C(C=CC=1)NC(OC(C)(C)C)=O KIGIRYPHYKALIK-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000005403 thiohaloalkoxy group Chemical group 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- NZUGDUYQNJZGFJ-UHFFFAOYSA-N trichloromethyl N-(4-bromo-3-methoxyphenyl)-N-(2-chloroethyl)carbamate Chemical compound BrC1=C(C=C(C=C1)N(C(OC(Cl)(Cl)Cl)=O)CCCl)OC NZUGDUYQNJZGFJ-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- HYUFXBPAIGJHRY-UHFFFAOYSA-N triphenylphosphane;dihydrochloride Chemical compound Cl.Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 HYUFXBPAIGJHRY-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- HFNHAPQMXICKCF-USJMABIRSA-N urotensin-ii Chemical compound N([C@@H](CC(O)=O)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@@H](C(C)C)C(O)=O)C(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)[C@@H](N)CCC(O)=O)[C@@H](C)O HFNHAPQMXICKCF-USJMABIRSA-N 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
本发明提供了式(I)化合物或其立体异构体、互变异构体或药学上可接受的盐,其中所有变量如本文中所定义。这些化合物为选择性ROCK抑制剂。本发明也涉及包含这些化合物的药物组合物及使用其治疗心血管、平滑肌、肿瘤学、神经病理学、自身免疫、纤维变性和/或炎性病症的方法。
Description
相关申请的交叉引用
本申请依照35 U.S.C. §119(e)有权主张2015年1月9日申请的美国临时专利申请号62/101,434的优先权,所述美国临时专利申请以其整体通过引用并入本文。
发明领域
本发明涉及新颖的环状脲衍生物、含有它们的组合物以及使用它们例如用于治疗或预防与异常Rho激酶活性相关的病症的方法。
发明背景
Rho-激酶(ROCK)是丝氨酸-苏氨酸蛋白激酶家族的成员。ROCK以两种亚型(ROCK1和ROCK2)存在(Ishizaki,T.等人,EMBO J.,15:1885-1893 (1996))。ROCK已鉴定为RhoA的效应物分子,其是在多种细胞信号传导途径中起关键作用的小GTP结合蛋白(G蛋白)。ROCK和RhoA广泛表达于组织中。RhoA/ROCK信号传导途径参与多种细胞功能,诸如ACTIN®组织、细胞粘附、细胞迁移和胞质分裂(Riento,K.等人,Nat. Rev. Mol. Cell Biol.,4:446-456(2003))。其也直接参与调控平滑肌收缩(Somlyo,A.P.,Nature,389:908-911 (1997))。在活化RhoA受体后,RhoA被活化,且进而,其活化ROCK。活化的ROCK磷酸化肌球蛋白轻链磷酸酯酶的肌球蛋白结合亚单位,从而抑制磷酸酯酶的活性并导致收缩。脉管系统中的平滑肌收缩使血压升高,从而导致高血压。
文献中有大量证据证明Rho A/ROCK信号传导途径在由例如以下的若干血管活性因子起始的信号转导中起重要作用:血管紧张素II (Yamakawa,T.等人,Hypertension,35:313-318 (2000))、尾加压素II (Sauzeau,V.等人,Circ. Res.,88:1102-1104 (2001))、内皮素-1 (Tangkijvanich,P.等人,Hepatology,33:74-80 (2001))、血清素 (Shimokawa,H.,Jpn. Circ. J.,64:1-12 (2000))、去甲肾上腺素(Martinez,M.C.等人,Am. J. Physiol.,279:H1228-H1238 (2000))和血小板衍生生长因子(PDGF) (Kishi,H.等人,J. Biochem.,128:719-722 (2000))。这些因子中许多与心血管疾病的发病机制相关。
文献中的其它研究(一些使用已知的ROCK抑制剂法舒地尔(Asano,T.等人,J. Pharmacol. Exp. Ther.,241:1033-1040 (1987))或Y-27632 (Uehata,M.等人,Nature,389:990-994 (1997)))进一步阐释ROCK和心血管疾病之间的关联。例如,已显示ROCK表达和活性在自发性高血压大鼠中升高,表明其与这些动物中高血压的发生的关联(Mukai,Y.等人,FASEB J.,15:1062-1064 (2001))。显示ROCK抑制剂Y-27632 (Uehata,M.等人,Nature,ibid.)可使三种大鼠高血压模型(包括自发性高血压大鼠模型、肾性高血压大鼠模型和醋酸脱氧皮质酮盐型高血压大鼠模型(deoxycortisone acetate salt hypertensiverat model))中的血压显著降低,而对对照大鼠中的血压仅具有较小效应。这增强ROCK与高血压之间的关联。
其它研究表明ROCK和动脉粥样硬化之间的关联。例如,ROCK的显性负性形式的基因转移抑制猪股动脉中的球囊损伤后新生内膜的形成(Eto,Y.等人,Am. J. Physiol. Heart Circ. Physiol.,278:H1744-H1750 (2000))。在类似模型中,ROCK抑制剂Y-27632也抑制大鼠中的新生内膜形成(Sawada,N.等人,Circulation,101:2030-2033 (2000))。在猪的IL-1β诱导的冠状动脉狭窄模型中,显示用ROCK抑制剂法舒地尔长期治疗渐进地减少冠状动脉狭窄,以及促进冠状动脉收缩性重塑的消退(Shimokawa, H.等人, Cardiovasc. Res., 51:169-177 (2001))。
其它调查表明ROCK抑制剂可用于治疗其它心血管疾病。例如,在大鼠中风模型中,显示法舒地尔减小梗塞面积和神经缺陷二者(Toshima,Y.,Stroke,31:2245-2250(2000))。显示ROCK抑制剂Y-27632改善Dahl 盐敏感型大鼠的充血性心力衰竭模型中的心室肥大、纤维变性和功能(Kobayashi, N.等人, Cardiovasc. Res., 55:757-767(2002))。
其它动物或临床研究已暗示包括以下的其它疾病中的ROCK:冠状动脉血管痉挛(Shimokawa,H.等人,Cardiovasc. Res.,43:1029-1039 (1999))、脑血管痉挛(Sato,M.等人,Circ. Res.,87:195-200 (2000))、缺血/再灌注损伤(Yada,T.等人,J. Am. Coll. Cardiol.,45:599-607 (2005))、肺高血压(Fukumoto,Y.等人,Heart,91:391-392(2005))、心绞痛(Shimokawa,H.等人,J. Cardiovasc. Pharmacol.,39:319-327 (2002))、肾病(Satoh,S.等人,Eur. J. Pharmacol.,455:169-174 (2002))和勃起功能障碍(Gonzalez-Cadavid,N.F.等人,Endocrine,23:167-176 (2004))。
在另一研究中,已证实RhoA/ROCK信号传导途径的抑制允许形成扰乱单核细胞的产生性迁移的多个竞争性板状伪足(Worthylake,R.A.等人,J. Biol. Chem.,278:13578-13584 (2003))。也已报导,Rho激酶的小分子抑制剂能够抑制体外MCP-1介导的趋化性(Iijima,H.,Bioorg. Med. Chem.,15:1022-1033 (2007))。由于免疫细胞迁移依赖RhoA/ROCK信号传导途径,因此可预料抑制Rho激酶也应为诸如类风湿性关节炎、牛皮癣和炎性肠病的疾病提供益处。
上述研究提供ROCK与心血管疾病(包括高血压、动脉粥样硬化、再狭窄、中风、心力衰竭、冠状动脉血管痉挛、脑血管痉挛、缺血/再灌注损伤、肺高血压和心绞痛)以及肾病和勃起功能障碍之间的关联的证据。鉴于已证实ROCK 对平滑肌的效应,ROCK抑制剂也可用于涉及平滑肌高反应性的其它疾病(包括哮喘和青光眼)中(Shimokawa,H.等人,Arterioscler. Thromb. Vase. Biol.,25:1767-1775 (2005))。此外,已指示Rho-激酶作为用于治疗各种其它疾病的药物靶标,包括气道发炎和高反应性(Henry,P.J.等人,Pulm. Pharmacol. Ther.,18:67-74 (2005))、癌症(Rattan,R.等人,J. Neurosci. Res.,83:243-255 (2006);Lepley,D.等人,Cancer Res.,65:3788-3795 (2005))、纤维变性疾病(Jiang,C.等人,Int. J. Mol. Sci.,13:8293-8307 (2012);Zhou,L.等人,Am. J. Nephrol.,34:468-475 (2011)),以及神经病症,诸如脊髓损伤、阿尔茨海默病、多发性硬化、中风和神经性疼痛(Mueller,B.K.等人,Nat. Rev. Drug Disc.,4:387-398 (2005);Sun,X.等人,J. Neuroimmunol.,180:126-134 (2006))。
对治疗心血管疾病的新药仍存在未满足的医学需求。在美国心脏病协会的心脏病和中风统计(Heart Disease and Stroke Statistics)的2012更新(Circulation,125:e2-e220 (2012))中,已报导心血管疾病占美国所有死亡的32.8%,且冠心病占美国总体死亡的~1/6。对这些数字有贡献的,已发现,~33.5%的成年美国人口患有高血压,且据估计在2010年,~660万美国成年人将患有心力衰竭。因此,尽管存在大量可用于治疗心血管疾病(CVD)的药物(包括利尿剂、β阻断剂、血管紧张素转换酶抑制剂、血管紧张素阻断剂和钙通道阻断剂),但对于许多患者而言,CVD仍然控制不良或对当前药物有抗性。
尽管调查中有ROCK抑制剂的许多报导(参见,例如,US 2008/0275062 A1),但法舒地尔是此时唯一销售的ROCK抑制剂。日本已批准静脉注射制剂用于治疗脑血管痉挛。仍需要用于治疗心血管疾病、癌症、神经病、肾病、纤维变性疾病、支气管哮喘、勃起功能障碍和青光眼的新的治疗剂(包括ROCK抑制剂)。
发明概述
本发明提供新颖的环状脲衍生物,包括其立体异构体、互变异构体、药学上可接受的盐或溶剂化物,其可用作Rho激酶的选择性抑制剂。
本发明也提供用于制备本发明化合物的方法和中间体。
本发明也提供药物组合物,其包含药学上可接受的载体和至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。
本发明化合物可用于治疗和/或预防与异常ROCK活性相关的疾病状态。
本发明化合物可用于疗法中。
本发明化合物可用于制造用于治疗和/或预防与异常ROCK活性相关的疾病状态的药物。
在另一个方面,本发明涉及治疗心血管或相关疾病的方法,该方法包括向需要此类治疗的患者给药如上文所述的本发明化合物。可治疗的此类疾病的实例包括,例如,高血压、动脉粥样硬化、再狭窄、中风、心力衰竭、肾衰竭、冠状动脉疾病、外周动脉疾病、冠状动脉血管痉挛、脑血管痉挛、缺血/再灌注损伤、肺高血压、心绞痛、勃起功能障碍和肾病。
在另一个方面,本发明涉及治疗涉及平滑肌高反应性的疾病(包括哮喘、勃起功能障碍和青光眼)的方法,该方法包括向需要此类治疗的患者给药如上文所述的本发明化合物。
在另一个方面,本发明涉及治疗至少部分由Rho激酶介导的疾病(包括纤维变性疾病、肿瘤、脊髓损伤、阿尔茨海默病、多发性硬化、中风、神经性疼痛、类风湿性关节炎、牛皮癣和炎性肠病)的方法,该方法包括向需要此类治疗的患者给药如上文所述的本发明化合物。
在其它方面,本发明涉及包含上述化合物的药物组合物、制备上述化合物的方法和这些方法中所使用的中间体。
本发明化合物可单独、与本发明的其它化合物组合、或与一种或多种(优选一至两种)其它药剂组合使用。
本发明的这些和其它特征将随本公开内容的继续以展开形式阐述。
发明详述
I. 本发明化合物
在一个方面,本发明尤其提供式(I)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
---是任选的键;
环A独立地选自
J1、J2、J3和J4独立地选自N和CR3;条件是J1、J2、J3和J4之一是N且J1、J2、J3和J4中不超过两个是N;
K独立地选自N和CR1;
R1独立地选自H、F、Cl、Br、OH、CN、NRaRa、被0-3个Re取代的-OC1-4烷基和被0-3个Re取代的C1-4烷基;
R2独立地选自H、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rCN、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R3独立地选自H、F、Cl、Br、CN、用0-3个Re取代的C1-4烷基、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rC(=O)(CH2)rNRaRa、-(CH2)rCN、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基、NRaRa和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rCN、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rC(=O)(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R8独立地选自C3-6环烷基、杂环基、芳基和杂芳基,其各自被0-5个R9取代;
R9独立地选自F、Cl、Br、C1-4烷基、C2-4烯基、C2-4炔基、硝基、-(CHRd)rS(O) p Rc、-(CHRd)rS(O) p NRaRa、-(CHRd)rNRaS(O) p Rc、-(CHRd)rORb、-(CHRd)rCN、-(CHRd)rNRaRa、-(CHRd)rNRaC(=O)Rb、-(CHRd)rNRaC(=O)NRaRa、-(CHRd)rC(=O)ORb、-(CHRd)rC(=O)Rb、-(CHRd)rOC(=O)Rb、-(CHRd)r-环烷基、-(CHRd)r-杂环基、-(CHRd)r-芳基和-(CHRd)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Rd在每次出现时独立地选自H和被0-5个Re取代的C1-4烷基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、-(CH2)r-芳基、-(CH2)r-杂芳基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、C(=O)NRfRf、NRfC(=O)Rd、S(O)pNRfRf、NRfS(O)pRd、NRfC(=O)ORd、OC(=O)NRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或
Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;且
在另一个方面,本发明提供
式(I)化合物或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
---是任选的键;
环A独立地选自
J1、J2、J3和J4独立地选自N和CH;条件是J1、J2、J3和J4中不超过两个是N;
K独立地选自N和CH;
R1独立地选自H、F、Cl、Br、OH、CN、NRaRa、被0-3个Re取代的-OC1-4烷基和被0-3个Re取代的C1-4烷基;
R2独立地选自H、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rCN、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rC(=O)(CH2)rNRaRa、-(CH2)rCN、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基、NRaRa和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rCN、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rC(=O)(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R8独立地选自芳基和杂芳基,其各自被0-5个R9取代;
R9独立地选自F、Cl、Br、C1-4烷基、C2-4烯基、C2-4炔基、硝基、-(CHRd)rS(O) p Rc、-(CHRd)rS(O) p NRaRa、-(CHRd)rNRaS(O) p Rc、-(CHRd)rORb、-(CHRd)rCN、-(CHRd)rNRaRa、-(CHRd)rNRaC(=O)Rb、-(CHRd)rNRaC(=O)NRaRa、-(CHRd)rC(=O)ORb、-(CHRd)rC(=O)Rb、-(CHRd)rOC(=O)Rb、-(CHRd)r-环烷基、-(CHRd)r-杂环基、-(CHRd)r-芳基和-(CHRd)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Rd在每次出现时独立地选自H和被0-5个Re取代的C1-4烷基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、-(CH2)r-芳基、-(CH2)r-杂芳基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、C(=O)NRfRf、NRfC(=O)Rd、S(O)pNRfRf、NRfS(O)pRd、NRfC(=O)ORd、OC(=O)NRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4;且
条件是
(1) R9不是被取代的哌嗪;
在另一个方面,本发明提供式(I)化合物或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自H、F、Cl、Br、OH、CN、NRaRa、被0-3个Re取代的-OC1-4烷基和被0-3个Re取代的C1-4烷基;
R2独立地选自H、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rCN、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rNRaS(O)pNRaRa和-(CH2)rNRaS(O)pRc;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、被0-3个Re取代的-(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R4独立地选自H、F、Cl、Br、OH、CN和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R8独立地选自
R9独立地选自F、Cl、Br、C1-4烷基、C2-4烯基、C2-4炔基、硝基、-(CHRd)rS(O) p Rc、-(CHRd)rS(O) p NRaRa、-(CHRd)rNRaS(O) p Rc、-(CHRd)rORb、-(CHRd)rCN、-(CHRd)rNRaRa、-(CHRd)rNRaC(=O)Rb、-(CHRd)rNRaC(=O)NRaRa、-(CHRd)rC(=O)ORb、-(CHRd)rC(=O)Rb、-(CHRd)rOC(=O)Rb、-(CHRd)r-环烷基、-(CHRd)r-杂环基、-(CHRd)r-芳基和-(CHRd)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代,且
其它变量如以上式(I)中所定义。
在另一个方面,本发明提供式(I)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自H、F、Cl、Br、OH、CN、NRaRa、被0-3个Re取代的-OC1-4烷基和被0-3个Re取代的C1-4烷基;
R2独立地选自H、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rCN、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rNRaS(O)pNRaRa和-(CH2)rNRaS(O)pRc;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、被0-3个Re取代的-(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R4独立地选自H、F、Cl、Br、OH、CN和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R8独立地选自
R9独立地选自F、Cl、Br、C1-4烷基、C2-4烯基、C2-4炔基、硝基、-(CHRd)rS(O) p Rc、-(CHRd)rS(O) p NRaRa、-(CHRd)rNRaS(O) p Rc、-(CHRd)rORb、-(CHRd)rCN、-(CHRd)rNRaRa、-(CHRd)rNRaC(=O)Rb、-(CHRd)rNRaC(=O)NRaRa、-(CHRd)rC(=O)ORb、-(CHRd)rC(=O)Rb、-(CHRd)rOC(=O)Rb、-(CHRd)r-环烷基、-(CHRd)r-杂环基、-(CHRd)r-芳基和-(CHRd)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;且
其它变量如以上式(I)中所定义。
在另一个方面,本发明提供式(II)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
---是任选的键;
环A独立地选自
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R2独立地选自H、F、Cl、Br、OH、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基、-(CH2)rORb和-C3-6环烷基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(II)化合物或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
---是任选的键;
环A独立地选自
K独立地选自N和CH;
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R2独立地选自H、F、Cl、Br、OH、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基和-(CH2)rORb;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;
r在每次出现时独立地选自0、1、2、3和4;且
其它变量如以上式(II)中所定义。
在另一个方面,本发明提供式(II)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R3独立地选自F、Cl、Br、CN、被0-3个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rS(O)pRc、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)Rb、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R4独立地选自H、F、Cl、Br、OH、CN和被0-3个Re取代的C1-4烷基;
R6和R7独立地选自H、CN、被0-4个Re取代的C1-4烷基、被0-3个Re取代的C2-4烯基、-(CH2)rORb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)ORb、-(CH2)rC(=O)ORb、-(CH2)rNRaS(O)pRc、被0-3个Re取代的-(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
或者,R6和R7与它们两者都连接的碳原子一起形成被0-5个Re取代的环烷基;或者,当n是2或3时,两个相邻R6基团可形成被0-5个Re取代的环烷基且两个R7基团都是氢;
R9独立地选自F、Cl、Br、CN、C1-4烷基、-(CHRd)rS(O) p Rc、-(CHRd)rS(O) p NRaRa、-(CHRd)rNRaS(O) p Rc、-(CHRd)rORb、-(CHRd)rCN、-(CHRd)rNRaRa、-(CHRd)rNRaC(=O)Rb、-(CHRd)rC(=O)ORb、-(CHRd)rC(=O)Rb、-(CHRd)rOC(=O)Rb、-(CHRd)rC(=O)NRaRa、-(CHRd)r-环烷基、-(CHRd)r-杂环基、-(CHRd)r-芳基和-(CHRd)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、CN、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Rd在每次出现时独立地选自H和被0-5个Re取代的C1-4烷基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、NH2、OH、OC1-5烷基、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
p在每次出现时独立地选自0、1和2;
r在每次出现时独立地选自0、1、2、3和4;且
其它变量如以上式(II)中所定义。
在另一个方面,本发明提供式(IIa)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
---是任选的键;
环A独立地选自
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R2独立地选自H、F、Cl、Br、OH、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基、-(CH2)rORb和-C3-6环烷基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R5、R10和R11独立地选自H、=O和被0-4个Re取代的C1-4烷基;条件是R5、R10和R11不都是H;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4;且
条件是
(1) R9不是被取代的哌嗪;
在另一个方面,本发明提供式(III)化合物:
或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
---是任选的键;
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基和-(CH2)rORb;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)rORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb和被0-3个Re取代的杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)rC(=O)NRaRa、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1和2;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(III)化合物或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自H;
R3独立地选自H、F、Cl、C1-4烷基和-OC1-3烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-ORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-3个Re取代的C1-4烷基、-(CH2)rORb和-(CH2)rC(=O)ORb;
R9独立地选自F、Cl、被0-3个Re取代的C1-4烷基、-ORb和被0-3个Re取代的杂环基;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、F、Cl、Br、CN、NO2、=O、CO2H、OH和OC1-4烷基;
n独立地选自1和2;
r在每次出现时独立地选自0、1、2和3;且
其它变量如以上式(III)中所定义。
在另一个方面,本发明提供式(IIIa)化合物
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R2独立地选自H和被0-4个Re取代的C1-4烷基;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基、-(CH2)rORb和-C3-6环烷基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R5、R10和R11独立地选自H、=O和被0-4个Re取代的C1-4烷基;条件是R5、R10和R11不都是H;
R6独立地选自H、被0-4个Re取代的C1-4烷基、-CH2ORb、-C(=O)Rb、NRaC(=O)Rb、-CH2NRaRa、-C(=O)NRaRa、-rC(=O)ORb和被0-3个Re取代的杂环基;
R7独立地选自H和C1-4烷基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)rC(=O)NRaRa、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1和2;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(IIIb)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、CN、C1-4烷基、-OC1-3烷基和C3-6环烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-CH2ORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-3个Re取代的C1-4烷基、-(CH2)rORb、-CH2NRaRa、-C(=O)NRaRa和-(CH2)rC(=O)ORb;
R7独立地选自H和C1-4烷基;
R9独立地选自F、Cl、被0-3个Re取代的C1-4烷基、-ORb和被0-3个Re取代的杂环基;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-6环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、F、Cl、Br、CN、NO2、=O、CO2H、OH和OC1-4烷基;
n独立地选自1和2;且
r在每次出现时独立地选自0、1、2和3。
在另一个方面,本发明提供式(IV)化合物:
或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
K独立地选自N和CH;
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、CN、被0-3个Re取代的C1-4烷基和-ORb;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb和被0-3个Re取代的杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-S(O) p Rc、-S(O) p NRaRa、-ORb、-NRaRa、-C(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-6环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1和2;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(IVa)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自H和CF3;
R3独立地选自H、CN、C1-4烷基、-OC1-3烷基和-C3-6环烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-CH2ORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-3个Re取代的C1-4烷基、-(CH2)rORb、-CH2NRaRa、-C(=O)NRaRa和-(CH2)rC(=O)ORb;
R7独立地选自H和C1-4烷基;
R9独立地选自F、Cl、被0-3个Re取代的C1-4烷基、-ORb和被0-3个Re取代的杂环基;
R10和R11独立地选自H、被0-4个Re取代的C1-4烷基;条件是R10和R11不都是H;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-6环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、F、Cl、Br、CN、NO2、=O、CO2H、OH和OC1-4烷基;
n独立地选自1和2;且
r在每次出现时独立地选自0、1、2和3。
在另一个方面,本发明提供式(V)化合物:
或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、CN、被0-3个Re取代的C1-4烷基和-ORb;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb和被0-3个Re取代的杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-S(O) p Rc、-S(O) p NRaRa、-ORb、-NRaRa、-C(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-6环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1和2;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(Va)化合物:
或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、CN、被0-3个Re取代的C1-4烷基和-ORb;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb和被0-3个Re取代的杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-S(O) p Rc、-S(O) p NRaRa、-ORb、-NRaRa、-C(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-6环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1和2;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(VI)化合物:
或其立体异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
K独立地选自N和CH;
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、CN、被0-3个Re取代的C1-4烷基和-ORb;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb和被0-3个Re取代的杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-S(O) p Rc、-S(O) p NRaRa、-ORb、-NRaRa、-C(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-6环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1和2;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(VIa)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
K独立地选自N和CH;
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、CN、被0-3个Re取代的C1-4烷基和-ORb;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb和被0-3个Re取代的杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-S(O) p Rc、-S(O) p NRaRa、-ORb、-NRaRa、-C(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-6环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1和2;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(VII)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
环A独立地选自
K独立地选自N和CR1;
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R2独立地选自H、F、Cl、Br、OH、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R8独立地选自
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(VIII)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
环A独立地选自
K独立地选自N和CR1;
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R2独立地选自H、F、Cl、Br、OH、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R8独立地选自
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(IX)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
环A独立地选自
K独立地选自N和CR1;
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R2独立地选自H、F、Cl、Br、OH、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R8独立地选自
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(X)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
环A独立地选自
K独立地选自N和CR1;
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R2独立地选自H、F、Cl、Br、OH、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R8独立地选自
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(XI)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自H、F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R2独立地选自H和被0-4个Re取代的C1-4烷基;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基、-(CH2)rORb和-C3-6环烷基;
R3独立地选自H、F、Cl、Br、CN、被0-3个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、被0-3个Re取代的-(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基和被0-3个Re取代的C1-4烷基;
R6独立地选自H、被OH取代的C1-4烷基、-CH2ORb、-C(=O)Rb、NRaC(=O)Rb、-CH2NRaRa、-C(=O)NRaRa、-rC(=O)ORb和被0-3个Re取代的杂环基;
R7独立地选自H和C1-4烷基;条件是R6和R7不都是H;当R7是C1-4烷基时,R6不是H;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-(CH2)rS(O) p Rc、-(CH2)rS(O) p NRaRa、-(CH2)rNRaS(O) p Rc、-(CH2)rORb、-(CH2)rCN、-(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)rOC(=O)Rb、-(CH2)rC(=O)NRaRa、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1和2;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(XII)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
R1独立地选自F、Cl、Br、CN、NRaRa和被0-4个Re取代的C1-4烷基;
R3独立地选自H、CN、被0-3个Re取代的C1-4烷基和-ORb;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)r ORb、C(=O)Rb和-C(=O)ORb;
R6独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rC(=O)Rb、-(CH2)rNRaC(=O)Rb、-(CH2)rC(=O)ORb和被0-3个Re取代的杂环基;
R9独立地选自F、Cl、Br、C1-4烷基、硝基、-S(O) p Rc、-S(O) p NRaRa、-ORb、-NRaRa、-C(=O)ORb、-(CH2)rC(=O)Rb、-(CH2)r-环烷基、-(CH2)r-杂环基、-(CH2)r-芳基和-(CH2)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的-(CH2)r-C3-6环烷基、被0-5个Re取代的-(CH2)r-芳基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、S(O)pNRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1和2;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4。
在另一个方面,本发明提供式(XIII)化合物:
或其立体异构体、对映异构体、非对映异构体、互变异构体、药学上可接受的盐、溶剂化物或前药,其中
环A独立地选自
J1、J2、J3和J4独立地选自N和CR3;
K独立地选自N和CR1;
R1独立地选自H、F、Cl、Br、OH、CN、NRaRa、被0-3个Re取代的-OC1-4烷基和被0-3个Re取代的C1-4烷基;
R2独立地选自H、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rCN、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R3独立地选自H、F、Cl、Br、CN、用0-3个Re取代的C1-4烷基、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rC(=O)(CH2)rNRaRa、-(CH2)rCN、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R4独立地选自H、F、Cl、Br、OH、CN、被0-3个Re取代的OC1-4烷基、NRaRa和被0-3个Re取代的C1-4烷基;
R5独立地选自H、=O、被0-4个Re取代的C1-4烷基、-(CH2)rORb、(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rCN、-(CH2)rC(=O)NRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)NRaRa、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb、-(CH2)rS(O)pRc、-(CH2)rC(=O)Rb、-(CH2)rNRaRa、-(CH2)rC(=O)NRaRa、-(CH2)rC(=O)(CH2)rNRaRa、-(CH2)rNRaC(=O)Rb、-(CH2)rNRaC(=O)ORb、-(CH2)rOC(=O)NRaRa、-(CH2)rNRaC(=O)NRaRa、-(CH2)rC(=O)ORb、-(CH2)rS(O)pNRaRa、-(CH2)rNRaS(O)pNRaRa、-(CH2)rNRaS(O)pRc、被0-3个Re取代的(CH2)r-C3-6碳环基和被0-3个Re取代的-(CH2)r-杂环基;
R8独立地选自C3-6环烷基、杂环基、芳基和杂芳基,其各自被0-5个R9取代;
R9独立地选自F、Cl、Br、C1-4烷基、C2-4烯基、C2-4炔基、硝基、-(CHRd)rS(O) p Rc、-(CHRd)rS(O) p NRaRa、-(CHRd)rNRaS(O) p Rc、-(CHRd)rORb、-(CHRd)rCN、-(CHRd)rNRaRa、-(CHRd)rNRaC(=O)Rb、-(CHRd)rNRaC(=O)NRaRa、-(CHRd)rC(=O)ORb、-(CHRd)rC(=O)Rb、-(CHRd)rOC(=O)Rb、-(CHRd)r-环烷基、-(CHRd)r-杂环基、-(CHRd)r-芳基和-(CHRd)r-杂芳基,其中所述烷基、环烷基、杂环基、芳基或杂芳基被0-4个Re取代;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;或Ra和Ra与它们两者都连接的氮原子一起形成被0-5个Re取代的杂环;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、被0-5个Re取代的-(CH2)r-C3-10碳环基和被0-5个Re取代的-(CH2)r-杂环基;
Rc在每次出现时独立地选自被0-5个Re取代的C1-6烷基、被0-5个Re取代的C2-6烯基、被0-5个Re取代的C2-6炔基、C3-6碳环基和杂环基;
Rd在每次出现时独立地选自H和被0-5个Re取代的C1-4烷基;
Re在每次出现时独立地选自被0-5个Rf取代的C1-6烷基、C2-6烯基、C2-6炔基、-(CH2)r-C3-6环烷基、-(CH2)r-C4-6杂环基、-(CH2)r-芳基、-(CH2)r-杂芳基、F、Cl、Br、CN、NO2、=O、CO2H、-(CH2)rORf、S(O)pRf、C(=O)NRfRf、NRfC(=O)Rd、S(O)pNRfRf、NRfS(O)pRd、NRfC(=O)ORd、OC(=O)NRfRf和-(CH2)rNRfRf;
Rf在每次出现时独立地选自H、F、Cl、Br、CN、OH、C1-5烷基、C3-6环烷基和苯基,或Rf和Rf与它们两者都连接的氮原子一起形成任选地被C1-4烷基取代的杂环;
n独立地选自1、2和3;
p在每次出现时独立地选自0、1和2;且
r在每次出现时独立地选自0、1、2、3和4;且
条件是R9不是被取代的哌嗪。
在另一个方面,本发明提供选自本申请中例举的化合物的任何亚组列表的化合物。
在另一个实施方案中,本发明化合物具有≤10 µM的ROCK IC50值。
在另一个实施方案中,本发明化合物具有≤1 µM的ROCK IC50值。
在另一个实施方案中,本发明化合物具有≤0.1 µM的ROCK IC50值。
在另一个实施方案中,本发明化合物具有≤0.05 µM的ROCK IC50值。
在另一个实施方案中,本发明化合物具有≤0.01 µM的ROCK IC50值。
II. 本发明的其它实施方案
在另一个实施方案中,本发明提供组合物,其包含至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。
在另一个实施方案中,本发明提供药物组合物,其包含药学上可接受的载体和治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。
在另一个实施方案中,本发明提供用于制备本发明化合物的方法。
在另一个实施方案中,本发明提供用于制备本发明化合物的中间体。
在另一个实施方案中,本发明提供进一步包含其它治疗剂的药物组合物。
在另一个实施方案中,本发明提供治疗和/或预防与异常ROCK活性相关的病况的方法,其包括向需要此类治疗和/或预防的患者给药治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物。如本文所用,术语“患者”涵盖所有哺乳动物物种。
如本文所用,“治疗(treating或treatment)”涵盖治疗哺乳动物(尤其人类)的疾病状态,并且包括:(a)抑制所述疾病状态,即,阻止其进展;和/或(b)减轻所述疾病状态,即,引起所述疾病状态消退。
如本文所用,“预防”是疾病状态的保护性治疗,其通过向患者给药治疗有效量的本发明化合物或其立体异构体、互变异构体、药学上可接受的盐或溶剂化物中的至少一种降低疾病状态的风险和/或使该风险降至最低和/或降低疾病状态复发的风险。可基于已知相比于一般群体增加患有临床疾病状态的风险的因素而选择用于预防疗法的患者。对于预防治疗,可呈现或可尚未呈现临床疾病状态的病况。“预防”治疗可分成(a)初级预防和(b)二级预防。初级预防被定义为治疗以降低尚未呈现临床疾病状态的患者的疾病状态的风险或使该风险降至最低,而二级预防被定义为使相同或类似临床疾病状态的复发或第二次发生的风险降至最低或降低该风险。
如本文所用,“预防”涵盖预防性治疗哺乳动物(尤其人类)的亚临床疾病状态,其旨在减小发生临床疾病状态的可能性。基于已知与一般群体相比患有临床疾病状态的风险增加的因素来选择用于预防性疗法的患者。
本发明可在不偏离其精神或基本属性下以其它特定形式体现。本发明涵盖本文所提及的本发明的优选方面的所有组合。应理解,本发明的任何和所有实施方案可与用于描述另外的实施方案的任何其它一个或多个实施方案结合。还应理解,实施方案的每一个别要素为其自身独立的实施方案。此外,实施方案的任何要素意欲与任何实施方案的任何和所有其它要素组合来描述其它实施方案。
III. 化学
在说明书和随附权利要求书中,给定化学式或名称在存在这种异构体的情况下应涵盖所有立体和光学异构体和其外消旋体。除非另外指出,否则所有手性(对映异构体和非对映异构体)和外消旋形式都在本发明的范围内。所述化合物中也可存在C=C双键、C=N双键、环系统等的许多几何异构体,且所有此类稳定异构体都涵盖于本发明中。描述本发明化合物的顺式-和反式-(或E-和Z-)几何异构体且可分离成异构体混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。可通过拆分外消旋形式或通过自光学活性起始材料合成来制备光学活性形式。用于制备本发明化合物和其中制得的中间体的所有方法都视为本发明的一部分。当制备对映异构体或非对映异构体产物时,其可通过常用方法(例如通过色谱法或分级结晶)进行分离。取决于方法条件,以游离(中性)或盐形式获得本发明的最终产物。这些最终产物的游离形式和盐都在本发明的范围内。若需要,则可将化合物的一种形式转化成另一形式。可将游离碱或酸转化成盐;可将盐转化成游离化合物或另一盐;可将本发明异构体化合物的混合物分离成个别异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在,其中氢原子换位至分子的其它部分上并由此重排分子的原子之间的化学键。应理解,可存在的所有互变异构体形式都包括在本发明内。
术语“立体异构体”是指构成相同但在其原子空间排列上不同的异构体。对映异构体和非对映异构体是立体异构体的实例。术语“对映异构体”是指互为镜像但不可重叠的一对分子物质之一。术语“非对映异构体”是指不为镜像的立体异构体。术语“外消旋体”或“外消旋混合物”是指由等摩尔量的两种对映异构体物质组成的组合物,其中所述组合物没有光学活性。
符号“R”和“S”代表手性碳原子周围的取代基的构型。异构体描述语“R”和“S”如本文所述用于指示相对于核心分子的原子构型且意欲如文献中所定义来使用(IUPACRecommendations 1996,Pure and Applied Chemistry,68:2193-2222 (1996))。
术语“手性”是指分子的使其不可能与其镜像重叠的结构特征。术语“纯手性”是指对映异构体纯度的状态。术语“光学活性”是指纯手性分子或手性分子的非外消旋混合物在偏振光平面上旋转的程度。
如本文所用,术语“烷基”或“亚烷基”意欲包括具有规定数量的碳原子的支链和直链二者的饱和脂肪族烃基团。例如,“C1-C10烷基”或“C1-10烷基”(或亚烷基)意欲包括C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。此外,例如,“C1-C6烷基”或“C1-6烷基”表示具有1至6个碳原子的烷基。烷基基团可以是未取代的或至少一个氢被另一化学基团替换而被取代。实例性烷基基团包括但不限于甲基(Me)、乙基(Et)、丙基(例如,正丙基和异丙基)、丁基(例如,正丁基、异丁基、叔丁基)和戊基(例如,正戊基、异戊基、新戊基)。
“烯基”或“亚烯基”意欲包括具有规定数量的碳原子和一个或多个、优选一至两个碳-碳双键(其可沿链存在于任何稳定点)的直链或支链构型的烃链。例如,“C2-C6烯基”或“C2-6烯基”(或亚烯基)意欲包括C2、C3、C4、C5和C6烯基。烯基的实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。
“炔基”或“亚炔基”意欲包括具有一个或多个、优选一至三个碳-碳三键(其可沿链存在于任何稳定点)的直链或支链构型的烃链。例如,“C2-C6炔基”或“C2-6炔基”(或亚炔基)意欲包括C2、C3、C4、C5和C6炔基;诸如乙炔基、丙炔基、丁炔基、戊炔基和己炔基。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1-C6烷氧基”或“C1-6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5和C6烷氧基。实例性烷氧基包括但不限于甲氧基、乙氧基、丙氧基(例如,正丙氧基和异丙氧基)和叔丁氧基。类似地,“烷基硫基”或“硫代烷氧基”代表通过硫桥连接的具有指定数量的碳原子的如上文所定义的烷基;例如甲基-S-和乙基-S-。
“卤代”或“卤素”包括氟(F)、氯(Cl)、溴(Br)和碘(I)。“卤代烷基”意欲包括被1个或多个卤素取代的具有规定数量碳原子的支链和直链二者的饱和脂肪族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例也包括“氟烷基”,其意欲包括被1个或多个氟原子取代的具有规定数量碳原子的支链和直链二者的饱和脂肪族烃基团。
“卤代烷氧基”或“卤代烷基氧基”代表通过氧桥连接的具有指定数量的碳原子的如上文所定义的卤代烷基。例如,“C1-C6卤代烷氧基”或“C1-6卤代烷氧基”意欲包括C1、C2、C3、C4、C5和C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地,“卤代烷基硫基”或“硫代卤代烷氧基”代表通过硫桥连接的具有指定数量的碳原子的如上文所定义的卤代烷基;例如三氟甲基-S-和五氟乙基-S-。
术语“环烷基”是指环状烷基,其包括单环、二环或多环环系统。“C3-C7环烷基”或“C3-7环烷基”意欲包括C3、C4、C5、C6和C7环烷基。实例性环烷基包括但不限于环丙基、环丁基、环戊基、环己基和降莰烷基。支链环烷基诸如1-甲基环丙基和2-甲基环丙基包括在“环烷基”的定义中。
如本文所用,“碳环”、“碳环基”或“碳环残基”意指任何稳定的3-、4-、5-、6-、7-或8-元单环或二环或7-、8-、9-、10-、11-、12-或13-元二环或三环烃环,任何所述环可以是饱和的、部分不饱和的、不饱和的或芳族的。此类碳环的实例包括但不限于环丙基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环庚烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯基、环辛二烯基、[3.3.0]二环辛烷、[4.3.0]二环壬烷、[4.4.0]二环癸烷(十氢萘)、[2.2.2]二环辛烷、芴基、苯基、萘基、茚满基、金刚烷基、蒽基和四氢萘基(四氢萘)。如上文所示,桥环也包括在碳环的定义内(例如,[2.2.2]二环辛烷)。除非另有说明,否则优选的碳环为环丙基、环丁基、环戊基、环己基、苯基和茚满基。当使用术语“碳环基”时,其意欲包括“芳基”。当一个或多个碳原子连接两个非毗邻碳原子时,出现桥环。优选的桥为一个或两个碳原子。应注意,桥总是将单环转化成三环。当环是桥接的时,对于该环所列举的取代基也可存在于桥上。
如本文所用,术语“二环碳环基”或“二环碳环基团”意指含有两个稠环且由碳原子组成的稳定的9-或10-元碳环环系统。两个稠环中,一个环是稠合至第二个环的苯并环;且第二个环是饱和的、部分不饱和的或不饱和的5-或6-元碳环。二环碳环基团可在任何碳原子处连接至其侧基,从而得到稳定结构。如果所得化合物是稳定的,则本文所述的二环碳环基团可在任何碳上被取代。二环碳环基团的实例是但不限于萘基、1,2-二氢萘基、1,2,3,4-四氢萘基和茚满基。
“芳基”是指单环或多环芳族烃,包括例如苯基、萘基和菲基。芳基部分是众所周知的且描述于例如Lewis,R.J.编辑,Hawley's Condensed Chemical Dictionary,第13版,John Wiley & Sons,Inc.,New York (1997)中。“C6或C10芳基”或“C6-10芳基”是指苯基和萘基。除非另有说明,否则“芳基”、“C6或C10芳基”或“C6-10芳基”或“芳族残基”可以是未取代的或被1至5个、优选1至3个下述基团取代:OH、OCH3、Cl、F、Br、I、CN、NO2、NH2、N(CH3)H、N(CH3)2、CF3、OCF3、C(=O)CH3、SCH3、S(=O)CH3、S(=O)2CH3、CH3、CH2CH3、CO2H和CO2CH3。
如本文所用,术语“苄基”是指其中一个氢原子被苯基替换的甲基,其中所述苯基可任选被1至5个、优选1至3个下述基团取代:OH、OCH3、Cl、F、Br、I、CN、NO2、NH2、N(CH3)H、N(CH3)2、CF3、OCF3、C(=O)CH3、SCH3、S(=O)CH3、S(=O)2CH3、CH3、CH2CH3、CO2H和CO2CH3。
如本文所用,术语“杂环(heterocycle)”、“杂环基”或“杂环(heterocyclicring)”意指稳定的3-、4-、5-、6-或7-元单环或二环或7-、8-、9-、10-、11-、12-、13-或14-元多环杂环,其为饱和的、部分不饱和的或完全不饱和的,且其含有碳原子和1、2、3或4个独立地选自N、O和S的杂原子;且包括其中任何上文所定义的杂环稠合至苯环的任何多环基团。氮和硫杂原子可任选为氧化的(即,N→O和S(O)p,其中p为0、1或2)。氮原子可以是取代的或未取代的(即,如果定义的话,则为N或NR,其中R为H或另一取代基)。杂环可在任何杂原子或碳原子处连接至其侧基,从而得到稳定结构。如果所得化合物是稳定的,则本文所述的杂环可在碳或氮原子上被取代。杂环中的氮可任选为季铵化的。优选的是当杂环中的S和O原子总数超过1时,则这些杂原子不彼此毗邻。优选的是杂环中的S和O原子总数不大于1。当使用术语“杂环”时,其意欲包括杂芳基。
桥环也包括于杂环的定义中。当一或多个原子(即,C、O、N或S)连接两个非毗邻碳或氮原子时,则产生桥环。桥环的实例包括(但不限于)一个碳原子、两个碳原子、一个氮原子、两个氮原子和碳-氮基团。应注意,桥总是将单环转化成三环。在环桥接时,针对环列举的取代基也可存于桥上。
杂环的实例包括但不限于吖啶基、氮杂环丁烷基、氮杂环辛四烯基(azocinyl)、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、吲哚啉基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异吲哚啉基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、萘啶基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基萘嵌间二氮杂苯基(perimidinyl)、羟吲哚基(oxindolyl)、嘧啶基、啡啶基、菲罗啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基(piperonyl)、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。含有例如上述杂环的稠环和螺环化合物也包括在内。
5-至10-元杂环的实例包括但不限于吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、哌嗪基、哌啶基、咪唑基、咪唑烷基、吲哚基、四唑基、异噁唑基、吗啉基、噁唑基、噁二唑基、噁唑烷基、四氢呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基、三唑基、苯并咪唑基、1H-吲唑基、苯并呋喃基、苯并硫代呋喃基、苯并四唑基、苯并三唑基、苯并异噁唑基、苯并噁唑基、羟吲哚基、苯并噁唑啉基、苯并噻唑基、苯并异噻唑基、靛红酰基、异喹啉基、八氢异喹啉基、四氢异喹啉基、四氢喹啉基、异噁唑并吡啶基、喹唑啉基、喹啉基、异噻唑并吡啶基、噻唑并吡啶基、噁唑并吡啶基、咪唑并吡啶基和吡唑并吡啶基。
5-至6-元杂环的实例包括但不限于吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、哌嗪基、哌啶基、咪唑基、咪唑烷基、吲哚基、四唑基、异噁唑基、吗啉基、噁唑基、噁二唑基、噁唑烷基、四氢呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基和三唑基。含有例如上述杂环的稠环和螺环化合物也包括在内。
如本文所用,术语“二环杂环”或“二环杂环基团”意指稳定的9-或10-元杂环环系统,其含有两个稠环且由碳原子和1、2、3或4个独立地选自N、O和S的杂原子组成。两个稠环中,一个环是5-或6-元单环芳族环,其包含5-元杂芳基环、6-元杂芳基环或苯并环,各自稠合至第二个环。第二个环是饱和的、部分不饱和的或不饱和的5-或6-元单环,且包含5-元杂环、6-元杂环或碳环(前提是当第二个环是碳环时,第一个环不为苯并环)。
二环杂环基团可在任何杂原子或碳原子处连接至其侧基,从而得到稳定结构。如果所得化合物是稳定的,则本文所述的二环杂环基团可在碳或氮原子上被取代。优选的是当杂环中的S和O原子总数超过1时,则这些杂原子不彼此毗邻。优选的是杂环中的S和O原子总数不大于1。
二环杂环基团的实例是但不限于喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、吲哚啉基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。
如本文所使用,术语“芳族杂环基团”或“杂芳基”指被取代和未被取代的芳族5-或6-元单环基团、9-或10-元双环基团和11-至14-元三环基团,其在所述环中的至少一个中具有至少一个杂原子(O、S或N),所述含杂原子的环优选地具有1个、2个或3个选自O、S和N的杂原子。含有杂原子的杂芳基的每一环可含有一或两个氧或硫原子和/或一至四个氮原子,前提为每一环中杂原子的总数为4或更小,且每一环具有至少一个碳原子。杂芳基可被取代或未被取代。氮原子可被取代或未被取代(即,若定义,则为N或NR,其中R为H或另一取代基)。氮和硫杂原子可任选被氧化(也即,N→O和S(O)p),且氮原子可任选被季铵化。
为双环或三环的杂芳基必须包括至少一个完全芳族环,但其它一或多个稠环可为芳族或非芳族。杂芳基可在任一环的任一可用氮或碳原子处连接。杂芳基环系统可含有0个、1个、2个或3个取代基。杂芳基包括(但不限于)吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、喹啉基、异喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、异噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、嘌呤基、咔唑基、苯并咪唑基、吲哚啉基、苯并二氧杂环戊烷基和苯并二氧杂环己烷。
术语“抗衡离子”用于表示带负电荷的物质,例如氯离子、溴离子、氢氧根、乙酸根和硫酸根。
当环结构内使用虚线环时,这指示所述环结构可以是饱和的、部分饱和的或不饱和的。
如本文中所提及,术语“取代的”意指至少一个氢原子被非氢基团替换,前提是维持正常的化合价且所述取代得到稳定化合物。当取代基是酮(keto)(即,=O)时,则原子上的2个氢被替换。酮取代基不存在于芳族部分上。当提及环系统(例如,碳环或杂环)被羰基或双键取代时,意指所述羰基或双键是环之一部分(即,在环内)。如本文所用,环双键为在两个毗邻环原子之间形成的双键(例如,C=C、C=N或N=N)。
其中在本发明化合物上存在氮原子(例如,胺)的情况下,可通过用氧化剂(例如,mCPBA和/或过氧化氢)处理而将其转化成N-氧化物,获得本发明的其它化合物。因此,所显示和要求保护的氮原子被视为涵盖所显示氮和其N-氧化物(N→O)衍生物二者。
当任何变量在化合物的任何构成或式中出现多于一次时,其在每次出现时的定义独立于其在每次其它出现时的定义。因此,例如,如果显示基团被0-3个R基团取代,则所述基团可任选被至多三个R基团取代,且在每次出现时R独立地选自R的定义。此外,取代基和/或变量的组合仅当所述组合得到稳定化合物时才是允许的。
当显示键合至取代基的键与连接环中两个原子的键交叉时,则所述取代基可键合至所述环上的任何原子上。当列举取代基但未指明所述取代基键合至给定式的化合物的其余部分上的原子时,则所述取代基可通过所述取代基中的任何原子来键合。取代基和/或变量的组合仅当所述组合得到稳定化合物时才是允许的。
短语“药学上可接受的”在本文中用于指以下那些化合物、材料、组合物和/或剂型:其在合理医学判断的范围内,适用于与人类和动物的组织接触而无过度的毒性、刺激性、过敏反应和/或其它问题或并发症,并与合理的益处/风险比率相称。
如本文中所用,“药学上可接受的盐”是指所公开化合物的衍生物,其中通过制备其酸式盐或碱式盐来修饰母体化合物。药学上可接受的盐的实例包括但不限于碱性基团诸如胺的无机或有机酸盐;和酸性基团诸如羧酸的碱性或有机盐。药学上可接受的盐包括例如自无毒无机或有机酸形成的母体化合物的常规无毒盐或季铵盐。例如,此类常规无毒盐包括衍生自无机酸的那些,所述无机酸诸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸;和制备自有机酸的盐,所述有机酸诸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲烷磺酸、乙烷二磺酸、草酸和羟乙磺酸。
本发明的药学上可接受的盐可通过常用化学方法自含有碱性或酸性部分的母体化合物合成。通常,可通过使这些化合物的游离酸或碱形式与化学计量量的适当碱或酸在水中或在有机溶剂中或在二者的混合物中反应来制备此类盐;通常,优选非水性介质,如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。适宜盐的列表见于Remington's Pharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA (1990)中,其公开内容以引用方式并入本文中。
此外,式I化合物可具有前药形式。本发明的范围和精神内的前药是在体内转化以提供生物活性剂(即,式I化合物)的任何化合物。前药的各种形式是本领域众所周知的。此类前药衍生物的实例,参见:
a) Bundgaard, H., 编, Design of Prodrugs, Elsevier (1985)和Widder, K.等人, 编, Methods in Enzymology, 112:309-396, Academic Press (1985);
b) Bundgaard, H., Chapter 5, "Design and Application of Prodrugs", A Textbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen, P. 等人, 编, Harwood Academic Publishers (1991);
c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);
d) Bundgaard, H. 等人, J. Pharm. Sci., 77:285 (1988); 和
e) Kakeya, N. 等人, Chem. Pharm. Bull., 32:692 (1984)。
含有羧基的化合物可形成生理学上可水解的酯,所述酯通过在体内水解以得到式I化合物本身来用作前药。由于在许多情况下水解主要在消化酶的影响下发生,因此优选口服给药此类前药。肠胃外给药可用于酯自身具有活性的情况或在血液中发生水解的那些情况。式I化合物的生理学上可水解酯的实例包括C1-6烷基、C1-6烷基苄基、4-甲氧基苄基、茚满基、邻苯二甲酰基、甲氧基甲基、C1-6烷酰氧基-C1-6烷基(例如,乙酰氧基甲基、新戊酰基氧基甲基或丙酰基氧基甲基)、C1-6烷氧基羰基氧基-C1-6烷基(例如,甲氧基羰基-氧基甲基或乙氧基羰基氧基甲基、甘胺酰基氧基甲基、苯基甘胺酰基氧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基)酯和用于例如青霉素和头孢菌素领域中的其它众所周知的生理学上可水解的酯。可通过本领域已知的常用技术来制备此类酯。
前药的制备是本领域众所周知的并描述于,例如,King,F.D.编辑,Medicinal Chemistry:Principles and Practice,The Royal Society of Chemistry,Cambridge,UK(1994);Testa,B.等人,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology,VCHA and Wiley-VCH,Zurich,Switzerland (2003);Wermuth,C.G.编辑,The Practice of Medicinal Chemistry,Academic Press,SanDiego,CA (1999)中。
本发明意欲包括在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。借助一般实例但不加以限制,氢的同位素包括氘和氚。氘在其核中具有一个质子和一个中子且其具有普通氢的两倍的质量。氘可通过诸如“2H”或“D”的符号来表示。在本文中术语“氘化”,其本身或用于修饰化合物或基团,是指用氘原子代替连接至碳的一个或多个氢原子。碳的同位素包括13C和14C。
同位素标记的本发明化合物通常可通过本领域技术人员已知的常用技术,或可通过与本文所述的那些类似的方法,使用适当同位素标记的试剂代替原本采用的未标记的试剂来制备。此类化合物具有多种潜在用途,例如,作为测定潜在医药化合物结合至靶蛋白或受体的能力的标准品和试剂,或用于使体内或体外结合至生物受体的本发明化合物成像。
“稳定的化合物”和“稳定的结构”意欲指示足够稳健以经受自反应混合物以有用程度的纯度分离并配制成有效治疗剂的化合物。优选地,本发明化合物不含N-卤素、S(O)2H或S(O)H基团。
术语“溶剂化物”意指本发明化合物与一种或多种溶剂分子(有机或无机)的物理缔合。此物理缔合包括氢键合。在某些情况下,例如,当一种或多种溶剂分子掺入结晶固体的晶格中时,溶剂化物将能够分离。溶剂化物中的溶剂分子可以规则排列和/或无序排列存在。溶剂化物可包含化学计量或非化学计量量的溶剂分子。“溶剂化物”涵盖溶液相和可分离溶剂化物二者。示例性溶剂化物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域普遍已知的。
如本文所用的缩写定义如下:“1 x”为一次,“2 x”为两次,“3 x”为三次,“℃”为摄氏度,“eq”为当量,“g”为克,“mg”为毫克,“L”为升,“mL”为毫升,“μL”为微升,“N”为当量,“M”为摩尔(molar),“mmol”为毫摩尔,“min”为分钟,“h”为小时,“rt”为室温,“RT”为保留时间,“atm”为大气压,“psi”为磅/平方英寸,“conc.”为浓,“sat”或“saturated”为饱和的,“MW”为分子量,“mp”为熔点,“ee”为对映异构体过量,“MS”或“Mass Spec”为质谱,“ESI”为电喷雾离子化质谱,“HR”为高分辨,“HRMS”为高分辨质谱,“LCMS”为液相色谱质谱,“HPLC”为高压液相色谱,“RP HPLC”为反相HPLC,“TLC”或“tlc”为薄层色谱,“NMR”为核磁共振光谱,“nOe”为核欧沃豪斯效应光谱(nuclear Overhauser effect spectroscopy),“1H”为质子,“δ”为德耳塔(delta),“s”为单峰,“d”为双重峰,“t”为三重峰,“q”为四重峰,“m”为多重峰,“br”为宽峰,“Hz”为赫兹,且“α”、“β”、“R”、“S”、“E”和“Z”为本领域技术人员熟悉的立体化学命名。
Me 甲基
Et 乙基
Pr 丙基
i-Pr 异丙基
Bu 丁基
i-Bu 异丁基
t-Bu 叔丁基
Ph 苯基
Bn 苄基
Boc 叔丁氧羰基
AcOH或HOAc 乙酸
AlCl3 氯化铝
AIBN 偶氮二异丁腈
BBr3 三溴化硼
BCl3 三氯化硼
BEMP 2-叔丁基亚氨基-2-二乙基氨基-1,3-二甲基全氢-1,3,2-二氮杂磷杂苯(diazaphosphorine)
BOP试剂 六氟磷酸苯并三唑-1-基氧基三(二甲基氨基)鏻
Burgess试剂 1-甲氧基-N-三乙基铵磺酰基-甲亚胺酸酯
CBz 苄氧羰基
CH2Cl2 二氯甲烷
CH3CN或ACN 乙腈
CDCl3 氘代-氯仿
CHCl3 氯仿
mCPBA或m-CPBA 间-氯过氧苯甲酸
Cs2CO3 碳酸铯
Cu(OAc)2 乙酸铜(II)
Cy2NMe N-环己基-N-甲基环己胺
DBU 1,8-二氮杂二环[5.4.0]十一-7-烯
DCE 1,2二氯乙烷
DCM 二氯甲烷
DEA 二乙胺
Dess-Martin 1,1,1-三(乙酰基氧基)-1,1-二氢-1,2-苯碘酰(beniziodoxol)-3-(1H)-酮
DIC或DIPCDI 二异丙基碳二亚胺
DIEA、DIPEA或 Hunig碱 二异丙基乙胺
DMAP 4-二甲基氨基吡啶
DME 1,2-二甲氧基乙烷
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
cDNA 互补DNA
Dppp (R)-(+)-1,2-双(二苯基膦基)丙烷
DuPhos (+)-1,2-双((2S,5S)-2,5-二乙基磷杂环戊基)苯
EDC N-(3-二甲基氨基丙基)-N΄-乙基碳二亚胺
EDCI N-(3-二甲基氨基丙基)-N΄-乙基碳二亚胺盐酸盐
EDTA 乙二胺四乙酸
(S,S)-EtDuPhosRh(I) 三氟甲磺酸(+)-1,2-双((2S,5S)-2,5-二乙基磷杂环戊基)苯(1,5-环辛二烯)铑(I)
Et3N或TEA 三乙胺
EtOAc 乙酸乙酯
Et2O 乙醚
EtOH 乙醇
GMF 玻璃微纤维过滤器
Grubbs (II) (1,3-双(2,4,6-三甲基苯基)-2-咪唑烷亚基)二氯(苯基亚甲基)(三环己基膦)钌
HCl 盐酸
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N',N′-四甲基脲鎓六氟磷酸盐
HEPES 4-(2-羟基乙基)哌嗪-1-乙烷磺酸
Hex 己烷
HOBt或HOBT 1-羟基苯并三唑
H2SO4 硫酸
K2CO3 碳酸钾
KOAc 乙酸钾
K3PO4 磷酸钾
LAH 氢化锂铝
LG 离去基团
LiOH 氢氧化锂
MeOH 甲醇
MgSO4 硫酸镁
MsOH或MSA 甲磺酸
NaCl 氯化钠
NaH 氢化钠
NaHCO3 碳酸氢钠
Na2CO3 碳酸钠
NaOH 氢氧化钠
Na2SO3 亚硫酸钠
Na2SO4 硫酸钠
NBS N-溴代琥珀酰亚胺
NCS N-氯代琥珀酰亚胺
NH3 氨
NH4Cl 氯化铵
NH4OH 氢氧化铵
OTf 三氟甲磺酸酯或三氟甲烷磺酸酯
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
Pd(OAc)2 乙酸钯(II)
Pd/C 碳载钯
Pd(dppf)Cl2 [1,1΄-双(二苯基膦基)-二茂铁]二氯钯(II)
Ph3PCl2 二氯化三苯基膦
PG 保护基团
POCl3 磷酰氯
i-PrOH或IPA 异丙醇
PS 聚苯乙烯
PyBOP 六氟磷酸苯并三唑-1-基-氧基三吡咯烷子基鏻
SEM-Cl 2-(三甲基甲硅烷基)乙氧基甲基氯化物
第2代XPhos预催化剂 氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'联苯)[2-(2'-氨基-1,1'-联苯)]钯(II),THF加合物
SiO2 二氧化硅
SnCl2 氯化锡(II)
TBAI 碘化四-正丁基铵
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TMSCHN2 三甲基甲硅烷基重氮甲烷
T3P® 丙烷膦酸酐
TRIS 三(羟基甲基)氨基甲烷。
可以以有机合成领域技术人员已知的多种方式来制备本发明化合物。
IV. 生物学
体外试验
可在30 µL 试验(含有20 mM HEPES,pH 7.5,20 mM MgCl2,0.015% Brij-35,4 mMDTT,5 µM ATP和1.5 µM肽底物(FITC-AHA-AKRRRLSSLRA-OH))中测定本发明化合物作为ROCK抑制剂的有效性。将化合物溶于DMSO中,从而使得DMSO的最终浓度为< 2%,并用Rho激酶变体起始反应。孵育后,通过加入EDTA终止反应,并使用LABCHIP® 3000读取器(CaliperLife Sciences)分离磷酸化肽和非磷酸化肽。对照由不含有化合物的试验组成,并且背景由含有酶和底物但从反应开始具有EDTA以抑制激酶活性的试验组成。以剂量-应答形式测试化合物,并计算每一化合物浓度下的激酶活性抑制。使用曲线-拟合程序拟合抑制数据以测定IC50;即,抑制50%的激酶活性所需的化合物浓度。
在上文所述的ROCK2试验中测试代表性实施例并发现具有ROCK抑制活性。下表A列出对于实例所测量的ROCK2 IC50值范围:A= 0 - 2 nM;B= 2.1 - 20 nM;C= 20.1 - 200nM;D= 200.1 - 2000 nM。
表A
V. 药物组合物、制剂和组合
本发明化合物可以这样的口服剂型给药,如片剂、胶囊剂(其各自包括持续释放或定时释放制剂)、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮剂、糖浆剂和乳剂。其也可以静脉内(推注或输注)、腹膜内、皮下或肌内形式给药,所有均使用药学领域的普通技术人员所众所周知的剂型。其可单独给药,但通常将与基于所选给药途径和标准药学实践选择的药物载体一起给药。
术语“药物组合物”意指包含本发明化合物与至少一种其它药学上可接受的载体的组合的组合物。“药学上可接受的载体”是指本领域通常接受用于将生物活性剂递送至动物(尤其哺乳动物)的介质,包括,即,辅剂、赋形剂或媒介物,诸如稀释剂、防腐剂、填充剂、流动调节剂、崩解剂、湿润剂、乳化剂、悬浮剂、甜味剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂,其取决于给药模式和剂型的性质。根据本领域普通技术人员所知范围内的许多因素来配制药学上可接受的载体。这些因素包括但不限于:所配制活性剂的类型和性质;含有所述药剂的组合物欲给药的患者;组合物的预期给药途径;和所靶向的治疗适应症。药学上可接受的载体包括水性和非水性液体介质,以及多种固体和半固体剂型。此类载体可包括除活性剂外的许多不同成分和添加剂,此类其它成分出于本领域普通技术人员所众所周知的多种原因(例如,活性剂的稳定、粘合剂等)而包括在制剂中。合适的药学上可接受的载体和其选择中所涉及的因素的描述见于多个容易获得的来源,例如,Remington's Pharmaceutical Sciences,第18版 (1990)。
当然,本发明化合物的剂量方案将根据已知因素而变化,诸如具体药剂的药效学特征和其给药模式和途径;接受者的物种、年龄、性别、健康状况、医学疾病状态和体重;症状的性质和程度;同时治疗的种类;治疗频率;给药途径;患者的肾和肝功能;和期望效应。医师或兽医可确定和开出预防、抵抗或阻止病症进展所需的药物的有效量。
根据通用指南,当用于所示效应时,各活性成分的每日口服剂量的范围将为约0.001-约1000mg/kg体重,优选约0.01-约100mg/kg体重/天,且最优选约0.1-约20mg/kg/天。在恒速输注期间,静脉内最优选剂量的范围将为约0.001-约10mg/kg/分钟。本发明化合物可以每日单次剂量给药,或每日总剂量可以每日两次、三次或四次的分开剂量给药。
本发明化合物也可通过肠胃外给药(例如,静脉内、动脉内、肌内或皮下)来给药。当静脉内或动脉内给药时,所述剂量可连续或间歇给药。此外,可开发用于肌内和皮下递送以确保逐步释放活性药物成分的制剂。
本发明化合物可经由局部使用合适的鼻内媒介物以鼻内形式给药,或使用透皮皮肤贴剂经由透皮途径给药。当以透皮递送系统的形式进行给药时,整个剂量方案中剂量给药当然将为连续的而非间歇的。
所述化合物通常以与针对预期给药形式(例如,口服片剂、胶囊剂、酏剂和糖浆剂)适当选择并与常规药物实践相符的合适的药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
例如,对于以片剂或胶囊剂形式的口服给药,所述活性药物组分可与口服无毒的药学上可接受的惰性载体组合,所述惰性载体诸如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露醇、山梨醇等;对于以液体形式的口服给药,所述口服药物组分可与任何口服无毒的药学上可接受的惰性载体组合,所述惰性载体诸如乙醇、甘油、水等。此外,当期望或必要时,也可将合适的粘合剂、润滑剂、崩解剂和着色剂掺入混合物中。合适的粘合剂包括淀粉、明胶、天然糖类(诸如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶(诸如阿拉伯胶、西黄蓍胶或海藻酸钠)、羧甲基纤维素、聚乙二醇、蜡等。这些剂型中所使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
本发明化合物也可以脂质体递送系统的形式给药,诸如小单层囊泡、大单层囊泡和多层囊泡。脂质体可形成自多种磷脂,诸如胆固醇、硬脂酰胺或磷脂酰胆碱类。
本发明化合物也可与作为可靶向药物载体的可溶性聚合物偶联。此类聚合物可包括聚乙烯基吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺-苯酚、聚羟乙基天门冬酰胺苯酚或被棕榈酰残基取代的聚环氧乙烷-聚赖氨酸。此外,本发明化合物可与可用于实现药物受控释放的一类生物可降解聚合物偶联,所述聚合物例如聚乳酸、聚乙醇酸、聚乳酸与聚乙醇酸的共聚物、聚ε己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲性嵌段共聚物。
适于给药的剂型(药物组合物)可含有约1毫克至约1000毫克活性成分/剂量单位。在这些药物组合物中,所述活性成分通常将以基于组合物总重量的约0.1-95重量%的量存在。
明胶胶囊剂可含有活性成分和粉末状载体,诸如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。类似的稀释剂可用于制备压制片剂。片剂和胶囊剂二者均可制成持续释放产品,以提供药物在数小时时段内的连续释放。压制片剂可以是包糖衣的或包薄膜衣的,以掩蔽任何不愉快的味道并保护片剂远离大气,或是包肠溶衣的,用于在胃肠道中选择性崩解。
用于口服给药的液体剂型可含有着色剂和矫味剂以提高患者接受度。
一般而言,水、合适的油、盐水、水性右旋糖(葡萄糖)以及相关的糖溶液和二醇类诸如丙二醇或聚乙二醇为用于肠胃外溶液剂的合适载体。用于肠胃外给药的溶液剂优选含有活性成分的水溶性盐、合适的稳定剂和缓冲物质(如有必要)。抗氧化剂诸如亚硫酸氢钠、亚硫酸钠或抗坏血酸(单独或组合)为合适的稳定剂。也使用柠檬酸和其盐和EDTA钠。此外,肠胃外溶液剂可含有防腐剂,诸如苯扎氯铵、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯和氯丁醇。
本发明化合物可单独给药或与一种或多种其它治疗剂组合给药。“组合给药”或“组合疗法”意指向所治疗的哺乳动物同时给药本发明化合物和一种或多种其它治疗剂。当组合给药时,每一组分可同时给药或在不同时间点以任何顺序连续给药。因此,可单独给药每一组分但时间足够接近以提供期望的治疗效应。
本发明化合物也可用作涉及抑制ROCK的测试或试验中的标准或参考化合物,例如用作质量标准或对照。此类化合物可提供于商业试剂盒中,例如,用于涉及ROCK的药物研究中。例如,本发明化合物可用作试验中的参考以与具有未知活性的化合物比较其已知活性。这将确保实验者合理实施试验且提供比较依据,尤其在测试化合物是参考化合物的衍生物的情况下。当开发新试验或方案时,可使用本发明化合物测试其有效性。
本发明也涵盖制品。如本文所用,制品意欲包括但不限于试剂盒和包装。本发明制品包含:(a)第一容器;(b)位于第一容器内的药物组合物,其中所述组合物包含:第一治疗剂,其包含:本发明化合物或其药学上可接受的盐形式;和(c)包装说明书(insert),其说明所述药物组合物可用于治疗心血管和/或炎性病症(如前文所定义)。在另一个实施方案中,所述包装说明书说明所述药物组合物可与第二治疗剂组合使用(如前文所定义)以治疗心血管和/或炎性病症。所述制品可进一步包含:(d)第二容器,其中组分(a)和(b)位于第二容器内且组分(c)位于第二容器内部或外部。位于第一和第二容器内意指各容器将物品保留在其边界内。
第一容器为用于容纳药物组合物的贮器。该容器可用于制造、储存、运送和/或个别/批量销售。第一容器意欲涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如,用于乳膏制剂),或用于制造、容纳、储存或分配药物产品的任何其它容器。
第二容器为用于容纳第一容器和任选包装说明书的容器。第二容器的实例包括但不限于盒(例如,纸盒或塑料盒)、篓、纸箱、袋(例如,纸袋或塑料袋)、小袋和大袋。包装说明书可经由胶带、胶水、U形钉或另一连接方法物理连接至第一容器外部,或其可放在第二容器内部,而无需连接至第一容器的任何物理方式。替代地,包装说明书位于第二容器外部。当位于第二容器外部时,优选的是包装说明书经由胶带、胶水、U形钉或另一连接方法物理连接。替代地,其可毗邻或接触第二容器外部而无物理连接。
包装说明书为标记、标签、标记物等,其记载与位于第一容器内的药物组合物相关的信息。所记载的信息通常将由管理销售制品的区域的管理机构(例如,美国食品与药品管理局)确定。优选地,包装说明书具体记载药物组合物获批用于的适应症。包装说明书可由任何材料制成,人们可在所述材料上读取包含于其中或其上的信息。优选地,包装说明书为可印刷材料(例如,纸、塑料、卡纸板、箔、胶粘纸或塑料等),其上已形成(例如,印刷或施加)期望的信息。
在下文描述示例性实施方案的过程中,本发明的其它特征将变得显而易见,给出所述实施方案用于说明本发明而不意欲成为其限制。以下实施例使用本文所公开的方法制备、分离和表征。
VI. 包括方案在内的一般合成
可通过有机化学领域技术人员可获得的方法来合成本发明化合物(Maffrand,J.P.等人,Heterocycles,16(1):35-37 (1981))。下文描述用于制备本发明化合物的一般合成方案。这些方案是说明性的且并非意欲限制本领域技术人员可用于制备本文所公开化合物的可能技术。本领域技术人员将明了制备本发明化合物的不同方法。此外,可以交替(alternate)顺序实施合成中的各个步骤以得到一种或多种期望化合物。
通过一般方案中所述的方法制备的本发明化合物的实例在下文所述的中间体和实施例部分中给出。可通过本领域技术人员已知的技术来实施制备纯手性实例。例如,可通过手性相制备型HPLC分离外消旋产物来制备纯手性化合物。替代地,可通过已知获得富含对映异构体的产物的方法来制备实施例化合物。这些包括但不限于在外消旋中间体中掺入手性辅助官能团以用于控制转换的非对映异构选择性,从而在裂解手性辅助官能团后提供富含对映异构体的产物。
可以有机合成领域技术人员已知的多种方式来制备本发明化合物。可使用下述方法以及合成有机化学领域中已知的合成方法或通过本领域技术人员所了解的其变化形式来合成本发明化合物。优选方法包括但不限于下文所述的那些。在适用于所使用试剂和材料和适用于所实现转变的溶剂或溶剂混合物中实施反应。有机合成领域的技术人员将理解,分子上存在的官能性应与所提出的转变一致。这有时需要加以判断以改变合成步骤的顺序或选择一种特定方法方案(与另一方案相比)以便获得期望的本发明化合物。
还将意识到,在计划该领域中的任何合成途径时的另一主要考虑为,谨慎选择用于保护本发明中所述化合物中所存在的反应性官能基的保护基团。描述用于经培训从业人员的许多替代方式的权威性报告为Greene等人(Protective Groups in Organic Synthesis,第4版,Wiley-Interscience (2006))。
方案1
方案1显示由胺1a合成化合物1f。用适当卤代醛或卤代酮的还原胺化得到胺1b。通过与异氰酸酯反应或用三光气、随后胺处理实现脲形成,以得到1c。1c用碱诸如NaH环化得到环状脲1d。该中间体可使用Pd催化与芳基或杂芳基硼酸直接偶联,以得到1f。或者,1d可经由Suzuki/Miyaura偶联而转化成硼酸/酯1e且随后经由使用Pd催化与适当芳基或杂芳基卤化物偶联而转化成化合物1f。
方案2
方案2显示通用结构2d的化合物的制备。化合物1a用二卤代酯烷基化以得到2a,其可用异氰酸酯或三光气、随后胺(H2NRʹ)处理以得到脲,所述脲自发环化或在加热下或任选用碱诸如NaH或K2CO3处理而环化,以得到2b。2b任选地通过用碱诸如LiHMDS或LDA去质子化,随后用亲电体RʹʹX处理而进一步官能化,以得到2c。酯部分任选地通过用碱诸如LiBH4还原、通过用烷基金属物质诸如Grignard试剂的处理而烷基化、或通过水解和与所得酸形成酰胺而进一步官能化,以得到2c。Suzuki偶联得到2d。
方案3
方案3显示通用结构3d的化合物的合成。RʹNH2与二卤代酯的反应得到3a。3a与异氰酸酯(与1a相关)或三光气反应,随后用胺1a处理得到脲,所述脲自发或在加热下或任选用碱诸如NaH或K2CO3处理环化,以得到3b。3b任选地通过用碱诸如LiHMDS或LDA去质子化,随后用亲电体RʹʹX处理而进一步官能化,以得到3c。酯部分任选地通过用碱诸如LiBH4还原、通过用烷基金属物质诸如Grignard试剂处理而烷基化、或通过水解和与所得酸形成酰胺而进一步官能化,以得到3c。Suzuki偶联得到3d。
方案4
方案4显示从异氰酸酯4a开始合成咪唑酮4f,所述异氰酸酯4a是市售的或可从胺前体经由用光气和碱诸如TEA处理来制备。用胺4b处理4a得到脲4c。通过用酸诸如HCl处理来实现环化,以得到4d。4d通过用碱诸如NaH或K2CO3和亲电体处理而烷基化得到4e。Suzuki偶联得到4f。
方案5
方案5显示从异氰酸酯4a开始合成咪唑烷二酮5d,所述异氰酸酯4a是市售的或可从胺前体经由用光气和碱诸如TEA处理来制备。4a用氨基酯5a处理得到脲,所述脲自发或在加热下或任选用碱诸如NaH或K2CO3处理而环化,以得到咪唑烷酮二酮5b。通过用碱诸如NaH或K2CO3和亲电体处理而烷基化得到5c。Suzuki偶联得到5d。
方案6
方案6显示以胺1a开始合成咪唑烷二酮6e,胺1a与6a一起进行使用还原剂诸如Na(OAc)3BH的还原胺化。在碱诸如吡啶中在加热下用脲处理6b得到6c。通过用碱诸如NaH或K2CO3和亲电体处理而烷基化得到6d。Suzuki偶联得到6e。
方案7
方案7显示从胺1a开始合成通用化合物7e。用异氰酸酯7a处理得到脲7b,所述异氰酸酯7a是市售的或可从胺前体经由用光气和碱诸如TEA处理来制备。用碱诸如NaH或K2CO3处理得到环化产物7c。通过用碱诸如NaH或K2CO3和亲电体处理而烷基化得到7d。Suzuki偶联得到7e。
经由正相或反相色谱法来实施中间体和最终产物的纯化。除非另外指明,否则使用预先充填的SiO2筒,使用己烷和EtOAc或DCM和MeOH的梯度洗脱实施正相色谱法。使用以下实施反相制备型HPLC:C18柱,使用溶剂A (90% H2O,10% MeOH,0.1% TFA)和溶剂B (10%H2O,90% MeOH,0.1% TFA,UV 220 nm)的梯度或溶剂A (90% H2O,10% ACN,0.1% TFA)和溶剂B (10% H2O,90% ACN,0.1% TFA,UV 220 nm)的梯度或溶剂A (98% H2O,2% ACN,0.05% TFA)和溶剂B (98% ACN,2% H2O,0.05% TFA,UV 220 nm)的梯度进行洗脱,(或) SunFire PrepC18 OBD 5µ 30 × 100 mm,25分钟,从0%至100% B的梯度,A = H2O/ACN/TFA 90:10:0.1,B= ACN/H2O/TFA 90:10:0.1 (或) Waters XBridge C18, 19 × 200 mm, 5-μm颗粒;保护柱:Waters XBridge C18, 19 × 10 mm, 5-μm颗粒;溶剂A:具有20-mM乙酸铵的水;溶剂B:95:5乙腈:水(具有20-mM乙酸铵);梯度:25-65% B经20分钟,然后在100% B下保持5分钟;流速:20 mL/min。
除非另有说明,否则借由反相分析型HPLC来实施最终产物的分析。
方法A:SunFire C18柱(3.5 μm C18, 3.0 × 150 mm)。使用经12分钟的10-100%溶剂B且然后100%溶剂B持续3分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05%TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
方法B:XBridge苯基柱(3.5 μm C18, 3.0 × 150 mm)。使用经12分钟的10-100%溶剂B且然后100%溶剂B持续3分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05%TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
方法C:Ascentis Express C18, 2.1 × 50 mm, 2.7-μm颗粒;溶剂A:95%水、5%乙腈、0.05% TFA;溶剂B:95%乙腈、5%水、0.1% TFA;温度:50℃;梯度:经4分钟的0-100% B,然后在100% B下保持1分钟;流速:1.1 mL/min。
方法D:Ascentis Express C18, 2.1 × 50 mm, 2.7-μm颗粒;溶剂A:95%水、5%乙腈,含有10 mM乙酸铵;溶剂B:95%乙腈、5%水,含有10 mM乙酸铵;温度:50℃;梯度:经4分钟的0-100% B,然后在100% B下保持1分钟;流速:1.1 mL/min。
方法E:Ascentis Express C18, 2.1 × 50 mm, 2.7-μm颗粒;溶剂A:95%水、5%乙腈、0.05% TFA;溶剂B:95%乙腈、5%水、0.1% TFA;温度:50℃;梯度:经3分钟的0-100% B,然后在100% B下保持1分钟;流速:1.1 mL/min。
方法F:Ascentis Express C18, 2.1 × 50 mm, 2.7-μm颗粒;溶剂A:95%水、5%乙腈,含有10 mM乙酸铵;溶剂B:95%乙腈、5%水,含有10 mM乙酸铵;温度:50℃;梯度:经3分钟的0-100% B,然后在100% B下保持1分钟;流速:1.1 mL/min。
方法G:SunFire C18柱(3.5 μm C18, 3.0 × 150 mm)。使用经25分钟的10-100%溶剂B且然后100%溶剂B持续5分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05%TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
方法H:XBridge苯基柱(3.5 μm C18, 3.0 × 150 mm)。使用经25分钟的10-100%溶剂B且然后100%溶剂B持续5分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05%TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
方法I:SunFire C18柱(3.5 μm, 4.6 × 150 mm)。使用经12分钟的10-100%溶剂B且然后100%溶剂B持续3分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05% TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
方法J:XBridge苯基柱(3.5 μm, 4.6 × 150 mm)。使用经12分钟的10-100%溶剂B且然后100%溶剂B持续3分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05% TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
方法K:SunFire C18柱(3.5 μm, 4.6 × 150 mm)。使用经25分钟的10-100%溶剂B且然后100%溶剂B持续5分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05% TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
方法L:XBridge苯基柱(3.5 μm, 4.6 × 150 mm)。使用经25分钟的10-100%溶剂B且然后100%溶剂B持续5分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05% TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
方法M:SunFire C18柱(3.5 μm, 4.6 × 150 mm)。使用经18分钟的10-100%溶剂B且然后100%溶剂B持续5分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05% TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
方法N:XBridge苯基柱(3.5 μm, 4.6 × 150 mm)。使用经18分钟的10-100%溶剂B且然后100%溶剂B持续5分钟的梯度洗脱(1.0 mL/min)。溶剂A为95%水、5%乙腈、0.05% TFA且溶剂B为5%水、95%乙腈、0.05% TFA,UV 220 nm。
SFC和手性纯度方法
方法I:CHIRALPAK® AD-H, 250 × 4.6 mm, 5.0-μm颗粒;CO2:60%,共溶剂:40%{0.2% DEA/IPA:A CN(1:1)},总流速:4.0 g/min,背压:100巴,温度:25℃,UV:218 nm。
方法II:CHIRALPAK® OD-H, 250 × 4.6 mm, 5.0-μm颗粒;CO2:60%,共溶剂:40%{0.2% DEA/IPA:A CN(1:1)},总流速:4.0 g/min,背压:104巴,温度:24.9℃,UV:287 nm。
方法III:CHIRALPAK® OJ-H, 250 × 4.6 mm, 5.0-μm颗粒;CO2:60%,共溶剂:30% (0.3% DEA/甲醇),总流速:4.0 g/min,背压:101巴,温度:23.6℃,UV:272 nm。
方法IV:CHIRALPAK® AS-H, 250 × 4.6 mm, 5.0-μm颗粒;CO2:60%,共溶剂:40%(0.3% DEA/甲醇),总流速:4.0 g/min,背压:102巴,温度:25.4℃,UV:272 nm。
方法V:CHIRALCEL® OJ-H, 250 × 4.6 mm, 5.0-μm颗粒;CO2:60%,共溶剂:40%(0.2% DEA/甲醇),总流速:4.0 g/min,背压:102巴,温度:24.6℃,UV:272 nm。
方法VI:Lux Cellulose-2, 250 × 4.6 mm, 5.0-μm颗粒;CO2:60%,共溶剂:35%(0.2% DEA/甲醇),总流速:3.0 g/min,背压:101巴,温度:23.6℃,UV:260 nm。
方法VII:CHIRALCEL® AS-H, 250 × 4.6 mm, 5.0-μm颗粒;CO2:60%,共溶剂:40% (0.2% DEA/甲醇),总流速:4.0 g/min,背压:101巴,温度:24.4℃,UV:270 nm。
方法VIII:CHIRALPAK® IC, 250 × 4.6 mm, 5.0-μm颗粒;CO2:60%,共溶剂:40%(0.2% DEA/甲醇),总流速:4.0 g/min,背压:101巴,温度:24.4℃,UV:270 nm。
方法IX:柱:CHIRALPAK® IF (250 × 4.6mm), 5 μ,流动相:0.2% DEA/乙醇,流速:1.0 ml/min。
方法X:柱:Lux Amylose 2 (250 × 4.6mm), 5 μ,流动相:0.2% DEA/正己烷:乙醇:5:95,流速:1.0 ml/min。
方法XI:柱:CHIRALCEL® OD-H (250 × 4.6mm), 5 μ,流动相:0.2% DEA/正己烷:乙醇:70:30,流速:1.0 ml/min。
方法XII:柱:CHIRALPAK® ID (250 × 4.6mm), 5 μ,流动相:含0.1% DEA的甲醇,流速:1.0 ml/min。
中间体1
4-溴-N-(2-氯乙基)苯胺
向4-溴苯胺(3.00 g,17.4 mmol)和2-氯乙醛(2.69 mL,20.9 mmol)于MeOH (25mL)中的溶液中添加氰基硼氢化钠(2.74 g,43.6 mmol),随后添加乙酸(1.00 mL,17.0mmol)。将混合物在室温下搅拌过夜。再添加氰基硼氢化钠(2.74 g,43.6 mmol)并将混合物搅拌1天。蒸发MeOH并将混合物用NaHCO3水溶液碱化并用乙酸乙酯(3×50 ml)萃取。将有机层干燥(Na2SO4)并蒸发。产物通过快速色谱(0-15% EtOAc/Hex梯度)纯化,以获得3.25 g(79%产率)作为无色油状物的中间体1。
中间体2
4-溴-N-(2-氯乙基)-3-甲氧基苯胺
向4-溴-3-甲氧基苯胺(4.00 g,19.8 mmol)和2-氯乙醛(3.05 mL,23.8 mmol)于MeOH (25 mL)中的溶液中添加氰基硼氢化钠(3.11 g,49.5 mmol),随后添加乙酸(1.13mL,19.8 mmol)。将混合物在室温下搅拌过夜。蒸发MeOH并将混合物用NaHCO3碱化并用乙酸乙酯(3×40 ml)萃取。干燥(Na2SO4)并蒸发有机层。产物通过快速色谱(0-15% EtOAc/己烷梯度)纯化,以获得3.20 g (61%产率)作为无色油状物的中间体2。
中间体3
4-溴-N-(2-氯乙基)-2-甲氧基苯胺
向4-溴-2-甲氧基苯胺(2.00 g,9.90 mmol)和2-氯乙醛(1.87 g,11.9 mmol)于甲醇(20 mL)中的溶液中添加氰基硼氢化钠(1.56 g,24.7 mmol)和乙酸(0.567 mL,9.90mmol)。将混合物在室温下搅拌过夜,然后浓缩。产物通过快速色谱(0-50% EtOAc/己烷梯度)纯化,以获得2.20 g (59%产率)作为黄色油状物的中间体3。
中间体4
2-溴-3-((4-溴苯基)氨基)丙酸乙酯
制备2-溴-3-((4-溴苯基)氨基)丙酸乙酯
向4-溴苯胺(20 g,116 mmol)于甲苯(100 mL)中的悬浮液中添加TEA (48.6 mL,349 mmol)并将混合物加热至50℃,然后逐滴添加2,3-二溴丙酸乙酯(16.90 mL,116mmol)/甲苯(50 mL)并将反应混合物在100℃下加热20小时。将反应混合物冷却至室温并用DCM (100 mL)和己烷稀释并过滤。浓缩滤液,以得到作为棕色固体的2-溴-3-((4-溴苯基)氨基)丙酸乙酯(5.8 g,11.8%产率)。
中间体5
1-(4-溴苯基)-3-(1-羟基-2-甲基丙-2-基)脲
制备1-(4-溴苯基)-3-(1-羟基-2-甲基丙-2-基)脲
向1-溴-4-异氰酸酯基(isocyanato)苯(500 mg,2.53 mmol)于DCM (25 mL)中的溶液中逐滴添加2-氨基-2-甲基丙-1-醇(270 mg,3.03 mmol)并将反应混合物在室温下搅拌16小时。将DCM浓缩至干燥并用己烷稀释残余物,过滤形成的固体并用己烷洗涤并在真空下干燥,以得到作为白色固体的中间体5 (1-(4-溴苯基)-3-(1-羟基-2-甲基丙-2-基)脲(0.7 g,97%产率)。
中间体6
制备1-(3-甲氧基苄基)氮杂环丙烷-2-甲酸乙酯
在室温下,向(3-甲氧基苯基)甲胺(2.0 g,14.58 mmol)于甲苯(30 mL)中的溶液中添加TEA (8.13 mL,58.3 mmol)和2,3-二溴丙酸乙酯(3.79 g,14.58 mmol)/甲苯(10mL),并将反应混合物在85℃下搅拌16小时。将反应混合物冷却至室温,过滤形成的固体并在真空下干燥,以得到作为黄色固体的中间体6 (1-(3-甲氧基苄基)氮杂环丙烷-2-甲酸乙酯) (4.2 g,76%产率)。
中间体7
制备2-氯-3-((3-甲氧基苄基)氨基)丙酸乙酯
在0℃下,向1-(3-甲氧基苄基)氮杂环丙烷-2-甲酸乙酯(4.2 g,17.85 mmol)于丙酮(45 mL)中的溶液中添加4 M HCl/二氧杂环己烷(13.39 mL,53.6 mmol),在室温下将反应混合物缓慢搅拌16小时。将反应物用NaHCO3 (100 mL)小心地淬灭并用EtOAc (2×100mL)萃取。将合并的有机层用水、盐水溶液洗涤,经Na2SO4干燥,过滤并浓缩。粗产物通过CombiFlash色谱(40 g REDISEP® SiO2柱,梯度洗脱;100% Hex持续5 min;0-60% EtOAc/Hex持续30 min)纯化,以得到作为黄色液体的中间体7,2-氯-3-((3-甲氧基苄基)氨基)丙酸乙酯(0.39 g,4.7%产率)。MS(ESI) m/z: 272.1 (M+H)+。
中间体8
制备1-(4-溴苯基)-3-(2-氯乙基)脲
在0℃下,向4-溴苯胺(5.00 g,29.1 mmol)于二氯甲烷(80 mL)中的混合物中缓慢添加1-氯-2-异氰酸酯基乙烷(2.98 mL,34.9 mmol)。将混合物在室温下搅拌16小时。将混合物浓缩。粗产物混合物通过用石油醚研磨来纯化,以得到6.00 g作为灰白色固体的中间体8 (74%产率)。
中间体9
1-(4-溴苯基)咪唑烷-2-酮
经30分钟向中间体6 (8.00 g,28.8 mmol)于THF (100 mL)中的冰冷的混合物中分数份添加氢化钠(2.08 g,860 mmol)。将混合物在室温下搅拌16小时,然后用冰淬灭并稀释于乙酸乙酯中。将有机层分离并用水和盐水洗涤,干燥(Na2SO4)并浓缩。该粗产物通过用己烷研磨来纯化,以得到作为灰白色固体的中间体9 (5.00 g,72%产率)。
中间体10
1-(5-溴-6-甲氧基吡啶-2-基)-3-(2-氯乙基)脲
在氮气气氛下,将5-溴-6-甲氧基吡啶-2-胺(1 g,4.93 mmol)溶解于二氯甲烷(30mL)中。冷却至0℃并逐滴添加异氰酸2-氯乙酯(2.079 g,19.70 mmol)并在室温下将反应混合物搅拌20小时。在减压下移除溶剂且获得的残余物用己烷洗涤并在抽吸下干燥,以得到作为灰白色固体的1-(5-溴-6-甲氧基吡啶-2-基)-3-(2-氯乙基)脲(1.12 g,3.60 mmol,73%产率)。
中间体11
1-(5-溴-6-甲氧基吡啶-2-基)咪唑烷-2-酮
在氮气气氛下,将1-(5-溴-6-甲氧基吡啶-2-基)-3-(2-氯乙基)脲(1.1 g,3.56mmol)溶解于THF (30 mL)中。冷却至0℃并添加氢化钠(于矿物油中的60%悬浮液) (0.428g,10.69 mmol)并在室温下将反应混合物搅拌6小时。添加MeOH (10 mL)并在减压下移除溶剂。将获得的固体用水洗涤并在抽吸下干燥,以得到作为灰白色固体的中间体11:1-(5-溴-6-甲氧基吡啶-2-基)咪唑烷-2-酮(0.84 g,3.04 mmol,85%产率)。
中间体12
1-(4-溴苯基)-3-(2,2-二甲氧基乙基)脲
向2,2-二甲氧基乙胺(3.01 mL,27.8 mmol)于二氯甲烷(100 mL)中的冰冷的混合物中逐滴添加1-溴-4-异氰酸酯基苯(5.5 g,27.8 mmol)并在环境温度下将混合物充分搅拌16小时。在真空中将反应混合物浓缩以得到粗物质,其用己烷研磨,以得到作为灰白色固体的1-(4-溴苯基)-3-(2,2-二甲氧基乙基)脲(8 g,22.17 mmol,80%产率)。
中间体13
1-(4-溴苯基)-1H-咪唑-2(3H)-酮
向1.5 M HCl/水(88 ml,132 mmol)中添加1-(4-溴苯基)-3-(2,2-二甲氧基乙基)脲(8 g,26.4 mmol)并将混合物在环境温度下充分搅拌20小时。然后通过使用饱和NaHCO3水溶液使反应混合物碱化并用DCM萃取产物。将合并的萃取物在水、随后盐水中洗涤,经无水硫酸钠干燥并在真空中浓缩,以得到作为灰白色固体的1-(4-溴苯基)-1H-咪唑-2(3H)-酮(5 g,18.61 mmol,70.5%产率)。
中间体14
(5-溴吡啶-2-基)氨基甲酸苯酯
向5-溴吡啶-2-胺(5 g,28.9 mmol)和吡啶(2.80 mL,34.7 mmol)于乙腈(100 mL)中的冰冷的混合物中添加氯甲酸苯酯(4.36 mL,34.7 mmol)并在环境温度下充分搅拌1小时。过滤反应混合物中形成的固体,用水洗涤并干燥,以得到作为灰白色固体的(5-溴吡啶-2-基)氨基甲酸苯酯(8.5 g,20.42 mmol,70.6%产率)。
中间体15
1-(5-溴吡啶-2-基)-3-(2,2-二甲氧基乙基)脲
向(5-溴吡啶-2-基)氨基甲酸苯酯(8.5 g,29.0 mmol)和吡啶(2.81 mL,34.8mmol)于THF (150 mL)中的混合物中添加2,2-二甲氧基乙胺(3.77 mL,34.8 mmol)并在70℃下加热16小时。将反应混合物用冰淬灭并用乙醚稀释。过滤沉淀的固体,用水洗涤并干燥,以得到作为灰白色固体的1-(5-溴吡啶-2-基)-3-(2,2-二甲氧基乙基)脲(7 g,22.27mmol,77%产率)。
中间体16
1-(5-溴吡啶-2-基)-1H-咪唑-2(3H)-酮
将1-(5-溴吡啶-2-基)-3-(2,2-二甲氧基乙基)脲(7 g,23.02 mmol)于2N HCl水溶液(200 ml,400 mmol)中的溶液在60℃下加热16小时。将反应混合物冷却至0℃并使用10% NaOH水溶液碱化至pH~8并用氯仿萃取。将合并的萃取物用水、随后盐水洗涤,经无水硫酸钠干燥并在真空中浓缩,以得到作为灰白色固体的1-(5-溴吡啶-2-基)-1H-咪唑-2(3H)-酮(4.6 g,18.31 mmol,80%产率)。
中间体17
制备1-(5-溴-4-甲基吡啶-2-基)-3-(2-氯乙基)脲
在0℃下,向5-溴-4-甲基吡啶-2-胺(2 g,10.69 mmol)于二氯甲烷(50 mL)中的混合物中缓慢添加1-氯-2-异氰酸酯基乙烷(1.095 mL,12.83 mmol)。在室温下将混合物搅拌16小时之后,将其浓缩。粗产物混合物通过用己烷研磨来纯化,以得到作为灰白色固体的1-(5-溴-4-甲基吡啶-2-基)-3-(2-氯乙基)脲(2.10 g,77%产率)。
中间体18
制备1-(5-溴-4-氟吡啶-2-基)-3-(2-氯乙基)脲
在0℃下,向5-溴-4-氟吡啶-2-胺(1.6 g,8.38 mmol)于二氯甲烷(30 mL)中的混合物中缓慢添加1-氯-2-异氰酸酯基乙烷(0.884 g,8.38 mmol)。在室温下将混合物搅拌16小时之后,将其浓缩。粗产物混合物通过用己烷研磨来纯化,以得到作为灰白色固体的1-(5-溴-4-氟吡啶-2-基)-3-(2-氯乙基)脲(1.50 g,60.4%产率)。
中间体19
1-(5-溴-4-氟吡啶-2-基)咪唑烷-2-酮
在氮气气氛下,将1-(5-溴-4-氟吡啶-2-基)-3-(2-氯乙基)脲(1.5 g,5.06 mmol)溶解于THF (30 mL)中。冷却至0℃并添加氢化钠(于矿物油中的60%悬浮液) (0.121 g,5.06 mmol)并在室温下将反应混合物搅拌6小时。添加MeOH (10 mL)并在减压下移除挥发物。获得的固体用水洗涤并在抽吸下干燥,以得到作为灰白色固体的1-(5-溴-4-氟吡啶-2-基)咪唑烷-2-酮(0.8 g,3.08 mmol,60.8%产率)。
中间体20
3-环丙基苯胺
在室温下,向3-溴苯胺(4 g,23.25 mmol)于甲苯(20 mL)中的脱气溶液中添加环丙基硼酸(3.99 g,46.5 mmol)、三环己基膦(1.304 g,4.65 mmol)、磷酸氢二钾(8.10 g,46.5 mmol)和乙酸钯(II) (0.522 g,2.325 mmol)。将反应物在氩气下在90℃下搅拌6小时。使反应混合物冷却至室温,用DCM稀释,用水洗涤,经硫酸钠干燥并浓缩以得到粗化合物。粗化合物通过CombiFlash (硅胶60-120,己烷-乙酸乙酯作为流动相0-80%)纯化,以得到3-环丙基苯胺(2.0 g,45%)。
中间体21
(3-环丙基苯基)氨基甲酸叔丁酯
向3-环丙基苯胺(2.0 g,15.02 mmol)于DCM (20 mL)中的溶液中添加TEA (5.23mL,37.5 mmol)和BOC2O (4.18 mL,18 mmol)。在将反应混合物搅拌4.5小时之后,将其用DCM稀释,用水洗涤,经硫酸钠干燥并浓缩,以得到粗化合物。粗化合物通过CombiFlash (硅胶60-120,己烷-乙酸乙酯作为流动相0-80%)纯化。在真空中浓缩所需级分,以得到(3-环丙基苯基)氨基甲酸叔丁酯(1.8 g)。
中间体22
(4-溴-3-环丙基苯基)氨基甲酸叔丁酯
向(3-环丙基苯基)氨基甲酸叔丁酯(1.8 g,7.72 mmol)于DMF (20 mL)中的溶液中添加1-溴吡咯烷-2,5-二酮(1.373 g,7.72 mmol)并将反应混合物搅拌3小时。将反应混合物用DCM稀释,用水洗涤,经硫酸钠干燥并浓缩,以得到粗化合物。粗化合物通过CombiFlash (硅胶60-120,石油醚-乙酸乙酯作为流动相0-80%)纯化。在真空中浓缩收集的级分,以得到(4-溴-3-环丙基苯基)氨基甲酸叔丁酯(1.8 g)。
中间体23
4-溴-3-环丙基苯胺
向(4-溴-3-环丙基苯基)氨基甲酸叔丁酯(1.8 g,7.72 mmol)于二氧杂环己烷(20mL)中的溶液中添加3 M HCl溶液(5 mL)并将反应混合物搅拌过夜,在真空中浓缩并分配于DCM和水之间。分离有机层,用水洗涤,经硫酸钠干燥并浓缩,以得到粗化合物。粗化合物通过CombiFlash (硅胶60-120,己烷-乙酸乙酯作为流动相0-100%)纯化。在真空中浓缩所需级分,以得到4-溴-3-环丙基苯胺(1.0 g)。
实施例1
1-(4-(1H-吡唑-4-基)苯基)-3-苯乙基咪唑烷-2-酮
实施例1A:1-(4-溴苯基)-1-(2-氯乙基)-3-苯乙基脲
向中间体1 (0.200 g,0.850 mmol)于苯(2 mL)中的溶液中添加(2-异氰酸酯基乙基)苯(0.142 mL,1.02 mmol)。将混合物在70℃下搅拌过夜。蒸发苯并将反应混合物用水(10 mL)稀释并用乙酸乙酯(3×10 mL)萃取。将有机层用盐水(20 mL)洗涤并经Na2SO4干燥并蒸发。产物通过快速色谱(0-30% EtOAc/Hex梯度)纯化,以获得0.24 g (74%产率)作为无色油状物的实施例1A。
实施例1B:1-(4-溴苯基)-3-苯乙基咪唑烷-2-酮
在0℃下,向实施例1A (0.220 g,0.576 mmol)于THF (5 mL)中的溶液中添加95%NaH (0.029 g,1.15 mmol)并在室温下将反应混合物搅拌1.5小时。将反应混合物冷却至0℃并用水稀释。所得沉淀物通过过滤收集,然后用乙醚洗涤并在真空下干燥,以获得0.18 g(90%产率)作为白色固体的实施例1B。
实施例1
向实施例1B (0.100 g,0.290 mmol)、 4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(0.128 g,0.434 mmol)于DMF (3 mL)和水(0.3 mL)中的溶液中添加K2CO3 (0.120 g,0.869 mmol)。将所得反应混合物使用N2气体脱气5分钟。将第2代XPhos预催化剂(0.046 g,0.058 mmol)添加至反应物中,将其再次脱气。然后将混合物加热至90℃持续2小时。冷却反应混合物并过滤,并浓缩滤液。产物通过制备型HPLC纯化,以得到15 mg (15%产率)实施例1。
表1中的以下实施例通过使用与实施例1中所示相同的程序制备。(2-异氰酸酯基乙基)苯用适当异氰酸酯取代。
实施例6
1-(3-氟苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
实施例6A:1-(4-溴-3-甲氧基苯基)-1-(2-氯乙基)-3-(3-氟苄基)脲
向中间体2 (0.300 g,1.13 mmol)于苯(3 mL)中的溶液中添加1-氟-3-(异氰酸酯基甲基)苯(0.189 mL,1.36 mmol)。将混合物在75℃下搅拌过夜。蒸发苯,然后将反应混合物用水(10 mL)稀释并用乙酸乙酯(3×10 mL)萃取。将有机层用盐水(20 mL)洗涤,经Na2SO4干燥并蒸发。油状物用10%乙醚/正己烷洗涤,以获得0.370 g (78%)作为黄色油状物的实施例6A。MS(ESI) m/z: 414.9 (M+H)+。
实施例6B
在0℃下,向实施例6A (0.350 g,0.842 mmol)于THF (5 mL)中的溶液中添加NaH(0.043 g,1.68 mmol)。将反应混合物在室温下搅拌1.5小时。将反应混合物冷却至0℃并用水稀释。通过过滤收集所得固体物质,用乙醚洗涤并干燥,以获得0.285 g (89%产率)作为白色固体的物质。
实施例6
向实施例6B (0.070 g,0.185 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(0.081 g,0.280 mmol)于DMF (3 mL)和水(0.3 mL)中的溶液中添加K2CO3 (0.077 g,0.55 mmol)。将所得反应混合物使用N2脱气5分钟。将第2代XPhos预催化剂(0.029 g,0.037 mmol)添加至反应物中,将其再次脱气。然后将混合物加热至90℃持续8小时。将反应混合物冷却至室温,然后经由CELITE®过滤,用EtOAc冲洗。浓缩滤液并将所得固体用Et2O、EtOAc和甲醇洗涤,以得到43 mg (62%产率)作为灰白色固体的实施例6。
实施例7
1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
根据制备实施例6的程序,用1-(异氰酸酯基甲基)-3-甲氧基苯取代1-氟-3-(异氰酸酯基甲基)苯得到实施例7。
实施例8
1-(4-氟苯乙基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
根据制备实施例6的程序,用1-氟-4-(2-异氰酸酯基乙基)苯取代1-氟-3-(异氰酸酯基甲基)苯得到实施例7。
实施例9
1-(3-氟苄基)-3-(2-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
实施例9A:1-(4-溴-2-甲氧基苯基)-1-(2-氯乙基)-3-(3-氟苄基)脲
向中间体3 (200 mg,0.756 mmol)于甲苯(4 mL)中的溶液中添加1-氟-3-(异氰酸酯基甲基)苯(171 mg,1.13 mmol)。将混合物在90℃下加热过夜。浓缩甲苯。将固体用石油醚洗涤并干燥,以得到作为棕色胶状固体的实施例9A (400 mg),其未经进一步纯化即用于以下步骤。MS(ESI) m/z: 415.4 (M+H)+。
实施例9B:1-(4-溴-2-甲氧基苯基)-3-(3-氟苄基)咪唑烷-2-酮
向实施例9A (400 mg,0.962 mmol)于THF (10 mL)中的溶液中添加NaH (77 mg,1.9 mmol)。将混合物在室温下搅拌过夜。再添加NaH (77 mg,1.9 mmol)并再搅拌混合物5小时。将反应物用冷水淬灭并用乙酸乙酯萃取。将合并的乙酸乙酯层用盐水洗涤,干燥(Na2SO4)并浓缩。残余物用10%乙醚/石油醚(3×5 mL)洗涤,然后干燥以得到220 mg作为胶状固体的实施例9B,其未经纯化即用于以下步骤。MS(ESI) m/z: 381.4 (M+H)+。
实施例9:1-(2-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
向实施例9B (100 mg,0.264 mmol)于DMF (2 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(155 mg,0.527 mmol)、K2CO3 (109 mg,0.791 mmol)和水(0.5 mL)。将混合物用氮气吹扫5分钟,且然后添加第2代XPhos预催化剂(12.5 mg,0.016 mmol)。将混合物在100℃下加热过夜。将反应物冷却至室温,用DMF稀释,过滤并通过制备型HPLC纯化,以得到30 mg (30%产率)实施例9。
实施例10
1-(2-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
根据制备实施例9的程序,用1-(异氰酸酯基甲基)-3-甲氧基苯取代1-氟-3-(异氰酸酯基甲基)苯得到实施例10。
实施例11
1-(2-氟苯乙基)-3-(2-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
根据制备实施例9的程序,用1-(异氰酸酯基甲基)-3-甲氧基苯取代1-氟-3-(异氰酸酯基甲基)苯得到实施例11。
实施例12
1-苄基-3-(2-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
根据制备实施例9的程序,用(异氰酸酯基甲基)苯取代1-氟-3-(异氰酸酯基甲基)苯得到实施例12。
实施例13
(R)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
实施例13A: (R)-1-(4-溴-3-甲氧基苯基)-1-(2-氯乙基)-3-(1-(3-甲氧基苯基)乙基)脲
在0℃下,向中间体2 (0.200 g,0.756 mmol)于CHCl3 (5 mL)中的溶液中添加TEA(0.316 mL,2.27 mmol),随后添加碳酸双(三氯甲基)酯(0.269 g,0.907 mmol),并在相同温度下将混合物搅拌2小时。添加(R)-1-(3-甲氧基苯基)乙胺(0.114 g,0.756 mmol)并将反应混合物搅拌过夜。将反应混合物用水稀释,通过5% HCl酸化并通过DCM萃取。将有机相经Na2SO4干燥并浓缩。将残余物用10%乙醚/己烷洗涤,以获得0.45 g (79%)作为黄色油状物的实施例13A。MS(ESI) m/z: 441.5 (M+H)+。
实施例13B:(R)-1-(4-溴-3-甲氧基苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
在0℃下,向实施例13A (0.330 g,0.747 mmol)于THF (5 mL)中的溶液中添加NaH(0.038 g,1.49 mmol),并将反应混合物在室温下搅拌2小时。将反应混合物冷却至0℃,用水稀释并用乙酸乙酯萃取。将有机层用盐水洗涤,经Na2SO4干燥并浓缩,以获得0.285 g(94%)作为深紫红色油状物的实施例13B。
实施例13
向实施例13B (0.070 g,0.17 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(0.076 g,0.26 mmol)于DMF (3 mL)和水(0.3 mL)中的溶液中添加K2CO3 (0.072 g,0.52 mmol)。将反应混合物使用N2脱气5分钟。添加第2代XPhos预催化剂(0.027 g,0.035 mmol),然后将反应混合物再次脱气。将混合物加热至90℃持续4小时。将反应混合物经由CELITE®过滤,用MeOH冲洗。蒸发滤液。将所得固体用水洗涤,然后通过制备型HPLC纯化,以得到14 mg (21%)作为淡黄色固体的实施例13。
实施例14
(R)-1-(2-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
根据制备实施例13的程序,用中间体3取代中间体2得到实施例14。
实施例15
1-(2-氟-5-甲氧基苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
实施例15A:(4-溴-3-甲氧基苯基)(2-氯乙基)氨基甲酸三氯甲酯
在0℃下,向4-溴-N-(2-氯乙基)-3-甲氧基苯胺(0.600 g,2.27 mmol)于CHCl3 (3mL)中的溶液中添加TEA (0.948 mL,6.80 mmol),随后添加碳酸双(三氯甲基)酯(0.808 g,2.72 mmol)。将混合物在0℃下搅拌2小时,然后浓缩,以得到0.900 g实施例15A,其未经纯化即使用。
实施例15B:1-(4-溴-3-甲氧基苯基)-1-(2-氯乙基)-3-(2-氟-5-甲氧基苄基)脲
在0℃下,向(2-氟-5-甲氧基苯基)甲胺(0.066 g,0.42 mmol)和TEA (0.118 mL,0.845 mmol)于CHCl3 (3 mL)中的溶液中添加实施例15A (0.120 g,0.282 mmol)于1 mlCHCl3中的溶液。将混合物在室温下搅拌过夜。将反应混合物用水稀释并用5% HCl酸化,然后通过DCM萃取。将有机层经Na2SO4干燥并蒸发以获得残余物。将残余物用乙醚(10 mL)萃取,将其浓缩以得到0.130 g作为黄色油状物的实施例15B,其未经进一步纯化即使用。MS(ESI) m/z: 445.5 (M+H)+。
实施例15C:1-(4-溴-3-甲氧基苯基)-3-(2-氟-5-甲氧基苄基)咪唑烷-2-酮
在0℃下,向实施例15B (0.110 g,0.247 mmol)于THF (5 mL)中的溶液中添加NaH(0.012 g,0.49 mmol)。将反应混合物在室温下搅拌8小时。将反应混合物冷却至0℃,用水稀释并用乙酸乙酯萃取。将有机层用盐水洗涤,经Na2SO4干燥并浓缩。残余物通过快速色谱(梯度洗脱0-20% EtOAc/Hex)纯化,以得到0.11 g (98%产率)作为淡黄色固体的实施例15C。
实施例15:1-(2-氟-5-甲氧基苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基) 咪唑烷-2-酮
向实施例15C (0.100 g,0.24 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(0.108 g,0.367 mmol)于DMF (3 mL)和水(0.3 mL)中的溶液中添加K2CO3 (0.101 g,0.733 mmol)。将所得反应混合物用N2脱气5分钟,然后添加第2代XPhos预催化剂(0.038 g,0.049 mmol)。将反应物再次脱气,然后加热至90℃持续6小时。将反应混合物经由CELITE®过滤,用MeOH冲洗。浓缩滤液并将所得固体用水洗涤。残余物通过制备型HPLC纯化,以得到7 mg (7%产率)实施例15。
实施例16
1-(2,6-二氟苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
根据制备实施例15的程序,用(2,6-二氟苯基)甲胺取代(2-氟-5-甲氧基苯基)甲胺得到实施例16。
实施例17
1-(2-氟苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
根据制备实施例15的程序,用(2-氟苯基)甲胺取代(2-氟-5-甲氧基苯基)甲胺得到实施例17。
实施例18
1-苄基-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
根据制备实施例15的程序,用苄胺取代(2-氟-5-甲氧基苯基)甲胺得到实施例18。
实施例19
3-(3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-3-(3-甲氧基苯基)丙酸,TFA
根据制备实施例15的程序,用3-氨基-3-(3-甲氧基苯基)丙酸甲酯, HCl取代(2-氟-5-甲氧基苯基)甲胺得到实施例19。
实施例20
3-(3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-3-(3-甲氧基苯基)丙酸甲酯
实施例20A:3-(3-(4-溴-3-甲氧基苯基)-3-(2-氯乙基)脲基)-3-(3-甲氧基苯基)丙酸甲酯
在0℃下,向3-氨基-3-(3-甲氧基苯基)丙酸甲酯, HCl (0.606 g,2.46 mmol)和TEA (1.15 mL,8.22 mmol)于CHCl3 (3 mL)中的溶液中添加实施例15A (0.700 g,1.64mmol)于1 mL CHCl3中的溶液。将混合物搅拌6小时,然后用水稀释,用5% HCl酸化并用DCM萃取。将有机层经Na2SO4干燥并浓缩,以获得1.80 g作为黄色油状物的实施例20A,其未经进一步纯化即使用。MS(ESI) m/z: 499.5 (M+H)+。
实施例20B:3-(3-(4-溴-3-甲氧基苯基)-2-氧代咪唑烷-1-基)-3-(3-甲氧基苯基)丙酸甲酯
实施例20C:3-(3-(4-溴-3-甲氧基苯基)-2-氧代咪唑烷-1-基)-3-(3-甲氧基苯基)丙酸
在0℃下,向实施例20A (1.40 g,2.80 mmol)于THF (5 mL)中的溶液中添加NaH(0.142 g,5.60 mmol)。将反应混合物在室温下搅拌2小时。将反应混合物冷却至0℃,然后用水稀释并用乙酸乙酯萃取。将有机层用盐水洗涤,经Na2SO4干燥并浓缩。残余物通过快速色谱(0-20% EtOAc/Hex)纯化,以得到0.30 g作为无色油状物的实施例20B。
将水相用5% HCl酸化,然后用EtOAc萃取。将有机相用盐水洗涤,干燥(Na2SO4)并浓缩,以得到0.15 g作为深紫红色油状物的实施例20C。MS(ESI) m/z: 449.1 (M+H)+。
实施例20D:4-(2-甲氧基-4-(3-(3-甲氧基-1-(3-甲氧基苯基)-3-氧代丙基)-2-氧代咪唑烷-1-基)苯基)-1H-吡唑-1-甲酸叔丁酯
向实施例20B (0.030 g,0.065 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(0.029 g,0.097 mmol)于二氧杂环己烷(3 mL)和水(0.3 mL)中的溶液中添加K2CO3 (0.027 g,0.19 mmol)。将反应混合物用N2脱气5分钟,然后添加第2代XPhos预催化剂(10.2 mg,0.013 mmol)。将反应物再次脱气,然后加热至90℃持续6小时。将反应混合物经由CELITE®过滤,用MeOH冲洗。蒸发滤液。将所得固体用水洗涤,以得到0.040 g实施例20D,其原样用于以下步骤。MS(ESI) m/z: 551.7 (M+H)+。
实施例20
向实施例20D (0.030 g,0.054 mmol)于MeOH中的溶液中添加NaBH4 (0.021 g,0.545 mmol)。将反应混合物在室温下搅拌过夜。蒸发甲醇并将混合物分配于乙酸乙酯和水之间。将有机层经Na2SO4干燥并浓缩。残余物通过制备型HPLC纯化,以得到5 mg (20%产率)实施例20。
实施例21
1-(3-羟基-1-(3-甲氧基苯基)丙基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
实施例21A:1-(4-溴-3-甲氧基苯基)-3-(3-羟基-1-(3-甲氧基苯基)丙基)咪唑烷-2-酮
在0℃下,向实施例20C (0.140 g,0.312 mmol)于THF (2 mL)中的溶液中逐滴添加甲硼烷-甲硫醚络合物(0.311 mL,3.12 mmol)。将反应混合物在50℃下搅拌1.5小时,然后浓缩。将残余物在室温下用6 N HCl/MeOH (2 mL)处理30分钟。将混合物用水稀释并用二氯甲烷(3 × 40 mL)萃取。将合并的萃取物经硫酸钠干燥,过滤并浓缩。产物通过快速色谱纯化,以得到0.030 g (22%产率)作为白色固体的实施例21A。MS(ESI) m/z: 435.6 (M+H)+。
实施例21
向实施例21A (0.030 g,0.069 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(0.030 g,0.103 mmol)于DMF (2 mL)和水(0.3 mL)中的溶液中添加K2CO3 (0.029 g,0.207 mmol)。将反应混合物用N2脱气5分钟,然后将第2代XPhos预催化剂(10.8 mg,0.014 mmol)添加至反应物中。将反应混合物再次脱气,然后加热至90℃持续6小时。将反应混合物经由CELITE®过滤,用MeOH冲洗。蒸发滤液。所得固体通过制备型HPLC纯化,以得到5 mg (17%产率)实施例21。
实施例22
1-(3-羟基-1-(3-甲氧基苯基)-3-甲基丁基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
实施例22A:1-(4-溴-3-甲氧基苯基)-3-(3-羟基-1-(3-甲氧基苯基)-3-甲基丁基)咪唑烷-2-酮
在0℃下,向实施例20B (0.070 g,0.151 mmol)于THF (2 mL)中的溶液中逐滴添加3M溴化甲基镁(0.201 mL,0.604 mmol)。将反应混合物在室温下搅拌2小时。将混合物用水稀释,然后用乙酸乙酯(3 × 20 mL)萃取。将合并的萃取物经硫酸钠干燥并浓缩,以得到0.080 g实施例22A,其未经进一步纯化即用于以下步骤。MS(ESI) m/z: 463.2 (M+H)+。
实施例22
向实施例22A (0.070 g,0.15 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(0.067 g,0.23 mmol)于DMF (2 mL)和水(0.3 mL)中的溶液中添加K2CO3 (0.063 g,0.45 mmol)。将反应混合物用N2脱气5分钟,然后添加第2代XPhos预催化剂(0.024 g,0.030 mmol)。将反应混合物再次脱气,然后在90℃下加热6小时。将反应混合物经由CELITE®过滤,用MeOH冲洗。蒸发滤液。所得固体通过制备型HPLC纯化,以得到4 mg (6%产率)实施例22。
实施例23
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
实施例23A:4-溴-N-(2-氯乙基)-3-乙基苯胺
向4-溴-3-乙基苯胺(5.00 g,25.0 mmol)和2-氯乙醛(4.82 mL,37.5 mmol)于MeOH (25 mL)中的溶液中添加氰基硼氢化钠(3.93 g,62.5 mmol),随后添加乙酸(1.43mL,25.0 mmol)。将混合物在室温下搅拌过夜,然后浓缩。将混合物用NaHCO3水溶液碱化,然后用乙酸乙酯(3 × 40 mL)萃取。干燥(Na2SO4)并浓缩有机层。残余物通过快速色谱(梯度洗脱:0-15% EtOAc/Hex)纯化,以得到4.50 g作为黄色油状物的实施例23A。
实施例23B:1-(4-溴-3-乙基苯基)-1-(2-氯乙基)-3-(3-甲氧基苄基)脲
在0℃下,向实施例23A (0.300 g,1.14 mmol)于CHCl3 (5 mL)中的溶液中添加TEA (0.478 mL,3.43 mmol),随后添加碳酸双(三氯甲基)酯(0.407 g,1.37 mmol)。将混合物在0℃下搅拌2小时,然后添加(3-甲氧基苯基)甲胺(0.188 g,1.37 mmol)并在室温下将反应混合物搅拌过夜。将反应混合物用水稀释,用5% HCl酸化并通过DCM萃取。将有机层经Na2SO4干燥并蒸发。将粗产物用10%乙醚/正己烷(30 mL)洗涤,以获得0.55 g作为黄色油状物的实施例23B,其未经进一步纯化即原样使用。MS(ESI) m/z: 425.0 (M+H)+。
实施例23C:1-(4-溴-3-乙基苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
在0℃下,向实施例23B (0.400 g,0.507 mmol)于THF (5 mL)中的溶液中添加NaH(0.026 g,1.02 mmol)。将反应混合物在室温下搅拌2小时,然后冷却至0℃并用水稀释。将混合物用乙酸乙酯(3 × 30 mL)萃取。将有机层用盐水洗涤,经Na2SO4干燥并浓缩成油状物,其用10%乙醚/正己烷洗涤,以得到0.230 g作为黄色油状物的实施例23C,其未经进一步纯化即原样使用。
实施例23
向实施例23 (0.070 g,0.15 mmol)于DMF (2 mL)和水(0.3 mL)中的溶液中添加K2CO3 (0.062 g,0.45 mmol)。将反应混合物用N2脱气5分钟,然后添加第2代XPhos预催化剂(0.023 g,0.030 mmol)。将反应混合物再次脱气,然后加热至90℃过夜。将反应混合物经由CELITE®过滤,用MeOH冲洗。浓缩滤液并通过制备型HPLC纯化残余物,以得到25 mg (32%产率)实施例23。
实施例24
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-氟苄基)咪唑烷-2-酮
根据合成实施例23的程序,用(3-氟苯基)甲胺取代(3-甲氧基苯基)甲胺得到实施例24。
实施例25
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(2-氟苄基)咪唑烷-2-酮
根据合成实施例23的程序,用(2-氟苯基)甲胺取代(3-甲氧基苯基)甲胺得到实施例25。
实施例26
1-苄基-3-(3-乙基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
根据合成实施例23的程序,用苄胺取代(3-甲氧基苯基)甲胺得到实施例26。
实施例27
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苯乙基)咪唑烷-2-酮,TFA
根据合成实施例23的程序,用苯乙胺取代(3-甲氧基苯基)甲胺得到实施例27。
实施例28
(R)-1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
根据合成实施例23的程序,用(R)-1-(3-甲氧基苯基)乙胺取代(3-甲氧基苯基)甲胺得到实施例28。
实施例29
3-(4-(1H-吡唑-4-基)苯基)-1-苄基-2-氧代咪唑烷-4-甲酸乙酯
实施例29A:3-(苄基胺基)-2-氯丙酸乙酯
向苄胺(1.00 g,9.33 mmol)于甲苯(15 mL)中的溶液中添加TEA (3.25 mL,23.3mmol)和2,3-二溴丙酸乙酯(1.36 mL,9.33 mmol)/甲苯(10 mL)。将混合物在80℃下搅拌过夜,然后浓缩。将残余物溶解于DCM (10 mL)中,然后用石油醚沉淀。过滤混合物并浓缩滤液,以得到黄色液体。将油状物溶解于丙酮(10 mL)中并冷却至0℃,然后用HCl (4 M,于二氧杂环己烷中) (3.0 mL,12 mmol)缓慢处理并升温至室温并在室温下搅拌2.5小时。将反应混合物浓缩以得到黄色液体,其用10% NaHCO3碱化并用乙酸乙酯萃取。将合并的有机相用盐水洗涤,经Na2SO4干燥并浓缩。残余物通过快速色谱(0-60% EtOAc/Hex)纯化,以得到600 mg作为黄色液体的实施例29A。MS(ESI) m/z: 244.2 (M+H)+。
实施例29B:1-苄基-3-(4-溴苯基)-2-氧代咪唑烷-4-甲酸乙酯
向实施例29A (600 mg,2.48 mmol)于甲苯(10 mL)中的溶液中添加1-溴-4-异氰酸酯基苯(541 mg,2.73 mmol)。将混合物在100℃下加热过夜。将反应混合物浓缩并通过快速色谱(0-100% EtOAc/Hex)纯化产物,以得到700 mg作为白色固体的实施例29B。
实施例29C:4-(4-(3-苄基-5-(乙氧基羰基)-2-氧代咪唑烷-1-基)苯基)-1H-吡唑-1-甲酸叔丁酯
向实施例29B (50 mg,0.124 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(54.7 mg,0.186 mmol)于二氧杂环己烷(5 mL)和水(0.5 mL)中的溶液中添加K2CO3 (42.8 mg,0.310 mmol)。将混合物用氮气脱气5分钟,然后添加第2代XPhos预催化剂(5.9 mg,7.4 µmol)。将混合物在85℃下加热1.5小时。将反应物用乙酸乙酯稀释,用水和盐水洗涤,干燥(Na2SO4)并浓缩,以得到实施例29C。产物未经进一步纯化即原样用于以下步骤。MS(ESI) m/z: 491.7 (M+H)+。
实施例29
向实施例29C (85 mg,0.173 mmol)于DCM (5 mL)中的溶液中添加TFA (0.25 mL,3.24 mmol),并将混合物在室温下搅拌3小时。蒸发混合物。残余物通过制备型HPLC纯化,以得到14 mg (20%产率)实施例29。
实施例30
3-(4-(1H-吡唑-4-基)苯基)-1-苄基-4-(羟基甲基)咪唑烷-2-酮
实施例30A:1-苄基-3-(4-溴苯基)-4-(羟基甲基)咪唑烷-2-酮
在室温下,向实施例29B (100 mg,0.248 mmol)于甲醇(5 mL)中的溶液中添加LiBH4 (13.5 mg,0.620 mmol)。将混合物在室温下搅拌过夜,然后蒸发溶剂。将残余物用水稀释并用EtOAc (2×)萃取。将合并的有机相用盐水洗涤,干燥(Na2SO4)并浓缩。残余物通过快速色谱(0-100% EtOAc/Hex)纯化,以得到实施例30A,其未经进一步纯化即原样使用。MS(ESI) m/z: 361.5 (M+H)+。
实施例30
向实施例30A (100 mg,0.277 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(122 mg,0.415 mmol)于DMF (3 mL)和水(0.5 mL)中的溶液中添加K2CO3 (96 mg,0.692 mmol)。将混合物脱气,然后添加第2代XPhos预催化剂(13 mg,0.017 mmol)。将混合物在85℃下加热2小时。将反应物用乙酸乙酯稀释,用水和盐水洗涤,干燥(Na2SO4),过滤并浓缩。将残余物溶解于TFA中并搅拌3小时。将混合物浓缩并通过制备型HPLC纯化产物,以得到4 mg实施例30。
实施例31
1-(2-(1H-吡唑-4-基)苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮,TFA
根据制备实施例15的程序,用(2-氯苯基)甲胺取代(2-氟-5-甲氧基苯基)甲胺得到实施例31。
实施例32
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟苄基)-2-氧代咪唑烷-4-甲酸
实施例32A:2-溴-3-((4-溴苯基)氨基)丙酸乙酯
向4-溴苯胺(1.0 g,5.8 mmol)于甲苯(15 mL)中的溶液中添加TEA (2.43 mL,17.4 mmol)。将混合物加热至50℃,然后逐滴添加2,3-二溴丙酸乙酯(0.845 mL,5.81mmol)于甲苯(4 mL)中的溶液。将混合物在100℃下加热2天。将混合物浓缩并通过快速色谱(0-4% EtOAc/Hex)纯化产物,以得到350 mg作为棕色液体的实施例32A。
实施例32B:1-(4-溴苯基)-3-(3-氟苄基)-2-氧代咪唑烷-4-甲酸乙酯
向实施例32A (350 mg,0.997 mmol)于甲苯(5 mL)中的溶液中添加1-氟-3-(异氰酸酯基甲基)苯(226 mg,1.50 mmol)。将混合物在100℃下加热过夜。将混合物浓缩并通过快速色谱(0-40% EtOAc/Hex)纯化残余物,以得到200 mg作为黄色固体且作为区域异构体的混合物的实施例32B。MS(ESI) m/z: 421.4 (M+H)+。
实施例32
向实施例32B (200 mg,0.475 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(279 mg,0.950 mmol)于DMF (5 mL)和水(0.5 mL)中的溶液中添加K2CO3 (197 mg,1.42 mmol)。将混合物脱气,然后用第2代XPhos预催化剂(22mg,0.028 mmol)处理并再次脱气。将混合物在100℃下加热过夜。将反应物用乙酸乙酯稀释,经由CELITE®过滤,用乙酸乙酯冲洗。浓缩滤液并通过制备型HPLC纯化残余物,以得到18 mg作为白色固体的实施例32。
实施例33
3-(4-(1H-吡唑-4-基)苯基)-1-(3-氟苄基)-2-氧代咪唑烷-4-甲酸
实施例33A:2-氯-3-((3-氟苄基)氨基)丙酸乙酯
向(3-氟苯基)甲胺(1.00 g,7.99 mmol)于甲苯(15 mL)中的溶液中添加TEA(4.46 mL,32.0 mmol)和2,3-二溴丙酸乙酯(2.08 g,7.99 mmol)/甲苯(10 mL)。将混合物在85℃下搅拌过夜。将反应混合物浓缩。将残余物溶解于DCM (10 mL)中并通过添加石油醚沉淀。通过过滤收集固体,然后溶解于丙酮(15 mL)中并冷却至0℃。向该溶液中添加4 MHCl/二氧杂环己烷,然后使混合物升温至室温并搅拌16小时。将反应混合物浓缩以得到黄色液体,其用10% NaHCO3碱化并用乙酸乙酯萃取。将合并的乙酸乙酯层用盐水洗涤,干燥(Na2SO4)并浓缩。残余物通过快速色谱(0-60% EtOAc/Hex)纯化,以得到850 mg作为黄色油状物的实施例33A。MS(ESI) m/z: 260.5 (M+H)+。
实施例33B:3-(3-(4-溴苯基)-1-(3-氟苄基)脲基)-2-氯丙酸乙酯
向2-氯-3-((3-氟苄基)氨基)丙酸乙酯(850 mg,3.27 mmol)于甲苯(10 mL)中的溶液中添加1-溴-4-异氰酸酯基苯(713 mg,3.60 mmol)。将混合物在100℃下加热过夜。将混合物浓缩,以得到1.80 g黄色固体,其原样用于以下步骤。MS(ESI) m/z: 457.5 (M+H)+。
实施例33C:3-(4-溴苯基)-1-(3-氟苄基)-2-氧代咪唑烷-4-甲酸甲酯
在0℃下,向实施例33B (1.80 g,3.93 mmol)于THF (10 mL)中的溶液中添加NaH(0.199 g,7.87 mmol)。将混合物在室温下搅拌4小时,然后将反应物用冰水淬灭并浓缩,以得到黄色胶质固体。将残余物溶解于甲醇(25 mL)中,然后将溶液用H2SO4 (0.868 mL,16.28mmol)处理并在室温下搅拌6小时。蒸发甲醇,然后将残余物用10% NaHCO3 (水溶液)碱化,然后用乙酸乙酯萃取。将合并的乙酸乙酯层用盐水洗涤,干燥(Na2SO4)并浓缩。残余物通过快速色谱(0-100% EtOAc/Hex)纯化,以得到1.00 g作为灰白色固体的实施例33C。
实施例33
向实施例33C (75 mg,0.184 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(108 mg,0.368 mmol)于DMF (3 mL)和水(0.5 mL)中的溶液中添加K2CO3 (76 mg,0.55 mmol)。将混合物脱气,然后添加第2代XPhos预催化剂(8.7 mg,0.011 mmol)。将混合物在85℃下加热3.5小时。将反应物用水(15 mL)稀释并经由CELITE®过滤。将滤液用乙酸乙酯(2 × 20 mL)洗涤。将水溶液酸化至pH 3并通过过滤收集所得固体。将固体用水和石油醚洗涤,以得到44.0 mg作为灰白色固体的实施例33。
实施例34
3-(4-(1H-吡唑-4-基)苯基)-1-(3-氟苄基)-2-氧代咪唑烷-4-甲酸甲酯
向实施例33A (200 mg,0.491 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(289 mg,0.982 mmol)于二氧杂环己烷(3 mL)和水(0.5 mL)中的溶液中添加K2CO3 (204 mg,1.47 mmol)。将混合物脱气,然后添加第2代XPhos预催化剂(23 mg,0.029 mmol)。将混合物在85℃下加热3.5小时。将反应物用水(15 mL)稀释并经由CELITE®过滤。将滤液用盐水洗涤,干燥(Na2SO4)并浓缩。将残余物溶解于DCM (5mL)中并用TFA (0.1 mL)处理并在室温下搅拌3小时。将混合物浓缩并通过制备型HPLC纯化残余物,以得到32 mg实施例34。
实施例35
3-(4-(1H-吡唑-4-基)苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸
根据制备实施例33的程序,用(3-甲氧基苯基)甲胺取代(3-氟苯基)甲胺得到实施例35。
实施例36
3-(4-(1H-吡唑-4-基)苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸乙酯
根据制备实施例34的程序,用(3-甲氧基苯基)甲胺取代(3-氟苯基)甲胺得到实施例36。
实施例37
1-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮
实施例37A:2-溴-3-((4-溴苯基)氨基)丙酸乙酯
向4-溴苯胺(4.00 g,23.3 mmol)于甲苯(25 mL)中的溶液中添加TEA (9.72 mL,69.8 mmol)。将混合物加热至50℃,然后逐滴添加2,3-二溴丙酸乙酯(3.38 mL,23.3mmol)/甲苯(25 mL)。将反应混合物在100℃下加热50小时,然后浓缩。将残余物溶解于最少DCM中并通过添加石油醚沉淀。过滤混合物并浓缩滤液。残余物通过快速色谱(0-30%EtOAc/己烷)纯化,以得到700 mg棕色胶质固体。
实施例37B:4-(4-(4-(乙氧基羰基)-3-(3-甲氧基苄基)-2-氧代咪唑烷-1-基)苯基)-1H-吡唑-1-甲酸叔丁酯
向实施例37A (300 mg,0.855 mmol)于甲苯(5 mL)中的溶液中添加1-(异氰酸酯基甲基)-3-甲氧基苯(209 mg,1.28 mmol)并在100℃下加热过夜。将混合物浓缩,然后通过快速色谱(0-60% EtOAc/Hex)纯化,以得到230 mg作为胶状固体的1-(4-溴苯基)-3-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸乙酯。向该产物和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(312 mg,1.06 mmol)于DMF (5 mL)和水(0.5 mL)中的溶液中添加K2CO3 (220 mg,1.59 mmol)。将混合物脱气,然后用第2代XPhos预催化剂(25 mg,0.032 mmol)处理并再次脱气。将混合物在85℃下加热3.5小时。将反应混合物用乙酸乙酯稀释,经由CELITE®床过滤,用乙酸乙酯冲洗。将滤液用盐水洗涤,干燥(Na2SO4)并浓缩。残余物通过快速色谱(0-100% EtOAc/Hex)纯化,以得到150 mg实施例37B。MS(ESI) m/z: 521.6 (M+H)+。
实施例37
向实施例37B (150 mg,0.288 mmol)于乙醇(5 mL)中的溶液中添加NaBH4 (54.5mg,1.441 mmol)。将混合物在室温下搅拌3小时。移除挥发物,然后将残余物分配于水和乙酸乙酯之间。将水相用乙酸乙酯萃取。将合并的有机相用盐水洗涤,干燥(Na2SO4),过滤并浓缩。残余物通过制备型HPLC纯化,以得到15 mg实施例37。
实施例38
1-(4-(1H-吡唑-4-基)苯基)-3-苄基-4-(羟基甲基)咪唑烷-2-酮
根据制备实施例37的程序,用(异氰酸酯基甲基)苯取代1-(异氰酸酯基甲基)-3-甲氧基苯得到实施例38。
实施例39
3-(4-(1H-吡唑-4-基)苯基)-1-(3-氟苄基)-4-(羟基甲基)咪唑烷-2-酮
根据制备实施例30的途径,用3-氟苄胺取代苄胺得到实施例39。
实施例40
4-(羟基甲基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
根据制备实施例37的程序,用4-溴-2-甲氧基苯胺取代4-溴苯胺得到实施例40。
实施例41
3-苄基-4-(羟基甲基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮
根据用于制备实施例37的通用途径制备实施例41。
实施例42
(+)-1-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮
实施例43
(-)-1-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮
将外消旋实施例37经由超临界流体色谱[柱:CHIRALPAK® OJ-H (250 × 4.6mm),5μm,共溶剂为4% (0.25% DEA/MeOH)]分成其对映异构体,以得到实施例42,随后为实施例43。
实施例42的数据:
实施例43的数据:
实施例44
(-)-1-(4-(1H-吡唑-4-基)苯基)-4-(2-羟基丙-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮
实施例45
(+)-1-(4-(1H-吡唑-4-基)苯基)-4-(2-羟基丙-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮
实施例44A:1-(4-溴苯基)-4-(2-羟基丙-2-基)-3-(3-甲氧基苄基) 咪唑烷-2-酮
在-20℃下,向1-(4-溴苯基)-3-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸乙酯(其作为实施例37中的中间体来制备) (270 mg,0.623 mmol)于THF (10 mL)中的溶液中添加溴化甲基镁(3 M,于乙醚中) (1.04 mL,3.12 mmol)。将混合物经2小时缓慢升温至16℃。将反应物用饱和NH4Cl淬灭并用乙酸乙酯萃取。将合并的乙酸乙酯层用盐水洗涤,干燥(Na2SO4)并浓缩,以得到190 mg作为粘稠黄色油状物的实施例44A,其未经进一步纯化即使用。MS(ESI) m/z: 419.1 (M+H)+。
实施例44和45
向实施例44A (190 mg,0.453 mmol)于DMF (3 mL)和水(0.5 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(200 mg,0.680 mmol)和K2CO3 (188 mg,1.36 mmol)。将混合物脱气,然后装入第2代XPhos预催化剂(21 mg,0.027 mmol)。将混合物脱气,然后在90℃下加热过夜。将反应混合物过滤,并将滤液用水稀释并用EtOAc萃取。将有机相用水和盐水洗涤,干燥(Na2SO4)并浓缩。产物通过制备型HPLC纯化,然后通过超临界流体色谱[柱:CHIRALPAK® IC (250 × 2.1 mm),5 μm,共溶剂为40% MeOH]分离对映异构体,以得到实施例44,随后为实施例45。
实施例44的数据:
实施例45的数据:
实施例46
(R)-1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
实施例46A:(R)-1-(4-溴苯基)-1-(2-氯乙基)-3-(1-(3-甲氧基苯基)乙基) 脲
在0℃下,向中间体1 (0.35 g,1.49 mmol)和三乙胺(0.624 mL,4.48 mmol)于氯仿(10 mL)中的混合物中添加三光气(0.531 g,1.79 mmol)。将反应混合物在室温下搅拌2小时,然后将反应混合物冷却至0℃并向其中逐滴添加(R)-1-(3-甲氧基苯基)乙胺 (0.226g, 1.492 mmol)。将反应混合物在室温下搅拌过夜。将反应混合物用水稀释,用0.5 N HCl酸化并用二氯甲烷(2 × 50 mL)萃取。将合并的有机萃取物用水和盐水洗涤,经Na2SO4干燥并浓缩,以得到实施例46A,其未经进一步纯化即使用。MS(ESI) m/z: 411.1 (M+H)+。
实施例46
根据制备实施例1的程序,将实施例46A转化成实施例46。
实施例47
(-)-3-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮
实施例48
(+)-3-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮
实施例47A:2-氯-3-((3-甲氧基苄基)氨基)丙酸乙酯
向(3-甲氧基苯基)甲胺(2.00 g,14.6 mmol)于甲苯(30 mL)中的溶液中添加TEA(8.13 mL,58.3 mmol)和2,3-二溴丙酸乙酯(3.79 g,14.6 mmol)/甲苯(10 mL)。将混合物在85℃下搅拌过夜。将反应混合物冷却至室温并过滤沉淀的固体。将滤液浓缩以得到黄色油状物。将油状物溶解于丙酮(45 mL)中,冷却至0℃并用4 M HCl/二氧杂环己烷(13.4 mL,53.6 mmol)处理。将混合物在室温下搅拌16小时。将反应混合物浓缩以得到黄色液体,其用10% NaHCO3碱化并用乙酸乙酯萃取。将合并的乙酸乙酯层用盐水洗涤,干燥(Na2SO4)并浓缩。产物通过快速色谱(0-60% EtOAc/Hex)纯化,以得到390 mg作为黄色液体的实施例47A。MS(ESI) m/z: 272.1 (M+H)+。
实施例47B:3-(4-溴苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸
向实施例47A (390 mg,1.44 mmol)于甲苯(10 mL)中的溶液中添加1-溴-4-异氰酸酯基苯(313 mg,1.58 mmol)。将混合物在100℃下加热16小时,然后浓缩。将残余物溶解于THF (10 mL)中并冷却至0℃,然后用NaH (69.9 mg,2.77 mmol)处理。将混合物在室温下搅拌过夜。将反应物用冰冷的水淬灭并用1.5 N HCl酸化至pH 2,然后用乙酸乙酯萃取。将合并的有机相用盐水洗涤,干燥(Na2SO4)并浓缩,以得到550 mg作为棕色胶状固体的实施例47B,其未经进一步纯化即用于以下步骤。MS(ESI) m/z: 405.1 (M+H)+。
实施例47C:3-(4-溴苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸乙酯
向实施例47B (550 mg,1.36 mmol)于乙醇(15 mL)中的溶液中添加H2SO4 (0.289mL,5.43 mmol)。将混合物在室温下搅拌过夜,然后浓缩。将残余物用10% NaHCO3水溶液碱化,然后用乙酸乙酯萃取。将合并的乙酸乙酯层用盐水洗涤,干燥(Na2SO4)并浓缩。残余物通过快速色谱(0-100% EtOAc/Hex)纯化,以得到180 mg作为胶质黄色固体的实施例47C。MS(ESI) m/z: 435.1 (M+H)+。
实施例47D:3-(4-溴苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮
在0℃下,向实施例47C (180 mg,0.415 mmol)于乙醇(10 mL)中的溶液中添加LiBH4 (36.2 mg,1.662 mmol)。将混合物在室温下搅拌过夜,然后浓缩。将产物分配于EtOAc和水之间。将水相用EtOAc萃取。将合并的有机相用盐水洗涤,干燥(Na2SO4)并浓缩,以得到140 mg作为黄色胶质固体的实施例47D。MS(ESI) m/z: 391.1 (M+H)+。
实施例47和48
向实施例47D (140 mg,0.358 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(137 mg,0.465 mmol)于DMF (3 mL)和水(0.5 mL)中的溶液中添加K2CO3 (148 mg,1.07 mmol)。将混合物脱气,然后装入第2代XPhos预催化剂(16.9 mg,0.021 mmol),脱气,然后在95℃下加热过夜。将反应物用水稀释并用乙酸乙酯萃取。将合并的有机相用盐水洗涤,干燥(Na2SO4)并浓缩。将残余物溶解于DCM (5 mL)中,然后用TFA (0.20 mL)处理。将混合物在室温下搅拌3小时,然后浓缩。产物通过制备型HPLC纯化,然后通过超临界流体色谱[柱:CHIRALPAK® AS-H (250 × 4.6 mm),5μ,共溶剂为45%(0.25% DEA/甲醇)]分离对映异构体,以得到19 mg实施例47和18 mg实施例48,两者都作为白色固体。
实施例47的数据:
实施例48的数据:
表2中的以下实施例以与实施例1类似的方式制备。适当异氰酸酯和硼酸用于各实施例。
实施例62
1-(4-(2-氨基吡啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮, TFA
实施例62A:1-(4-溴苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
在0℃下,向中间体1 (1.00 g,4.26 mmol)于CHCl3 (10 mL)中的溶液中添加TEA(1.78 mL,12.8 mmol),随后添加碳酸双(三氯甲基)酯(1.52 g,5.12 mmol)。将混合物在0℃下搅拌2小时,然后添加(3-甲氧基苯基)甲胺(0.828 mL,6.40 mmol)并在室温下将反应混合物搅拌过夜。将反应混合物用水(10 mL)稀释并通过5% HCl酸化。将混合物通过DCM萃取。将有机层干燥(Na2SO4)并蒸发以获得黄色油状物。将产物溶解于THF (15 mL)中并冷却至0℃并用NaH (0.203 g,8.05 mmol)处理。将反应混合物在室温下搅拌1.5小时,然后冷却至0℃并用水处理。通过过滤收集所得沉淀物。MS(ESI) m/z: 361.0 (M+H)+。
实施例62B: 1-(3-甲氧基苄基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)咪唑烷-2-酮
向实施例62B (0.800 g,2.22 mmol)和4,4,4ʹ,4ʹ,5,5,5ʹ,5ʹ-八甲基-2,2ʹ-二(1,3,2-二氧杂硼杂环戊烷)(0.675 g,2.66 mmol)于二氧杂环己烷(10 mL)中的溶液中添加乙酸钾(0.652 g,6.64 mmol),并将所得反应混合物脱气。添加Pd(dppf)Cl2 CH2Cl2络合物(0.181 g,0.221 mmol),并将混合物再次脱气,然后加热至90℃持续6小时。经由CELITE®过滤混合物,然后浓缩滤液。将残余物用水稀释并用乙酸乙酯(3 × 50 ml)萃取。将合并的有机层干燥(Na2SO4)并浓缩。通过快速色谱(0-20% EtOAc/Hex)纯化物质,以获得0.850 g作为白色固体的实施例62B。
实施例62
向实施例62B (0.080 g,0.196 mmol)、4-氯吡啶-2-胺(0.025 g,0.196 mmol)于DMF (2 mL)和水(0.3 mL)中的溶液中添加K2CO3 (0.081 g,0.588 mmol)。将混合物使用N2脱气,然后装入第2代XPhos预催化剂(0.031 g,0.039 mmol),并将反应物再次脱气。然后将混合物在90℃下加热过夜。将反应混合物经由CELITE®过滤,用MeOH冲洗并蒸发滤液。产物通过制备型HPLC纯化,以得到1 mg实施例62。
实施例63
1-(4-(2-氨基嘧啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
根据制备实施例62的程序,制备实施例63。
实施例64
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
根据制备实施例62的程序,制备实施例64。
实施例65
1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮
根据制备实施例62的程序,制备实施例65。
实施例66
1-(4-(1H-吡唑-4-基)苯基)-3-(2-甲氧基苯乙基)-1H-咪唑-2(3H)-酮
实施例66A:1-(4-溴苯基)-3-(2,2-二甲氧基乙基)脲
在0℃下,向2,2-二甲氧基乙胺(1.64 mL,15.2 mmol)于二氯甲烷(50 mL)中的混合物中逐滴添加1-溴-4-异氰酸酯基苯(3.00 g,15.2 mmol)。将混合物在环境温度下搅拌16小时,然后在真空中浓缩。将粗产物用石油醚研磨,以得到作为灰白色固体的实施例66A(4.50 g,96%产率)。
实施例66B:1-(4-溴苯基)-1H-咪唑-2(3H)-酮
向1.5 M HCl (49.5 ml,74.2 mmol)中添加1-(4-溴苯基)-3-(2,2-二甲氧基乙基)脲(4.50 g,14.8 mmol)。将混合物在环境温度下搅拌20小时,然后将反应混合物用饱和NaHCO3水溶液碱化。将产物用DCM萃取并将合并的萃取物用水和盐水洗涤,干燥(Na2SO4)并浓缩,以得到作为灰白色固体的实施例66B (3.00 g,79%产率)。
实施例66C:1-(4-溴苯基)-3-(2-甲氧基苯乙基)-1H-咪唑-2(3H)-酮
向实施例66B (0.10 g,0.42 mmol)和K2CO3 (0.116 g,0.837 mmol)于乙腈(5 mL)中的混合物中添加1-(2-溴乙基)-2-甲氧基苯(0.135 g,0.627 mmol)。将混合物在环境温度下搅拌16小时,然后将反应混合物经由CELITE®过滤并浓缩滤液。将残余物溶解于乙酸乙酯中,用水和盐水洗涤,干燥(Na2SO4)并浓缩,以得到作为黄色油状物的实施例66C,其未经进一步纯化即用于以下步骤。MS(ESI) m/z: 373.0 (M+H)+。
实施例66
将实施例66C (0.45 g,0.615 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(0.239 g,1.23 mmol)和K2CO3 (0.255 g,1.85 mmol)于DMF (3 mL)和水(1 mL)中的混合物用N2脱气。添加第2代XPhos预催化剂(0.073 g,0.092 mmol)并将混合物在100℃下加热16小时。将反应混合物经由CELITE®过滤。将滤液用乙酸乙酯稀释并用水和盐水洗涤,然后浓缩。产物通过制备型HPLC纯化,以得到5 mg作为淡黄色固体的实施例66。
遵循用于制备实施例66的途径制备表3中的实施例。
实施例80
3-(4-(1H-吡唑-4-基)苯基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮
实施例80A:3-(4-溴苯基)咪唑烷-2,4-二酮
向1-溴-4-异氰酸酯基苯(500 mg,2.53 mmol)于吡啶(9 mL)中的溶液中添加2-氨基乙酸乙酯, HCl (352 mg,2.53 mmol)。将混合物在室温下搅拌2小时,然后浓缩成黄色胶质固体。将固体在100℃下于2M HCl水溶液(10 mL)中加热过夜,然后冷却至室温。将混合物用水稀释,然后通过过滤收集所得沉淀物,用水和石油醚洗涤并干燥,以得到500 mg作为白色固体的实施例80A,其未经进一步纯化即使用。MS(ESI) m/z: 255.4 (M+H)+。
实施例80B:3-(4-溴苯基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮
向实施例80A (150 mg,0.588 mmol)于DMF (3 mL)中的溶液中添加K2CO3 (122mg,0.882 mmol)和1-(溴甲基)-3-甲氧基苯(118 mg,0.588 mmol)。将混合物在室温下搅拌2小时。将混合物用水稀释,然后通过过滤收集所得沉淀物。将固体用水和石油醚洗涤并干燥,以得到170 mg作为灰白色固体的实施例80B,其未经进一步纯化即使用。
实施例80
向实施例80B (100 mg,0.267 mmol)于DMF (3 mL)和水(0.3 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(118 mg,0.400 mmol)和K2CO3 (111 mg,0.800 mmol)。将混合物用N2脱气,然后添加第2代XPhos预催化剂(12.6 mg,0.016 mmol)并将混合物再次脱气。将混合物在100℃下加热过夜,然后冷却至室温并过滤。滤液通过制备型HPLC纯化,以得到18 mg实施例80。
表4中的以下实施例以类似于实施例80的方式制备。
实施例98
3-苄基-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮
实施例98A:2-((4-溴-3-甲氧基苯基)氨基)乙酸乙酯
向4-溴-3-甲氧基苯胺(2.50 g,12.4 mmol)和2-氧代乙酸乙酯(2.94 mL,14.9mmol)于甲醇(30 mL)中的溶液中添加氰基硼氢化钠(1.17 g,18.6 mmol)和乙酸(0.708mL,12.4 mmol)。将混合物在室温下搅拌过夜,然后浓缩以移除甲醇。将产物用饱和NaHCO3水溶液中和,然后通过过滤收集所得沉淀物并用水和石油醚洗涤。产物通过快速色谱(0-100% EtOAc/Hex)纯化,以得到2.00 g作为白色固体的实施例98A。
实施例98B:1-(4-溴-3-甲氧基苯基)咪唑烷-2,4-二酮
向实施例98A (2.00 g,6.94 mmol)于吡啶(10 mL)中的溶液中添加脲(1.04 g,17.4 mmol)。将混合物在125℃下加热50小时,然后冷却至室温并用石油醚处理。通过过滤收集所得沉淀物。将固体再溶解于DCM中并用石油醚处理以得到沉淀物,沉淀物通过过滤收集,以得到1.90 g作为白色固体的实施例98B。
实施例98C:3-苄基-1-(4-溴-3-甲氧基苯基)咪唑烷-2,4-二酮
向实施例98B (200 mg,0.702 mmol)于DMF (2 mL)中的溶液中添加K2CO3 (145mg,1.052 mmol)和苄基溴(120 mg,0.702 mmol)。将混合物在室温下搅拌3小时,然后用水稀释,以得到沉淀物,收集沉淀物。将固体用水和石油醚洗涤并干燥,以得到120 mg作为黄色固体的实施例98C。
实施例98
向实施例98A (120 mg,0.32 mmol)于DMF (3 mL)和水(0.3 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(113 mg,0.384 mmol)和K2CO3 (133 mg,0.959 mmol)。将混合物用N2脱气,然后添加第2代XPhos预催化剂(15.1 mg,0.019 mmol)。将混合物再次脱气,然后在100℃下过夜。将反应物用水稀释并用乙酸乙酯萃取。将合并的乙酸乙酯相用水和盐水溶液洗涤,干燥(Na2SO4)并浓缩。残余物通过制备型HPLC纯化,以得到4 mg实施例98。
表5中的以下实施例以类似于实施例98的方式制备。
实施例116
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-3-甲氧基苄基)咪唑烷-2-酮
实施例116A:1-(4-溴苯基)-3-(2-氯乙基)脲
在0℃下,向4-溴苯胺(5.00 g,29.1 mmol)于二氯甲烷(80 mL)中的混合物中缓慢添加1-氯-2-异氰酸酯基乙烷(2.98 mL,34.9 mmol)。将混合物在室温下搅拌16小时。将混合物浓缩。将粗产物混合物通过用石油醚研磨来纯化,以得到6.00 g作为灰白色固体的实施例116A (74%产率)。
实施例116B:1-(4-溴苯基)咪唑烷-2-酮
向实施例116A (8.00 g,28.8 mmol)于THF (100 mL)中的冰冷的混合物中经30分钟分数份添加氢化钠(2.08 g,860 mmol)。将混合物在室温下搅拌16小时,然后用冰淬灭并稀释于乙酸乙酯中。将有机层分离并用水和盐水洗涤,干燥(Na2SO4)并浓缩。该粗产物通过用石油醚研磨来纯化,以得到作为灰白色固体的实施例116B (5.00 g,72%产率)。
实施例116C:1-(4-溴苯基)-3-(2-氟-3-甲氧基苄基)咪唑烷-2-酮
在0℃下,向实施例116B (0.200 g,0.830 mmol)于THF (10 mL)中的混合物中添加氢化钠(0.050 g,2.07 mmol)。将混合物在室温下搅拌10分钟,然后冷却至0℃并用1-(溴甲基)-2-氟-3-甲氧基苯(0.363 g,1.66 mmol)处理。将混合物在70℃下加热4小时。将反应混合物用冰淬灭并用乙酸乙酯稀释。将有机层分离并用水和盐水洗涤,干燥(Na2SO4)并浓缩。将该粗产物通过用乙醚研磨来纯化,以得到0.180 g (55%产率)作为灰白色固体的实施例116C。
实施例116
根据制备实施例98的程序,实施例116C (100 mg,0.264 mmol)得到20 mg (20%产率)作为灰白色固体的实施例116。
表6中的以下实施例以类似于实施例116的方式制备。
实施例121:3-(4-(1H-吡唑-4-基)苯基)-5-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮
实施例121A:(S)-3-(4-溴苯基)-5-(羟基甲基)咪唑烷-2,4-二酮
在0℃下,向4-溴苯胺(500 mg,2.91 mmol)于THF (10 mL)中的溶液中添加三光气(431 mg,1.45 mmol),随后逐滴添加TEA (1.22 mL,8.72 mmol)。将混合物在室温下搅拌30分钟,然后添加(S)-2-氨基-3-羟基丙酸乙酯(387 mg,2.91 mmol)和TEA (1.22 mL,8.72mmol)于THF (10 mL)中的悬浮液。将混合物在室温下搅拌2.5小时,然后浓缩。将残余物用水处理并过滤所得悬浮液。将滤液用EtOAc萃取。将有机相用盐水洗涤,干燥(Na2SO4)并浓缩,以得到300 mg (21%产率)作为灰白色固体的实施例121A。
实施例121B:3-(4-溴苯基)-5-(羟基甲基)-1-(3-甲氧基苄基) 咪唑烷-2,4-二酮
向实施例121A (200 mg,0.702 mmol)于DMF (5 mL)中的溶液中添加K2CO3 (145mg,1.05 mmol)和1-(溴甲基)-3-甲氧基苯(141 mg,0.702 mmol)。将混合物在室温下搅拌3小时。将混合物用水稀释并用乙酸乙酯萃取。将合并的有机相用盐水洗涤并浓缩。产物通过快速色谱(0-100% EtOAc/Hex)纯化,以得到150 mg (46%产率)作为白色固体的实施例121B。
实施例121
根据制备实施例98的程序,实施例121B (150 mg,0.370 mmol)得到25 mg (17%产率)作为黄色固体的实施例121。
实施例122
(R)-1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
实施例122A:制备(R)-1-(4-溴苯基)-1-(2-氯乙基)-3-(1-(3-甲氧基苯基)乙基)脲
在0℃下,在氮气气氛下,向4-溴-N-(2-氯乙基)苯胺(3 g,12.8 mmol)和TEA(5.35 mL,38.4 mmol)于氯仿(100 mL)中的搅拌溶液中添加三光气(4.18 g,14.1 mmol),并使反应混合物在室温下搅拌。在2小时之后,将反应混合物再次冷却至0℃并逐滴添加(R)-1-(3-甲氧基苯基)乙胺(1.93 g,12.8 mmol),并将反应混合物在室温下搅拌16小时。将反应混合物用DCM (100 mL)稀释,用0.1M HCl (50 mL)、饱和NaHCO3、盐水溶液洗涤。将有机层经Na2SO4干燥、过滤并浓缩。粗产物通过CombiFlash色谱(40 g REDISEP® SiO2柱,用20-30% EtOAc/己烷洗脱)纯化,以得到实施例122A (2.8 g,55%产率)白色固体。
实施例122B:制备(R)-1-(4-溴苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
在0℃下,向实施例122A (2.8 g,6.80 mmol)于THF (50 mL)中的溶液中添加NaH(0.544 g,13.6 mmol,60%,于矿物油中),使反应混合物在室温下搅拌16小时,用10% NH4Cl溶液(100 mL)淬灭并用EtOAc (2 × 50 mL)萃取。将合并的有机层用盐水(1 × 50 mL)洗涤,经Na2SO4干燥,过滤并浓缩。粗产物通过快速色谱(40 g REDISEP® SiO2柱,用30%EtOAc/己烷洗脱)纯化,以得到作为白色固体的实施例122B (2.4 g,71.5%产率)。
制备(R)-1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
实施例122B (400 mg,1.066 mmol)、磷酸氢二钾(464 mg,2.66 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(376 mg,1.279mmol)于1,4-二氧杂环己烷(20 mL)和水(0.2 mL)的混合物中的溶液用氮气吹扫10分钟且随后装入第2代XPhos预催化剂(25.2 mg,0.032 mmol)并在90℃下加热至回流2小时。将二氧杂环己烷浓缩,将残余物用EtOAc (100 mL)稀释,用水、盐水洗涤,经Na2SO4干燥,过滤并浓缩。粗产物通过制备型HPLC (方法信息:柱:Gemini NX-C18 (100mm × 21.2mm × 5μ),流动相A:10 mM乙酸铵/水,流动相B:乙腈,流速:16 mL/min,时间(min)/%B:0/30,10/65)纯化,以得到作为白色固体的实施例122 (180 mg,45.3%产率)。
HPLC RT-14.82纯度96.99%和13.69纯度98.6%和97.6% ee,手性HPLC RT = 15.64min, [α]24.7 D= 174.00 (c 0.1, MeOH)。
实施例123和124 (对映异构体1和2)
1-(4-(1H-吡唑-4-基)苯基)-4-(2-羟基丙-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮
实施例123A:制备1-(4-溴苯基)-4-(2-羟基丙-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮
在-20℃下,向1-(4-溴苯基)-3-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸乙酯(270mg,0.623 mmol)于THF (10 mL)中的溶液中添加溴化甲基镁(3 M,于乙醚中) (1.039 mL,3.12 mmol)并将反应混合物在相同温度下搅拌2小时。将反应物用饱和NH4Cl溶液淬灭,用EtOAc (2 × 25 mL)萃取。将合并的有机萃取物用盐水洗涤,经Na2SO4干燥并浓缩,以得到作为粘稠黄色液体的实施例123A (190 mg,58%产率)。MS(ESI) m/z: 419.1 (M+H)+。
实施例123和124
向实施例123A (190 mg,0.453 mmol)于DMF (3 mL)中的溶液中添加K2CO3 (188mg,1.359 mmol)和水(0.5 mL),将反应混合物用氮气吹扫10分钟且随后装入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(200 mg,0.680 mmol)和第2代XPhos预催化剂(21.39 mg,0.027 mmol),并再次用氮气吹扫10分钟并在90℃下加热16小时。将反应混合物冷却,用水稀释,用EtOAc (2 × 25 mL)萃取,将合并的有机层用水、盐水溶液洗涤,经Na2SO4干燥,过滤并浓缩。粗产物通过制备型HPLC (柱:SunFire C18 (150× 19mm, 5μ),溶剂A (90%水、10% ACN、0.1% HCOOH)和溶剂B (10%水、90% ACN、0.1%HCOOH,UV 220 nm)纯化。粗品进行SFC纯化以分离对映异构体。将级分浓缩,以得到作为白色固体的实施例123 (对映异构体1,38 mg,19.5%产率)。
作为白色固体的实施例124 (对映异构体2,37 mg,19.1%产率)。
实施例125
(R)-1-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮
实施例125A:制备(S)-2-(3-(4-溴苯基)脲基)-3-羟基丙酸乙酯
在室温下,在氮气下,经10分钟时间向三光气(3.19 g,10.75 mmol)于DCM (100mL)中的溶液中缓慢添加4-溴苯胺(5.0 g,29.1 mmol)和DIPEA (5.58 mL,32.0 mmol)于DCM (50 mL)中的混合物,然后在室温下搅拌30分钟。添加(S)-2-氨基-3-羟基丙酸乙酯、HCl (4.93 g,29.1 mmol)和DIPEA (10.66 mL,61.0 mmol)于DCM (75 mL)中的溶液。将反应混合物搅拌2.5小时。将反应混合物浓缩,并将残余物溶解于EtOAc中并用水、盐水洗涤,经Na2SO4干燥并浓缩。将残余物溶解于DCM中并通过添加己烷来沉淀。将固体过滤并用己烷洗涤并干燥,以得到作为白色固体的(S)-2-(3-(4-溴苯基)脲基)-3-羟基丙酸乙酯(9.0 g,94%产率)。
实施例125B:制备(S)-2-(3-(4-溴苯基)脲基)-3-((叔丁基二甲基甲硅烷基)氧基)丙酸乙酯
在0℃下,向(S)-2-(3-(4-溴苯基)脲基)-3-羟基丙酸乙酯(12 g,36.2 mmol)于THF (250 mL)中的溶液中添加咪唑(4.93 g,72.5 mmol)、TBDMS-Cl (8.19 g,54.4 mmol)和DMAP (1.328 g,10.87 mmol)。将反应物缓慢升温至室温并搅拌16小时。将反应物用EtOAc (100 mL)稀释,用水(2 × 100 mL)、盐水溶液洗涤,经Na2SO4干燥并浓缩。粗产物通过快速色谱 (120g REDISEP® SiO2柱,用40% EtOAc/正己烷洗脱)纯化,以得到作为白色固体的(S)-2-(3-(4-溴苯基)脲基)-3-((叔丁基二甲基甲硅烷基)氧基)丙酸乙酯(13.5 g,84%产率)。
实施例125C:制备(R)-1-(4-溴苯基)-3-(1-((叔丁基二甲基甲硅烷基)氧基)-3-羟基丙-2-基)脲
在0℃下,向(S)-2-(3-(4-溴苯基)脲基)-3-((叔丁基二甲基甲硅烷基)氧基)丙酸乙酯(8.75 g,19.64 mmol)于THF (100 mL)中的溶液中添加NaBH4 (2.230 g,58.9 mmol)和水(50 mL)。使反应混合物升温至室温并搅拌16小时。将反应物缓慢用水(100 mL)淬灭,用EtOAc (2 × 100 mL)萃取。将有机相用盐水洗涤,经Na2SO4干燥并浓缩。粗产物通过快速色谱(120g REDISEP® SiO2柱,用40% EtOAc/正己烷洗脱)纯化,以得到作为白色胶质固体的(R)-1-(4-溴苯基)-3-(1-((叔丁基二甲基甲硅烷基)氧基)-3-羟基丙-2-基)脲(6.0 g,76%产率)。
实施例125D:制备(R)-1-(4-溴苯基)-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)咪唑烷-2-酮
在0℃下,向(R)-1-(4-溴苯基)-3-(1-((叔丁基二甲基甲硅烷基)氧基)-3-羟基丙-2-基)脲(1.0 g,2.479 mmol)于THF (60 mL)中的溶液中添加叔丁醇钾(0.668 g,5.95mmol),随后添加对甲苯磺酰氯(0.567 g,2.97 mmol)。将混合物在0℃下搅拌40分钟。将反应物升温至室温并经由CELITE®垫过滤,用THF冲洗CELITE®垫。浓缩滤液。粗产物通过快速色谱(40g REDISEP® SiO2柱,用100% EtOAc/正己烷洗脱)纯化,以得到作为白色固体的(R)-1-(4-溴苯基)-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)咪唑烷-2-酮(500 mg,52.3%产率)。MS(ESI) m/z: 385.6 (M+H)+。
实施例125E:制备(R)-1-(4-溴苯基)-4-(((叔丁基二甲基甲硅烷基)氧基)甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮
在0℃下,经10分钟向实施例125D (520 mg,1.349 mmol)于THF (20 mL)中的溶液中逐份添加NaH (108 mg,2.70 mmol,60%,于矿物油中)。然后添加1-(溴甲基)-3-甲氧基苯(353 mg,1.754 mmol)并将反应混合物在室温下搅拌2.5小时。将反应混合物用甲醇淬灭,在减压下浓缩。粗产物通过快速色谱(40g REDISEP® SiO2柱,用100%己烷持续3 min;0-100% EtOAc/己烷持续30 min进行洗脱)纯化,以得到作为白色胶质固体的实施例125E(580 mg,85%产率)。
实施例125F:制备(R)-1-(4-溴苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮
在室温下,向实施例125E (580 mg,1.147 mmol)于THF (15 mL)中的溶液中添加TBAF (1 M,于THF中) (1.61 mL,1.61 mmol)并搅拌3小时。将反应混合物用EtOAc稀释,用10% NaHCO3溶液和盐水洗涤。将有机层经Na2SO4干燥并浓缩。将粗产物用DCM/己烷再结晶,以得到作为白色固体的实施例125F (280 mg,62.5%产率)。
实施例125
向实施例125F (100 mg,0.256 mmol)于二氧杂环己烷(8 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(113 mg,0.383 mmol)、磷酸三钾(109 mg,0.511 mmol)和水(1 mL)。将反应混合物用氮气吹扫10分钟且然后添加第2代XPhos预催化剂(12.07 mg,0.015 mmol)并用氮气再次吹扫10分钟。将混合物在80℃下加热3小时。将反应物冷却至室温并用EtOAc稀释,用水和盐水洗涤,经Na2SO4干燥,过滤并浓缩。将粗产物溶解于DCM (8 mL)中并添加TFA (0.3 mL,3.89 mmol)。将混合物在室温下搅拌4小时。将反应混合物浓缩至干燥并通过制备型HPLC纯化来纯化,以得到作为白色固体的实施例125 (26 mg,27%产率)。
实施例126和127
3-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮(对映异构体1和2)
实施例126A:制备3-(3-(4-溴苯基)-1-(3-甲氧基苄基)脲基)-2-氯丙酸乙酯
向2-氯-3-((3-甲氧基苄基)氨基)丙酸乙酯(390 mg,1.435 mmol)于甲苯(10 mL)中的溶液中添加1-溴-4-异氰酸酯基苯(313 mg,1.579 mmol)。将反应混合物在100℃下加热16小时。将混合物浓缩至干燥,以得到作为棕色胶状固体的3-(3-(4-溴苯基)-1-(3-甲氧基苄基)脲基)-2-氯丙酸乙酯(0.65 g,13.5%产率)。粗产物未经纯化即进一步使用。MS(ESI) m/z: 471.2 (M+H)+。
实施例126B:3-(4-溴苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸
在0℃下,向3-(3-(4-溴苯基)-1-(3-甲氧基苄基)脲基)-2-氯丙酸乙酯(650 mg,1.384 mmol)于THF (10 mL)中的溶液中添加NaH (69.9 mg,2.77 mmol,60%,于矿物油中)。将混合物在室温下搅拌16小时。将反应混合物缓慢用冰水(25 mL)淬灭,然后用EtOAc (2× 25 mL)萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并浓缩,以得到作为黄色胶质固体的3-(4-溴苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸(0.55 g,34%产率)。MS(ESI) m/z: 405.1 (M+H)+。
实施例126C:制备3-(4-溴苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸乙酯
向3-(4-溴苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸(550 mg,1.357mmol)于乙醇(15 mL)中的溶液中添加H2SO4 (0.289 mL,5.43 mmol)。将反应混合物在室温下搅拌16小时。将反应混合物用NaHCO3 (50 mL)缓慢淬灭,然后用EtOAc (2 × 50 mL)萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并浓缩。粗产物通过快速色谱(24gREDISEP® SiO2梯度洗脱;100% Hex持续5 min;0-100% EtOAc/Hex持续30 min)纯化,以得到作为黄色胶质固体的3-(4-溴苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸乙酯(0.18 g,14.3%产率)。
实施例126D:制备3-(4-溴苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮
在0℃下,向3-(4-溴苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸乙酯(180mg,0.415 mmol)于乙醇(10 mL)中的溶液中添加LiBH4 (36.2 mg,1.662 mmol)。使混合物在室温下搅拌16小时。浓缩乙醇。将残余物用水(50 mL)稀释,然后用EtOAc (2 × 50 mL)萃取。将合并的有机层用水和盐水溶液洗涤,经Na2SO4干燥,过滤并浓缩,以得到作为淡黄色胶质固体的3-(4-溴苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮(140 mg,52%产率)。粗产物未经进一步纯化即用于下一步骤。
实施例126E:制备4-(4-(5-(羟基甲基)-3-(3-甲氧基苄基)-2-氧代咪唑烷-1-基)苯基)-1H-吡唑-1-甲酸叔丁酯
向3-(4-溴苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮(140 mg,0.358mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(137 mg,0.465 mmol)于DMF (3 mL)中的溶液中添加K2CO3 (148 mg,1.073 mmol)和水(0.5mL)。将混合物用氮气吹扫10分钟且然后添加第2代XPhos预催化剂(16.89 mg,0.021 mmol)并将反应混合物在95℃下加热16小时。将反应混合物用水(25 mL)稀释,然后用EtOAc (2× 25 mL)萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥,过滤并浓缩,以得到作为棕色胶状固体的3-(4-溴苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮(250 mg,51%产率)。粗产物未经进一步纯化即用于下一步骤。MS(ESI) m/z: 479.3 (M+H)+。
制备3-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮
在室温下,向4-(4-(5-(羟基甲基)-3-(3-甲氧基苄基)-2-氧代咪唑烷-1-基)苯基)-1H-吡唑-1-甲酸叔丁酯(250 mg,0.522 mmol)于DCM (5 mL)中的溶液中添加TFA(0.201 mL,2.61 mmol)。将反应混合物搅拌3小时,然后浓缩。将残余物用己烷和乙醚洗涤,然后通过制备型HPLC纯化残余物。对映异构体通过超临界流体色谱[CHIRALPAK® AS-H(250 × 4.6)mm, 5μ,共溶剂为45% (0.25% DEA/甲醇)]分离,以得到作为白色固体的实施例126,对映异构体1 (19 mg,9.4%产率)。
较慢洗脱峰为对映异构体2,即实施例127 (18 mg,9.0%产率),白色固体。
表7中的以下实施例通过使用与实施例122至127中所示相同的程序制备。
实施例137
1-(4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮
实施例137A:制备1-(4-溴苯基)-4,4-二甲基咪唑烷-2-酮
在0℃下,向1-(4-溴苯基)-3-(1-羟基-2-甲基丙-2-基)脲(700 mg,2.438 mmol)和叔丁醇钾(657 mg,5.85 mmol)于THF中的搅拌悬浮液中逐滴添加对甲苯磺酰氯(558 mg,2.93 mmol)于THF (10 mL)中的溶液。将反应混合物在相同温度下搅拌2小时。将反应混合物用水(25 mL)缓慢淬灭,然后用EtOAc (2 × 25 mL)萃取。将合并的有机层用盐水洗涤,经Na2SO4干燥并浓缩。粗产物1-(4-溴苯基)-4,4-二甲基咪唑烷-2-酮(0.4 g,61%产率,白色固体)未经进一步纯化即使用。
实施例137B:制备1-(4-溴苯基)-3-(3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮
向1-(4-溴苯基)-4,4-二甲基咪唑烷-2-酮(200 mg,0.743 mmol)于THF (10 mL)中的溶液中添加NaH (59.4 mg,1.486 mmol,60%,于矿物油中)和1-(溴甲基)-3-甲氧基苯(224 mg,1.115 mmol)。将反应物在室温下搅拌16小时。将反应混合物用冰水(25 mL) 缓慢淬灭,然后用EtOAc (2 × 25 mL)萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥,过滤并浓缩。粗产物通过快速色谱(12g REDISEP® SiO2柱,梯度洗脱;100% Hex持续5 min;0-100% EtOAc/Hex持续20 min.)纯化,以得到作为白色固体的1-(4-溴苯基)-3-(3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮(160 mg,55%产率)。
实施例137:制备1-(4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮
向1-(4-溴苯基)-3-(3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮(160 mg,0.411mmol)于DMF (4 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(169 mg,0.575 mmol)、K2CO3 (170 mg,1.233 mmol)和水(0.4mL)。将反应混合物用氮气吹扫5分钟并装入第2代XPhos预催化剂(19.4 mg,0.025 mmol),在90℃下将反应混合物搅拌16小时。将反应混合物冷却至室温,经由CELITE®垫过滤,浓缩滤液。粗产物通过基于LC-MS的制备型HPLC纯化,以得到作为淡黄色固体的1-(4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮(63 mg,40.5%产率)。
表8中的以下实施例通过使用与实施例137中所示相同的程序制备。
实施例153
3-(4-(1H-吡唑-4-基)苯基)-5-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮
实施例153A:制备(S)-3-(4-溴苯基)-5-(羟基甲基)咪唑烷-2,4-二酮
在0℃下,向4-溴苯胺(500 mg,2.91 mmol)于THF (10 mL)中的溶液中逐滴添加三光气(431 mg,1.453 mmol)和TEA (1.215 mL,8.72 mmol)。将混合物在室温下搅拌30分钟,然后添加(S)-2-氨基-3-羟基丙酸乙酯(387 mg,2.91 mmol)和TEA (1.22 mL,8.72 mmol)于THF (10 mL)中的溶液。将混合物在室温下搅拌2.5小时。将THF蒸发并将残余物用水稀释。将所得固体过滤并在真空下干燥,以得到作为白色固体的(S)-3-(4-溴苯基)-5-(羟基甲基)咪唑烷-2,4-二酮(300 mg,20.5%产率)。
实施例153B:制备(S)-3-(4-溴苯基)-5-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮
向(S)-3-(4-溴苯基)-5-(羟基甲基)咪唑烷-2,4-二酮(200 mg,0.702 mmol)于DMF (5 mL)中的溶液中添加K2CO3 (145 mg,1.052 mmol)和1-(溴甲基)-3-甲氧基苯(141mg,0.702 mmol)。将反应混合物在室温下搅拌3小时。将反应混合物用水(25 mL)稀释,然后用EtOAc (2 × 25 mL)萃取。将合并的有机层用水和盐水洗涤,经Na2SO4干燥,过滤并浓缩。粗产物通过快速色谱(12g REDISEP® SiO2梯度洗脱;100% Hex持续5 min;0-100% EtOAc/Hex持续20 min)纯化,以得到作为白色固体的(S)-3-(4-溴苯基)-5-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮(150 mg,46%产率)。
实施例153:制备3-(4-(1H-吡唑-4-基)苯基)-5-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮
向3-(4-溴苯基)-5-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮(150 mg,0.370 mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(108 mg,0.555 mmol)于二氧杂环己烷(5 mL)中的溶液中添加磷酸三钾(196 mg,0.925 mmol)和水(0.5 mL)。将反应混合物用氮气吹扫10分钟,然后装入第2代XPhos预催化剂(17.47 mg,0.022 mmol)并用氮气再次吹扫10分钟。将混合物在75℃下加热2.5小时。将反应混合物冷却,然后用乙酸乙酯稀释。将有机相用水和盐水洗涤,经Na2SO4干燥并浓缩。将固体溶解于DCM (10 mL)中并用TFA (0.198 mL,2.57 mmol)处理。将混合物在室温下搅拌3小时,然后浓缩。将残余物用己烷和乙醚洗涤,然后通过制备型HPLC纯化,以得到实施例153 (25 mg,17%)。
实施例154和155
1-(4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮(对映异构体1和2)
实施例154A:制备2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸
在0℃下,向1-(4-溴苯基)咪唑烷-2-酮(2.5 g,10.37 mmol)于THF (10 mL)中的悬浮液中添加60% NaH (1.25 g,31.1 mmol)。在10分钟之后,添加2-溴-2-(3-甲氧基苯基)乙酸甲酯(3.76 g,14.52 mmol)并将混合物升温至室温并搅拌16小时。将反应物用甲醇淬灭,然后浓缩。将残余物溶解于NaHCO3的饱和溶液中并用乙醚洗涤。将水相酸化至pH 2。用乙酸乙酯萃取混合物。将合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并浓缩,以得到作为黄色固体的2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸(2.3 g,54.7%产率)。
实施例154B和155A:制备1-(4-溴苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮 (对映异构体1和对映异构体2)
在0℃下,向2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸(700mg,1.73 mmol)于THF (10 mL)中的溶液中添加甲硼烷-甲硫醚络合物(0.984 mL,10.4mmol)。在10分钟之后,将混合物升温至室温并在室温下搅拌16小时。将反应物用甲醇小心淬灭,然后浓缩。残余物通过快速色谱(装载于DCM中,梯度洗脱0-100% EtOAc/Hex持续30min.)纯化,以得到胶质固体(600 mg)。对映异构体通过超临界流体色谱(SFC) [柱:CHIRALCEL® OD-H(250 × 21mm, 5μ),共溶剂20% (0.2% DEA/甲醇)分离,以得到较快洗脱的作为黄色固体的1-(4-溴苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮(实施例154B,对映异构体1,0.170 g,25.2%产率)。
和作为黄色固体的1-(4-溴苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮(较慢洗脱的实施例155A,对映异构体2,0.140 g,20.7%产率)。
实施例154:制备1-(4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮 (对映异构体1)
向实施例154B (100 mg,0.256 mmol)于DMF (5 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(113 mg,0.383 mmol)、K2CO3 (106 mg,0.767 mmol)和水(0.5 mL)。将混合物用氮气吹扫10分钟,然后装入第2代XPhos预催化剂(12.1 mg,0.015 mmol)。将混合物用氮气再次吹扫10分钟,然后在90℃下在密封管中加热16小时。将反应混合物浓缩以得到灰白色固体(250 mg),其通过反相色谱纯化,以得到作为白色固体的1-(4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮(对映异构体1,0.140 g,20.7%产率)。
对映异构体2实施例155根据实施例154中所示的程序从实施例155A起始来制备。
实施例156和157
1-(4-(1H-吡唑-4-基)苯基)-3-(2-甲氧基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮(对映异构体1和2)
实施例156A和157A:制备1-(4-溴苯基)-3-(2-甲氧基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮 (对映异构体1和2)
向60% NaH (14.72 mg,0.613 mmol)中添加外消旋1-(4-溴苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮(80 mg,0.204 mmol)于THF (5 mL)中的溶液。将混合物在室温下搅拌30分钟,然后添加甲基碘(0.051 mL,0.818 mmol)。将所得混合物在室温下搅拌16小时。将反应物用甲醇淬灭,然后浓缩。残余物通过快速色谱(梯度洗脱;0-100%EtOAc/己烷)纯化,以得到外消旋产物。对映异构体通过SFC [柱:CHIRALCEL® OD-H(250× 4.6 mm, 5μ),共溶剂20%甲醇]分离,以得到作为黄色胶质固体的对映异构体1实施例156A (0.035 g,42.2%产率)。
作为黄色胶质固体的对映异构体2,实施例157A (0.035 g,42.2%产率)。
实施例156:制备1-(4-(1H-吡唑-4-基)苯基)-3-(2-甲氧基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
向实施例155A (35 mg,0.086 mmol)于DMF (5 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(30.5 mg,0.104 mmol)、K2CO3 (35.8 mg,0.259 mmol)和水(0.5 mL)。将混合物用氮气吹扫10分钟,然后添加第2代XPhos预催化剂(4.1 mg,5.18 µmol)。将混合物用氮气再次吹扫10分钟,且然后在90℃下在密封管中加热16小时。将反应物冷却至室温并过滤。滤液经由制备型HPLC纯化,以得到作为白色固体的1-(4-(1H-吡唑-4-基)苯基)-3-(2-甲氧基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮(0.010 g,30.5%产率)。
实施例157:制备1-(4-(1H-吡唑-4-基)苯基)-3-(2-甲氧基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮
使用实施例156中的类似程序以实施例157A开始来制备实施例157 (对映异构体2):
表9中的以下实施例以类似于实施例154和155的方式制备。
实施例286和287
1-(4-(1H-吡唑-4-基)苯基)-3-(1-羟基-2-(3-甲氧基苯基)丙-2-基)咪唑烷-2-酮 (对映异构体1和2)
实施例286A:制备2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸甲酯
在0℃下,向2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸(2.4g,5.92 mmol)于甲醇(50 mL)中的溶液中逐滴添加亚硫酰氯(1.297 mL,17.77 mmol)。将反应混合物在室温下搅拌16小时。将反应混合物浓缩。将残余物分配于NaHCO3的饱和溶液和乙酸乙酯之间。将合并的有机层用水和盐水洗涤,经Na2SO4干燥并浓缩。残余物通过快速色谱(梯度洗脱;0-100% EtOAc/己烷)纯化,以得到作为黄色固体的2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸甲酯(2.2 g,89.0%产率)。
实施例286B:制备2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)丙酸甲酯
向密封管中添加2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸甲酯(1.7 g,4.05 mmol)、叔丁醇钾(1.36 g,12.2 mmol)、甲基碘(1.268 mL,20.27 mmol)和18-冠醚-6 (0.536 g,2.03 mmol)。将反应混合物在室温下搅拌16小时,然后经由CELITE®过滤,用THF冲洗。浓缩滤液。残余物通过快速色谱(乙酸乙酯/己烷洗脱剂)纯化以得到黄色固体,其从DCM/己烷再结晶,以得到作为白色固体的2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)丙酸甲酯(1.2 g,68.0%产率)。
实施例286C:制备2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)丙酸
向2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)丙酸甲酯(300 mg,0.692 mmol)于THF (10 mL)和甲醇(3 mL)中的溶液中添加LiOH (41.5 mg,1.731 mmol)和水(3 mL)。将反应混合物在75℃下加热16小时,然后浓缩以得到。将所得残余物酸化至pH2。沉淀的固体通过过滤收集,用水和己烷洗涤并干燥,以得到作为白色固体的2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)丙酸(0.250 g,86.0%产率)。
实施例286D和287A:制备1-(4-溴苯基)-3-(1-羟基-2-(3-甲氧基苯基)丙-2-基)咪唑烷-2-酮 (对映异构体1和对映异构体2)
在0℃下,向2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)丙酸(250mg,0.596 mmol)于THF (10 mL)中的溶液中逐滴添加甲硼烷-甲硫醚络合物(0.566 mL,5.96 mmol)。在10分钟之后,将反应混合物升温至室温并搅拌16小时。将反应物用甲醇小心淬灭并在真空中浓缩混合物。粗产物通过快速色谱(梯度洗脱;0-100% EtOAc/己烷)纯化,以得到外消旋产物。对映异构体通过SFC [柱:CHIRALPAK® AS-H (250 × 21)mm, 5μ,共溶剂30% 0.2% DEA/甲醇]分离,以得到作为黄色固体的实施例286D (对映异构体1,0.090g,37.2%产率)。
且得到作为黄色固体的实施例287A (对映异构体2,0.080 g,33.1%产率)。
实施例286 (对映异构体1)
向实施例286D (90 mg,0.222 mmol)于DMF (2 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(91 mg,0.311 mmol)、K2CO3 (92 mg,0.666 mmol)和水(0.4 mL)。将反应混合物用氮气吹扫5分钟并装入第2代XPhos预催化剂(10.5 mg,0.013 mmol)。将混合物用氮气再次吹扫3分钟并在90℃下加热16小时。将反应混合物冷却至室温,过滤并浓缩滤液。残余物通过制备型HPLC纯化,以得到作为白色固体的实施例286 (0.054 g,61.3%产率)。
使用与实施例286类似的程序从实施例287A制备实施例287。
实施例288
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸(对映异构体2)
实施例288A:2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸
在0℃下,向1-(4-溴苯基)咪唑烷-2-酮(0.500 g,2.074 mmol)于THF (10 mL)中的混合物中添加58% NaH (0.257 g,6.22 mmol)。将混合物在室温下搅拌10分钟,然后冷却至0℃。添加2-溴-2-(3-甲氧基苯基)乙酸甲酯(0.806 g,3.11 mmol)并将混合物在室温下搅拌过夜。将反应混合物用冰淬灭并用1.5N HCl酸化。将混合物用EtOAc萃取。将有机层用水和盐水洗涤,经硫酸钠干燥并在真空中浓缩。粗产物通过用Et2O (10 mL)和己烷(20 mL)研磨来纯化,然后通过快速色谱(梯度洗脱0-70% EtOAc/Hex)纯化,以得到2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸(0.550 g,1.357 mmol,65.4%产率)。m/z: 405 (M+H)+。
实施例288
向实施例288A (0.130 g,0.321 mmol)于DMF (3 mL)、水(0.3 mL)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(142 mg,0.48 mmol)中的溶液中添加K2CO3 (0.133 g,0.962 mmol)。将混合物使用N2气体脱气5分钟。将第2代XPhos预催化剂(0.025 g,0.032 mmol)添加至反应物中,将其再次脱气且随后加热至90℃过夜。混合物通过制备型HPLC纯化,然后通过手性SFC分离对映异构体。第二峰的浓缩得到实施例288 (6.5 mg)。
手性纯度:96.26% ee (RT = 9.1 min),通过手性SFC分析柱测定:CHIRALPAK®IC (250 × 4.6) mm, 5μ,流动相:0.2% DEA/MeOH。
实施例289和290
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-N-乙基-2-(3-甲氧基苯基)乙酰胺 (对映异构体1和2)
实施例289A:制备2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-N-乙基-2-(3-甲氧基苯基)乙酰胺
向2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸(0.250 g,0.47 mmol)于DCM (20 mL)中的溶液中添加亚硫酰氯(0.360 mL,4.94 mmol)和一滴DMF。将反应混合物在室温下搅拌2小时。在真空中移除DCM和过量亚硫酰氯。将获得的残余物溶解于THF中,添加至乙胺(2 M,于THF中) (1.180 mL,2.360 mmol)和DIPEA (0.247 mL,1.416mmol)于DCM (10 mL)中的溶液并将混合物在室温下搅拌16小时。将反应混合物浓缩以得到黄色固体,其通过快速色谱(梯度洗脱;0-100% EtOAc/己烷)纯化,以得到作为白色固体的2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-N-乙基-2-(3-甲氧基苯基)乙酰胺(0.120 g,59.0%产率)。
实施例289和290:2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-N-乙基-2-(3-甲氧基苯基)乙酰胺 (对映异构体1和对映异构体2)
向实施例289A (120 mg,0.278 mmol)于DMF (6 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(114 mg,0.389 mmol)、K2CO3 (115 mg,0.833 mmol)和水(0.4 mL)。将反应混合物用氮气吹扫5分钟并装入第2代XPhos预催化剂(13.10 mg,0.017 mmol)并用氮气再次吹扫。将混合物在90℃下加热16小时,然后冷却,过滤。将滤液浓缩以得到胶质固体(300 mg),其通过制备型HPLC纯化。对映异构体通过SFC [柱:CHIRALCEL® OJ-H(250 × 21)mm, 5μ,共溶剂30% DEA/甲醇]分离,以得到作为白色固体的实施例289 (对映异构体1,0.036 g,30%产率)。
且得到作为白色固体的实施例290 (对映异构体2,0.034 g,29%产率)。
表11中的以下实施例以类似于实施例289和290的方式制备。
实施例304
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)-N-甲基丙酰胺 (对映异构体1)
实施例304A:制备2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)丙酸 (对映异构体1)
向2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)丙酸甲酯(900 mg,2.08 mmol)于THF (20 mL)和甲醇(10 mL)的混合物中的溶液中添加LiOH (249 mg,10.39mmol)和水(5 mL)。将反应混合物在75℃下加热16小时,然后浓缩。将残余物用HCl溶液酸化至pH 2并过滤沉淀的固体,用水和己烷洗涤并干燥,以得到白色胶质固体。将残余物与甲苯一起共蒸发以得到白色固体(700 mg)。对映异构体通过SFC [柱:CHIRALPAK® AS-H (250× 21)mm, 5μ,共溶剂10% (0.2% DEA/甲醇)]分离,以得到作为白色固体的实施例304A(对映异构体1,0.240 g,27.5%产率)。
实施例304B:制备2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)-N-甲基丙酰胺 (对映异构体1)
向实施例304A (0.240 g,0.572 mmol)于DCM (8 mL)中的溶液中添加SOCl2和一滴DMF。将反应混合物在室温下搅拌2小时,然后浓缩。将获得的残余物溶解于THF中并将所得溶液添加至甲胺(2 M,于THF中) (0.021 g,0.685 mmol)和DIPEA (0.072 mL,0.411mmol)于THF (5 mL)中的溶液中。将反应混合物在室温下搅拌16小时且然后浓缩以得到黄色固体。残余物通过快速色谱(梯度洗脱;0-100% EtOAc/己烷)纯化,以得到作为白色固体的实施例304B (0.045 g,76.0%产率)。
实施例304:制备2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)-N-甲基丙酰胺 (对映异构体1)
向2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)-N-甲基丙酰胺(45mg,0.104 mmol)于DMF (2 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(42.9 mg,0.146 mmol)、K2CO3 (43.2 mg,0.312 mmol)和水(0.4 mL)。将反应混合物用氮气吹扫5分钟并装入第2代XPhos预催化剂(4.91 mg,6.25µmol)。将混合物用氮气再次吹扫3分钟,然后在90℃下加热16小时。将反应物冷却至室温并过滤。滤液通过制备型HPLC纯化,以得到作为灰白色固体的实施例304 (对映异构体1,0.015 g,34.5%产率)。
表12中的以下实施例以类似于实施例304的方式制备。
实施例309和310
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)-2-(甲基氨基)乙基)咪唑烷-2-酮 (对映异构体1和对映异构体2)
实施例309A:制备2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)-N-甲基乙酰胺
向2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸(500 mg,1.24mmol)于DMF (3 mL)中的溶液中添加甲胺盐酸盐(167 mg,2.468 mmol)、TEA (0.860 mL,6.17 mmol)和HATU (704 mg,1.851 mmol)。将反应混合物在室温下搅拌16小时,然后用水稀释,搅拌30分钟。将沉淀的固体通过过滤收集并用水和己烷洗涤,以得到作为黄色固体的2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)-N-甲基乙酰胺(0.200 g,39%产率)。
实施例309B:制备1-(4-溴苯基)-3-(1-(3-甲氧基苯基)-2-(甲基氨基)乙基)咪唑烷-2-酮
在0℃下,向2-(3-(4-溴苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)-N-甲基乙酰胺(200 mg,0.478 mmol)于THF (10 mL)中的溶液中添加甲硼烷-甲硫醚络合物(0.454mL,4.78 mmol)。将反应混合物在0℃下搅拌10分钟,然后在室温下搅拌16小时。将反应物用甲醇淬灭,然后浓缩。向胶质固体中添加1.5N HCL (12 mL)并将混合物95℃加热16小时。将反应混合物冷却至室温,用饱和NaHCO3溶液中和,用乙酸乙酯萃取。将合并的乙酸乙酯层用水和盐水洗涤,经Na2SO4干燥并浓缩,以得到作为黄色胶质固体的1-(4-溴苯基)-3-(1-(3-甲氧基苯基)-2-(甲基氨基)乙基)咪唑烷-2-酮(0.080 g,41%产率)。
制备实施例309和310 (对映异构体1和对映异构体2)
向1-(4-溴苯基)-3-(1-(3-甲氧基苯基)-2-(甲基氨基)乙基)咪唑烷-2-酮(80mg,0.198 mmol)于DMF (4 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(81 mg,0.277 mmol)、K2CO3 (82 mg,0.594 mmol)和水(0.4 mL)。将反应混合物用氮气吹扫5分钟并装入第2代XPhos预催化剂(9.34 mg,0.012mmol)。将混合物用氮气再次吹扫3分钟,然后在90℃下加热16小时。将反应混合物冷却,过滤并浓缩滤液。获得的残余物通过制备型HPLC纯化,以得到外消旋产物(140 mg)。对映异构体通过SFC [柱:CHIRALPAK® AS-H (250 ×21)mm, 5μ,共溶剂30% (0.2% DEA/甲醇)]分离,以得到作为灰白色固体的实施例309 (对映异构体1,0.013 g,16%产率)。
且得到作为淡黄色固体的实施例310 (对映异构体2,0.008 g,10%产率)。
实施例311
(S)-1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(4-氟-3-甲氧基苄基)-4-(羟基甲基)咪唑烷-2-酮
实施例311A:(5-溴吡啶-2-基)氨基甲酸苯酯
向5-溴吡啶-2-胺(1.5 g,8.67 mmol)于THF (30 mL)中的溶液中添加吡啶(0.686g,8.67 mmol)。将混合物冷却至0℃,然后逐滴添加氯甲酸苯酯(1.561 g,9.97 mmol)。将反应混合物在室温下搅拌1小时。通过过滤收集沉淀物并用水洗涤并在抽吸下干燥,以得到作为灰白色固体的(5-溴吡啶-2-基)氨基甲酸苯酯(2.52 g,8.56 mmol,99%产率)。
实施例311B:(S)-1-(1-(苄基氧基)-3-羟基丙-2-基)-3-(5-溴吡啶-2-基)脲
将(5-溴吡啶-2-基)氨基甲酸苯酯(0.25 g,0.853 mmol)、(S)-2-氨基-3-(苄基氧基)丙-1-醇盐酸盐(0.186 g,0.853 mmol)和三乙胺(0.594 mL,4.26 mmol)于THF (10 mL)中的混合物在75℃下搅拌15小时。蒸发溶剂,然后将所得残余物悬浮于水中并搅拌30分钟。通过过滤收集沉淀物并干燥,以得到作为灰白色固体的(S)-1-(1-(苄基氧基)-3-羟基丙-2-基)-3-(5-溴吡啶-2-基)脲(0.32 g,98%产率)。
实施例311C: (S)-4-((苄基氧基)甲基)-1-(5-溴吡啶-2-基)咪唑烷-2-酮
在0℃下,向(S)-1-(1-(苄基氧基)-3-羟基丙-2-基)-3-(5-溴吡啶-2-基)脲(0.32g,0.842 mmol)和叔丁醇钾(0.236 g,2.104 mmol)于THF (10 mL)中的混合物中逐滴添加对甲苯磺酰氯(0.152 g,0.800 mmol)于THF (2.5 mL)中的溶液。将反应混合物在0℃下搅拌90分钟,然后用饱和NH4Cl水溶液(10 mL)淬灭。将混合物用水(20 mL)稀释并用EtOAc (2× 20 mL)萃取。将合并的有机萃取物用水和盐水洗涤,经Na2SO4干燥并浓缩。粗产物通过快速色谱(用30-40% EtOAc/己烷洗脱)纯化,以得到作为灰白色固体的(S)-4-((苄基氧基)甲基)-1-(5-溴吡啶-2-基)咪唑烷-2-酮(0.1 g,27%产率)。
实施例311D:(S)-4-((苄基氧基)甲基)-1-(5-溴吡啶-2-基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮
在0℃下,向(S)-4-((苄基氧基)甲基)-1-(5-溴吡啶-2-基)咪唑烷-2-酮(125 mg,0.345 mmol)于DMF (4 mL)中的溶液中添加氢化钠(矿物油中的60%悬浮液) (48.3 mg,1.208 mmol)。将反应混合物在10℃下搅拌30分钟,然后逐滴添加4-(溴甲基)-1-氟-2-甲氧基苯(151 mg,0.690 mmol)。将反应混合物在室温下搅拌3小时,然后用饱和NH4Cl水溶液(10 mL)淬灭。将混合物用水(40 mL)稀释并用EtOAc (2 × 50 mL)萃取。将合并的有机萃取物用水和盐水洗涤,经Na2SO4干燥并浓缩以得到粗产物,其通过快速色谱(用10-20%EtOAc/己烷洗脱)纯化,以得到作为无色油状物的(S)-4-((苄基氧基)甲基)-1-(5-溴吡啶-2-基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮(135 mg,59%产率)。
实施例311E:制备(S)-1-(5-(1H-吡唑-4-基)吡啶-2-基)-4-((苄基氧基)甲基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮
在密封管中混合(S)-4-((苄基氧基)甲基)-1-(5-溴吡啶-2-基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮(180 mg,0.360 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(169 mg,0.576 mmol)和碳酸钾(149 mg,1.079 mmol)/DMF (10 mL)和水(5 mL)。将反应混合物用氮气脱气,然后添加第2代XPhos预催化剂(28.3mg,0.036 mmol)并将混合物在95℃下搅拌6小时。将反应混合物冷却至室温并过滤。浓缩滤液并通过制备型HPLC纯化残余物,以得到作为灰白色固体的实施例311E (52 mg,30%产率)。
制备实施例311
向(S)-1-(5-(1H-吡唑-4-基)吡啶-2-基)-4-((苄基氧基)甲基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮(25 mg,0.051 mmol)于甲醇(15 mL)中的溶液中添加Pd-C (60 mg,0.056 mmol)并将反应混合物在高压釜中在3.5 kg压力下氢化15小时。将反应混合物用氮气脱气,经CELITE®过滤并浓缩滤液。残余物通过制备型HPLC纯化,以得到(S)-1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(4-氟-3-甲氧基苄基)-4-(羟基甲基)咪唑烷-2-酮(1.7 mg,8%产率)。
表13中的以下实施例以类似于实施例311的方式制备。
实施例316
1-(3ʹ-氟-2-甲氧基-[3,4ʹ-联吡啶]-6-基)-3-(3-甲氧基苄基)咪唑烷-2-酮
实施例316A:1-(5-溴-6-甲氧基吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮
在0℃下,向1-(5-溴-6-甲氧基吡啶-2-基)咪唑烷-2-酮(0.2 g,0.735 mmol)于DMF (6 mL)中的溶液中添加氢化钠(矿物油中的60%悬浮液) (0.103 g,2.57 mmol)。将反应混合物在10℃下搅拌30分钟。逐滴添加1-(溴甲基)-3-甲氧基苯(0.369 g,1.838 mmol)并将反应混合物在室温下搅拌3小时。将反应混合物用饱和NH4Cl水溶液(10 mL)淬灭,用水(40 mL)稀释并用EtOAc (2 × 50 mL)萃取。将合并的有机萃取物用水和盐水洗涤,经Na2SO4干燥并浓缩以得到粗产物。粗产物通过快速色谱(用10-20% EtOAc/己烷洗脱)纯化,以得到作为灰白色固体的1-(5-溴-6-甲氧基吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮(0.255 g,82%产率)。
制备实施例316
在密封管中,将1-(5-溴-6-甲氧基吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮(50 mg,0.127 mmol)、3-氟吡啶-4-硼酸频哪醇酯(34.1 mg,0.153 mmol)和磷酸三钾(67.6mg,0.319 mmol)合并在1,4-二氧杂环己烷(4 mL)和水(1.2 mL)中。将反应管用氮气脱气,然后添加PdCl2(dppf)-DCM加合物(12.5 mg,0.015 mmol)并将混合物在100℃下搅拌5小时。将反应混合物冷却至室温,用水(20 mL)稀释并用EtOAc (2 × 20 mL)萃取。将合并的有机萃取物用水和盐水洗涤,经Na2SO4干燥并浓缩。残余物通过制备型HPLC纯化,以得到1-(3ʹ-氟-2-甲氧基-[3,4ʹ-联吡啶]-6-基)-3-(3-甲氧基苄基)咪唑烷-2-酮(34 mg,65%产率)。
表14中的以下实施例以类似于实施例316的方式制备。
实施例321
1-(4-溴苯基)-3-(3-氟苄基)-1H-咪唑-2(3H)-酮
实施例321A:制备1-(4-溴苯基)-3-(3-氟苄基)-1H-咪唑-2(3H)-酮
向1-(4-溴苯基)-1H-咪唑-2(3H)-酮(0.3 g,1.255 mmol)和K2CO3 (0.347 g,2.510 mmol)于DMF (5 mL)中的混合物中添加1-(溴甲基)-3-氟苯(0.231 mL,1.882mmol)。将反应混合物在80℃下加热8小时。将反应混合物用冰淬灭并用乙酸乙酯稀释。将有机层分离并用水和盐水洗涤,经硫酸钠干燥并浓缩。粗产物使用快速仪器(2% MeOH/CHCl3)纯化,以得到作为灰白色固体的1-(4-溴苯基)-3-(3-氟苄基)-1H-咪唑-2(3H)-酮(0.38 g,1.073 mmol,85%产率)。
制备1-(4-溴苯基)-3-(3-氟苄基)-1H-咪唑-2(3H)-酮
将1-(4-溴苯基)-3-(3-氟苄基)-1H-咪唑-2(3H)-酮(0.15 g,0.432 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(0.252 g,1.296 mmol)和K2CO3(0.18 g,1.3 mmol)于DMF (3 mL)和水(1 mL)中的混合物通过向其中鼓泡N2气体10分钟而脱气。向反应混合物中添加第2代XPhos预催化剂(0.017 g,0.022 mmol)并将反应混合物在90℃下加热4小时。将反应混合物冷却至室温,经由CELITE®过滤并将滤液用乙酸乙酯稀释。将有机相用水、然后盐水洗涤并在真空中浓缩。该粗固体通过制备型HPLC纯化,以得到作为灰白色固体的实施例321 (68 mg,0.200 mmol,46%产率)。
实施例322
制备1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮
将1-(3-甲氧基苄基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-1H-咪唑-2(3H)-酮(0.1 g,0.246 mmol)、4-溴-1H-吡咯并[2,3-b]吡啶(0.097 g,0.492 mmol)和K2CO3 (0.102 g,0.738 mmol)于1,4-二氧杂环己烷(5 mL)和水(1 mL)中的混合物通过吹扫N2气体而脱气。向反应混合物中添加二氯化1,1ʹ-双(二苯基膦基)二茂铁-钯(II)二氯甲烷络合物(0.020 g,0.025 mmol)并将反应混合物在90℃下加热16小时。将反应混合物冷却至室温,经由CELITE®过滤并将滤液用乙酸乙酯稀释。将有机相用水、随后盐水洗涤,经硫酸钠干燥并浓缩。产物通过制备型HPLC纯化,以得到作为灰白色固体的1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮(11.5 mg,11%产率)。
实施例323和324
1-(4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮 (对映异构体1和2)
实施例323A:制备2-(3-(4-溴苯基)-2-氧代-2,3-二氢-1H-咪唑-1-基)-2-(3-甲氧基苯基)乙酸甲酯
向1-(4-溴苯基)-1H-咪唑-2(3H)-酮(2.5 g,10.46 mmol)和K2CO3 (3.61 g,26.1mmol)于乙腈(50 mL)中的混合物中添加2-溴-2-(3-甲氧基苯基)乙酸甲酯(3.25 g,12.55mmol)并将反应混合物在70℃下加热16小时。将反应混合物经由CELITE®过滤并在真空中浓缩滤液。获得的残余物用乙酸乙酯萃取,用水、随后盐水洗涤,经无水硫酸钠干燥并浓缩。粗产物使用快速仪器(18%乙酸乙酯/石油醚)纯化,以得到作为棕色糊状物质的2-(3-(4-溴苯基)-2-氧代-2,3-二氢-1H-咪唑-1-基)-2-(3-甲氧基苯基)乙酸甲酯(1.9 g,39%产率)。MS(ESI) m/z: 417.0 (M+H)+。
实施例323B:制备1-(4-溴苯基)-3-(2-羟基-1-(3-甲氧基苯基) 乙基)-1H-咪唑-2(3H)-酮
在-10℃下,向2-(3-(4-溴苯基)-2-氧代-2,3-二氢-1H-咪唑-1-基)-2-(3-甲氧基苯基)乙酸甲酯(750 mg,1.797 mmol)于THF (5 mL)中的混合物中非常缓慢地添加LAH(1.797 mL,1.797 mmol)。使反应混合物升温至室温并搅拌16小时。将反应混合物冷却至0℃并用10% NaOH水溶液淬灭。将反应混合物用乙酸乙酯萃取。将合并的有机层用水、随后盐水洗涤,经硫酸钠干燥并浓缩。粗产物使用快速色谱(16%乙酸乙酯/石油醚)纯化,以得到作为灰白色半固体的1-(4-溴苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮(560 mg,80%产率)。
实施例323和324 (对映异构体1和对映异构体2)
将1-(4-溴苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮(100mg,0.257 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(91 mg,0.308 mmol)和磷酸三钾(164 mg,0.771 mmol)于1,4-二氧杂环己烷(5 mL)和水(0.5 mL)中的混合物通过用N2气体吹扫10分钟而脱气。添加第2代XPhos预催化剂(10.11 mg,0.013 mmol)并将反应混合物在70℃下加热2小时。将反应混合物冷却至室温,经由CELITE®过滤并将滤液用乙酸乙酯稀释。将有机相用水、随后盐水洗涤并浓缩。将产物溶解于DCM (5 mL)中,冷却至0℃并用三氟乙酸(1 mL)处理。将混合物在室温下充分搅拌3小时。将反应混合物浓缩以得到粗产物,其通过制备型HPLC纯化,以得到外消旋产物。对映异构体通过SFC [柱:WHELK-O® 1 (R,R) (250 × 4.6)mm, 5μ,共溶剂为40% (0.2% DEA/甲醇)分离,以得到作为灰白色固体的实施例323 (对映异构体1;12 mg,0.031 mmol,12%产率)和作为灰白色固体的实施例324 (对映异构体2;15 mg,0.040 mmol,15%产率)。
手性纯度: 100% ee (RT 5.87), 通过手性SFC分析柱测定:WHELK-O® 1 (R,R)(250 ×4.6)mm, 5μ,流动相:40% (0.2% DEA/甲醇); SOR: [α]25.1 D= -92 (c 0.05,DMSO)。
实施例325和326
1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮 (对映异构体1和2)
实施例325A:制备1-(4-溴苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮
在0℃下,向1-(4-溴苯基)-1H-咪唑-2(3H)-酮(1.25 g,5.23 mmol)于DMF (30mL)中的混合物中添加氢化钠(0.376 g,15.69 mmol)。将混合物在室温下搅拌10分钟,然后冷却至0℃。将1-(1-溴乙基)-3-甲氧基苯(2.249 g,10.46 mmol)添加至混合物中,然后在60℃下加热16小时。将反应混合物冷却至室温并用冰淬灭并用乙酸乙酯稀释。将有机层分离并用水、随后盐水洗涤,经无水硫酸钠干燥并在真空中浓缩以得到粗产物,其通过快速色谱(2% MeOH/CHCl3)纯化,以得到作为灰白色半固体的1-(4-溴苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮(1.3 g,3.48 mmol,66.6%产率)。
实施例325B:制备1-(1-(3-甲氧基苯基)乙基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-1H-咪唑-2(3H)-酮
1-(4-溴苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮(150 mg,0.402mmol)、双(频哪醇合)二硼(204 mg,0.804 mmol)和乙酸钾(118 mg,1.21 mmol)于1,4-二氧杂环己烷(5 mL)中的混合物通过用N2气体吹扫而充分脱气。添加二氯化1,1ʹ-双(二苯基膦基)二茂铁-钯(II)二氯甲烷络合物(32.8 mg,0.040 mmol)并将混合物在100℃下加热16小时。将反应混合物冷却至室温,经由CELITE®过滤,用乙酸乙酯稀释并用水、随后盐水洗涤并浓缩。粗产物通过快速色谱(20%乙酸乙酯/石油醚)纯化,以得到作为灰白色半固体的1-(1-(3-甲氧基苯基)乙基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-1H-咪唑-2(3H)-酮(180 mg,0.377 mmol,94%产率)。MS(ESI) m/z: 421.2 (M+H)+。
实施例325和326
4-溴-1H-吡咯并[2,3-b]吡啶-1-甲酸叔丁酯(100 mg,0.337 mmol)和1-(1-(3-甲氧基苯基)乙基)-3-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-1H-咪唑-2(3H)-酮(170 mg,0.404 mmol)和K2CO3 (140 mg,1.010 mmol)于1,4-二氧杂环己烷(5mL)和水(0.5 mL)中的混合物通过吹扫N2气体而脱气。添加二氯化1,1ʹ-双(二苯基膦基)二茂铁-钯(II)二氯甲烷络合物(13.74 mg,0.017 mmol)并将混合物在90℃下加热16小时。将反应混合物经由CELITE®过滤并将滤液用乙酸乙酯稀释。将有机相用水、随后盐水洗涤并浓缩。粗产物通过制备型HPLC纯化,以得到作为灰白色固体的外消旋化合物。该对映异构体通过使用柱CHIRALPAK® AS-H (250 × 21)mm, 5μ,共溶剂/20%甲醇的SFC分离,以得到作为灰白色固体的实施例325 (对映异构体1,17 mg,0.041 mmol,12.25%产率)。
手性纯度: 100% ee (RT 11.88 min), 通过手性SFC分析柱测定:CHIRALPAK®OJ-H (250 × 4.6)mm, 5μ,流动相:20% (0.2% DEA/甲醇); SOR: [α]25.1 D= -164 (c0.05, MeOH),且得到作为灰白色固体的实施例326 (对映异构体2,10 mg,0.024 mmol,7.15%产率)。
手性纯度: 98.1366% ee (RT 13.27min), 通过手性SFC分析柱测定:CHIRALPAK® OJ-H (250 × 4.6)mm, 5μ,流动相:20% (0.2% DEA/甲醇);SOR; [α]25.3 D= +152 (c0.05, MeOH)。
实施例327
制备1-(4-(2-氟吡啶-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮 (对映异构体1)
将2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶(134 mg,0.603 mmol)、1-(4-溴苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮(150 mg,0.402 mmol)和K2CO3 (167 mg,1.206 mmol)于1,4-二氧杂环己烷(5 mL)和水(0.5 mL)中的混合物通过用N2气体吹扫而充分脱气。添加二氯化1,1ʹ-双(二苯基膦基)二茂铁-钯(II)二氯甲烷络合物(16.41 mg,0.020 mmol)并将混合物在90℃下加热16小时。将反应混合物冷却,经由CELITE®过滤并将滤液用乙酸乙酯稀释。将有机相用水、随后盐水洗涤并在真空中浓缩。将粗产物通过制备型HPLC纯化,以得到作为灰白色固体的外消旋产物。对映异构体通过SFC纯化[柱CHIRALPAK® AS-H (250 × 21)mm, 5μ,共溶剂为20%甲醇]分离,以得到作为淡棕色胶质固体的实施例327 (对映异构体I) (14 mg,0.035 mmol,9%产率)。
手性纯度: 100% ee (rt=4.34 min), 通过手性SFC分析柱测定:CHIRALPAK®AS-H (250 × 4.6)mm, 5μ,流动相:20% (0.2% DEA/甲醇);SOR: [α]25.1 D= +176.800 (c0.05, MeOH)。
表15中的以下实施例通过使用与实施例321至327中所示相同的程序制备。
实施例423
1-(4-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮
实施例423A:1-(5-溴-4-甲氧基吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮
在0℃下,向1-(5-溴-4-氟吡啶-2-基)咪唑烷-2-酮(100 mg,0.385 mmol)于THF(5 mL)中的溶液中添加NaH (9.23 mg,0.385 mmol)。将混合物在0℃下搅拌30分钟。经10分钟时间向其中添加1-(溴甲基)-3-甲氧基苯(77 mg,0.385 mmol)。使反应混合物升温至室温并搅拌过夜。将反应混合物用甲醇(5 mL)淬灭并蒸发溶剂。将固体溶解于乙酸乙酯中并用水(50 mL)和盐水(20 mL)洗涤。将有机层经Na2SO4干燥,过滤并在减压下浓缩以得到粗品。粗化合物通过快速色谱(2%-20%乙酸乙酯/石油醚梯度洗脱)纯化,以得到作为白色固体的1-(5-溴-4-甲氧基吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮(110 mg,73%)。
制备1-(4-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮
向1-(5-溴-4-甲氧基吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮(100 mg,0.246mmol)于DMF (5 mL)中的溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-甲酸叔丁酯(87 mg,0.295 mmol)、K2CO3 (102 mg,0.738 mmol)和水(0.2mL)。将反应混合物用氮气吹扫5分钟并装入第2代XPhos预催化剂(5.81 mg,7.38 µmol)。将混合物用氮气再次吹扫3分钟,然后在90℃下加热16小时。将反应物冷却至室温并过滤,并浓缩滤液。残余物通过制备型HPLC纯化,以得到作为灰白色固体的1-(4-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮(0.0164 g,16%产率)。
表16中的以下实施例遵循与以上诸个实施例类似的途径制备。
Claims (14)
1.根据式(I)的化合物:
或其对映异构体、药学上可接受的盐,其中
---是任选的键;
环A独立地选自
J1、J2、J3和J4独立地选自N和CR3;条件是J1、J2、J3和J4之一是N且J1、J2、J3和J4中不超过两个是N;
K独立地选自N和CR1;
R1独立地选自H、F、Cl、Br和C1-4烷基;
R2独立地选自H;
R3独立地选自H、F、Cl、Br、CN、C1-4烷基、-(CH2)rORb和-(CH2)rNRaRa;
R5独立地选自H、被0-4个Re取代的C1-4烷基和-(CH2)rORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb和-(CH2)rC(=O)ORb;
R8独立地选自C3-6环烷基、3-7-元杂环基、C6-10芳基和5-6-元杂芳基,其各自被0-5个R9取代;
R9独立地选自F、Cl、Br、C1-4烷基、-(CHRd)rORb、-(CHRd)rCN和-(CHRd)rC(=O)ORb,其中所述烷基被0-4个Re取代;
Ra在每次出现时独立地选自H和C1-6烷基;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基和-(CH2)r-C3-10碳环基;
Rd在每次出现时独立地选自H;
Re在每次出现时独立地选自-(CH2)r-C3-6环烷基、F、Cl、Br和-(CH2)rORf;
Rf在每次出现时独立地选自H;
n独立地选自1、2和3;且
r在每次出现时独立地选自0、1和2。
3.根据式(IIa)的化合物:
或其对映异构体、药学上可接受的盐,其中
---是任选的键;
环A独立地选自
K独立地选自CR1;
R1独立地选自H;
R2独立地选自H;
R3独立地选自H和-(CH2)rORb;
R4独立地选自H、OC1-4烷基和C1-4烷基;
R5、R10和R11独立地选自H、=O和被0-4个Re取代的C1-4烷基;条件是R5、R10和R11不都是H;
R6和R7独立地选自H和C1-4烷基;
R9独立地选自F、Cl、Br和-(CH2)rORb;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基和-(CH2)r-C3-10碳环基;
Re在每次出现时独立地选自-(CH2)r-C3-6环烷基、F、Cl、Br和-(CH2)rORf;
Rf在每次出现时独立地选自H;
n独立地选自1、2和3;且
r在每次出现时独立地选自0、1和2。
4.权利要求3的化合物,其具有式(IIIa):
或其对映异构体、药学上可接受的盐,其中
R1独立地选自H;
R2独立地选自H;
R3独立地选自H和-(CH2)rORb;
R4独立地选自H、OC1-4烷基和C1-4烷基;
R5、R10和R11独立地选自H、=O和被0-4个Re取代的C1-4烷基;条件是R5、R10和R11不都是H;
R6独立地选自H和C1-4烷基;
R7独立地选自H和C1-4烷基;
R9独立地选自F、Cl、Br和-(CH2)rORb;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基和-(CH2)r-C3-10碳环基;
Re在每次出现时独立地选自-(CH2)r-C3-6环烷基、F、Cl、Br和-(CH2)rORf;
Rf在每次出现时独立地选自H;
n独立地选自1和2;且
r在每次出现时独立地选自0、1和2。
6.权利要求1的化合物,其具有式(VII):
或其对映异构体、药学上可接受的盐,其中
环A独立地选自
R1独立地选自H、F、Cl、Br和C1-4烷基;
R2独立地选自H;
R3独立地选自H、F、Cl、Br、OH、CN、OC1-4烷基和C1-4烷基;
R5独立地选自H、被0-4个Re取代的C1-4烷基和-(CH2)rORb;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基和-(CH2)rORb;
R8独立地选自
R9独立地选自F、Cl、Br、C1-4烷基、-(CH2)rORb、-(CH2)rCN和-(CH2)rC(=O)ORb,其中所述烷基被0-4个Re取代;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基和-(CH2)r-C3-10碳环基;
Re在每次出现时独立地选自-(CH2)r-C3-6环烷基、F、Cl、Br和-(CH2)rORf;
Rf在每次出现时独立地选自H;
n独立地选自1、2和3;且
r在每次出现时独立地选自0、1和2。
7.根据式(XI)的化合物:
或其对映异构体、药学上可接受的盐,其中
R1独立地选自H;
R2独立地选自H;
R3独立地选自H;
R4独立地选自H、F、Cl、Br、OC1-4烷基和C1-4烷基;
R6独立地选自H、被OH取代的C1-4烷基、-CH2ORb、-CH2NRaRa、-C(=O)NRaRa和-(CH2)rC(=O)ORb;
R7独立地选自H和C1-4烷基;条件是R6和R7不都是H;当R7是C1-4烷基时,R6不是H;
R9独立地选自-(CH2)rORb;
Ra在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基和-(CH2)r-C3-10环烷基;
Rb在每次出现时独立地选自H和C1-6烷基;
Re在每次出现时独立地选自-(CH2)rORf;
Rf在每次出现时独立地选自H;
n独立地选自1和2;且
r在每次出现时独立地选自0、1和2。
9.根据式(XIII)的化合物:
或其对映异构体、药学上可接受的盐,其中
环A独立地选自
J1、J2、J3和J4独立地选自N和CR3;
K独立地选自N和CR1;
R1独立地选自H、F、Cl、Br和NRaRa;
R2独立地选自H;
R3独立地选自H、F、Cl、Br、CN、C1-4烷基和-(CH2)rORb;
R5独立地选自H;
R6和R7独立地选自H、被0-4个Re取代的C1-4烷基、-(CH2)rORb和-(CH2)rC(=O)ORb;
R8独立地选自C3-6环烷基、3-7-元杂环基、C6-10芳基和5-6-元杂芳基,其各自被0-5个R9取代;
R9独立地选自F、Cl、Br、C1-4烷基和-(CH2)rORb;
Ra在每次出现时独立地选自H和C1-6烷基;
Rb在每次出现时独立地选自H、被0-5个Re取代的C1-6烷基和-(CH2)r-C3-10碳环基;
Re在每次出现时独立地选自F、Cl、Br和-(CH2)rORf;
Rf在每次出现时独立地选自H;
n独立地选自1、2和3;且
r在每次出现时独立地选自0、1和2。
10.化合物或其对映异构体、药学上可接受的盐,所述化合物选自:
1-(4-(1H-吡唑-4-基)苯基)-3-苯乙基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-苄基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(4-氟苄基)咪唑烷-2-酮;
1-(4-氟苯乙基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(3-氟苄基)-3-(2-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(2-氟苯乙基)-3-(2-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-苄基-3-(2-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
(R)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
(R)-1-(2-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(2-氟-5-甲氧基苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(2,6-二氟苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
3-(3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-3-(3-甲氧基苯基)丙酸,TFA;
3-(3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-3-(3-甲氧基苯基)丙酸甲酯;
1-(3-羟基-1-(3-甲氧基苯基)丙基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(3-羟基-1-(3-甲氧基苯基)-3-甲基丁基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-氟苄基)咪唑烷-2-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(2-氟苄基)咪唑烷-2-酮;
1-苄基-3-(3-乙基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苯乙基)咪唑烷-2-酮,TFA;
(R)-1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
3-(4-(1H-吡唑-4-基)苯基)-1-苄基-2-氧代咪唑烷-4-甲酸乙酯;
3-(4-(1H-吡唑-4-基)苯基)-1-苄基-4-(羟基甲基)咪唑烷-2-酮;
1-(2-(1H-吡唑-4-基)苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮,TFA;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟苄基)-2-氧代咪唑烷-4-甲酸;
3-(4-(1H-吡唑-4-基)苯基)-1-(3-氟苄基)-2-氧代咪唑烷-4-甲酸;
3-(4-(1H-吡唑-4-基)苯基)-1-(3-氟苄基)-2-氧代咪唑烷-4-甲酸甲酯;
3-(4-(1H-吡唑-4-基)苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸;
3-(4-(1H-吡唑-4-基)苯基)-1-(3-甲氧基苄基)-2-氧代咪唑烷-4-甲酸乙酯;
1-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-苄基-4-(羟基甲基)咪唑烷-2-酮;
3-(4-(1H-吡唑-4-基)苯基)-1-(3-氟苄基)-4-(羟基甲基)咪唑烷-2-酮;
4-(羟基甲基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
3-苄基-4-(羟基甲基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
(+)-1-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
(-)-1-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
(-)-1-(4-(1H-吡唑-4-基)苯基)-4-(2-羟基丙-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
(+)-1-(4-(1H-吡唑-4-基)苯基)-4-(2-羟基丙-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
(R)-1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
(-)-3-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮;
(+)-3-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮;
1-(3-氟苄基)-3-(4-(3-氟吡啶-4-基)苯基)咪唑烷-2-酮;
1-(4-(3-氟吡啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(3-氟苄基)-3-(4-(2-氟吡啶-4-基)苯基)咪唑烷-2-酮;
1-苄基-3-(4-(3-氟吡啶-4-基)苯基)咪唑烷-2-酮;
1-(4-(3-氟吡啶-4-基)苯基)-3-苯乙基咪唑烷-2-酮;
1-(4-(2-氟吡啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(3-氟苄基)-3-(4-(吡啶-4-基)苯基)咪唑烷-2-酮,TFA;
1-(2-氟苄基)-3-(4-(吡啶-4-基)苯基)咪唑烷-2-酮,TFA;
1-(2-氟-5-甲氧基苄基)-3-(3-甲氧基-4-(吡啶-4-基)苯基)咪唑烷-2-酮,TFA;
1-(3-氟苄基)-3-(3-甲氧基-4-(吡啶-4-基)苯基)咪唑烷-2-酮,TFA;
1-苄基-3-(4-(异噁唑-4-基)苯基)咪唑烷-2-酮;
1-(3-氟苄基)-3-(4-(异噁唑-4-基)苯基)咪唑烷-2-酮;
1-(4-(2-氨基吡啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮,TFA;
1-(4-(2-氨基嘧啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(7H-吡咯并[2,3-d]嘧啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-甲氧基苯乙基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(4-氟苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2,6-二氟苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟苯乙基)-1H-咪唑-2(3H)-酮;
(+)-1-(4-(1H-吡唑-4-基)苯基)-3-(1-苯基乙基)-1H-咪唑-2(3H)-酮;
(-)-1-(4-(1H-吡唑-4-基)苯基)-3-(1-苯基乙基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-(二氟甲氧基)苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-苯乙基-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-5-甲氧基苄基)-1H-咪唑-2(3H)-酮;
3-(4-(1H-吡唑-4-基)苯基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮;
3-(4-(1H-吡唑-4-基)苯基)-1-(3-氟苄基)咪唑烷-2,4-二酮;
3-(4-(1H-吡唑-4-基)苯基)-1-(2-氯苄基)咪唑烷-2,4-二酮;
3-(4-(1H-吡唑-4-基)苯基)-1-(2,5-二氟苄基)咪唑烷-2,4-二酮;
3-(4-(1H-吡唑-4-基)苯基)-1-(3-氟-5-甲氧基苄基)咪唑烷-2,4-二酮;
3-(4-(1H-吡唑-4-基)苯基)-1-苯乙基咪唑烷-2,4-二酮;
3-(4-(1H-吡唑-4-基)苯基)-1-(2-氟苄基)咪唑烷-2,4-二酮;
3-(4-(1H-吡唑-4-基)苯基)-1-苄基咪唑烷-2,4-二酮;
1-苄基-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮;
1-(2-氯苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮;
1-(3-氟苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮;
1-(2-氟苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮,TFA;
1-(2,5-二氟苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮,TFA;
3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮,TFA;
1-(3-氟-5-甲氧基苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮,TFA;
3-(4-(1H-吡唑-4-基)苯基)-1-(1-苯基乙基)咪唑烷-2,4-二酮;
3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-1-(1-苯基乙基)咪唑烷-2,4-二酮;
3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-1-苯乙基咪唑烷-2,4-二酮;
3-苄基-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮;
3-(2-氟苄基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮;
3-(3-氟苄基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮;
3-(3-氟-5-甲氧基苄基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮;
3-(2,6-二氟苄基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮;
1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯乙基咪唑烷-2,4-二酮;
3-(2-氯苄基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)咪唑烷-2,4-二酮;
1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2,4-二酮;
1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(1-苯基乙基)咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2,6-二氟苄基)咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-苯基乙基)咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-苄基咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氯苄基)咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-苯乙基咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟苄基)咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2,5-二氟苄基)咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-4-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(5-氟-2-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-5-甲氧基苄基)咪唑烷-2-酮;
3-(4-(1H-吡唑-4-基)苯基)-5-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮;
(R)-1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-4-(2-羟基丙-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
(R)-1-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
3-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2-酮;
(R)-1-(4-(1H-吡唑-4-基)苯基)-3-(4-氟-3-甲氧基苄基)-4-(羟基甲基)咪唑烷-2-酮;
(S)-1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)-4-(羟基甲基)咪唑烷-2-酮;
(R)-1-(4-溴苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
(S)-1-(4-(1H-吡唑-4-基)苯基)-3-(4-氟-3-甲氧基苄基)-4-(羟基甲基)咪唑烷-2-酮;
(4R)-1-(4-(1H-吡唑-4-基)苯基)-4-(羟基甲基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
4-(羟基甲基)-1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
(R)-1-(4-(3-氟吡啶-4-基)苯基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-4-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(4-氟-3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟苄基)-4,4-二甲基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-(二氟甲氧基)苄基)-4,4-二甲基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-(环丙基甲氧基)苄基)-4,4-二甲基咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)-4,4-二甲基咪唑烷-2-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
3-(3-氟-5-甲氧基苄基)-4,4-二甲基-1-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
3-(4-氟-3-甲氧基苄基)-4,4-二甲基-1-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
3-(4-(1H-吡唑-4-基)苯基)-5-(羟基甲基)-1-(3-甲氧基苄基)咪唑烷-2,4-二酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-甲氧基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(2-羟基-1-(3-甲氧基苯基)乙基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-苯基乙基)咪唑烷-2-酮;
1-(2-羟基-1-(3-甲氧基苯基)乙基)-3-(3-甲基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮,TFA;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮,TFA;
1-(3-(环丙基甲氧基)苄基)-3-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮,TFA;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(4-氟-3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-氟-5-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-4-乙基-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-4-乙基-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-(环丙基甲氧基)苄基)-4-乙基咪唑烷-2-酮;
1-(3-氟-5-甲氧基苄基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-甲氧基苄基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(1-(3-甲氧基苯基)乙基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(3-氟-5-甲氧基苄基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(3-(环丙基甲氧基)苄基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-甲氧基苄基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(1-(3-甲氧基苯基)乙基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(4-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(1-(3-甲氧基苯基)乙基)-3-(3-甲基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(4-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-(环丙基甲氧基)苯基)乙基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-氟-5-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(4-氟-3-甲氧基苄基)-3-(6-(甲基氨基)-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-氟-5-甲氧基苄基)-3-(6-(甲基氨基)-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-(环丙基甲氧基)苄基)-3-(6-(甲基氨基)-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-甲氧基苄基)-3-(6-(甲基氨基)-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(1-(3-(环丙基甲氧基)苯基)乙基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3′-氟-2-甲基-[3,4′-联吡啶]-6-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(1-(3-氟-5-甲氧基苯基)乙基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(1-(4-氟-3-甲氧基苯基)乙基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-(环丙基甲氧基)-4-氟苄基)-3-(6-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(环己基甲基)咪唑烷-2-酮;
1-(1-(3-(环丙基甲氧基)苯基)乙基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(4-氟-3-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-(环丙基甲氧基)-4-氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(2-氟-5-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(5-氟-2-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(2,3-二氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-(环丙基甲氧基)-5-氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-氟-2-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(环己基甲基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(1-(3-氟-5-甲氧基苯基)乙基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(1-(4-氟-3-甲氧基苯基)乙基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-(二氟甲氧基)苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲基苄基)咪唑烷-2-酮;
3-((3-(5-(1H-吡唑-4-基)吡啶-2-基)-2-氧代咪唑烷-1-基)甲基)苄腈;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3,5-二甲基苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-氯苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3,4-二氟苄基)咪唑烷-2-酮;
3-((3-(5-(1H-吡唑-4-基)吡啶-2-基)-2-氧代咪唑烷-1-基)甲基)苯甲酸;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-(三氟甲基)苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3,4-二氯苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(吡啶-3-基甲基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(吡啶-2-基甲基)咪唑烷-2-酮;
1-(2-氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(2,4-二氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(2,5-二氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3,5-二氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-氟-2-甲基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(4-氟-2-甲基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(5-氟-2-甲基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(4-氟-2-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(2-氟-3-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(吡啶-3-基甲基)咪唑烷-2-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-((四氢呋喃-2-基)甲基)咪唑烷-2-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-((5-甲基-1,2,4-噁二唑-3-基)甲基)咪唑烷-2-酮;
1-(3-氯苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-4-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(5-氟-2-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-2-甲氧基苄基)咪唑烷-2-酮;
1-(1-(3-(环丙基甲氧基)苯基)乙基)-3-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(1-(3-乙氧基苯基)乙基)-3-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-氟-5-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(4-氟-3-甲氧基苯基)乙基)咪唑烷-2-酮;
(R)-1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(3-氟-5-甲氧基苄基)-3-(3-甲基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)-3-(三氟甲基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)-3-(三氟甲基)苯基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
5-(3-(3-甲氧基苄基)-2-氧代咪唑烷-1-基)-2-(1H-吡唑-4-基)苄腈;
5-(3-(3-氟-5-甲氧基苄基)-2-氧代咪唑烷-1-基)-2-(1H-吡唑-4-基)苄腈;
5-(3-(4-氟-3-甲氧基苄基)-2-氧代咪唑烷-1-基)-2-(1H-吡唑-4-基)苄腈;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(4-氟-3-甲氧基苄基)-3-(3-甲基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮,TFA;
1-(4-(1H-吡唑-4-基)-3-(三氟甲基)苯基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(3-(环丙基甲氧基)苄基)-3-(3-甲基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(3-(环丙基甲氧基)苄基)-3-(3-乙基-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-羟基-2-(3-甲氧基苯基)丙-2-基)咪唑烷-2-酮;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酸;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-N-乙基-2-(3-甲氧基苯基)乙酰胺;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)-N-甲基乙酰胺;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-N-异丁基-2-(3-甲氧基苯基)乙酰胺;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)乙酰胺;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-N-(环丙基甲基)-2-(3-甲氧基苯基)乙酰胺;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-N-甲基-2-苯基乙酰胺;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-N-环丙基-2-(3-甲氧基苯基)乙酰胺;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-N-(2-羟基-2-甲基丙基)-2-(3-甲氧基苯基)乙酰胺;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)-N-甲基丙酰胺;
2-(3-(4-(1H-吡唑-4-基)苯基)-2-氧代咪唑烷-1-基)-2-(3-甲氧基苯基)丙酰胺;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)-2-(甲基氨基)乙基)咪唑烷-2-酮;
(S)-1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(4-氟-3-甲氧基苄基)-4-(羟基甲基)咪唑烷-2-酮;
(S)-1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-氟-5-甲氧基苄基)-4-(羟基甲基)咪唑烷-2-酮;
(R)-1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-氟-5-甲氧基苄基)-4-(羟基甲基)咪唑烷-2-酮;
(S)-1-(5-(1H-吡唑-4-基)吡啶-2-基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮,TFA;
1-(3′-氟-2-甲氧基-[3,4′-联吡啶]-6-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(6-甲氧基-5-(1H-吡咯并[2,3-b]吡啶-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(2′-氟-2-甲氧基-[3,4′-bi吡啶]-6-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(6-甲氧基-5-(5-甲基-1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(4-溴苯基)-3-(3-氟苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(4-(2-氟吡啶-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟苯乙基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-苯基乙基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-(二氟甲氧基)苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-苯乙基-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2-氟-5-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(3-氟-5-甲氧基苄基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-1H-咪唑-2(3H)-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-氟-5-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(4-氟-3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-(环丙基甲氧基)苄基)-1H-咪唑-2(3H)-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(4-氟-3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
2-(3-(5-(1H-吡唑-4-基)吡啶-2-基)-2-氧代-2,3-二氢-1H-咪唑-1-基)-2-(3-甲氧基苯基)乙酸;
2-(3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-氧代-2,3-二氢-1H-咪唑-1-基)-2-(3-甲氧基苯基)乙酸;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-(环丙基甲氧基)苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(2-羟基-1-(3-甲氧基苯基)乙基)-3-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-1H-咪唑-2(3H)-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-氟-5-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(1-(3-乙氧基苯基)乙基)-3-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-氟-5-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-乙氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-乙氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(1-(3-(环丙基甲氧基)苯基)乙基)-3-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(2-氟-5-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(5-氟-2-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(2,3-二氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(3-(环丙基甲氧基)-4-氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(3-(环丙基甲氧基)苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(3-氟-2-甲基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(4-氟-2-甲基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(5-氟-2-甲基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(4-氟-2-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(4-(3-氟吡啶-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(6-乙基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(4-氟-3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(1-(4-氟-3-甲氧基苯基)乙基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(1-(4-氟-3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-氟-5-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(3-(环丙基甲氧基)-5-氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-(环丙基甲氧基)-5-氟苄基)-1H-咪唑-2(3H)-酮;
1-(1-(3-氟-5-甲氧基苯基)乙基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(4-(2-氨基嘧啶-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-甲氧基苯基)乙基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-2-甲基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(4-氟-2-甲基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(5-氟-2-甲基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(3-氟-2-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2,3-二氟苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(4-氟-3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2,5-二氟苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(2,4-二氟苄基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(吡啶-3-基甲基)-1H-咪唑-2(3H)-酮;
1-(4-(1H-吡唑-4-基)苯基)-3-(4-氟-2-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(3-氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(2,4-二氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(2,5-二氟苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(3-氟-2-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(吡啶-3-基甲基)-1H-咪唑-2(3H)-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-((四氢呋喃-2-基)甲基)-1H-咪唑-2(3H)-酮;
1-(3-(二氟甲氧基)苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(环己基甲基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;
1-(4-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(5-氟-2-甲氧基苄基)-3-(3-氟-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(3-氟-4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(3-氟-4-(1H-吡唑-4-基)苯基)-3-(2-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(2-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(3-氟-4-(1H-吡唑-4-基)苯基)-3-(2-氟-6-甲氧基苄基)咪唑烷-2-酮;
1-(3-氟-4-(1H-吡唑-4-基)苯基)-3-(3-氟-4-甲氧基苄基)咪唑烷-2-酮;
1-(2-氟-3-甲氧基苄基)-3-(3-氟-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(4-氟-3-甲氧基苄基)-3-(3-氟-4-(1H-吡唑-4-基)苯基)咪唑烷-2-酮;
1-(6-(1H-吡唑-4-基)吡啶-3-基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-(环丙基甲氧基)苄基)咪唑烷-2-酮;
1-(6-(1H-吡唑-4-基)吡啶-3-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(6-(1H-吡唑-4-基)吡啶-3-基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(6-(1H-吡唑-4-基)吡啶-3-基)-3-(3-(环丙基甲氧基)苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(3-氟-4-(1H-吡唑-4-基)苯基)-3-(3-异丁氧基苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-异丁氧基苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(2,5-二氟-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(2,5-二氟-4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(2,5-二氟-4-(1H-吡唑-4-基)苯基)-3-(4-氟-3-甲氧基苄基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(4-氟-3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-(环丙基甲氧基)苄基)-4,4-二甲基咪唑烷-2-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(3-乙基-4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)-1H-咪唑-2(3H)-酮;
1-(3-(环丙基甲氧基)苄基)-3-(3-乙基-4-(1H-吡唑-4-基)苯基)-1H-咪唑-2(3H)-酮;
(S)-1-(4-(1H-吡唑-4-基)苯基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(3-氟-4-(1H-吡唑-4-基)苯基)-3-(2-羟基-1-(3-甲氧基苯基)乙基)咪唑烷-2-酮;
1-(5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-氟-5-甲氧基苄基)-4,4-二甲基咪唑烷-2-酮;
1-(3-氟-5-甲氧基苄基)-3-(4-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-甲氧基苄基)-3-(4-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(3-氟-5-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-环丙基-4-(1H-吡唑-4-基)苯基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(3-环丙基-4-(1H-吡唑-4-基)苯基)-3-(3-氟-5-甲氧基苄基)咪唑烷-2-酮;
1-(1-(3-甲氧基苯基)乙基)-3-(4-甲基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(3-氟-5-甲氧基苄基)-3-(4-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
1-(4-乙氧基-5-(1H-吡唑-4-基)吡啶-2-基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
(R)-1-(5-(1H-吡唑-4-基)吡啶-2-基)-4-(羟基甲基)-3-(3-甲氧基苄基)咪唑烷-2-酮;
1-(3-(环丙基甲氧基)苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)咪唑烷-2-酮;
(S)-1-(4-(1H-吡唑-4-基)苯基)-3-(3-(环丙基甲氧基)苄基)-4-(羟基甲基)咪唑烷-2-酮;
1-(4-氟-3-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮;和
1-(3-氟-5-甲氧基苄基)-3-(6-甲氧基-5-(1H-吡唑-4-基)吡啶-2-基)-1H-咪唑-2(3H)-酮。
11.药物组合物,其包含一种或多种根据权利要求1-10中任一项所述的化合物和药学上可接受的载体或稀释剂。
12.根据权利要求1-10中任一项所述的化合物在制备用于预防和/或治疗与异常Rho激酶活性相关的病症的药物中的用途。
13.权利要求12的用途,其中所述病症选自:心血管病症、平滑肌相关病症、纤维变性疾病、炎性疾病、神经性病症、肿瘤学病症和自身免疫性病症。
14.权利要求13的用途,其中所述心血管病症选自心绞痛、动脉粥样硬化、中风、脑血管疾病、心力衰竭、冠状动脉疾病、心肌梗塞、外周血管疾病、狭窄、血管痉挛、高血压和肺高血压。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562101434P | 2015-01-09 | 2015-01-09 | |
US62/101434 | 2015-01-09 | ||
PCT/US2016/012560 WO2016112236A1 (en) | 2015-01-09 | 2016-01-08 | Cyclic ureas as inhibitors of rock |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107406426A CN107406426A (zh) | 2017-11-28 |
CN107406426B true CN107406426B (zh) | 2020-11-20 |
Family
ID=55310909
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680012270.1A Active CN107406426B (zh) | 2015-01-09 | 2016-01-08 | 作为rock抑制剂的环状脲类 |
Country Status (8)
Country | Link |
---|---|
US (1) | US10123993B2 (zh) |
EP (1) | EP3242873B1 (zh) |
JP (1) | JP6779214B2 (zh) |
CN (1) | CN107406426B (zh) |
AR (1) | AR103990A1 (zh) |
ES (1) | ES2815681T3 (zh) |
TW (1) | TW201630899A (zh) |
WO (1) | WO2016112236A1 (zh) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AR103990A1 (es) | 2015-01-09 | 2017-06-21 | Bristol Myers Squibb Co | Ureas cíclicas como inhibidoras de rock |
WO2016144936A1 (en) | 2015-03-09 | 2016-09-15 | Bristol-Myers Squibb Company | Lactams as inhibitors of rock |
WO2017046739A1 (en) * | 2015-09-15 | 2017-03-23 | Glaxosmithkline Intellectual Property (No.2) Limited | Imidazolidinone derivatives as inhibitors of perk |
UY37073A (es) | 2016-01-13 | 2017-07-31 | Bristol-Myers Squibb Company Una Corporación Del Estado De Delaware | Salicilamidas espiroheptanos y compuestos relacionados como inhibidores de rock, y las composiciones que los contienen |
ES2781309T3 (es) * | 2016-05-27 | 2020-09-01 | Bristol Myers Squibb Co | Triazolonas y tetrazolonas como inhibidores de ROCK |
CN110049977B (zh) * | 2016-07-07 | 2022-01-18 | 百时美施贵宝公司 | 作为强效和选择性rock抑制剂的内酰胺、环状脲和氨基甲酸酯及三唑酮衍生物 |
CN109689639B (zh) | 2016-07-07 | 2022-02-18 | 百时美施贵宝公司 | 作为rock抑制剂的螺内酰胺 |
CN109661396B (zh) | 2016-07-07 | 2022-07-01 | 百时美施贵宝公司 | 作为rock抑制剂的螺稠合环状脲 |
CN110023291B (zh) * | 2016-11-30 | 2023-07-18 | 百时美施贵宝公司 | 三环rho激酶抑制剂 |
CN110869360B (zh) | 2017-07-12 | 2023-12-15 | 百时美施贵宝公司 | 作为rock抑制剂的苯乙酰胺类 |
TW201908293A (zh) | 2017-07-12 | 2019-03-01 | 美商必治妥美雅史谷比公司 | 作為rock抑制劑之5員及雙環雜環醯胺 |
WO2019014303A1 (en) | 2017-07-12 | 2019-01-17 | Bristol-Myers Squibb Company | 5-OR 6,6-CHANNEL BICYCLIC CHAINS AND AMINOHETEROCYCLIC AMINOHETEROCYCLIC INHIBITORS FOR THE TREATMENT OF CARDIAC INSUFFICIENCY |
EP3652167B1 (en) | 2017-07-12 | 2021-06-02 | Bristol-Myers Squibb Company | Spiroheptanyl hydantoins as rock inhibitors |
KR20200083543A (ko) * | 2017-11-03 | 2020-07-08 | 브리스톨-마이어스 스큅 컴퍼니 | 디아자스피로 rock 억제제 |
WO2020113094A1 (en) | 2018-11-30 | 2020-06-04 | Nuvation Bio Inc. | Pyrrole and pyrazole compounds and methods of use thereof |
CN112759550A (zh) * | 2019-11-04 | 2021-05-07 | 上海科技大学 | 一种平滑受体拮抗剂 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009078992A1 (en) * | 2007-12-17 | 2009-06-25 | Amgen Inc. | Linear tricyclic compounds as p38 kinase inhibitors |
WO2014134391A1 (en) * | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
WO2014134388A1 (en) * | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
WO2015107053A1 (en) * | 2014-01-20 | 2015-07-23 | F. Hoffmann-La Roche Ag | N-phenyl-lactam derivatives capable of stimulating neurogenesis and their use in the treatment of neurological disorders |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH07183769A (ja) * | 1993-12-22 | 1995-07-21 | Fuji Electric Co Ltd | ラッチ回路 |
EP1713775A4 (en) | 2004-01-30 | 2009-08-12 | Smithkline Beecham Corp | CHEMICAL COMPOUNDS |
WO2006048727A1 (en) * | 2004-11-02 | 2006-05-11 | Pfizer Products Inc. | Piperazinylphenalkyl lactam/amine ligands for the 5ht1b receptor |
EP1922306A2 (en) * | 2005-09-02 | 2008-05-21 | Astellas Pharma Inc. | Amide derivatives as rock inhibitors |
EP2237852B1 (en) * | 2007-12-17 | 2013-11-20 | Peshina, William F. | Oval cage coupler for filter cages |
WO2010036316A1 (en) * | 2008-09-24 | 2010-04-01 | Yangbo Feng | Urea and carbamate compounds and analogs as kinase inhibitors |
JP5769326B2 (ja) * | 2010-10-19 | 2015-08-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Rhoキナーゼ阻害薬 |
WO2014113620A2 (en) | 2013-01-18 | 2014-07-24 | Bristol-Myers Squibb Company | Phthalazinones and isoquinolinones as rock inhibitors |
EP2968276A4 (en) | 2013-03-15 | 2017-02-15 | President and Fellows of Harvard College | Hybrid necroptosis inhibitors |
US9663529B2 (en) | 2013-07-02 | 2017-05-30 | Bristol-Myers Squibb Company | Tricyclic pyrido-carboxamide derivatives as rock inhibitors |
AR096788A1 (es) | 2013-07-02 | 2016-02-03 | Bristol Myers Squibb Co | Compuestos tricíclicos de carboxamida como inhibidores potentes de rock |
US9673408B2 (en) | 2013-07-31 | 2017-06-06 | Udc Ireland Limited | Luminescent diazabenzimidazole carbene metal complexes |
US9682960B2 (en) | 2013-12-19 | 2017-06-20 | Endorecherche, Inc. | Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety |
US9902702B2 (en) | 2014-07-15 | 2018-02-27 | Bristol-Myers Squibb Company | Spirocycloheptanes as inhibitors of rock |
ES2838573T3 (es) | 2014-08-21 | 2021-07-02 | Bristol Myers Squibb Co | Derivados de benzamida ligados como inhibidores potentes de ROCK |
AR103990A1 (es) | 2015-01-09 | 2017-06-21 | Bristol Myers Squibb Co | Ureas cíclicas como inhibidoras de rock |
WO2016144936A1 (en) | 2015-03-09 | 2016-09-15 | Bristol-Myers Squibb Company | Lactams as inhibitors of rock |
UY37073A (es) | 2016-01-13 | 2017-07-31 | Bristol-Myers Squibb Company Una Corporación Del Estado De Delaware | Salicilamidas espiroheptanos y compuestos relacionados como inhibidores de rock, y las composiciones que los contienen |
-
2016
- 2016-01-08 AR ARP160100053A patent/AR103990A1/es unknown
- 2016-01-08 TW TW105100631A patent/TW201630899A/zh unknown
- 2016-01-08 CN CN201680012270.1A patent/CN107406426B/zh active Active
- 2016-01-08 ES ES16703378T patent/ES2815681T3/es active Active
- 2016-01-08 EP EP16703378.6A patent/EP3242873B1/en active Active
- 2016-01-08 WO PCT/US2016/012560 patent/WO2016112236A1/en active Application Filing
- 2016-01-08 JP JP2017536259A patent/JP6779214B2/ja active Active
- 2016-01-08 US US15/541,725 patent/US10123993B2/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009078992A1 (en) * | 2007-12-17 | 2009-06-25 | Amgen Inc. | Linear tricyclic compounds as p38 kinase inhibitors |
WO2014134391A1 (en) * | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
WO2014134388A1 (en) * | 2013-02-28 | 2014-09-04 | Bristol-Myers Squibb Company | Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors |
WO2015107053A1 (en) * | 2014-01-20 | 2015-07-23 | F. Hoffmann-La Roche Ag | N-phenyl-lactam derivatives capable of stimulating neurogenesis and their use in the treatment of neurological disorders |
Also Published As
Publication number | Publication date |
---|---|
US20180000788A1 (en) | 2018-01-04 |
WO2016112236A1 (en) | 2016-07-14 |
ES2815681T3 (es) | 2021-03-30 |
TW201630899A (zh) | 2016-09-01 |
US10123993B2 (en) | 2018-11-13 |
CN107406426A (zh) | 2017-11-28 |
AR103990A1 (es) | 2017-06-21 |
JP6779214B2 (ja) | 2020-11-04 |
JP2018501285A (ja) | 2018-01-18 |
EP3242873A1 (en) | 2017-11-15 |
EP3242873B1 (en) | 2020-07-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107406426B (zh) | 作为rock抑制剂的环状脲类 | |
JP6770053B2 (ja) | Rock阻害剤としてのフタラジノンおよびイソキノリノン | |
JP7225317B2 (ja) | 強力で選択的なrock阻害剤としてのラクタム、環状尿素、およびカルバメート、およびトリアゾロン誘導体 | |
US10829501B2 (en) | Spiroheptane salicylamides and related compounds as inhibitors of ROCK | |
KR102449652B1 (ko) | Rock의 억제제로서의 스피로-융합 시클릭 우레아 | |
US11884661B2 (en) | 3-substituted propionic acids as αV integrin inhibitors | |
EP3652168B1 (en) | 5-membered and bicyclic heterocyclic amides as inhibitors of rock | |
EP3016951B1 (en) | Tricyclic pyrido-carboxamide derivatives as rock inhibitors | |
CN109153663B (zh) | 作为rock抑制剂的三唑酮类化合物和四唑酮类化合物 | |
EP3548468B1 (en) | Tricyclic rho kinase inhibitors | |
EP3652165B1 (en) | Five membered-aminoheterocyclic and 5,6-or 6,6-membered bicyclic aminoheterocyclic inhibitors of rock for the treatment of heart failure | |
EP3268360A1 (en) | Lactams as inhibitors of rock | |
JP2019520398A (ja) | Rock阻害剤としてのスピロラクタム |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |