WO2012114268A1 - Benzamide derivatives as p2x7 receptor antagonists - Google Patents
Benzamide derivatives as p2x7 receptor antagonists Download PDFInfo
- Publication number
- WO2012114268A1 WO2012114268A1 PCT/IB2012/050780 IB2012050780W WO2012114268A1 WO 2012114268 A1 WO2012114268 A1 WO 2012114268A1 IB 2012050780 W IB2012050780 W IB 2012050780W WO 2012114268 A1 WO2012114268 A1 WO 2012114268A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chloro
- hydroxy
- benzamide
- cyclohexylmethyl
- pyrimidin
- Prior art date
Links
- 150000003936 benzamides Chemical class 0.000 title abstract description 58
- 102100037602 P2X purinoceptor 7 Human genes 0.000 title description 18
- 101710189965 P2X purinoceptor 7 Proteins 0.000 title description 12
- 239000002464 receptor antagonist Substances 0.000 title description 5
- 229940044551 receptor antagonist Drugs 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 547
- -1 hydroxy, hydroxymethyl Chemical group 0.000 claims description 210
- 150000003839 salts Chemical class 0.000 claims description 157
- 125000000217 alkyl group Chemical group 0.000 claims description 152
- 229910052739 hydrogen Inorganic materials 0.000 claims description 94
- 239000001257 hydrogen Substances 0.000 claims description 94
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 74
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 65
- 208000002193 Pain Diseases 0.000 claims description 62
- 230000036407 pain Effects 0.000 claims description 55
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 54
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 54
- 125000001153 fluoro group Chemical group F* 0.000 claims description 51
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 30
- 238000011282 treatment Methods 0.000 claims description 30
- 201000010099 disease Diseases 0.000 claims description 29
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 125000004414 alkyl thio group Chemical group 0.000 claims description 25
- 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 24
- 208000035475 disorder Diseases 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- 230000002265 prevention Effects 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 19
- 125000003282 alkyl amino group Chemical group 0.000 claims description 18
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- 201000011510 cancer Diseases 0.000 claims description 14
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 13
- 230000002757 inflammatory effect Effects 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 125000004043 oxo group Chemical group O=* 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 208000010668 atopic eczema Diseases 0.000 claims description 8
- 230000001363 autoimmune Effects 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 208000017520 skin disease Diseases 0.000 claims description 8
- 208000020084 Bone disease Diseases 0.000 claims description 7
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 7
- 230000000172 allergic effect Effects 0.000 claims description 7
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 7
- 230000000626 neurodegenerative effect Effects 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- 208000012659 Joint disease Diseases 0.000 claims description 6
- 208000025609 Urogenital disease Diseases 0.000 claims description 6
- 230000003187 abdominal effect Effects 0.000 claims description 6
- 210000000988 bone and bone Anatomy 0.000 claims description 6
- 208000030533 eye disease Diseases 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- 230000000414 obstructive effect Effects 0.000 claims description 6
- KLSPCWAPBBAWKM-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[1-hydroxy-1-(2-oxo-1h-pyrimidin-6-yl)ethyl]benzamide Chemical compound C1=CNC(=O)N=C1C(O)(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 KLSPCWAPBBAWKM-UHFFFAOYSA-N 0.000 claims description 5
- 230000001900 immune effect Effects 0.000 claims description 5
- BHLKCQLKZOSFOX-UHFFFAOYSA-N 2-chloro-5-(2-chloropyrimidin-4-yl)oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(OC=2N=C(Cl)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 BHLKCQLKZOSFOX-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- NXAUAFVWKOGUNY-UHFFFAOYSA-N 2-chloro-5-(2,4-difluoro-n-methylanilino)-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=C(F)C=C(F)C=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 NXAUAFVWKOGUNY-UHFFFAOYSA-N 0.000 claims description 3
- YOTUREPBXGUWJT-UHFFFAOYSA-N 2-chloro-5-(2,4-difluoroanilino)-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(NC=2C(=CC(F)=CC=2)F)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 YOTUREPBXGUWJT-UHFFFAOYSA-N 0.000 claims description 3
- RTJQFNDQLCBGMQ-UHFFFAOYSA-N 2-chloro-5-(2-chloropyridin-4-yl)oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(OC=2C=C(Cl)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 RTJQFNDQLCBGMQ-UHFFFAOYSA-N 0.000 claims description 3
- UXDAAVCONPUBLE-UHFFFAOYSA-N 2-chloro-5-(2-chloropyrimidin-4-yl)sulfanyl-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(SC=2N=C(Cl)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 UXDAAVCONPUBLE-UHFFFAOYSA-N 0.000 claims description 3
- HXVGRDUTZGTUPT-UHFFFAOYSA-N 2-chloro-5-(2-chloropyrimidin-4-yl)sulfinyl-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(S(=O)C=2N=C(Cl)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 HXVGRDUTZGTUPT-UHFFFAOYSA-N 0.000 claims description 3
- ZXEXRDJWGNCRCH-UHFFFAOYSA-N 2-chloro-5-(2-fluoro-n-methylanilino)-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=CC=C(F)C=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 ZXEXRDJWGNCRCH-UHFFFAOYSA-N 0.000 claims description 3
- BFLHWUYKCXQDMH-UHFFFAOYSA-N 2-chloro-5-(2-fluoroanilino)-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(NC=2C(=CC=CC=2)F)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 BFLHWUYKCXQDMH-UHFFFAOYSA-N 0.000 claims description 3
- MQROXKMBSIMHOG-UHFFFAOYSA-N 2-chloro-5-(4-fluoropyridin-2-yl)oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(OC=2N=CC=C(F)C=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 MQROXKMBSIMHOG-UHFFFAOYSA-N 0.000 claims description 3
- CPILTGBJYLFSOB-UHFFFAOYSA-N 2-chloro-5-(6-chloropyrazin-2-yl)oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(OC=2N=C(Cl)C=NC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 CPILTGBJYLFSOB-UHFFFAOYSA-N 0.000 claims description 3
- VVUMNWGVKVOMQV-UHFFFAOYSA-N 2-chloro-5-(6-chloropyridazin-3-yl)oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(OC=2N=NC(Cl)=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 VVUMNWGVKVOMQV-UHFFFAOYSA-N 0.000 claims description 3
- PACNFZBIUUAUOA-UHFFFAOYSA-N 2-chloro-5-(6-fluoropyridin-2-yl)oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(OC=2N=C(F)C=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 PACNFZBIUUAUOA-UHFFFAOYSA-N 0.000 claims description 3
- HDLWIXDJDLUKSD-UHFFFAOYSA-N 2-chloro-5-[(2,4-dioxopyrimidin-1-yl)methyl]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(CN2C(NC(=O)C=C2)=O)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 HDLWIXDJDLUKSD-UHFFFAOYSA-N 0.000 claims description 3
- QYSNKNOAOPCHTH-UHFFFAOYSA-N 2-chloro-5-[(2,6-dichloropyrimidin-4-yl)-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(Cl)=NC(Cl)=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 QYSNKNOAOPCHTH-UHFFFAOYSA-N 0.000 claims description 3
- JWXOHYHUPZYLJH-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-(2-methoxyethyl)amino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(CCOC)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 JWXOHYHUPZYLJH-UHFFFAOYSA-N 0.000 claims description 3
- OJTAWNJIDJJVSB-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-(2-methylpropyl)amino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(CC(C)C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 OJTAWNJIDJJVSB-UHFFFAOYSA-N 0.000 claims description 3
- RFZGPJGPXKDFKW-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-(2-phenoxyethyl)amino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(N(CCOC=2C=CC=CC=2)C=2N=C(Cl)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 RFZGPJGPXKDFKW-UHFFFAOYSA-N 0.000 claims description 3
- MLYYTYWZMODBDE-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-(cyclopentylmethyl)amino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(N(CC2CCCC2)C=2N=C(Cl)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 MLYYTYWZMODBDE-UHFFFAOYSA-N 0.000 claims description 3
- BEONWKPDUUYDJJ-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-ethylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(CC)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 BEONWKPDUUYDJJ-UHFFFAOYSA-N 0.000 claims description 3
- ZBPLZSYZBAUDLL-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[(1-hydroxycycloheptyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCCC1 ZBPLZSYZBAUDLL-UHFFFAOYSA-N 0.000 claims description 3
- YZFKHIJFRWDPHF-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 YZFKHIJFRWDPHF-UHFFFAOYSA-N 0.000 claims description 3
- MQSSMLNMKFJYEC-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[(1-hydroxycyclooctyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCCCC1 MQSSMLNMKFJYEC-UHFFFAOYSA-N 0.000 claims description 3
- JMRRVFOKYYIXRT-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[(1-hydroxycyclopentyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCC1 JMRRVFOKYYIXRT-UHFFFAOYSA-N 0.000 claims description 3
- LDVJFCDVGJOCMC-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[(1-methoxycyclohexyl)methyl]benzamide Chemical compound C=1C(N(C)C=2N=C(Cl)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(OC)CCCCC1 LDVJFCDVGJOCMC-UHFFFAOYSA-N 0.000 claims description 3
- OASOLFKBBFNYSO-CYBMUJFWSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[(1r)-1-cyclohexylethyl]benzamide Chemical compound N([C@H](C)C1CCCCC1)C(=O)C(C(=CC=1)Cl)=CC=1N(C)C1=CC=NC(Cl)=N1 OASOLFKBBFNYSO-CYBMUJFWSA-N 0.000 claims description 3
- GJJZQTONKSYAHV-QGZVFWFLSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[(1s)-1-cyclohexyl-2-hydroxyethyl]benzamide Chemical compound C1([C@@H](CO)NC(=O)C=2C(Cl)=CC=C(C=2)N(C)C=2N=C(Cl)N=CC=2)CCCCC1 GJJZQTONKSYAHV-QGZVFWFLSA-N 0.000 claims description 3
- DMWNVBKOBFEMAI-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[(4,4-difluoro-1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCC(F)(F)CC1 DMWNVBKOBFEMAI-UHFFFAOYSA-N 0.000 claims description 3
- AAGQSFZVWQXWFQ-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[[1-(hydroxymethyl)cyclohexyl]methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(CO)CCCCC1 AAGQSFZVWQXWFQ-UHFFFAOYSA-N 0.000 claims description 3
- YCKGQPBKAAQNKQ-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-propan-2-ylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(C(C)C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 YCKGQPBKAAQNKQ-UHFFFAOYSA-N 0.000 claims description 3
- QCQYIEAFJWNGEZ-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)-propylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(CCC)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 QCQYIEAFJWNGEZ-UHFFFAOYSA-N 0.000 claims description 3
- HBXPDLVMFVTJAA-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)amino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(NC=2N=C(Cl)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 HBXPDLVMFVTJAA-UHFFFAOYSA-N 0.000 claims description 3
- AUOYOPLLTKIHCT-UHFFFAOYSA-N 2-chloro-5-[(3-chloropyrazin-2-yl)-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound N=1C=CN=C(Cl)C=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 AUOYOPLLTKIHCT-UHFFFAOYSA-N 0.000 claims description 3
- KHBKMQHLQOPSLL-UHFFFAOYSA-N 2-chloro-5-[(5-chloropyrazin-2-yl)-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1N=C(Cl)C=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 KHBKMQHLQOPSLL-UHFFFAOYSA-N 0.000 claims description 3
- UWJZAGOASYZOBL-UHFFFAOYSA-N 2-chloro-5-[(6-chloro-2-methoxypyrimidin-4-yl)-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound COC1=NC(Cl)=CC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 UWJZAGOASYZOBL-UHFFFAOYSA-N 0.000 claims description 3
- NNGYTFGKVSBSSJ-UHFFFAOYSA-N 2-chloro-5-[(6-chloro-2-oxo-1h-pyrimidin-4-yl)-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C1=C(Cl)NC(=O)N=C1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 NNGYTFGKVSBSSJ-UHFFFAOYSA-N 0.000 claims description 3
- BCLMJLSRGUEIRD-UHFFFAOYSA-N 2-chloro-5-[(6-chloropyrazin-2-yl)-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1N=CC(Cl)=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 BCLMJLSRGUEIRD-UHFFFAOYSA-N 0.000 claims description 3
- IEUJWNUJMIMQRU-UHFFFAOYSA-N 2-chloro-5-[(6-chloropyridazin-3-yl)-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C=C(Cl)N=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 IEUJWNUJMIMQRU-UHFFFAOYSA-N 0.000 claims description 3
- ZXRLLMYCAPYKGW-UHFFFAOYSA-N 2-chloro-5-[6-(dimethylamino)pyrazin-2-yl]oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound CN(C)C1=CN=CC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 ZXRLLMYCAPYKGW-UHFFFAOYSA-N 0.000 claims description 3
- SATNPOXZLNYOSW-UHFFFAOYSA-N 2-chloro-5-[[2-(dimethylamino)pyrimidin-4-yl]-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound CN(C)C1=NC=CC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 SATNPOXZLNYOSW-UHFFFAOYSA-N 0.000 claims description 3
- FZBNCLJUGNNGAQ-UHFFFAOYSA-N 2-chloro-5-[[6-(dimethylamino)pyrazin-2-yl]-methylamino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound CN(C)C1=CN=CC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 FZBNCLJUGNNGAQ-UHFFFAOYSA-N 0.000 claims description 3
- AAWJORPQDVBCSD-UHFFFAOYSA-N 2-chloro-5-[cyclopentylmethyl-(2-methoxypyrimidin-4-yl)amino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound COC1=NC=CC(N(CC2CCCC2)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 AAWJORPQDVBCSD-UHFFFAOYSA-N 0.000 claims description 3
- QTZYEMPOGTUXPM-UHFFFAOYSA-N 2-chloro-5-[difluoro-(2-oxo-1h-pyrimidin-6-yl)methyl]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(C(F)(F)C2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 QTZYEMPOGTUXPM-UHFFFAOYSA-N 0.000 claims description 3
- SIIRNKWJCRZCQE-UHFFFAOYSA-N 2-chloro-5-[ethyl-(2-oxo-1h-pyrimidin-6-yl)amino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C1=CNC(=O)N=C1N(CC)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 SIIRNKWJCRZCQE-UHFFFAOYSA-N 0.000 claims description 3
- PWQMEPWIXYSULD-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycycloheptyl)methyl]-5-[(2-methylsulfanylpyrimidin-4-yl)amino]benzamide Chemical compound CSC1=NC=CC(NC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCCC2)=N1 PWQMEPWIXYSULD-UHFFFAOYSA-N 0.000 claims description 3
- BUQZLKUTLJHMGY-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycycloheptyl)methyl]-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C1=CNC(=O)N=C1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCCC1 BUQZLKUTLJHMGY-UHFFFAOYSA-N 0.000 claims description 3
- VDAMXVGCWYLMFG-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(1-methyl-6-oxopyridin-2-yl)oxybenzamide Chemical compound C1=CC(=O)N(C)C(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=C1 VDAMXVGCWYLMFG-UHFFFAOYSA-N 0.000 claims description 3
- CDKACKQADJGGFI-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(2-methoxypyrimidin-4-yl)sulfanylbenzamide Chemical compound COC1=NC=CC(SC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 CDKACKQADJGGFI-UHFFFAOYSA-N 0.000 claims description 3
- VWMXCOGYULEYTK-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(2-methoxypyrimidin-4-yl)sulfinylbenzamide Chemical compound COC1=NC=CC(S(=O)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 VWMXCOGYULEYTK-UHFFFAOYSA-N 0.000 claims description 3
- ICVVHZTZWQZOJD-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(2-methoxypyrimidin-4-yl)sulfonylbenzamide Chemical compound COC1=NC=CC(S(=O)(=O)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 ICVVHZTZWQZOJD-UHFFFAOYSA-N 0.000 claims description 3
- NKGILMKPSJCLMX-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(2-oxo-1h-pyrimidine-6-carbonyl)benzamide Chemical compound C=1C(C(=O)C2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 NKGILMKPSJCLMX-UHFFFAOYSA-N 0.000 claims description 3
- PBCQWBOWGQYVOE-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(5-methoxypyridazin-3-yl)oxybenzamide Chemical compound COC1=CN=NC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=C1 PBCQWBOWGQYVOE-UHFFFAOYSA-N 0.000 claims description 3
- NJEIYSUCSWMITN-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(6-methoxypyrazin-2-yl)oxybenzamide Chemical compound COC1=CN=CC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 NJEIYSUCSWMITN-UHFFFAOYSA-N 0.000 claims description 3
- QAOLEHNAGMKNFX-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(6-methoxypyridazin-3-yl)oxybenzamide Chemical compound N1=NC(OC)=CC=C1OC1=CC=C(Cl)C(C(=O)NCC2(O)CCCCC2)=C1 QAOLEHNAGMKNFX-UHFFFAOYSA-N 0.000 claims description 3
- HFEMNRUPYDBPDD-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(6-methoxypyridin-2-yl)oxybenzamide Chemical compound COC1=CC=CC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 HFEMNRUPYDBPDD-UHFFFAOYSA-N 0.000 claims description 3
- GOIDXPUIZFMVLF-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(n-methylanilino)benzamide Chemical compound C=1C=C(Cl)C(C(=O)NCC2(O)CCCCC2)=CC=1N(C)C1=CC=CC=C1 GOIDXPUIZFMVLF-UHFFFAOYSA-N 0.000 claims description 3
- NIZXTPYPJZCXFY-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(pyrazin-2-ylamino)benzamide Chemical compound C=1C(NC=2N=CC=NC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 NIZXTPYPJZCXFY-UHFFFAOYSA-N 0.000 claims description 3
- UYMMQEPGDVTWDV-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(pyridin-2-ylmethyl)benzamide Chemical compound C=1C(CC=2N=CC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 UYMMQEPGDVTWDV-UHFFFAOYSA-N 0.000 claims description 3
- DXUJXGSCPQLXRV-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(pyrimidin-2-ylamino)benzamide Chemical compound C=1C(NC=2N=CC=CN=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 DXUJXGSCPQLXRV-UHFFFAOYSA-N 0.000 claims description 3
- NRFZXBXWYIFFFR-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(pyrimidin-4-ylamino)benzamide Chemical compound C=1C(NC=2N=CN=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 NRFZXBXWYIFFFR-UHFFFAOYSA-N 0.000 claims description 3
- ZQYJTTSIPXKWSJ-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(pyrimidin-5-ylamino)benzamide Chemical compound C=1C(NC=2C=NC=NC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 ZQYJTTSIPXKWSJ-UHFFFAOYSA-N 0.000 claims description 3
- QZJNLAQZOMWVBE-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(1-methyl-2-oxopyridin-3-yl)amino]benzamide Chemical compound O=C1N(C)C=CC=C1NC1=CC=C(Cl)C(C(=O)NCC2(O)CCCCC2)=C1 QZJNLAQZOMWVBE-UHFFFAOYSA-N 0.000 claims description 3
- AJKGMNLXETWCCC-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(1-methyl-6-oxopyridin-2-yl)amino]benzamide Chemical compound C1=CC(=O)N(C)C(NC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=C1 AJKGMNLXETWCCC-UHFFFAOYSA-N 0.000 claims description 3
- SNBSAHLBBJARBV-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-methoxypyrimidin-4-yl)-(2-methylpropyl)amino]benzamide Chemical compound COC1=NC=CC(N(CC(C)C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 SNBSAHLBBJARBV-UHFFFAOYSA-N 0.000 claims description 3
- IDBPQWOSOBBIRG-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-methoxypyrimidin-4-yl)-(2-phenoxyethyl)amino]benzamide Chemical compound COC1=NC=CC(N(CCOC=2C=CC=CC=2)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 IDBPQWOSOBBIRG-UHFFFAOYSA-N 0.000 claims description 3
- OOXXYXIWAUJZRW-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-methoxypyrimidin-4-yl)-methylamino]benzamide Chemical compound COC1=NC=CC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 OOXXYXIWAUJZRW-UHFFFAOYSA-N 0.000 claims description 3
- UAEOEFSGJHSJBT-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-methoxypyrimidin-4-yl)methyl]benzamide Chemical compound COC1=NC=CC(CC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 UAEOEFSGJHSJBT-UHFFFAOYSA-N 0.000 claims description 3
- PVGPZEGFWJYZRD-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-methylpyrazol-3-yl)amino]benzamide Chemical compound CN1N=CC=C1NC1=CC=C(Cl)C(C(=O)NCC2(O)CCCCC2)=C1 PVGPZEGFWJYZRD-UHFFFAOYSA-N 0.000 claims description 3
- IUWDNUVRVZQJBL-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-methylsulfanylpyrimidin-4-yl)methyl]benzamide Chemical compound CSC1=NC=CC(CC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 IUWDNUVRVZQJBL-UHFFFAOYSA-N 0.000 claims description 3
- IZGCOYLLUSMBJW-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)-(2-phenoxyethyl)amino]benzamide Chemical compound C=1C(N(CCOC=2C=CC=CC=2)C2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 IZGCOYLLUSMBJW-UHFFFAOYSA-N 0.000 claims description 3
- XBVJYBJYTUUXRY-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)-propan-2-ylamino]benzamide Chemical compound C1=CNC(=O)N=C1N(C(C)C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 XBVJYBJYTUUXRY-UHFFFAOYSA-N 0.000 claims description 3
- HAPLKVDEXDLQLY-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)-propylamino]benzamide Chemical compound C1=CNC(=O)N=C1N(CCC)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 HAPLKVDEXDLQLY-UHFFFAOYSA-N 0.000 claims description 3
- WGDUAXUPXRXWIB-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound OC1=NC=CC(NC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 WGDUAXUPXRXWIB-UHFFFAOYSA-N 0.000 claims description 3
- TZGZESMICNOALI-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)methyl]benzamide Chemical compound C=1C(CC2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 TZGZESMICNOALI-UHFFFAOYSA-N 0.000 claims description 3
- ZGACOZDKIJUXKQ-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)oxy]benzamide Chemical compound C=1C(OC=2NC(=O)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 ZGACOZDKIJUXKQ-UHFFFAOYSA-N 0.000 claims description 3
- VFMSFNBMUAXYTM-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)sulfanyl]benzamide Chemical compound C=1C(SC2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 VFMSFNBMUAXYTM-UHFFFAOYSA-N 0.000 claims description 3
- GRMZCFSCCQKLAQ-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-oxopyridin-1-yl)methyl]benzamide Chemical compound C=1C(CN2C(C=CC=C2)=O)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 GRMZCFSCCQKLAQ-UHFFFAOYSA-N 0.000 claims description 3
- YVIIKHYFJSYMPM-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-oxopyrimidin-1-yl)methyl]benzamide Chemical compound C=1C(CN2C(N=CC=C2)=O)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 YVIIKHYFJSYMPM-UHFFFAOYSA-N 0.000 claims description 3
- UVYALTHEIIHRPF-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(4-methoxypyrimidin-2-yl)-methylamino]benzamide Chemical compound COC1=CC=NC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 UVYALTHEIIHRPF-UHFFFAOYSA-N 0.000 claims description 3
- DJIRABCGSGYGFN-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(4-methylsulfanylpyrimidin-2-yl)amino]benzamide Chemical compound CSC1=CC=NC(NC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 DJIRABCGSGYGFN-UHFFFAOYSA-N 0.000 claims description 3
- VFDQGDNMASFNRE-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(5-methoxypyrazin-2-yl)-methylamino]benzamide Chemical compound C1=NC(OC)=CN=C1N(C)C1=CC=C(Cl)C(C(=O)NCC2(O)CCCCC2)=C1 VFDQGDNMASFNRE-UHFFFAOYSA-N 0.000 claims description 3
- JZVJDBTVCUYHST-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(6-methoxypyrazin-2-yl)-methylamino]benzamide Chemical compound COC1=CN=CC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 JZVJDBTVCUYHST-UHFFFAOYSA-N 0.000 claims description 3
- GHVMWWIKQCYMGZ-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(6-methoxypyridazin-3-yl)-methylamino]benzamide Chemical compound N1=NC(OC)=CC=C1N(C)C1=CC=C(Cl)C(C(=O)NCC2(O)CCCCC2)=C1 GHVMWWIKQCYMGZ-UHFFFAOYSA-N 0.000 claims description 3
- RBPNTTPRDDOWJM-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(6-methoxypyrimidin-4-yl)-methylamino]benzamide Chemical compound C1=NC(OC)=CC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 RBPNTTPRDDOWJM-UHFFFAOYSA-N 0.000 claims description 3
- JZLVNDOMLBGYCI-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(6-oxo-1h-pyrazin-2-yl)oxy]benzamide Chemical compound C=1C(OC=2NC(=O)C=NC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 JZLVNDOMLBGYCI-UHFFFAOYSA-N 0.000 claims description 3
- NKJMRJKCCPGNHX-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(6-oxo-1h-pyridazin-3-yl)oxy]benzamide Chemical compound C=1C(OC2=NNC(=O)C=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 NKJMRJKCCPGNHX-UHFFFAOYSA-N 0.000 claims description 3
- URFRAYBSAVIWBK-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(6-oxo-1h-pyridin-2-yl)amino]benzamide Chemical compound C=1C(NC=2NC(=O)C=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 URFRAYBSAVIWBK-UHFFFAOYSA-N 0.000 claims description 3
- LAHXEWXYUXUPRD-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(6-oxo-1h-pyridin-2-yl)oxy]benzamide Chemical compound C=1C(OC=2NC(=O)C=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 LAHXEWXYUXUPRD-UHFFFAOYSA-N 0.000 claims description 3
- ZWFBKXXOTBZFTM-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[1-hydroxy-1-(2-methoxypyrimidin-4-yl)ethyl]benzamide Chemical compound COC1=NC=CC(C(C)(O)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 ZWFBKXXOTBZFTM-UHFFFAOYSA-N 0.000 claims description 3
- XJLAKJWEDFMXEF-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[2-(methylamino)pyrimidin-4-yl]oxybenzamide Chemical compound CNC1=NC=CC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 XJLAKJWEDFMXEF-UHFFFAOYSA-N 0.000 claims description 3
- QDSIDHBDKRKAGE-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[2-methoxyethyl(pyrazin-2-yl)amino]benzamide Chemical compound C=1N=CC=NC=1N(CCOC)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 QDSIDHBDKRKAGE-UHFFFAOYSA-N 0.000 claims description 3
- APQABIZYQRGELN-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[2-methoxyethyl(pyrimidin-2-yl)amino]benzamide Chemical compound N=1C=CC=NC=1N(CCOC)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 APQABIZYQRGELN-UHFFFAOYSA-N 0.000 claims description 3
- LOUHFLHKDNMEBN-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[2-methoxyethyl(pyrimidin-5-yl)amino]benzamide Chemical compound C=1C=C(Cl)C(C(=O)NCC2(O)CCCCC2)=CC=1N(CCOC)C1=CN=CN=C1 LOUHFLHKDNMEBN-UHFFFAOYSA-N 0.000 claims description 3
- SVSITLNDOPCCAK-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[2-methoxyethyl-(2-methoxypyrimidin-4-yl)amino]benzamide Chemical compound C=1C=NC(OC)=NC=1N(CCOC)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 SVSITLNDOPCCAK-UHFFFAOYSA-N 0.000 claims description 3
- BURMJEVKVUMBBG-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[2-methoxyethyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C1=CNC(=O)N=C1N(CCOC)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 BURMJEVKVUMBBG-UHFFFAOYSA-N 0.000 claims description 3
- RASTXQMNBVIPAD-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[2-methylpropyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C1=CNC(=O)N=C1N(CC(C)C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 RASTXQMNBVIPAD-UHFFFAOYSA-N 0.000 claims description 3
- QZKQUUYSRFQJRZ-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[6-(methylamino)pyrazin-2-yl]oxybenzamide Chemical compound CNC1=CN=CC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 QZKQUUYSRFQJRZ-UHFFFAOYSA-N 0.000 claims description 3
- HVCOOUPMZWJEIC-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[6-(methylamino)pyridin-2-yl]oxybenzamide Chemical compound CNC1=CC=CC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 HVCOOUPMZWJEIC-UHFFFAOYSA-N 0.000 claims description 3
- PREDBEMSBINAPW-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[[1-(2-methoxyethyl)-6-oxopyridin-2-yl]-methylamino]benzamide Chemical compound C1=CC(=O)N(CCOC)C(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=C1 PREDBEMSBINAPW-UHFFFAOYSA-N 0.000 claims description 3
- WWNOOCANUQBNKE-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[[1-(2-methoxyethyl)-6-oxopyridin-2-yl]amino]benzamide Chemical compound C1=CC(=O)N(CCOC)C(NC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=C1 WWNOOCANUQBNKE-UHFFFAOYSA-N 0.000 claims description 3
- HBWGUPHERCFEHF-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl(pyrazin-2-yl)amino]benzamide Chemical compound C=1N=CC=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 HBWGUPHERCFEHF-UHFFFAOYSA-N 0.000 claims description 3
- XLJDAYOGJSVZGP-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl(pyrimidin-2-yl)amino]benzamide Chemical compound N=1C=CC=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 XLJDAYOGJSVZGP-UHFFFAOYSA-N 0.000 claims description 3
- DEGZNUWAWOFQAB-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl(pyrimidin-4-yl)amino]benzamide Chemical compound C=1C=NC=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 DEGZNUWAWOFQAB-UHFFFAOYSA-N 0.000 claims description 3
- GXODOGHGEGAXOS-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(1-methyl-2-oxopyrimidin-4-yl)amino]benzamide Chemical compound C1=CN(C)C(=O)N=C1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 GXODOGHGEGAXOS-UHFFFAOYSA-N 0.000 claims description 3
- QKSHDLOYBQKSDU-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(2-methylpyrazol-3-yl)amino]benzamide Chemical compound C=1C=C(Cl)C(C(=O)NCC2(O)CCCCC2)=CC=1N(C)C1=CC=NN1C QKSHDLOYBQKSDU-UHFFFAOYSA-N 0.000 claims description 3
- LVGIPTGKZIAHCD-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C1=CNC(=O)N=C1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 LVGIPTGKZIAHCD-UHFFFAOYSA-N 0.000 claims description 3
- WZPVCFNCADWZCE-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(3-methyl-2-oxopyrimidin-4-yl)amino]benzamide Chemical compound C=1C=NC(=O)N(C)C=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 WZPVCFNCADWZCE-UHFFFAOYSA-N 0.000 claims description 3
- FHTYFVVJUWGXEH-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(4-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C=1C(=O)NC=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 FHTYFVVJUWGXEH-UHFFFAOYSA-N 0.000 claims description 3
- BTLVEQHGRFAFFF-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(6-oxo-1h-pyrazin-2-yl)amino]benzamide Chemical compound C=1N=CC(=O)NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 BTLVEQHGRFAFFF-UHFFFAOYSA-N 0.000 claims description 3
- WIQABUSHDISVCL-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(6-oxo-1h-pyridazin-3-yl)amino]benzamide Chemical compound C1=CC(=O)NN=C1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 WIQABUSHDISVCL-UHFFFAOYSA-N 0.000 claims description 3
- NTGXBYCRKXAHCR-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(6-oxo-1h-pyridin-2-yl)amino]benzamide Chemical compound C=1C=CC(=O)NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 NTGXBYCRKXAHCR-UHFFFAOYSA-N 0.000 claims description 3
- UMFYBEBXSOEMQA-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(6-oxo-1h-pyrimidin-2-yl)amino]benzamide Chemical compound N=1C=CC(=O)NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 UMFYBEBXSOEMQA-UHFFFAOYSA-N 0.000 claims description 3
- PSFOYCWLKDPLLH-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-[2-(methylamino)pyrimidin-4-yl]amino]benzamide Chemical compound CNC1=NC=CC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 PSFOYCWLKDPLLH-UHFFFAOYSA-N 0.000 claims description 3
- IPIWPOVJVQSSOD-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[n-(2-methoxyethyl)anilino]benzamide Chemical compound C=1C=C(Cl)C(C(=O)NCC2(O)CCCCC2)=CC=1N(CCOC)C1=CC=CC=C1 IPIWPOVJVQSSOD-UHFFFAOYSA-N 0.000 claims description 3
- DVFHODDHOSJMMC-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-pyrazin-2-yloxybenzamide Chemical compound C=1C(OC=2N=CC=NC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 DVFHODDHOSJMMC-UHFFFAOYSA-N 0.000 claims description 3
- PSSPUMSDSWKNGQ-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-pyridazin-3-yloxybenzamide Chemical compound C=1C(OC=2N=NC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 PSSPUMSDSWKNGQ-UHFFFAOYSA-N 0.000 claims description 3
- BXZYOKJIZPTVKS-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-pyridin-2-yloxybenzamide Chemical compound C=1C(OC=2N=CC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 BXZYOKJIZPTVKS-UHFFFAOYSA-N 0.000 claims description 3
- PMNIJURPBXUAKQ-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-pyridin-2-ylsulfanylbenzamide Chemical compound C=1C(SC=2N=CC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 PMNIJURPBXUAKQ-UHFFFAOYSA-N 0.000 claims description 3
- IUIOUNGUYGGJHT-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-pyridin-2-ylsulfinylbenzamide Chemical compound C=1C(S(=O)C=2N=CC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 IUIOUNGUYGGJHT-UHFFFAOYSA-N 0.000 claims description 3
- NZVCDTSLLLXSMM-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-pyridin-2-ylsulfonylbenzamide Chemical compound C=1C(S(=O)(=O)C=2N=CC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 NZVCDTSLLLXSMM-UHFFFAOYSA-N 0.000 claims description 3
- AYSFDAHTLRIYCE-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-pyridin-3-yloxybenzamide Chemical compound C=1C(OC=2C=NC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 AYSFDAHTLRIYCE-UHFFFAOYSA-N 0.000 claims description 3
- JIYPTLKQPGMHOQ-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-pyridin-4-yloxybenzamide Chemical compound C=1C(OC=2C=CN=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 JIYPTLKQPGMHOQ-UHFFFAOYSA-N 0.000 claims description 3
- AKAAIZUOXMAICU-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-pyrimidin-4-yloxybenzamide Chemical compound C=1C(OC=2N=CN=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 AKAAIZUOXMAICU-UHFFFAOYSA-N 0.000 claims description 3
- MJDGXAVKEXLUEA-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclopentyl)methyl]-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C=1C=NC(=O)NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCC1 MJDGXAVKEXLUEA-UHFFFAOYSA-N 0.000 claims description 3
- QWDRIQNFHYDYBS-UHFFFAOYSA-N 2-chloro-n-[(1-methoxycyclohexyl)methyl]-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C=1C(N(C)C=2NC(=O)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(OC)CCCCC1 QWDRIQNFHYDYBS-UHFFFAOYSA-N 0.000 claims description 3
- XYZUUNVYPQOPKU-CYBMUJFWSA-N 2-chloro-n-[(1r)-1-cyclohexylethyl]-5-[(2-methylsulfanylpyrimidin-4-yl)amino]benzamide Chemical compound CSC1=NC=CC(NC=2C=C(C(Cl)=CC=2)C(=O)N[C@H](C)C2CCCCC2)=N1 XYZUUNVYPQOPKU-CYBMUJFWSA-N 0.000 claims description 3
- DYUQFVNFCXRXNB-CYBMUJFWSA-N 2-chloro-n-[(1r)-1-cyclohexylethyl]-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound N([C@H](C)C1CCCCC1)C(=O)C(C(=CC=1)Cl)=CC=1N(C)C=1C=CNC(=O)N=1 DYUQFVNFCXRXNB-CYBMUJFWSA-N 0.000 claims description 3
- FZIDHLRXIUZJFK-QGZVFWFLSA-N 2-chloro-n-[(1s)-1-cyclohexyl-2-hydroxyethyl]-5-[(2-methylsulfanylpyrimidin-4-yl)amino]benzamide Chemical compound CSC1=NC=CC(NC=2C=C(C(Cl)=CC=2)C(=O)N[C@H](CO)C2CCCCC2)=N1 FZIDHLRXIUZJFK-QGZVFWFLSA-N 0.000 claims description 3
- WFMVQUVNGQIDKD-QGZVFWFLSA-N 2-chloro-n-[(1s)-1-cyclohexyl-2-hydroxyethyl]-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C1([C@@H](CO)NC(=O)C=2C(Cl)=CC=C(C=2)N(C)C2=NC(=O)NC=C2)CCCCC1 WFMVQUVNGQIDKD-QGZVFWFLSA-N 0.000 claims description 3
- MARLYCOQCXNMEM-UHFFFAOYSA-N 2-chloro-n-[(4,4-difluoro-1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)methyl]benzamide Chemical compound C=1C(CC2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCC(F)(F)CC1 MARLYCOQCXNMEM-UHFFFAOYSA-N 0.000 claims description 3
- CGUNJOOKMFEAHV-UHFFFAOYSA-N 2-chloro-n-[(4,4-difluoro-1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)oxy]benzamide Chemical compound C=1C(OC2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCC(F)(F)CC1 CGUNJOOKMFEAHV-UHFFFAOYSA-N 0.000 claims description 3
- GSYBKPYLEVHNCR-UHFFFAOYSA-N 2-chloro-n-[(4,4-difluoro-1-hydroxycyclohexyl)methyl]-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C=1C=NC(=O)NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCC(F)(F)CC1 GSYBKPYLEVHNCR-UHFFFAOYSA-N 0.000 claims description 3
- ZQVVCNAIQGQGSR-UHFFFAOYSA-N 2-chloro-n-[[1-(hydroxymethyl)cyclohexyl]methyl]-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C=1C=NC(=O)NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(CO)CCCCC1 ZQVVCNAIQGQGSR-UHFFFAOYSA-N 0.000 claims description 3
- KWHOUJQKPVQBJW-UHFFFAOYSA-N 5-[(2-chloropyrimidin-4-yl)-methylamino]-n-[(1-hydroxycyclohexyl)methyl]-2-methylbenzamide Chemical compound C=1C=NC(Cl)=NC=1N(C)C(C=1)=CC=C(C)C=1C(=O)NCC1(O)CCCCC1 KWHOUJQKPVQBJW-UHFFFAOYSA-N 0.000 claims description 3
- XAPPQVXUIYTVDT-UHFFFAOYSA-N 5-[benzyl-(2-chloropyrimidin-4-yl)amino]-2-chloro-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(N(CC=2C=CC=CC=2)C=2N=C(Cl)N=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 XAPPQVXUIYTVDT-UHFFFAOYSA-N 0.000 claims description 3
- MZMPWWSJPJDWFF-UHFFFAOYSA-N 5-[benzyl-(2-methoxypyrimidin-4-yl)amino]-2-chloro-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound COC1=NC=CC(N(CC=2C=CC=CC=2)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 MZMPWWSJPJDWFF-UHFFFAOYSA-N 0.000 claims description 3
- UMZDWXRUZSHYIL-UHFFFAOYSA-N 5-[benzyl-(2-oxo-1h-pyrimidin-6-yl)amino]-2-chloro-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(N(CC=2C=CC=CC=2)C2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 UMZDWXRUZSHYIL-UHFFFAOYSA-N 0.000 claims description 3
- PZSVKYNKWLEVBM-UHFFFAOYSA-N 5-anilino-2-chloro-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(NC=2C=CC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 PZSVKYNKWLEVBM-UHFFFAOYSA-N 0.000 claims description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- NPTODAWCUPQPCC-UHFFFAOYSA-N n-[(1-carbamoylcyclohexyl)methyl]-2-chloro-5-[(2-chloropyrimidin-4-yl)-methylamino]benzamide Chemical compound C=1C=NC(Cl)=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(C(N)=O)CCCCC1 NPTODAWCUPQPCC-UHFFFAOYSA-N 0.000 claims description 3
- KMPCALQLNURNLH-UHFFFAOYSA-N n-[(1-hydroxycyclohexyl)methyl]-2-methyl-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C1=CNC(=O)N=C1N(C)C(C=1)=CC=C(C)C=1C(=O)NCC1(O)CCCCC1 KMPCALQLNURNLH-UHFFFAOYSA-N 0.000 claims description 3
- LYBFBCPSKPRPLZ-UHFFFAOYSA-N 2-chloro-5-(6-chloropyridin-2-yl)oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(OC=2N=C(Cl)C=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 LYBFBCPSKPRPLZ-UHFFFAOYSA-N 0.000 claims description 2
- FULVNVNEBQYRAU-UHFFFAOYSA-N 2-chloro-5-[fluoro-(2-oxo-1h-pyrimidin-6-yl)methyl]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(C(F)C2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 FULVNVNEBQYRAU-UHFFFAOYSA-N 0.000 claims description 2
- MZARZOWRLWXWPW-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(2-methoxypyrimidin-4-yl)oxybenzamide Chemical compound COC1=NC=CC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 MZARZOWRLWXWPW-UHFFFAOYSA-N 0.000 claims description 2
- ZUDPSLCBWUTNAZ-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(2-methoxypyrimidin-4-yl)amino]benzamide Chemical compound COC1=NC=CC(NC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 ZUDPSLCBWUTNAZ-UHFFFAOYSA-N 0.000 claims description 2
- MXCWLNJFACDXMG-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(6-methylsulfonylpyrimidin-4-yl)amino]benzamide Chemical compound C=1C(S(C)(=O)=O)=NC=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 MXCWLNJFACDXMG-UHFFFAOYSA-N 0.000 claims description 2
- PFAGOMTUZLZJRM-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-[6-(methylamino)pyrazin-2-yl]amino]benzamide Chemical compound CNC1=CN=CC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 PFAGOMTUZLZJRM-UHFFFAOYSA-N 0.000 claims description 2
- ATRFQBJQJYCULA-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclooctyl)methyl]-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C=1C=NC(=O)NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCCCC1 ATRFQBJQJYCULA-UHFFFAOYSA-N 0.000 claims description 2
- NHJWPPARIQKEIT-UHFFFAOYSA-N n-[(1-hydroxycyclohexyl)methyl]-5-[(2-methoxypyrimidin-4-yl)-methylamino]-2-methylbenzamide Chemical compound COC1=NC=CC(N(C)C=2C=C(C(C)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 NHJWPPARIQKEIT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- KLSPCWAPBBAWKM-IBGZPJMESA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[(1s)-1-hydroxy-1-(2-oxo-1h-pyrimidin-6-yl)ethyl]benzamide Chemical compound C=1C([C@@](O)(C)C2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 KLSPCWAPBBAWKM-IBGZPJMESA-N 0.000 claims 1
- IYMQBOQYFYZZPI-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl(pyridin-2-yl)amino]benzamide;2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(pyridin-2-ylamino)benzamide Chemical compound C=1C(NC=2N=CC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1.C=1C=CC=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 IYMQBOQYFYZZPI-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 5
- 229910052727 yttrium Inorganic materials 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 731
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 344
- 238000000034 method Methods 0.000 description 326
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 148
- 239000000243 solution Substances 0.000 description 144
- 239000011541 reaction mixture Substances 0.000 description 130
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 84
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
- 235000019439 ethyl acetate Nutrition 0.000 description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- 239000005711 Benzoic acid Substances 0.000 description 49
- 238000004440 column chromatography Methods 0.000 description 49
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 46
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 44
- 239000012074 organic phase Substances 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000002904 solvent Substances 0.000 description 39
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 125000004432 carbon atom Chemical group C* 0.000 description 29
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- 239000002253 acid Substances 0.000 description 25
- MBTGBRYMJKYYOE-UHFFFAOYSA-N 2,6-difluoropyridine Chemical compound FC1=CC=CC(F)=N1 MBTGBRYMJKYYOE-UHFFFAOYSA-N 0.000 description 24
- 239000012267 brine Substances 0.000 description 22
- 125000006239 protecting group Chemical group 0.000 description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 19
- 230000001684 chronic effect Effects 0.000 description 19
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 19
- DXIAEURKHWGAFH-UHFFFAOYSA-N 1-(aminomethyl)cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NCC1(O)CCCCC1 DXIAEURKHWGAFH-UHFFFAOYSA-N 0.000 description 18
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 235000010233 benzoic acid Nutrition 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 15
- UTVCLUZQPSRKMY-UHFFFAOYSA-N 2-chloro-5-hydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1Cl UTVCLUZQPSRKMY-UHFFFAOYSA-N 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 229910000024 caesium carbonate Inorganic materials 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 208000011580 syndromic disease Diseases 0.000 description 14
- 208000004296 neuralgia Diseases 0.000 description 13
- 208000021722 neuropathic pain Diseases 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 0 Cc1ccc(*)c(C(O)=O)c1 Chemical compound Cc1ccc(*)c(C(O)=O)c1 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 230000008878 coupling Effects 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 10
- 230000001154 acute effect Effects 0.000 description 10
- 239000013058 crude material Substances 0.000 description 10
- 208000014674 injury Diseases 0.000 description 10
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- 230000000638 stimulation Effects 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 201000008482 osteoarthritis Diseases 0.000 description 9
- 208000035824 paresthesia Diseases 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 8
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 8
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 8
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 8
- 101001098175 Homo sapiens P2X purinoceptor 7 Proteins 0.000 description 8
- 201000002481 Myositis Diseases 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 206010016654 Fibrosis Diseases 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 7
- 208000036142 Viral infection Diseases 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 208000006673 asthma Diseases 0.000 description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 6
- GWRSATNRNFYMDI-UHFFFAOYSA-N 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound FC=1C=C(NC=2N=C3N(C4CCCC4)CC(F)(F)C(=O)N(C)C3=CN=2)C(OC)=CC=1C(=O)NC1CCN(C)CC1 GWRSATNRNFYMDI-UHFFFAOYSA-N 0.000 description 6
- 201000005569 Gout Diseases 0.000 description 6
- 208000004454 Hyperalgesia Diseases 0.000 description 6
- 206010065390 Inflammatory pain Diseases 0.000 description 6
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 6
- 208000008930 Low Back Pain Diseases 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 206010047112 Vasculitides Diseases 0.000 description 6
- 206010047115 Vasculitis Diseases 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 230000009400 cancer invasion Effects 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 208000002551 irritable bowel syndrome Diseases 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 239000002480 mineral oil Substances 0.000 description 6
- 235000010446 mineral oil Nutrition 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000035807 sensation Effects 0.000 description 6
- 230000035945 sensitivity Effects 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 230000008733 trauma Effects 0.000 description 6
- 206010044652 trigeminal neuralgia Diseases 0.000 description 6
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 6
- 230000009385 viral infection Effects 0.000 description 6
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 5
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 5
- 208000003456 Juvenile Arthritis Diseases 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 206010003246 arthritis Diseases 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000004761 fibrosis Effects 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 201000006417 multiple sclerosis Diseases 0.000 description 5
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 201000003068 rheumatic fever Diseases 0.000 description 5
- 201000000306 sarcoidosis Diseases 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [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 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- 125000006083 1-bromoethyl group Chemical group 0.000 description 4
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 4
- 208000000094 Chronic Pain Diseases 0.000 description 4
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 4
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 4
- 208000011231 Crohn disease Diseases 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- 208000007465 Giant cell arteritis Diseases 0.000 description 4
- 208000019695 Migraine disease Diseases 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 description 4
- 201000003146 cystitis Diseases 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 206010022000 influenza Diseases 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- DLSYOOCTSGXXCP-UHFFFAOYSA-N methyl 2-chloro-5-iodobenzoate Chemical compound COC(=O)C1=CC(I)=CC=C1Cl DLSYOOCTSGXXCP-UHFFFAOYSA-N 0.000 description 4
- 206010027599 migraine Diseases 0.000 description 4
- 208000031225 myocardial ischemia Diseases 0.000 description 4
- 230000020477 pH reduction Effects 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 206010039083 rhinitis Diseases 0.000 description 4
- 201000005671 spondyloarthropathy Diseases 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 206010043207 temporal arteritis Diseases 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 3
- JQCSUVJDBHJKNG-UHFFFAOYSA-N 1-methoxy-ethyl Chemical group C[CH]OC JQCSUVJDBHJKNG-UHFFFAOYSA-N 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 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
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- ZNGINKJHQQQORD-UHFFFAOYSA-N 2-trimethylsilylethanol Chemical compound C[Si](C)(C)CCO ZNGINKJHQQQORD-UHFFFAOYSA-N 0.000 description 3
- GUSWJGOYDXFJSI-UHFFFAOYSA-N 3,6-dichloropyridazine Chemical compound ClC1=CC=C(Cl)N=N1 GUSWJGOYDXFJSI-UHFFFAOYSA-N 0.000 description 3
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 3
- XCAMEGPUILTZSU-UHFFFAOYSA-N 4-chloro-2-methoxypyrimidine Chemical compound COC1=NC=CC(Cl)=N1 XCAMEGPUILTZSU-UHFFFAOYSA-N 0.000 description 3
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 3
- CLNNBQDAAGDAHI-UHFFFAOYSA-N 6-chloro-1h-pyridin-2-one Chemical compound OC1=CC=CC(Cl)=N1 CLNNBQDAAGDAHI-UHFFFAOYSA-N 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 3
- 208000006820 Arthralgia Diseases 0.000 description 3
- 206010006002 Bone pain Diseases 0.000 description 3
- 208000006561 Cluster Headache Diseases 0.000 description 3
- 206010009900 Colitis ulcerative Diseases 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 3
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 3
- 208000005171 Dysmenorrhea Diseases 0.000 description 3
- 206010013935 Dysmenorrhoea Diseases 0.000 description 3
- 206010014561 Emphysema Diseases 0.000 description 3
- 208000001640 Fibromyalgia Diseases 0.000 description 3
- 206010018364 Glomerulonephritis Diseases 0.000 description 3
- 206010018634 Gouty Arthritis Diseases 0.000 description 3
- 206010019233 Headaches Diseases 0.000 description 3
- 208000023105 Huntington disease Diseases 0.000 description 3
- 208000035154 Hyperesthesia Diseases 0.000 description 3
- 206010065952 Hyperpathia Diseases 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 206010028836 Neck pain Diseases 0.000 description 3
- 206010062501 Non-cardiac chest pain Diseases 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 3
- 208000004983 Phantom Limb Diseases 0.000 description 3
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 3
- 208000004550 Postoperative Pain Diseases 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 208000008765 Sciatica Diseases 0.000 description 3
- 208000006045 Spondylarthropathies Diseases 0.000 description 3
- 208000010040 Sprains and Strains Diseases 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 206010043269 Tension headache Diseases 0.000 description 3
- 208000008548 Tension-Type Headache Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 206010064390 Tumour invasion Diseases 0.000 description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 208000005298 acute pain Diseases 0.000 description 3
- 150000001351 alkyl iodides Chemical class 0.000 description 3
- 206010053552 allodynia Diseases 0.000 description 3
- 238000002266 amputation Methods 0.000 description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000007333 cyanation reaction Methods 0.000 description 3
- CGZZMOTZOONQIA-UHFFFAOYSA-N cycloheptanone Chemical compound O=C1CCCCCC1 CGZZMOTZOONQIA-UHFFFAOYSA-N 0.000 description 3
- 230000006735 deficit Effects 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 201000006549 dyspepsia Diseases 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 3
- 231100000869 headache Toxicity 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 208000021731 hypoalgesia Diseases 0.000 description 3
- 230000036032 hypoalgesia Effects 0.000 description 3
- 208000034783 hypoesthesia Diseases 0.000 description 3
- 230000001524 infective effect Effects 0.000 description 3
- 230000004968 inflammatory condition Effects 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 3
- LBNPBOFVHYOPIB-UHFFFAOYSA-N methyl 5-amino-2-chlorobenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1Cl LBNPBOFVHYOPIB-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 125000006606 n-butoxy group Chemical group 0.000 description 3
- 201000001119 neuropathy Diseases 0.000 description 3
- 230000007823 neuropathy Effects 0.000 description 3
- 230000001473 noxious effect Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000008058 pain sensation Effects 0.000 description 3
- 201000001245 periodontitis Diseases 0.000 description 3
- 208000033808 peripheral neuropathy Diseases 0.000 description 3
- 208000030062 persistent idiopathic facial pain Diseases 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000003226 pyrazolyl group Chemical group 0.000 description 3
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 125000005920 sec-butoxy group Chemical group 0.000 description 3
- 230000009155 sensory pathway Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 208000020431 spinal cord injury Diseases 0.000 description 3
- 230000003068 static effect Effects 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 208000004371 toothache Diseases 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 201000008827 tuberculosis Diseases 0.000 description 3
- 208000009935 visceral pain Diseases 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XBWOPGDJMAJJDG-SSDOTTSWSA-N (1r)-1-cyclohexylethanamine Chemical compound C[C@@H](N)C1CCCCC1 XBWOPGDJMAJJDG-SSDOTTSWSA-N 0.000 description 2
- VJJORIDDPKCJTI-MRVPVSSYSA-N (2s)-2-amino-2-cyclohexylethanol Chemical compound OC[C@@H](N)C1CCCCC1 VJJORIDDPKCJTI-MRVPVSSYSA-N 0.000 description 2
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 2
- MGAXYKDBRBNWKT-UHFFFAOYSA-N (5-oxooxolan-2-yl)methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1OC(=O)CC1 MGAXYKDBRBNWKT-UHFFFAOYSA-N 0.000 description 2
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 2
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 2
- TZTXTIBZSSSFDI-UHFFFAOYSA-N 1-pyridin-2-ylpropan-2-one Chemical compound CC(=O)CC1=CC=CC=N1 TZTXTIBZSSSFDI-UHFFFAOYSA-N 0.000 description 2
- IAJINJSFYTZPEJ-UHFFFAOYSA-N 1h-pyrimidin-3-ium-2-one;chloride Chemical compound Cl.O=C1N=CC=CN1 IAJINJSFYTZPEJ-UHFFFAOYSA-N 0.000 description 2
- DPVIABCMTHHTGB-UHFFFAOYSA-N 2,4,6-trichloropyrimidine Chemical compound ClC1=CC(Cl)=NC(Cl)=N1 DPVIABCMTHHTGB-UHFFFAOYSA-N 0.000 description 2
- LSEAAPGIZCDEEH-UHFFFAOYSA-N 2,6-dichloropyrazine Chemical compound ClC1=CN=CC(Cl)=N1 LSEAAPGIZCDEEH-UHFFFAOYSA-N 0.000 description 2
- IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 2
- ROGPYTUXSIHYMV-UHFFFAOYSA-N 2-chloro-5-[2-(dimethylamino)pyrimidin-4-yl]oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound CN(C)C1=NC=CC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 ROGPYTUXSIHYMV-UHFFFAOYSA-N 0.000 description 2
- ZYRAOOAYFVDHOL-UHFFFAOYSA-N 2-chloro-5-[cyclopentylmethyl-(2-oxo-1h-pyrimidin-6-yl)amino]-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound C=1C(N(CC2CCCC2)C2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 ZYRAOOAYFVDHOL-UHFFFAOYSA-N 0.000 description 2
- SGBFMVFSLBFPIF-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-(pyridin-2-ylamino)benzamide Chemical compound C=1C(NC=2N=CC=CC=2)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 SGBFMVFSLBFPIF-UHFFFAOYSA-N 0.000 description 2
- CPDUYDUPZOTVKO-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl(pyridin-2-yl)amino]benzamide Chemical compound C=1C=CC=NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(O)CCCCC1 CPDUYDUPZOTVKO-UHFFFAOYSA-N 0.000 description 2
- UDABYSLFEBRPGC-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(4-methylsulfanylpyrimidin-2-yl)amino]benzamide Chemical compound CSC1=CC=NC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 UDABYSLFEBRPGC-UHFFFAOYSA-N 0.000 description 2
- IHZXGKVMBQFQNF-UHFFFAOYSA-N 2-chloro-n-[(1-hydroxycyclohexyl)methyl]-5-[methyl-(6-methylsulfanylpyrimidin-4-yl)amino]benzamide Chemical compound C1=NC(SC)=CC(N(C)C=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 IHZXGKVMBQFQNF-UHFFFAOYSA-N 0.000 description 2
- RLXFQMSVVMKIAV-UHFFFAOYSA-N 2-chloro-n-[(4,4-difluoro-1-hydroxycyclohexyl)methyl]-5-[(2-oxo-1h-pyrimidin-6-yl)sulfanyl]benzamide Chemical compound C=1C(SC2=NC(=O)NC=C2)=CC=C(Cl)C=1C(=O)NCC1(O)CCC(F)(F)CC1 RLXFQMSVVMKIAV-UHFFFAOYSA-N 0.000 description 2
- GELVZYOEQVJIRR-UHFFFAOYSA-N 2-chloropyrazine Chemical compound ClC1=CN=CC=N1 GELVZYOEQVJIRR-UHFFFAOYSA-N 0.000 description 2
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 2
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- 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 2
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 2
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 2
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- SECBGKYJKCNDID-UHFFFAOYSA-N 4-iodo-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(I)=N1 SECBGKYJKCNDID-UHFFFAOYSA-N 0.000 description 2
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 2
- 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 2
- 208000030507 AIDS Diseases 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000026872 Addison Disease Diseases 0.000 description 2
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 2
- 208000032671 Allergic granulomatous angiitis Diseases 0.000 description 2
- 208000035939 Alveolitis allergic Diseases 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000023328 Basedow disease Diseases 0.000 description 2
- 208000009137 Behcet syndrome Diseases 0.000 description 2
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 2
- 208000002691 Choroiditis Diseases 0.000 description 2
- 208000006344 Churg-Strauss Syndrome Diseases 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- 108010091326 Cryoglobulins Proteins 0.000 description 2
- 201000003883 Cystic fibrosis Diseases 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- 206010012442 Dermatitis contact Diseases 0.000 description 2
- 208000006926 Discoid Lupus Erythematosus Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 206010014954 Eosinophilic fasciitis Diseases 0.000 description 2
- 208000018428 Eosinophilic granulomatosis with polyangiitis Diseases 0.000 description 2
- 208000027445 Farmer Lung Diseases 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 229910003803 Gold(III) chloride Inorganic materials 0.000 description 2
- 208000015023 Graves' disease Diseases 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- 208000003695 Histiocytic Necrotizing Lymphadenitis Diseases 0.000 description 2
- 206010069070 Histiocytic necrotising lymphadenitis Diseases 0.000 description 2
- 206010061246 Intervertebral disc degeneration Diseases 0.000 description 2
- 208000015282 Kikuchi-Fujimoto disease Diseases 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 208000009829 Lewy Body Disease Diseases 0.000 description 2
- 201000002832 Lewy body dementia Diseases 0.000 description 2
- 201000003088 Limited Scleroderma Diseases 0.000 description 2
- 208000024140 Limited cutaneous systemic sclerosis Diseases 0.000 description 2
- 201000009906 Meningitis Diseases 0.000 description 2
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 2
- 208000019022 Mood disease Diseases 0.000 description 2
- 201000002795 Muckle-Wells syndrome Diseases 0.000 description 2
- 208000021642 Muscular disease Diseases 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 201000009623 Myopathy Diseases 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 2
- 206010029164 Nephrotic syndrome Diseases 0.000 description 2
- 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 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- 208000010191 Osteitis Deformans Diseases 0.000 description 2
- 206010031264 Osteonecrosis Diseases 0.000 description 2
- 208000027868 Paget disease Diseases 0.000 description 2
- 206010033645 Pancreatitis Diseases 0.000 description 2
- 108010064255 Paraproteins Proteins 0.000 description 2
- 102000015094 Paraproteins Human genes 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 206010065159 Polychondritis Diseases 0.000 description 2
- 208000003971 Posterior uveitis Diseases 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 208000021386 Sjogren Syndrome Diseases 0.000 description 2
- 201000009594 Systemic Scleroderma Diseases 0.000 description 2
- 206010042953 Systemic sclerosis Diseases 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- 208000001106 Takayasu Arteritis Diseases 0.000 description 2
- 208000000491 Tendinopathy Diseases 0.000 description 2
- 206010043255 Tendonitis Diseases 0.000 description 2
- 206010043561 Thrombocytopenic purpura Diseases 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 208000034327 Tumor necrosis factor receptor 1 associated periodic syndrome Diseases 0.000 description 2
- 208000025851 Undifferentiated connective tissue disease Diseases 0.000 description 2
- 208000017379 Undifferentiated connective tissue syndrome Diseases 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 206010046996 Varicose vein Diseases 0.000 description 2
- ULHRKLSNHXXJLO-UHFFFAOYSA-L Yo-Pro-1 Chemical compound [I-].[I-].C1=CC=C2C(C=C3N(C4=CC=CC=C4O3)C)=CC=[N+](CCC[N+](C)(C)C)C2=C1 ULHRKLSNHXXJLO-UHFFFAOYSA-L 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 206010002022 amyloidosis Diseases 0.000 description 2
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 201000004984 autoimmune cardiomyopathy Diseases 0.000 description 2
- 201000003308 autosomal dominant familial periodic fever Diseases 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 230000010072 bone remodeling Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 208000010353 central nervous system vasculitis Diseases 0.000 description 2
- 201000002676 cerebral atherosclerosis Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 201000001352 cholecystitis Diseases 0.000 description 2
- 208000013116 chronic cough Diseases 0.000 description 2
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 208000018631 connective tissue disease Diseases 0.000 description 2
- 208000010247 contact dermatitis Diseases 0.000 description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 2
- 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 description 2
- 208000037329 crystal arthropathy Diseases 0.000 description 2
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 2
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 208000018180 degenerative disc disease Diseases 0.000 description 2
- 230000003412 degenerative effect Effects 0.000 description 2
- 230000003210 demyelinating effect Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 208000037765 diseases and disorders Diseases 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 208000022195 farmer lung disease Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- RJHLTVSLYWWTEF-UHFFFAOYSA-K gold trichloride Chemical compound Cl[Au](Cl)Cl RJHLTVSLYWWTEF-UHFFFAOYSA-K 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 201000006334 interstitial nephritis Diseases 0.000 description 2
- 208000021600 intervertebral disc degenerative disease Diseases 0.000 description 2
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 208000027202 mammary Paget disease Diseases 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 206010063344 microscopic polyangiitis Diseases 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 230000036651 mood Effects 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- ITAOSGCKEXNROV-UHFFFAOYSA-N n-[(1-carbamoylcyclohexyl)methyl]-2-chloro-5-[methyl-(2-oxo-1h-pyrimidin-6-yl)amino]benzamide Chemical compound C=1C=NC(=O)NC=1N(C)C(C=1)=CC=C(Cl)C=1C(=O)NCC1(C(N)=O)CCCCC1 ITAOSGCKEXNROV-UHFFFAOYSA-N 0.000 description 2
- 201000009240 nasopharyngitis Diseases 0.000 description 2
- 201000008383 nephritis Diseases 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 238000007248 oxidative elimination reaction Methods 0.000 description 2
- 208000012111 paraneoplastic syndrome Diseases 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 208000028169 periodontal disease Diseases 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 201000006292 polyarteritis nodosa Diseases 0.000 description 2
- 208000005987 polymyositis Diseases 0.000 description 2
- 230000037452 priming Effects 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 2
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 210000001525 retina Anatomy 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 2
- 231100000075 skin burn Toxicity 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- 201000004595 synovitis Diseases 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 210000001738 temporomandibular joint Anatomy 0.000 description 2
- 201000004415 tendinitis Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 2
- 208000027185 varicose disease Diseases 0.000 description 2
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [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 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 description 1
- XPIJMQVLTXAGME-UHFFFAOYSA-N 1,1-dimethoxycyclohexane Chemical compound COC1(OC)CCCCC1 XPIJMQVLTXAGME-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- NHCGQHAZAQDUDS-UHFFFAOYSA-N 1,2-dimethylimidazole;hydroiodide Chemical compound [I-].C[NH+]1C=CN=C1C NHCGQHAZAQDUDS-UHFFFAOYSA-N 0.000 description 1
- ARSMIBSHEYKMJT-UHFFFAOYSA-M 1,3-dimethylimidazolium iodide Chemical compound [I-].CN1C=C[N+](C)=C1 ARSMIBSHEYKMJT-UHFFFAOYSA-M 0.000 description 1
- OWUQPXVIOASEHZ-UHFFFAOYSA-N 1-(aminomethyl)cycloheptan-1-ol;hydrochloride Chemical compound Cl.NCC1(O)CCCCCC1 OWUQPXVIOASEHZ-UHFFFAOYSA-N 0.000 description 1
- IPWBFGUBXWMIPR-UHFFFAOYSA-N 1-bromo-2-fluorobenzene Chemical compound FC1=CC=CC=C1Br IPWBFGUBXWMIPR-UHFFFAOYSA-N 0.000 description 1
- JZUMPNUYDJBTNO-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 JZUMPNUYDJBTNO-UHFFFAOYSA-N 0.000 description 1
- BTUGGGLMQBJCBN-UHFFFAOYSA-N 1-iodo-2-methylpropane Chemical compound CC(C)CI BTUGGGLMQBJCBN-UHFFFAOYSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NTINZJSVKOXJSQ-UHFFFAOYSA-N 1-trimethylsilyloxycycloheptane-1-carbonitrile Chemical compound C[Si](C)(C)OC1(C#N)CCCCCC1 NTINZJSVKOXJSQ-UHFFFAOYSA-N 0.000 description 1
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 1
- YKLDMAPEGQYZRT-UHFFFAOYSA-N 2,4-difluoro-1-iodobenzene Chemical compound FC1=CC=C(I)C(F)=C1 YKLDMAPEGQYZRT-UHFFFAOYSA-N 0.000 description 1
- WLAKUAILRGATSL-UHFFFAOYSA-N 2,4-difluoropyridine Chemical compound FC1=CC=NC(F)=C1 WLAKUAILRGATSL-UHFFFAOYSA-N 0.000 description 1
- JVSDZAGCHKCSGR-UHFFFAOYSA-N 2,5-dichloropyrazine Chemical compound ClC1=CN=C(Cl)C=N1 JVSDZAGCHKCSGR-UHFFFAOYSA-N 0.000 description 1
- FILKGCRCWDMBKA-UHFFFAOYSA-N 2,6-dichloropyridine Chemical compound ClC1=CC=CC(Cl)=N1 FILKGCRCWDMBKA-UHFFFAOYSA-N 0.000 description 1
- CEAYNFNEQAOJJD-UHFFFAOYSA-N 2-(6-chloropyridazin-3-yl)oxyethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOC1=CC=C(Cl)N=N1 CEAYNFNEQAOJJD-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- JJFOBACUIRKUPN-UHFFFAOYSA-N 2-bromoethoxybenzene Chemical compound BrCCOC1=CC=CC=C1 JJFOBACUIRKUPN-UHFFFAOYSA-N 0.000 description 1
- FGSAQRJRWCZLOB-UHFFFAOYSA-N 2-chloro-4-fluoropyridine Chemical compound FC1=CC=NC(Cl)=C1 FGSAQRJRWCZLOB-UHFFFAOYSA-N 0.000 description 1
- VAATWVRXPRDPPM-UHFFFAOYSA-N 2-chloro-4-methylsulfanylpyrimidine Chemical compound CSC1=CC=NC(Cl)=N1 VAATWVRXPRDPPM-UHFFFAOYSA-N 0.000 description 1
- RRGJDNJPUAQCAH-UHFFFAOYSA-N 2-chloro-5-(2-fluoroanilino)benzoic acid Chemical compound C1=C(Cl)C(C(=O)O)=CC(NC=2C(=CC=CC=2)F)=C1 RRGJDNJPUAQCAH-UHFFFAOYSA-N 0.000 description 1
- FCVXTFFBJYZCMM-UHFFFAOYSA-N 2-chloro-5-(2-methoxypyrimidin-4-yl)sulfanylbenzoic acid Chemical compound COC1=NC=CC(SC=2C=C(C(Cl)=CC=2)C(O)=O)=N1 FCVXTFFBJYZCMM-UHFFFAOYSA-N 0.000 description 1
- WPEHRPCSWXVXRC-UHFFFAOYSA-N 2-chloro-5-(6-fluoropyridin-2-yl)oxybenzoic acid Chemical compound C1=C(Cl)C(C(=O)O)=CC(OC=2N=C(F)C=CC=2)=C1 WPEHRPCSWXVXRC-UHFFFAOYSA-N 0.000 description 1
- BWJUKOOZTVOVKB-UHFFFAOYSA-N 2-chloro-5-(pyrimidin-4-ylamino)benzoic acid Chemical compound C1=C(Cl)C(C(=O)O)=CC(NC=2N=CN=CC=2)=C1 BWJUKOOZTVOVKB-UHFFFAOYSA-N 0.000 description 1
- XNWGPGVUBCHBLC-UHFFFAOYSA-N 2-chloro-5-[(2-chloropyrimidin-4-yl)amino]benzoic acid Chemical compound C1=C(Cl)C(C(=O)O)=CC(NC=2N=C(Cl)N=CC=2)=C1 XNWGPGVUBCHBLC-UHFFFAOYSA-N 0.000 description 1
- SDMVYLAXDOGTKT-UHFFFAOYSA-N 2-chloro-5-[(6-chloro-2-methoxypyrimidin-4-yl)-methylamino]benzoic acid Chemical compound COC1=NC(Cl)=CC(N(C)C=2C=C(C(Cl)=CC=2)C(O)=O)=N1 SDMVYLAXDOGTKT-UHFFFAOYSA-N 0.000 description 1
- AXPFFTMDTWJYQD-UHFFFAOYSA-N 2-chloro-5-[6-(dimethylamino)pyridin-2-yl]oxy-n-[(1-hydroxycyclohexyl)methyl]benzamide Chemical compound CN(C)C1=CC=CC(OC=2C=C(C(Cl)=CC=2)C(=O)NCC2(O)CCCCC2)=N1 AXPFFTMDTWJYQD-UHFFFAOYSA-N 0.000 description 1
- HSRPALUEAAYZBK-UHFFFAOYSA-N 2-chloro-5-[methyl(pyrazin-2-yl)amino]benzoic acid Chemical compound C=1N=CC=NC=1N(C)C1=CC=C(Cl)C(C(O)=O)=C1 HSRPALUEAAYZBK-UHFFFAOYSA-N 0.000 description 1
- LEBWXJZAWTVKFL-UHFFFAOYSA-N 2-chloro-5-methylbenzoic acid Chemical compound CC1=CC=C(Cl)C(C(O)=O)=C1 LEBWXJZAWTVKFL-UHFFFAOYSA-N 0.000 description 1
- XWSSFRJLOZQOCX-UHFFFAOYSA-N 2-chloro-6-methoxypyrazine Chemical compound COC1=CN=CC(Cl)=N1 XWSSFRJLOZQOCX-UHFFFAOYSA-N 0.000 description 1
- VAVGOGHLNAJECD-UHFFFAOYSA-N 2-chloro-6-methoxypyridine Chemical compound COC1=CC=CC(Cl)=N1 VAVGOGHLNAJECD-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- XXUNIGZDNWWYED-UHFFFAOYSA-N 2-methylbenzamide Chemical compound CC1=CC=CC=C1C(N)=O XXUNIGZDNWWYED-UHFFFAOYSA-N 0.000 description 1
- JESRNIJXVIFVOV-UHFFFAOYSA-N 2-methylpyrazol-3-amine Chemical compound CN1N=CC=C1N JESRNIJXVIFVOV-UHFFFAOYSA-N 0.000 description 1
- JZSAUQMXKHBZEO-UHFFFAOYSA-N 3,5-dichloropyridazine Chemical compound ClC1=CN=NC(Cl)=C1 JZSAUQMXKHBZEO-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
- YDUGVOUXNSWQSW-UHFFFAOYSA-N 3-bromo-1h-pyridin-2-one Chemical compound OC1=NC=CC=C1Br YDUGVOUXNSWQSW-UHFFFAOYSA-N 0.000 description 1
- XBJLKXOOHLLTPG-UHFFFAOYSA-N 3-chloro-6-methoxypyridazine Chemical compound COC1=CC=C(Cl)N=N1 XBJLKXOOHLLTPG-UHFFFAOYSA-N 0.000 description 1
- AEVSSZHXGJAPIE-UHFFFAOYSA-N 3-chloropyrazin-2-amine Chemical compound NC1=NC=CN=C1Cl AEVSSZHXGJAPIE-UHFFFAOYSA-N 0.000 description 1
- IBWYHNOFSKJKKY-UHFFFAOYSA-N 3-chloropyridazine Chemical compound ClC1=CC=CN=N1 IBWYHNOFSKJKKY-UHFFFAOYSA-N 0.000 description 1
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NYYSPVRERVXMLJ-UHFFFAOYSA-N 4,4-difluorocyclohexan-1-one Chemical compound FC1(F)CCC(=O)CC1 NYYSPVRERVXMLJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- DFOHHQRGDOQMKG-UHFFFAOYSA-N 4-chloro-2-methylsulfanylpyrimidine Chemical compound CSC1=NC=CC(Cl)=N1 DFOHHQRGDOQMKG-UHFFFAOYSA-N 0.000 description 1
- ADHCFMUHIKEUCC-UHFFFAOYSA-N 4-chloropyrimidine;dihydrochloride Chemical compound Cl.Cl.ClC1=CC=NC=N1 ADHCFMUHIKEUCC-UHFFFAOYSA-N 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- ZHFJIITZHYWVAL-UHFFFAOYSA-N 5-(bromomethyl)-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC(CBr)=CC=C1Cl ZHFJIITZHYWVAL-UHFFFAOYSA-N 0.000 description 1
- GYCPLYCTMDTEPU-UHFFFAOYSA-N 5-bromopyrimidine Chemical compound BrC1=CN=CN=C1 GYCPLYCTMDTEPU-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 206010000748 Acute febrile neutrophilic dermatosis Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 206010002921 Aortitis Diseases 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- XBCXJKGHPABGSD-UHFFFAOYSA-N CN(C=CC(N1)=O)C1=O Chemical compound CN(C=CC(N1)=O)C1=O XBCXJKGHPABGSD-UHFFFAOYSA-N 0.000 description 1
- DVVGIUUJYPYENY-UHFFFAOYSA-N CN(C=CC=C1)C1=O Chemical compound CN(C=CC=C1)C1=O DVVGIUUJYPYENY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 208000009248 Congenital Hip Dislocation Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 1
- 208000019872 Drug Eruptions Diseases 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 206010065563 Eosinophilic bronchitis Diseases 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 206010015218 Erythema multiforme Diseases 0.000 description 1
- 206010016207 Familial Mediterranean fever Diseases 0.000 description 1
- 208000032678 Fixed drug eruption Diseases 0.000 description 1
- 208000005232 Glossitis Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000003810 Interleukin-18 Human genes 0.000 description 1
- 108090000171 Interleukin-18 Proteins 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- 108010092694 L-Selectin Proteins 0.000 description 1
- 102000016551 L-selectin Human genes 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 206010024434 Lichen sclerosus Diseases 0.000 description 1
- 239000012097 Lipofectamine 2000 Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- 206010028735 Nasal congestion Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 241001420836 Ophthalmitis Species 0.000 description 1
- 206010031149 Osteitis Diseases 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 208000004362 Penile Induration Diseases 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 208000020758 Peyronie disease Diseases 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- 208000002200 Respiratory Hypersensitivity Diseases 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 206010039094 Rhinitis perennial Diseases 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- 208000007893 Salpingitis Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Chemical group 0.000 description 1
- 208000010265 Sweet syndrome Diseases 0.000 description 1
- 206010042742 Sympathetic ophthalmia Diseases 0.000 description 1
- 206010057970 Toxic skin eruption Diseases 0.000 description 1
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 208000035222 X-linked skeletal dysplasia-intellectual disability syndrome Diseases 0.000 description 1
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000004115 adherent culture Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000010085 airway hyperresponsiveness Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 208000002353 alcoholic hepatitis Diseases 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 206010068168 androgenetic alopecia Diseases 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 229910052586 apatite Inorganic materials 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 125000003943 azolyl group Chemical class 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 208000010217 blepharitis Diseases 0.000 description 1
- 208000018339 bone inflammation disease Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229910052801 chlorine Chemical group 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 208000002849 chondrocalcinosis Diseases 0.000 description 1
- 208000017760 chronic graft versus host disease Diseases 0.000 description 1
- 201000009151 chronic rhinitis Diseases 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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 1
- IIRFCWANHMSDCG-UHFFFAOYSA-N cyclooctanone Chemical compound O=C1CCCCCCC1 IIRFCWANHMSDCG-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- 208000014906 developmental dysplasia of the hip Diseases 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 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
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 206010014665 endocarditis Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 201000001564 eosinophilic gastroenteritis Diseases 0.000 description 1
- 201000010063 epididymitis Diseases 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 201000010934 exostosis Diseases 0.000 description 1
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 1
- 208000024711 extrinsic asthma Diseases 0.000 description 1
- 208000012587 fixed pigmented erythema Diseases 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 208000007565 gingivitis Diseases 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 201000010930 hyperostosis Diseases 0.000 description 1
- 230000004047 hyperresponsiveness Effects 0.000 description 1
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 201000009863 inflammatory diarrhea Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 201000010659 intrinsic asthma Diseases 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- DUMSKQUKLVSSII-UHFFFAOYSA-N iodomethylcyclopentane Chemical compound ICC1CCCC1 DUMSKQUKLVSSII-UHFFFAOYSA-N 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 201000004614 iritis Diseases 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- MHYSFKOKQLFDIB-UHFFFAOYSA-N lithium;2-trimethylsilylethanolate Chemical compound [Li+].C[Si](C)(C)CC[O-] MHYSFKOKQLFDIB-UHFFFAOYSA-N 0.000 description 1
- 230000001589 lymphoproliferative effect Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- ACVKFIYOVXQWEM-UHFFFAOYSA-N methyl 1-(aminomethyl)cyclohexane-1-carboxylate Chemical compound COC(=O)C1(CN)CCCCC1 ACVKFIYOVXQWEM-UHFFFAOYSA-N 0.000 description 1
- YZZZREHIEOLWQY-UHFFFAOYSA-N methyl 2-chloro-5-(dimethylcarbamothioyloxy)benzoate Chemical compound COC(=O)C1=CC(OC(=S)N(C)C)=CC=C1Cl YZZZREHIEOLWQY-UHFFFAOYSA-N 0.000 description 1
- HLELKXOEUVJFNE-UHFFFAOYSA-N methyl 2-chloro-5-(dimethylcarbamoylsulfanyl)benzoate Chemical compound COC(=O)C1=CC(SC(=O)N(C)C)=CC=C1Cl HLELKXOEUVJFNE-UHFFFAOYSA-N 0.000 description 1
- JWGUQBQKGSNGID-UHFFFAOYSA-N methyl 2-chloro-5-(pyridin-2-ylamino)benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(NC=2N=CC=CC=2)=C1 JWGUQBQKGSNGID-UHFFFAOYSA-N 0.000 description 1
- KXBJUVZSYORROI-UHFFFAOYSA-N methyl 2-chloro-5-(pyrimidin-2-ylamino)benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(NC=2N=CC=CN=2)=C1 KXBJUVZSYORROI-UHFFFAOYSA-N 0.000 description 1
- LJKIEQPFZJTSES-UHFFFAOYSA-N methyl 2-chloro-5-[(2,6-dichloropyrimidin-4-yl)amino]benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(NC=2N=C(Cl)N=C(Cl)C=2)=C1 LJKIEQPFZJTSES-UHFFFAOYSA-N 0.000 description 1
- JWTSDJIZSGGBCG-UHFFFAOYSA-N methyl 2-chloro-5-[(2-methylpyrazol-3-yl)amino]benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(NC=2N(N=CC=2)C)=C1 JWTSDJIZSGGBCG-UHFFFAOYSA-N 0.000 description 1
- QCADPJYYFADBJA-UHFFFAOYSA-N methyl 2-chloro-5-[(3-chloropyrazin-2-yl)-methylamino]benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(N(C)C=2C(=NC=CN=2)Cl)=C1 QCADPJYYFADBJA-UHFFFAOYSA-N 0.000 description 1
- AJVIITINFIZLRQ-UHFFFAOYSA-N methyl 2-chloro-5-[(4-methylsulfanylpyrimidin-2-yl)amino]benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(NC=2N=C(SC)C=CN=2)=C1 AJVIITINFIZLRQ-UHFFFAOYSA-N 0.000 description 1
- JNHMSUQBZCLWLZ-UHFFFAOYSA-N methyl 2-chloro-5-[(5-chloropyrazin-2-yl)amino]benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(NC=2N=CC(Cl)=NC=2)=C1 JNHMSUQBZCLWLZ-UHFFFAOYSA-N 0.000 description 1
- DREVNEUBMXCPFH-UHFFFAOYSA-N methyl 2-chloro-5-[(6-chloropyridazin-3-yl)amino]benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(NC=2N=NC(Cl)=CC=2)=C1 DREVNEUBMXCPFH-UHFFFAOYSA-N 0.000 description 1
- NTMVGZSCQSGVLU-UHFFFAOYSA-N methyl 2-chloro-5-[2-(2-trimethylsilylethoxy)pyrimidine-4-carbonyl]benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(C(=O)C=2N=C(OCC[Si](C)(C)C)N=CC=2)=C1 NTMVGZSCQSGVLU-UHFFFAOYSA-N 0.000 description 1
- IINOEEDLIMIWHC-UHFFFAOYSA-N methyl 2-chloro-5-[methyl(pyrimidin-4-yl)amino]benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(N(C)C=2N=CN=CC=2)=C1 IINOEEDLIMIWHC-UHFFFAOYSA-N 0.000 description 1
- IGFHPDXOVOVSBB-UHFFFAOYSA-N methyl 2-chloro-5-[methyl-(6-methylsulfanylpyrimidin-4-yl)amino]benzoate Chemical compound C1=C(Cl)C(C(=O)OC)=CC(N(C)C=2N=CN=C(SC)C=2)=C1 IGFHPDXOVOVSBB-UHFFFAOYSA-N 0.000 description 1
- CQKITZCDGUDSHE-UHFFFAOYSA-N methyl 2-chloro-5-formylbenzoate Chemical compound COC(=O)C1=CC(C=O)=CC=C1Cl CQKITZCDGUDSHE-UHFFFAOYSA-N 0.000 description 1
- UCNCJYKKAJVLQK-UHFFFAOYSA-N methyl 2-chloro-5-hydroxybenzoate Chemical compound COC(=O)C1=CC(O)=CC=C1Cl UCNCJYKKAJVLQK-UHFFFAOYSA-N 0.000 description 1
- TVGKPVDDCDQBRC-UHFFFAOYSA-N methyl 2-methyl-5-nitrobenzoate Chemical compound COC(=O)C1=CC([N+]([O-])=O)=CC=C1C TVGKPVDDCDQBRC-UHFFFAOYSA-N 0.000 description 1
- CATAJHNFXWLJRA-UHFFFAOYSA-N methyl 5-(bromomethyl)-2-chlorobenzoate Chemical compound COC(=O)C1=CC(CBr)=CC=C1Cl CATAJHNFXWLJRA-UHFFFAOYSA-N 0.000 description 1
- JNPZKGOLYSCSEL-UHFFFAOYSA-N methyl 5-amino-2-methylbenzoate Chemical compound COC(=O)C1=CC(N)=CC=C1C JNPZKGOLYSCSEL-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 210000000274 microglia Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- PHWISQNXPLXQRU-UHFFFAOYSA-N n,n-dimethylcarbamothioyl chloride Chemical compound CN(C)C(Cl)=S PHWISQNXPLXQRU-UHFFFAOYSA-N 0.000 description 1
- SFMJNHNUOVADRW-UHFFFAOYSA-N n-[5-[9-[4-(methanesulfonamido)phenyl]-2-oxobenzo[h][1,6]naphthyridin-1-yl]-2-methylphenyl]prop-2-enamide Chemical compound C1=C(NC(=O)C=C)C(C)=CC=C1N1C(=O)C=CC2=C1C1=CC(C=3C=CC(NS(C)(=O)=O)=CC=3)=CC=C1N=C2 SFMJNHNUOVADRW-UHFFFAOYSA-N 0.000 description 1
- 125000006126 n-butyl sulfonyl group Chemical group 0.000 description 1
- 125000002004 n-butylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004708 n-butylthio group Chemical group C(CCC)S* 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 125000006124 n-propyl sulfonyl group Chemical group 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 230000003959 neuroinflammation Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 208000005963 oophoritis Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 208000010403 panophthalmitis Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 1
- 208000022719 perennial allergic rhinitis Diseases 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 210000002856 peripheral neuron Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 208000017983 photosensitivity disease Diseases 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 208000009954 pyoderma gangrenosum Diseases 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 208000017022 seasonal allergic rhinitis Diseases 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 208000025869 skeletal dysplasia-intellectual disability syndrome Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000008409 synovial inflammation Effects 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 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
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 230000005951 type IV hypersensitivity Effects 0.000 description 1
- 208000027930 type IV hypersensitivity disease Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000003156 vasculitic effect Effects 0.000 description 1
- 208000001319 vasomotor rhinitis Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 208000010484 vulvovaginitis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/74—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system of the same carbon skeleton
-
- 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
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- 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
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
-
- 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
-
- 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
- A61P37/08—Antiallergic agents
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/22—Nitrogen and oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
- C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to benzamide derivatives of formula (I) and their use as pharmaceuticals.
- the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as P2X 7 receptor antagonists.
- P2X7 receptors belong to the family of P2X ionotropic receptors that are activated by extracellular nucleotides, in particular adenosine triphosphate (ATP).
- P2RX7 is distinguished from other P2X family members by the high concentrations (mM range) of ATP required to activate it and its ability to form a large pore upon prolonged or repeated stimulation (North, R. A., Physiol. Rev. 2002, 82(4), 1013-67; Surprenant, A., Rassendren, F. et al., Science 1996, 272(5262), 735-8; Virginio, C, MacKenzie, A. et al., J.
- P2RX7 is present on many cell types, especially ones known to be involved in inflammatory and immune processes. This is reflected within both the periphery and the CNS as Lipopolysaccharide S (LPS) priming of monocytes and microglia followed by ATP stimulation has been shown to lead to the local release and processing of I L1 ⁇ and other family members including IL18 through a P2RX7 mediated mechanism. Indeed mice lacking the P2X7 receptor are unable to release ⁇ _1 ⁇ following LPS priming and ATP stimulation providing further evidence of its role in this pathway (Solle, M., Labasi, J. et al., J. Biol.
- LPS Lipopolysaccharide S
- P2RX7 is also expressed on epithelial and endothelial cells (Ferrari, D., Chiozzi, P. et al., Neuropharmacology 1997, 36(9), 1295-301 ; Wiley, J. S., Chen, J. R. et al., Ciba Found Symp. 1996, 198, 149-60 and 160-5; North, R. A., Physiol. Rev. 2002, 82(4), 1013-67).
- diseases associated with the central nervous system such as stroke or injury and diseases associated with neuro-degeneration and neuroinflammation such as Alzheimer's disease, Huntington's disease, epilepsy, Amyotrophic lateral sclerosis, acute spinal cord injury additionally to meningitis, sleep disorders, mood and anxiety disorders as well as chronic and neuropathic and inflammatory pain.
- peripheral inflammatory disorders and autoimmune diseases including but not limited to rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airways hyper-responsiveness, septic shock, bronchitis, glomerulonephritis, irritable bowel disease, skin injury, lung emphysema, Limb girdle dystrophy type 2B, fibrosis, Syndrome of synovitis Acne Pustulosis, atherosclerosis, burn injury, spinal cord injury, Hyperostosis Osteitis, Crohn's disease, ulcerative colitis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, trauma, meningitis, osteoporosis, burn injury, ischemic heart disease, and varicose veins and trauma, are all examples where the involvement of P2X7 channels has been implicated.
- P2X7 antagonists that can be efficiently used in treating neuropathic pain, chronic inflammatory pain, inflammation, and neurodegenerative conditions.
- the present invention relates to benzamide derivatives of formula (I),
- n 1 , 2, 3 or 4 (and preferably 2, 3 or 4);
- Y represents -C(R 7 R 8 )-, -N(R 9 )-, -0-, -S-, -S(0)-, or -S(0) 2 -;
- R 1 represents
- ⁇ a 6-membered heteroaryl group which is unsubstituted or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkyl- sulfonyl, (C 1 -C 4 )alkyl-amino and di-[(C 1 -C 4 )alkyl]-amino;
- R 2 represents chloro or methyl (and preferably chloro);
- R 3 represents hydrogen and R 4 represents hydroxy, hydroxy-(Ci-C 4 )alkyl, -CONH 2 or (Ci-C 4 )alkoxy (and preferably hydroxy, hydroxymethyl or methoxy); or
- R 3 represents (Ci-C 4 )alkyl or hydroxy-(Ci-C 4 )alkyl (and preferably methyl or hydroxymethyl) and R 4 represents hydrogen;
- R 5 represents hydrogen or fluoro
- R 6 represents hydrogen or fluoro
- R 7 and R 8 represent independently from each other hydrogen, fluoro, hydroxy or (Ci- C 4 )alkyl, with the proviso that R 8 is different from fluoro or hydroxy if R 7 represents hydroxy;
- R 7 and R 8 together represent an oxo-group
- R 9 represents hydrogen, (d-C 4 )alkyl, (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl-(C 1 - C 4 )alkyl, phenyl-(d-C 4 )alkyl, or phenyloxy-(C 1 -C 4 )alkyl;
- the compounds of formula (I) according to embodiment 1 may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond may be present in the (Z)- or (E)-configuration unless indicated otherwise.
- the compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
- the following paragraphs provide definitions of the various chemical moieties for the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader or narrower definition.
- alkyl refers to a straight or branched chain alkyl group containing one to four carbon atoms.
- (C x -C y )alkyl refers to an alkyl group as defined before containing x to y carbon atoms.
- a (CrC 4 )alkyl group contains from one to four carbon atoms.
- Representative examples of alkyl groups include methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec- butyl and ferf-butyl.
- (C 1 -C 4 )alkyl group is a substituent to a 5-membered heteroaryl group
- the term "(C 1 -C 4 )alkyl” means (C 1 -C 4 )alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec-butyl and ferf-butyl. Preferred is methyl.
- (Ci-C 4 )alkyl group is a substituent to a 6-membered heteroaryl group
- the term "(CrC 4 )alkyl” means (Ci-C 4 )alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec-butyl and ferf-butyl. Preferred is methyl.
- (CrC 4 )alkyl group is a substituent to a heterocyclyl group
- the term "(CrC 4 )alkyl” means (Ci-C 4 )alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec-butyl and ferf-butyl. Preferred is methyl.
- R 3 represents "(CrC 4 )alkyl”
- the term means (CrC 4 )alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec-butyl and ferf-butyl. Preferred is methyl.
- R 7 " or "R 8 " represent "(Ci-C 4 )alkyl”
- the term means (CrC 4 )alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec-butyl and ferf-butyl. Preferred is methyl.
- R 9 represents "(C 1 -C 4 )alkyl"
- the term means (C 1 -C 4 )alkyl groups as defined above. Examples of said groups are methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec-butyl and ferf-butyl. Preferred are methyl, ethyl, n-propyl and / ' so-butyl. More preferred are methyl and ethyl and most preferred is methyl.
- alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined above.
- (C x -C y )alkoxy refers to an alkoxy group as defined before containing x to y carbon atoms.
- a (CrC 4 )alkoxy group contains from one to four carbon atoms.
- Representative examples of alkoxy groups include methoxy, ethoxy, n-propoxy, / ' so-propoxy, n-butoxy, / ' so-butoxy, sec- butoxy and ferf-butoxy.
- (Ci-C 4 )alkoxy group is a substituent to a 6-membered heteroaryl group
- the term "(CrC 4 )alkoxy” means (CrC 4 )alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, / ' so-propoxy, n-butoxy, / ' so-butoxy, sec-butoxy and ferf- butoxy. Preferred is methoxy.
- R 4 represents "(CrC 4 )alkoxy"
- the term means (CrC 4 )alkoxy groups as defined above. Examples of said groups are methoxy, ethoxy, n-propoxy, / ' so-propoxy, n-butoxy, / ' so-butoxy, sec-butoxy and ferf-butoxy. Preferred is methoxy.
- alkylthio used alone or in combination, refers to an alkyl-S- group wherein the alkyl group is as defined above.
- (C x -C y )alkylthio (x and y each being an integer) refers to an alkylthio group as defined before containing x to y carbon atoms.
- a (CrC 4 )alkylthio group contains from one to four carbon atoms.
- alkylthio groups include methylthio, ethylthio, n-propylthio, / ' so-propylthio, n- butylthio, / ' so-butylthio, sec-butylthio and ferf-butylthio.
- (CrC 4 )alkylthio group is a substituent to a 6-membered heteroaryl group
- the term "(d-C 4 )alkylthio" means (CrC 4 )alkylthio groups as defined above. Examples of said groups are methylthio, ethylthio, n-propylthio, / ' so-propylthio, n-butylthio, / ' so-butylthio, sec- butylthio and ferf-butylthio. Preferred is methylthio.
- (Ci-C 4 )alkyl-amino refers to an amino group (-NH 2 ) in which one hydrogen atom has been replaced by a (CrC 4 )alkyl group as defined above.
- Representative examples of (Ci-C 4 )alkyl-amino groups include methylamino, ethylamino, n-propylamino, / ' so-propylamino, n-butylamino, / ' so-butylamino, sec-butylamino and ferf-butylamino. Preferred is methylamino.
- di-[(Ci-C 4 )alkyl]-amino refers to an amino group (-NH 2 ) in which each of the two hydrogen atoms has been replaced by a (C 1 -C 4 )alkyl group as defined above, wherein the two (C 1 -C 4 )alkyl groups may be the same or different.
- Representative examples of di-[(C 1 -C 4 )alkyl]-amino groups include, but are not limited to, dimethylamino, methyl-ethyl-amino and diethylamino. Preferred is dimethylamino.
- (Ci-C 4 )alkyl-sulfonyl used alone or in combination, refers to an (d-C 4 )alkyl- S(0) 2 - group wherein the (Ci-C 4 )alkyl group is as defined above.
- (Ci-C 4 )alkyl-sulfonyl groups include methyl-sulfonyl, ethyl-sulfonyl, n-propyl- sulfonyl, / ' so-propyl-sulfonyl, n-butyl-sulfonyl, / ' so-butyl-sulfonyl, sec-butyl-sulfonyl and tert- butyl-sulfonyl.
- Preferred is methyl-sulfonyl.
- hydroxy-(CrC 4 )alkyl refers to an alkyl group as defined before containing from one to four carbon atoms in which one hydrogen atom has been replaced with hydroxy.
- hydroxy-(Ci-C 4 )alkyl groups include, but are not limited to, hydroxy-methyl, 1 - hydroxy-ethyl, 2-hydroxy-ethyl, 1 -hydroxy-propyl, 2-hydroxy-propyl, 3-hydroxy-propyl, 1 - hydroxy-1 -methyl-ethyl and 2-hydroxy-1 -methyl-ethyl.
- R 3 represents "hydroxy-(C 1 -C 4 )alkyl"
- the term means hydroxy-(C 1 -C 4 )alkyl groups as defined above. Examples of said groups include, but are not limited to, hydroxy- methyl, 1 -hydroxy-ethyl, 2-hydroxy-ethyl, 1 -hydroxy-propyl, 2-hydroxy-propyl, 3-hydroxy- propyl, 1 -hydroxy-1 -methyl-ethyl and 2-hydroxy-1 -methyl-ethyl. Preferred is hydroxy- methyl.
- R 4 represents "hydroxy-(CrC 4 )alkyl"
- the term means hydroxy-(Ci-C 4 )alkyl groups as defined above. Examples of said groups include, but are not limited to, hydroxy- methyl, 1 -hydroxy-ethyl, 2-hydroxy-ethyl, 1 -hydroxy-propyl, 2-hydroxy-propyl, 3-hydroxy- propyl, 1 -hydroxy-1 -methyl-ethyl and 2-hydroxy-1 -methyl-ethyl. Preferred is hydroxy- methyl.
- (Ci-C2)alkoxy-(CrC 4 )alkyl refers to an alkyl group as defined before containing from one to four carbon atoms in which one hydrogen atom has been replaced with (d- C 2 )alkoxy as defined before.
- Examples of (Ci-C 2 )alkoxy-(Ci-C 4 )alkyl groups include, but are not limited to, methoxy-methyl, ethoxy-methyl, 1 -methoxy-ethyl, 1 -ethoxy-ethyl, 2- methoxy-ethyl, 2-ethoxy-ethyl, 1-methoxy-propyl, 1-ethoxy-propyl, 2-methoxy-propyl, 2- ethoxy-propyl, 3-methoxy-propyl, 3-ethoxy-propyl, 1 -methoxy-1 -methyl-ethyl, 1-ethoxy-1 - methyl-ethyl, 2-methoxy-1 -methyl-ethyl and 2-ethoxy-1 -methyl-ethyl.
- (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl group is a substituent to a heterocyclyl group
- the term "(C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl” means (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl groups as defined above.
- Examples of said groups include, but are not limited to, methoxy-methyl, ethoxy- methyl, 1 -methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 1-methoxy- propyl, 1 -ethoxy-propyl, 2-methoxy-propyl, 2-ethoxy-propyl, 3-methoxy-propyl, 3-ethoxy- propyl, 1 -methoxy-1 -methyl-ethyl, 1 -ethoxy-1 -methyl-ethyl, 2-methoxy-1 -methyl-ethyl and 2-ethoxy-1 -methyl-ethyl.
- Preferred are 2-methoxy-ethyl and 2-ethoxy-ethyl; and most preferred is 2-methoxy-ethyl.
- R 9 represents "(Ci-C 2 )alkoxy-(Ci-C 4 )alkyl" the term means (Ci-C 2 )alkoxy-(Ci- C 4 )alkyl groups as defined above.
- said groups include, but are not limited to, methoxy-methyl, ethoxy-methyl, 1-methoxy-ethyl, 1-ethoxy-ethyl, 2-methoxy-ethyl, 2- ethoxy-ethyl, 1 -methoxy-propyl, 1 -ethoxy-propyl, 2-methoxy-propyl, 2-ethoxy-propyl, 3- methoxy-propyl, 3-ethoxy-propyl, 1-methoxy-1 -methyl-ethyl, 1 -ethoxy-1 -methyl-ethyl, 2- methoxy-1 -methyl-ethyl and 2-ethoxy-1 -methyl-ethyl.
- (C 3 -C 6 )cycloalkyl used alone or in combination, means a cycloalkyl group with 3 to 6 carbon atoms.
- Examples of (C 3 -C 6 )cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- (C 3 -C 6 )cycloalkyl-(C 1 -C 4 )alkyl refers to an alkyl group as defined before containing from one to four carbon atoms in which one hydrogen atom has been replaced with (C 3 -C 6 )cycloalkyl as defined before.
- Examples of (C 3 -C 6 )cycloalkyl-(Ci-C 4 )alkyl groups include, but are not limited to, cyclopropyl-methyl, cyclobutyl-methyl, cyclopentyl- methyl, cyclohexyl-methyl, 1 -cyclopropyl-ethyl, 1-cyclobutyl-ethyl, 1 -cyclopentyl-ethyl, 1 - cyclohexyl-ethyl, 2-cyclopropyl-ethyl, 2-cyclobutyl-ethyl, 2-cyclopentyl-ethyl, 2-cyclohexyl- ethyl, 3-cyclopropyl-propyl, 3-cyclobutyl-propyl, 3-cyclopentyl-propyl and 3-cyclohexyl- propyl.
- phenyl-(CrC 4 )alkyl refers to an alkyl group as defined before containing from one to four carbon atoms in which one hydrogen atom has been replaced with phenyl.
- phenyl-(d-C 4 )alkyl groups include, but are not limited to, phenyl-methyl (benzyl), 1-phenyl-ethyl, 2-phenyl-ethyl, 1 -phenyl-propyl, 2-phenyl-propyl, 3-phenyl-propyl, 1-phenyl-1 -methyl-ethyl and 2-phenyl-1-methyl-ethyl.
- Preferred are benzyl and 2-phenyl- ethyl and most preferred is benzyl.
- phenyloxy-(C 1 -C 4 )alkyl refers to an alkyl group as defined before containing from one to four carbon atoms in which one hydrogen atom has been replaced with phenyloxy (or in an alternative phrase: phenoxy).
- phenyloxy-(C 1 -C 4 )alkyl groups include, but are not limited to, phenyloxy-methyl, 1 -phenyloxy-ethyl, 2-phenyloxy- ethyl, 1-phenyloxy-propyl, 2-phenyloxy-propyl, 3-phenyloxy-propyl, 1-phenyloxy-1 -methyl- ethyl and 2-phenyloxy-1 -methyl-ethyl.
- phenyloxy-methyl and 2-phenyloxy- ethyl are preferred and most preferred is 2-phenyloxy-ethyl.
- halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro and most preferably fluoro.
- 5-membered heteroaryl used alone or in combination, means a 5-membered monocyclic aromatic ring containing 1 , 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulphur (and preferably containing 1 or 2 nitrogen atoms).
- Examples of such 5-membered heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl and triazolyl.
- pyrrolyl imidazolyl and pyrazolyl and most preferred is pyrazolyl (notably pyrazol-3-yl).
- the above-mentioned 5-membered heteroaryl groups are unsubstituted or mono- or di-substituted with (C 1 -C 4 )alkyl (preferably methyl).
- a preferred example of such unsubstituted or mono- or di-substituted 5-membered heteroaryl groups is 2-methyl-2H- pyrazol-3-yl.
- 6-membered heteroaryl used alone or in combination, means a 6-membered monocyclic aromatic ring containing 1 or 2 nitrogen atoms.
- 6- membered heteroaryl groups are pyridyl, pyrimidyl, pyridazinyl and pyrazinyl. Preferred is pyridyl.
- the above-mentioned 6-membered heteroaryl groups are unsubstituted or mono- or di-substituted, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, (Ci-C 4 )alkylthio, (Ci- C 4 )alkyl-sulfonyl, (C-i-C 4 )alkyl-amino and di-[(C-i-C 4 )alkyl]-amino.
- the substituents are independently selected from the group consisting of halogen (notably fluoro or chloro), hydroxy and (Ci-C 4 )alkoxy (notably methoxy).
- halogen notably fluoro or chloro
- hydroxy and (Ci-C 4 )alkoxy notably methoxy.
- 6-membered heteroaryl groups are pyridin-2-yl, 4-fluoro-pyridin-2-yl, 6-fl uoro-py rid in-2-yl , 6-chloro-pyridin-2-yl, 6-hydroxy-pyridin-2-yl, 6- methoxy-pyridin-2-yl, 6-methylamino-pyridin-2-yl, 6-dimethylamino-pyridin-2-yl, pyridin-3- yl, pyridin-4-yl, 2-chloro-pyridin-4-yl, pyrimidin-2-yl, 4-hydroxy-pyrimidin-2-yl, 4-methoxy
- pyridin-2-yl 4-fluoro-pyridin-2-yl, 6-fluoro- pyridin-2-yl, 6-hydroxy-pyridin-2-yl, 6-methoxy-pyridin-2-yl and 2-hydroxy-pyrimidin-4-yl.
- 6-membered heteroaryl groups may be present in different tautomeric forms (e.g. in case said heteroaryl groups are substituted with at least one hydroxy group). Examples of such tautomers are given in the formulas below:
- tautomers are within the scope of the present invention. Even though one tautomer may be described, the present invention includes all tautomers of the present compounds. Especially, any given chemical name does represent not only the specifically named chemical compound but also the different tautomeric forms thereof. In solution, tautomers exist usually as mixtures of different tautomeric forms; in the solid state usually one tautomeric form predominates.
- heterocyclyl used alone or in combination, means a 6-membered monocyclic ring containing 1 or 2 double bonds (preferably 2 double bonds) and 1 or 2 nitrogen atoms, wherein one or two carbon atoms adjacent to said nitrogen atoms are substituted with an oxo-group.
- the heterocyclyl group may be attached to the rest of the molecule via a nitrogen atom or a carbon atom.
- a heterocyclyl group representing R 1 is preferably attached to the rest of the molecule via a nitrogen atom.
- a heterocyclyl group representing R 1 is preferably attached to the rest of the molecule via a carbon atom.
- heterocyclyl groups are unsubstituted or mono- or di- substituted with (C 1 -C 4 )alkyl or (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl (and preferably unsubstituted or mono-substituted with (C 1 -C 4 )alkyl).
- Preferred heterocyclyl groups are selected from the group of radicals as depicted in groups G1 and/or G2 below:
- G1 heterocyclyl groups, attached to the rest of the molecule via a nitrogen atom (as depicted by the arrow):
- G2 heterocyclyl groups, attached to the rest of the molecule via a carbon atom (; depicted by the arrow):
- a further embodiment of the invention relates to benzamide derivatives according to embodiment 1 ), wherein
- n 1 , 2, 3 or 4 (and preferably 2, 3 or 4);
- Y represents -C(R 7 R 8 )-, -N(R 9 )-, -0-, -S-, -S(O)-, or -S(0) 2 -;
- R 1 represents • a 5-membered heteroaryl group which is unsubstituted or mono- or di-substituted with (Ci-C 4 )alkyl;
- R 2 represents chloro or methyl (and preferably chloro);
- R 3 represents hydrogen and R 4 represents hydroxy, hydroxy-(Ci-C 4 )alkyl, -CONH 2 or (Ci-C 4 )alkoxy (and preferably hydroxy, hydroxymethyl or methoxy); or
- R 3 represents (Ci-C 4 )alkyl or hydroxy-(Ci-C 4 )alkyl (and preferably methyl or hydroxymethyl) and R 4 represents hydrogen;
- R 5 represents hydrogen or fluoro
- R 6 represents hydrogen or fluoro
- R 7 and R 8 represent independently from each other hydrogen or fluoro; or R 7 and R 8 together represent an oxo-group;
- R 9 represents hydrogen, (Ci-C 4 )alkyl, (Ci-C 2 )alkoxy-(Ci-C 4 )alkyl, (C 3 -C 6 )cycloalkyl-(Ci- C 4 )alkyl, phenyl-(Ci-C 4 )alkyl, or phenyloxy-(Ci-C 4 )alkyl;
- a further embodiment of the invention relates to benzamide derivatives according to embodiment 1 ), wherein
- n 2, 3 or 4;
- Y represents -C(R 7 R 8 )-, -N(R 9 )-, -0-, or -S-;
- R 1 represents a 6-membered heteroaryl group which is unsubstituted or mono- or di- substituted, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, (Ci-C 4 )alkoxy, (Ci-C 4 )alkylthio, (Ci-C 4 )alkyl-sulfonyl, (Ci-C 4 )alkyl- amino and di-[(Ci-C 4 )alkyl]-amino (preferably halogen, hydroxy and (Ci-C 4 )alkoxy);
- R 2 represents chloro;
- R 3 represents hydrogen and R 4 represents hydroxy or hydroxy-(Ci-C 4 )alkyl (and preferably hydroxy or hydroxymethyl); or
- R 3 represents (Ci-C 4 )alkyl or hydroxy-(Ci-C 4 )alkyl (and preferably methyl or hydroxymethyl) and R 4 represents hydrogen;
- R 5 represents hydrogen or fluoro
- R 6 represents hydrogen or fluoro
- R 7 and R 8 represent independently from each other hydrogen, fluoro, hydroxy or (Ci- C 4 )alkyl, with the proviso that R 8 is different from fluoro or hydroxy if R 7 represents hydroxy;
- R 7 and R 8 together represent an oxo-group
- R 9 represents hydrogen, (d-C 4 )alkyl, (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl-(C 1 - C 4 )alkyl, phenyl-(d-C 4 )alkyl, or phenyloxy-(C 1 -C 4 )alkyl (and preferably hydrogen or (d- C 4 )alkyl);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) or 2), wherein
- n 2, 3 or 4;
- Y represents -C(R 7 R 8 )-, -N(R 9 )-, -0-, or -S-;
- R 1 represents a 6-membered heteroaryl group which is unsubstituted or mono- or di- substituted, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, (Ci-C 4 )alkoxy, (Ci-C 4 )alkylthio, (Ci-C 4 )alkyl-sulfonyl, (Ci-C 4 )alkyl- amino and di-[(Ci-C 4 )alkyl]-amino (preferably halogen, hydroxy and (Ci-C 4 )alkoxy);
- R 2 represents chloro
- R 3 represents hydrogen and R 4 represents hydroxy or hydroxy-(Ci-C 4 )alkyl (and preferably hydroxy or hydroxymethyl); or
- R 3 represents (C 1 -C 4 )alkyl or hydroxy-(C 1 -C 4 )alkyl (and preferably methyl or hydroxymethyl) and R 4 represents hydrogen;
- R 5 represents hydrogen or fluoro
- R 6 represents hydrogen or fluoro
- R 7 and R 8 represent independently from each other hydrogen or fluoro; or R 7 and R 8 together represent an oxo-group;
- R 9 represents hydrogen, (d-C 4 )alkyl, (Ci-C 2 )alkoxy-(Ci-C 4 )alkyl, (C 3 -C 6 )cycloalkyl-(Ci- C 4 )alkyl, phenyl-(Ci-C 4 )alkyl, or phenyloxy-(Ci-C 4 )alkyl (and preferably hydrogen or (Ci- C 4 )alkyl);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) or 2), wherein
- n 1 , 2, 3 or 4 (and preferably 2, 3 or 4);
- Y represents -C(R 7 R 8 )-, -N(R 9 )-, -0-, -S-, -S(O)-, or -S(0) 2 -;
- R 1 represents
- R 2 represents chloro or methyl (and preferably chloro);
- R 3 represents hydrogen and R 4 represents hydroxy, hydroxy-(C 1 -C 4 )alkyl, -CONH 2 or (C 1 -C 4 )alkoxy (and preferably hydroxy, hydroxymethyl or methoxy);
- R 5 represents hydrogen or fluoro
- R 6 represents hydrogen or fluoro
- R 7 and R 8 represent independently from each other hydrogen or fluoro; or R 7 and R 8 together represent an oxo-group; and R 9 represents hydrogen, (d-C 4 )alkyl, (Ci-C 2 )alkoxy-(Ci-C 4 )alkyl, (C 3 -C 6 )cycloalkyl-(Ci- C 4 )alkyl, phenyl-(Ci-C 4 )alkyl, or phenyloxy-(Ci-C 4 )alkyl;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) or 2), wherein
- n 2, 3 or 4;
- Y represents -C(R 7 R 8 )-, -N(R 9 )-, -0-, or -S-;
- R 1 represents a 6-membered heteroaryl group which is unsubstituted or mono- or di- substituted (preferably unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, hydroxy, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkyl-sulfonyl, (C 1 -C 4 )alkyl-amino and di-[(C 1 -C 4 )alkyl]-amino (preferably halogen, hydroxy and (C 1 -C 4 )alkoxy);
- R 2 represents chloro
- R 3 represents hydrogen and R 4 represents hydroxy or hydroxy-(Ci-C 4 )alkyl (and preferably hydroxy or hydroxymethyl);
- R 5 represents hydrogen or fluoro
- R 6 represents hydrogen or fluoro
- R 7 and R 8 represent independently from each other hydrogen or fluoro; or R 7 and R 8 together represent an oxo-group;
- R 9 represents hydrogen, (Ci-C 4 )alkyl, (Ci-C 2 )alkoxy-(Ci-C 4 )alkyl, (C 3 -C 6 )cycloalkyl-(Ci- C 4 )alkyl, phenyl-(Ci-C 4 )alkyl, or phenyloxy-(Ci-C 4 )alkyl (and preferably hydrogen or (Ci- C 4 )alkyl);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) or 2), wherein
- n 1 , 2, 3 or 4 (and preferably 2, 3 or 4);
- Y represents -C(R 7 R 8 )-, -N(R 9 )-, -0-, or -S- (preferably -N(R 9 )-);
- R 1 represents a 6-membered heteroaryl group which is unsubstituted or mono- or di- substituted, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, (Ci-C 4 )alkylthio, (Ci-C 4 )alkyl-sulfonyl, (Ci-C 4 )alkyl-amino and di-[(Ci-C 4 )alkyl]-amino (preferably halogen, hydroxy and (Ci- C 4 )alkylthio);
- R 2 represents chloro
- R 3 represents (Ci-C 4 )alkyl or hydroxy-(Ci-C 4 )alkyl (and preferably methyl or hydroxymethyl) and R 4 represents hydrogen;
- R 5 represents hydrogen or fluoro (preferably hydrogen);
- R 6 represents hydrogen or fluoro (preferably hydrogen);
- R 7 and R 8 represent independently from each other hydrogen or fluoro; or R 7 and R 8 together represent an oxo-group;
- R 9 represents hydrogen, (d-C 4 )alkyl, (C 1 -C 2 )alkoxy-(C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl-(C 1 - C 4 )alkyl, phenyl-(d-C 4 )alkyl, or phenyloxy-(C 1 -C 4 )alkyl (preferably hydrogen or (d- C 4 )alkyl);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) or 2), wherein
- n 2;
- Y represents -N(R 9 )-
- R 1 represents a 6-membered heteroaryl group which is unsubstituted or mono- or di- substituted (preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, hydroxy and (Ci-C 4 )alkylthio (preferably halogen and hydroxy);
- R 2 represents chloro
- R 3 represents (Ci-C 4 )alkyl or hydroxy-(Ci-C 4 )alkyl (and preferably methyl or hydroxymethyl) and R 4 represents hydrogen;
- R 5 represents hydrogen
- R 6 represents hydrogen; and R 9 represents hydrogen or (Ci-C 4 )alkyl (and preferably hydrogen or methyl);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), wherein
- n 2, 3 or 4 (preferably 2 or 3 and most preferably 2);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), wherein
- n 3 or 4;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) or 10), wherein
- Y represents -C(R 7 R 8 )-, -N(R 9 )-, -0-, or -S-;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) or 10), wherein
- Y represents -C(R 7 R 8 )-, -0-, or -S-;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) or 10), wherein
- Y represents -C(R 7 R 8 )-
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 10), wherein
- Y represents -N(R 9 )-
- a further embodiment of the invention relates to benzamide derivatives accord any one of embodiments 1 ) to 7), 9) or 10), wherein Y represents -0-;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) or 10), wherein
- Y represents -S-, -S(O)-, or -S(0) 2 - (preferably -S-);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ), 2), 5) or 9) to 16), wherein
- R 1 represents
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ), 2), 5) or 9) to 16), wherein
- R 1 represents
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ), 2), 5) or 9) to 16), wherein R 1 represents a 5-membered heteroaryl group which is unsubstituted or mono- or di- substituted (preferably mono-substituted) with (Ci-C 4 )alkyl (preferably methyl);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 16), wherein
- R 1 represents a 6-membered heteroaryl group which is unsubstituted or mono- or di- substituted, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, (Ci-C 4 )alkyl, (Ci-C 4 )alkoxy, (Ci-C 4 )alkylthio, (Ci-C 4 )alkyl-sulfonyl, (Ci-C 4 )alkyl-amino and di-[(C-i-C 4 )alkyl]-amino (preferably from halogen, hydroxy and methoxy; and most preferably from halogen and hydroxy);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 16), wherein
- R 1 represents a 6-membered heteroaryl group which is unsubstituted or mono-substituted (preferably mono-substituted), wherein the substituents are independently selected from the group consisting of halogen, hydroxy and (Ci-C 4 )alkoxy (preferably from fluoro, chloro, hydroxy and methoxy; and most preferably from fluoro, chloro and hydroxy);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ), 2), 5) or 9) to 16), wherein
- R 1 represents a phenyl group which is unsubstituted or mono- or di-substituted with halogen (preferably fluoro);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ), 2), 5) or 9) to 16), wherein
- R 1 represents a heterocyclyl group which is unsubstituted or mono- or di-substituted (preferably unsubstituted or mono-substituted) with (Ci-C 4 )alkyl or (d-C 2 )alkoxy-(Ci- C 4 )alkyl;
- a further embodiment of the invention relates to benzamide derivatives according to embodiment 23), wherein the heterocyclyl group is selected from groups G1 and/or G2;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 24), wherein
- R 2 represents chloro
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ), 2), 5) or 9) to 24), wherein
- R 2 represents methyl
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ), 2), 5) or 9) to 26), wherein
- R 3 represents hydrogen and R 4 represents hydroxy, hydroxy-(C 1 -C 4 )alkyl, -CONH 2 or (C 1 -C 4 )alkoxy (and preferably hydroxy, hydroxymethyl or methoxy);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 6) or 9) to 26), wherein
- R 3 represents hydrogen and R 4 represents hydroxy or hydroxy-(Ci-C 4 )alkyl (and preferably hydroxy or hydroxymethyl);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 6) or 9) to 26), wherein
- R 3 represents hydrogen and R 4 represents hydroxy
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 6) or 9) to 26), wherein
- R 3 represents hydrogen and R 4 represents hydroxy-(Ci-C 4 )alkyl (preferably hydroxymethyl);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 4) or 7) to 26), wherein
- R 3 represents (Ci-C 4 )alkyl or hydroxy-(Ci-C 4 )alkyl (and preferably methyl or hydroxymethyl) and R 4 represents hydrogen;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 4) or 7) to 26), wherein
- R 3 represents (Ci-C 4 )alkyl (preferably methyl) and R 4 represents hydrogen;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 4) or 7) to 26), wherein
- R 3 represents hydroxy-(C 1 -C 4 )alkyl (preferably hydroxymethyl) and R 4 represents hydrogen;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 33), wherein
- R 5 and R 6 both represent hydrogen
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7) or 9) to 33), wherein
- R 5 and R 6 both represent fluoro
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7) or 9) to 33), wherein
- R 5 represents hydrogen and R 6 represents fluoro
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ), 3) or 9) to 36), wherein R 7 and R 8 represent independently from each other hydrogen, fluoro, hydroxy or (Ci- C 4 )alkyl, with the proviso that R 8 is different from fluoro or hydroxy if R 7 represents hydroxy;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7) or 9) to 36), wherein
- R 7 and R 8 represent independently from each other hydrogen or fluoro
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7) or 9) to 36), wherein
- R 7 and R 8 both represent hydrogen
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7) or 9) to 36), wherein
- R 7 and R 8 both represent fluoro
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7) or 9) to 36), wherein
- R 7 represents hydrogen and R 8 represents fluoro
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ), 3) or 9) to 36), wherein
- R 7 represents hydrogen or (Ci-C 4 )alkyl (preferably (Ci-C 4 )alkyl) and R 8 represents hydroxy;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7) or 9) to 36), wherein
- R 7 and R 8 together represent an oxo-group
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7) or 9) to 43), wherein
- R 9 represents hydrogen, methyl, ethyl, n-propyl, / ' so-propyl, / ' so-butyl, 2-methoxy-ethyl, cyclopentyl-methyl, benzyl, or 2-phenyloxy-ethyl;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 43), wherein
- R 9 represents hydrogen or (d-C 4 )alkyl (preferably methyl, ethyl, n-propyl, / ' so-propyl or /so-butyl);
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) to 38), 41 ), 42) or 44) to 45), wherein,
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) to 38), 41 ), 42) or 44) to 45), wherein,
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 4), 7) to 26) or 31 ) to 47), wherein
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 4), 7) to 26) or 31 ) to 47), wherein
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) to 33) or 35) to 49), wherein, in case n is different from 2 and at least one of R 5 and R 6 is different from hydrogen, the carbon atom, which is attached to the group R 4 , has (S)-configuration;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) to 33) or 35) to 49), wherein,
- n is different from 2 and at least one of R 5 and R 6 is different from hydrogen, the carbon atom, which is attached to the group R 4 , has (R)-configuration;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) to 33) or 35) to 51 ), wherein,
- n is different from 2 and one of R 5 or R 6 represents fluoro, the carbon atom, which is attached to the groups R 5 and R 6 , has (S)-configuration;
- a further embodiment of the invention relates to benzamide derivatives according to any one of embodiments 1 ) to 7), 9) to 33) or 35) to 51 ), wherein,
- n is different from 2 and one of R 5 or R 6 represents fluoro, the carbon atom, which is attached to the groups R 5 and R 6 , has (R)-configuration;
- Preferred compounds of formula (I) as defined in embodiment 1 ) are selected from the group consisting of:
- stereogenic center which is not specifically assigned, may be in absolute (R)- or absolute (S)-configuration.
- stereogenic center which is not specifically assigned, may be in absolute (R)- or absolute (S)-configuration.
- the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
- Isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
- the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
- salts refers to non-toxic, inorganic or organic acid and/or base addition salts, Lit. e.g. "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217. Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.
- compounds of formula (I) are suitable for use as medicaments.
- compounds of formula (I) modulate the P2X 7 receptor, i.e. they act as P2X 7 receptor antagonists, and are useful for the prevention or treatment of diseases which are associated with the activation of the P2X 7 receptor such as pain; neurodegenerative and neuroinflammatory diseases; bone and joint diseases; obstructive diseases of the airways; cardiovascular diseases; eye diseases; skin diseases; abdominal and gastrointestinal tract diseases; genitourinary diseases; cancer; other auto-immune and allergic disorders; and other disorders with an inflammatory or immunological component.
- Pain refers to acute pain; chronic pain; pain associated with sprains and strains; chronic articular pain; pain associated with rheumatic fever; musculoskeletal pain; lower back and neck pain; inflammatory pain; neuropathic pain; visceral pain; pain associated with influenza or other viral infections; pain associated with cancer and tumor invasion; joint and bone pain; atypical facial pain; pain associated with migraine, toothache and dysmenorrhea; headache including tension headache and cluster headaches; pain associated with myocardial ischemia; pain associated with functional bowel disorders; sympathetically maintained pain; myositis; pain associated with cancer chemotherapy; and post operative pain.
- Neuropathic pain includes especially diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV-related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
- neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
- normally non-painful sensations such as "pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
- Chronic articular pain conditions include especially rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
- Pain associated with functional bowel disorders includes especially non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome.
- Neurodegenerative and neuro- inflammatory diseases include Alzheimer's disease and other dementing disorders including, but not limited to, Creutzfeldt-Jakob disease (CJD) and new variant Creutzfeldt-Jakob disease (nvCJD); Amyotrophic lateral sclerosis, amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; Huntington's disease; Lewy Body dementia; and Parkinson's disease.
- CJD Creutzfeldt-Jakob disease
- nvCJD new variant Creutzfeldt-Jakob disease
- cerebral atherosclerosis and vasculitis cerebral atherosclerosis and vasculitis
- temporal arteritis myasthenia gravis
- Huntington's disease Lewy Body dementia
- Bone and joint diseases include arthritides such as rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy; intervertebral disc degeneration; temporomandibular joint degeneration; bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis; polychondritis; scleroderma; mixed connective tissue disorder; spondyloarthropathies; periodontal disease such as periodontitis; arthritides associated with or including osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis; Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and un
- Obstructive diseases of the airways include asthma, including bronchial, allergic, intrinsic, and extrinsic asthma, exercise-induced, drug- induced (including aspirin and NSAID-induced) and dust- induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper- responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection
- COPD chronic obstructive pulmonary disease
- bronchitis including infectious and eosinophilic bronchitis; emphysema; bronchie
- Cardiovascular diseases include atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis; inflammatory and autoimmune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; and disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins.
- Eye diseases include blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; and infections of the eyes including viral , fungal, and bacterial infections.
- the compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of skin diseases.
- Skin diseases include psoriasis, skin burn, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Web
- the compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of abdominal and gastrointestinal tract diseases.
- Abdominal and gastrointestinal tract diseases include hepatitis, including autoimmune, alcoholic and viral hepatitis; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; non-inflammatory diarrhea; glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; Coeliac disease, irritable bowel disease/syndrome, and food-related allergies which may have effects remote from the gut, for example migraine, rhinitis or eczema; allograft rejection including acute and chronic allograft rejection following, for example, transplantation of kidney,
- the compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of genitourinary diseases.
- Genitourinary diseases include nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; and erectile dysfunction, both male and female.
- the compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of cancer.
- the treatment of cancer includes the treatment of brain tumors, prostate, lung, breast, ovarian, bowel and colon, stomach, pancreatic, skin and bone marrow (including leukaemias) and lymphoproliferative systems, such as non-Hodgkin's and Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumor recurrences, and paraneoplastic syndromes.
- the compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of other auto-immune and allergic disorders.
- Other auto-immune and allergic disorders include Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-lgE syndrome, and antiphospholipid syndrome.
- the compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of other disorders with an inflammatory or immunological component.
- Other disorders with an inflammatory or immunological component include acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and paraneoplastic syndromes.
- AIDS acquired immune deficiency syndrome
- leprosy leprosy
- Sezary syndrome Sezary syndrome
- paraneoplastic syndromes paraneoplastic syndromes.
- the compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of mood, sleep and anxiety disorders.
- the compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof, are suitable for the prevention or treatment of injury induced trauma and spinal cord injury.
- compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of diseases selected from one, several or all of the following groups of diseases and disorders:
- Pain wherein pain refers to acute pain; chronic pain; pain associated with sprains and strains; chronic articular pain; pain associated with rheumatic fever; musculoskeletal pain; lower back and neck pain; inflammatory pain; neuropathic pain; visceral pain; pain associated with influenza or other viral infections; pain associated with cancer and tumor invasion; joint and bone pain; atypical facial pain; pain associated with migraine, toothache and dysmenorrhea; headache including tension headache and cluster headaches; pain associated with myocardial ischemia; pain associated with functional bowel disorders; sympathetically maintained pain; myositis; pain associated with cancer chemotherapy; and post operative pain;
- Neuropathic pain includes especially diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV- related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
- neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways
- Chronic articular pain conditions include especially rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis;
- Pain associated with functional bowel disorders includes especially non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome;
- Neurodegenerative and neuro-inflammatory diseases such as Alzheimer's disease and other dementing disorders including, but not limited to, Creutzfeldt-Jakob disease (CJD) and new variant Creutzfeldt-Jakob disease (nvCJD); amyloidosis; Amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; Huntington's disease; Lewy Body dementia; and Parkinson's disease;
- CJD Creutzfeldt-Jakob disease
- nvCJD new variant Creutzfeldt-Jakob disease
- amyloidosis amyloidosis
- Amyotrophic lateral sclerosis multiple sclerosis and other demyelinating syndromes
- cerebral atherosclerosis and vasculitis cerebral atherosclerosis and vasculitis
- temporal arteritis myasthenia gravis
- Huntington's disease
- Bone and joint diseases such as arthritides such as rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy; intervertebral disc degeneration; temporomandibular joint degeneration; bone remodelling disease such as osteoporosis, Paget's disease or osteonecrosis; polychondritis; scleroderma; mixed connective tissue disorder; spondyloarthropathies; periodontal disease such as periodontitis; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositits and polymyositis; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic
- Obstructive diseases of the airways such as chronic obstructive pulmonary disease (COPD); cystic fibrosis; lung emphysema; sarcoidosis; farmer's lung and related diseases; lung fibrosis, including fibrosis complicating tuberculosis; and chronic cough associated with inflammatory and secretory conditions of the airways;
- COPD chronic obstructive pulmonary disease
- cystic fibrosis fibrosis
- lung emphysema sarcoidosis
- farmer's lung and related diseases lung fibrosis, including fibrosis complicating tuberculosis
- chronic cough associated with inflammatory and secretory conditions of the airways such as chronic obstructive pulmonary disease (COPD); cystic fibrosis; lung emphysema; sarcoidosis; farmer's lung and related diseases; lung fibrosis, including fibrosis complicating tuberculosis; and chronic cough associated with inflammatory and
- Cardiovascular diseases such as inflammatory and auto-immune cardiomyopathies
- Eye diseases such as degenerative or inflammatory disorders affecting the retina
- Skin diseases such as psoriasis, skin burn, atopic dermatitis, contact dermatitis or other eczematous dermatoses; and discoid lupus erythematosus;
- Abdominal and gastrointestinal tract diseases such as fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic; Crohn's disease; colitis including ulcerative colitis; and irritable bowel disease/syndrome;
- Genitourinary diseases such as nephritis including interstitial and glomerulonephritis; nephrotic syndrome; and cystitis including acute and chronic (interstitial) cystitis; and
- compounds of formula (I) according to any one of embodiments 1 ) to 55), or pharmaceutically acceptable salts thereof are suitable for the prevention or treatment of diseases selected from one, several or all of the following groups of diseases and disorders:
- Pain wherein pain refers to acute pain; chronic pain; pain associated with sprains and strains; chronic articular pain; pain associated with rheumatic fever; musculoskeletal pain (preferred); lower back and neck pain; inflammatory pain; neuropathic pain (preferred); visceral pain; pain associated with influenza or other viral infections; pain associated with cancer and tumor invasion; joint and bone pain; atypical facial pain; pain associated with migraine, toothache and dysmenorrhea; headache including tension headache and cluster headaches; pain associated with myocardial ischemia; pain associated with functional bowel disorders; sympathetically maintained pain; myositis; pain associated with cancer chemotherapy; and post operative pain;
- Neuropathic pain includes especially diabetic neuropathy, sciatica, non-specific lower back pain, trigeminal neuralgia, multiple sclerosis pain, fibromyalgia, HIV- related neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and pain resulting from physical trauma, amputation, phantom limb syndrome, spinal surgery, cancer, toxins or chronic inflammatory conditions.
- neuropathic pain conditions include pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia);
- normally non-painful sensations such as "pins and needles” (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static, thermal or cold allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia);
- Chronic articular pain conditions include especially rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis;
- Pain associated with functional bowel disorders includes especially non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome;
- COPD Chronic obstructive pulmonary disease
- the invention also relates to the use of a compound of formula (I) according to any one of embodiments 1 ) to 55) for the preparation of pharmaceutical compositions for the treatment and/or prophylaxis of the above-mentioned diseases.
- the present invention also relates to pharmaceutically acceptable salts and to pharmaceutical compositions and formulations of compounds of formula (I) according to any one of embodiments 1 ) to 55).
- a pharmaceutical composition according to the present invention contains at least one compound of formula (I) according to any one of embodiments 1 ) to 55) (or a pharmaceutically acceptable salt thereof) as the active agent and optionally carriers and/or diluents and/or adjuvants.
- the compounds of formula (I) according to any one of embodiments 1 ) to 55) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).
- compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
- the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) according to any one of embodiments 1 ) to 55), or a pharmaceutically acceptable salt thereof.
- any reference to a compound of formula (I) in this text is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
- the preferences indicated for the compounds of formula (I) of course apply mutatis mutandis to the salts and pharmaceutically acceptable salts of the compounds of formula (I).
- the term “about” (or alternatively “around”) placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
- the term “about” (or alternatively “around”) placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C.
- room temperature rt as used herein refers to a temperature of about 25°C.
- the compounds of Formula (I) can be manufactured by the methods given below, by the methods given in the Examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.
- the generic groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , n and Y might be incompatible with the assembly illustrated in the schemes below and will therefore require the use of protecting groups (PG).
- protecting groups is well known in the art (see for example "Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups are as necessary in place.
- the compounds of formula V can be prepared (Scheme 1 ) by a Buchwald-Hartwig type of reaction, using a commercially available iodide of formula VII (or a commercially available aniline of formula VIII, respectively) and an aniline of formula R 1 -NH 2 (or a halide, preferably an iodide of formula R 1 -X, respectively), in the presence of a suitable palladium catalyst such as palladium(ll) acetate or tris(dibenzylideneacetone) dipalladium, in the presence of a suitable ligand such as 2,2'-bis(diphenylphosphino)-1 , 1 '- binaphthalene or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, in the presence of a suitable base such as Cs 2 C0 3 or sodium phenoxide and heating in a suitable solvent such as dioxane at a temperature between 90°C and 120°C.
- the compounds of formula VI can be prepared (Scheme 1 ) by alkylation of a compound of formula V using an appropriate alkyl iodide or bromide of formula R 9 -X, in the presence of a suitable base such as Cs 2 C0 3 or potassium carbonate and in the presence of a suitable organic solvent such as DMF or THF, preferably at a temperature between RT and 60°C.
- a suitable base such as Cs 2 C0 3 or potassium carbonate
- a suitable organic solvent such as DMF or THF
- the compounds of formula III (or IV, respectively) can be prepared (Scheme 1 ) by hydrolysis of a compound of formula V (or VI, respectively) using standard conditions such as NaOH or LiOH in a mixture of water and a suitable organic solvent such as THF, MeOH or EtOH, preferably at a temperature between RT and 45°C.
- the compounds of formula la can be prepared (Scheme 1 ) by coupling an acid of formula III (or IV, respectively) with an amine of formula II using standard amide coupling reagents such as TBTU, EDC.HCI / HOBT, HATU, PyBOP or PyCloP in the presence of a suitable base such as NEt 3 or DIPEA and in a suitable solvent such as DCM, THF or DMF, preferably at a temperature between RT and 45°C.
- standard amide coupling reagents such as TBTU, EDC.HCI / HOBT, HATU, PyBOP or PyCloP
- a suitable base such as NEt 3 or DIPEA
- a suitable solvent such as DCM, THF or DMF
- the compounds of formula lb can be prepared (Scheme 1 ) by alkylation of a compound of formula la with an appropriate alkyl iodide or bromide of formula R 9 -X using standard conditions such as a suitable base (preferably Cs 2 C0 3 ) and a suitable organic solvent such as DMF or THF, preferably at a temperature between RT and 45°C.
- a suitable base preferably Cs 2 C0 3
- a suitable organic solvent such as DMF or THF
- the compounds of formula IX can be prepared (Scheme 2) by an aromatic nucleophilic substitution of a commercially available phenol or thiophenol, respectively of formula XI with a halide (preferably a bromide or iodide) of formula R 1 -X, in the presence of a suitable base such as Cs 2 C0 3 and heating in a suitable sovent such as DMSO at a temperature between 60°C and 1 10°C.
- a suitable base such as Cs 2 C0 3
- a suitable sovent such as DMSO
- the compounds of formula lc can be prepared (Scheme 2) by coupling an acid of formula IX with an amine of formula II using standard amide coupling conditions such as those already described for the synthesis of the compounds of formula la and lb (Scheme 1 ).
- the compounds of formula Id can be prepared (Scheme 2) by oxidation of a compound of formula lc, wherein Y represents S, using a suitable oxidating reagent such as 3- chloroperbenzoic acid in a suitable solvent such as DCM at a temperature around 0°C.
- the compounds of formula le can be prepared (Scheme 2) by oxidation of a compound of formula lc, wherein Y represents S, using a suitable oxidating reagent such as 3- chloroperbenzoic acid in a suitable solvent such as DCM at a temperature around RT.
- the compounds of formula XX can be prepared (Scheme 3) by bromination of a commercially available compound of formula XXI, wherein R 2 represents chloro, using a suitable brominating reagent such as N-bromosuccinimide in the presence of a radical initiator such as 2,2'-azobis(2-methylpropionitrile) and heating in a suitable solvent such as chlorobenzene at a temperature between 90 and 120°C.
- a suitable brominating reagent such as N-bromosuccinimide
- a radical initiator such as 2,2'-azobis(2-methylpropionitrile
- the compounds of formula XVIII can be prepared (Scheme 3) by coupling an acid of formula XX with an amine of formula II using standard amide coupling conditions such as EDC.HCI / HOBT, PyBOP in the presence of a suitable base such as DIPEA and in a suitable solvent such as DCM, preferably at a temperature between RT and 45°C. In such conditions, the consecutive substitution of the bromide atom in compound of formula XX with the 1 -oxy-benzotriazole group (-OBt) from HOBT is observed.
- standard amide coupling conditions such as EDC.HCI / HOBT, PyBOP
- a suitable base such as DIPEA
- a suitable solvent such as DCM
- a suitable base such as potassium carbonate or Cs 2 C0 3
- a suitable solvent such as DMF or 1 ,2-dimethoxyethane at a temperature around 90°C.
- the compounds of formula XVI can be prepared (Scheme 3) by esterification of compounds of formula XX using standard conditions such as heating in a suitable solvent such as MeOH in the presence of a suitable acid such as sulphuric acid at a temperature around 70°C.
- the compounds of formula XVII, wherein Z represents -CH 2 CN can be prepared (Scheme 3) by nucleophilic substitution of a compound of formula XVI with a cyanide precursor such as trimethylsilylcyanide in the presence of a suitable base such as potassium carbonate or Cs 2 C0 3 and heating in a suitable solvent such as CH 3 CN at a temperature between RT and 60°C.
- a cyanide precursor such as trimethylsilylcyanide
- the compounds of formula XVII, wherein Z represents -CHO can be prepared (Scheme 3) by an oxidative cleavage of a compound of formula XVI with an oxidative reagent such as 4-methylmorpholine-N-oxide and heating in a suitable solvent such as dioxane at a temperature around 100°C.
- the compounds of formula XIII can be prepared (Scheme 3) by a Negishi type reaction.
- the compound of formula XVI can be transformed into an organozinc reagent in the presence of preactivated zinc dust in a suitable solvent such as THF.
- the cross coupling reaction proceeds by the reaction of the organozinc reagent with a halide of formula R 1 -X, in the presence of a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium, in the optional presence of a suitable ligand such as tri-2-furylphosphine and in a suitable solvent such as THF at a temperature around RT.
- a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) or tris(dibenzylideneacetone)dipalladium
- the compounds of formula XIV can be prepared (Scheme 3) by deprotonation of a cyanomethyl derivative of formula XVII, wherein Z represents -CH 2 CN, at the ocarbon atom with a base such as NaH in a suitable solvent such as DMF at a temperature around RT and subsequent reaction of the obtained anion with a halide of formula R 1 -X wherein R 1 is a 2-chloro-pyrimidin-4-yl or 2-(2-(trimethylsilyl)ethoxy)-pyrimidin-4-yl group.
- the consecutive oxidative cleavage of the carbon-cyanide bond proceeds in the presence of atmospheric air and additional amounts of a suitable base such as NaH in a suitable solvent such as DMF at a temperature around RT.
- the compounds of formula XIV can be prepared (Scheme 3) by an aroylation of a halide of formula R 1 -X wherein R 1 is a 2-methoxy-pyrimidin-4-yl group by an aromatic adehyde of formula XVII, wherein Z represents -CHO, in the presence of an azolium salt such as 1 ,3-dimethylimidazolium iodide and a base such as NaH in a suitable solvent such as dioxane at a temperature around 100°C.
- an azolium salt such as 1 ,3-dimethylimidazolium iodide
- a base such as NaH
- the compounds of formula XV, wherein R 7 and/or R 8 represent fluoro can be prepared (Scheme 3) by the fluorination of a ketone of formula XIV, in the presence of a fluorinating reagent such as bis(2-methoxyethyl)aminosulfur trifluoride at a temperature around 90°C.
- a fluorinating reagent such as bis(2-methoxyethyl)aminosulfur trifluoride at a temperature around 90°C.
- the compounds of formula XV, wherein one of R 7 or R 8 represents hydrogen and the other represents fluoro can be prepared (Scheme 3) by a two-step procedure.
- the ketone of formula XIV can be reduced using standard conditions such as NaBH 4 in the presence of a suitable solvent such as MeOH at a temperature around RT.
- the resulting alcohol can be fluorinated using a fluorinating reagent such as bis(2- methoxyethyl)
- the compounds of formula XV wherein one of R 7 or R 8 represents (C C 4 )alkyl and the other represents hydroxy, can be prepared (Scheme 3) by the addition of a Grignard reagent of formula R 7 -MgX or R 8 -MgX (wherein X represents a bromine or a chlorine atom) to the ketone of formula XIV in the presence of a suitable solvent such as THF or Et 2 0 at a temperature between -15°C and RT.
- a suitable solvent such as THF or Et 2 0 at a temperature between -15°C and RT.
- the compounds of formula XII can be prepared (Scheme 3) by hydrolysis of a compound of formula XIII, XIV or XV using standard conditions such as those already described for the synthesis of the compounds of formula III and IV (Scheme 1 ).
- the compounds of formula Ig can be prepared (Scheme 3) by coupling an acid of formula XII with an amine of formula II using standard amide coupling conditions such as those already described for the synthesis of the compounds of formula la and lb (Scheme 1 ).
- Y represents C(R 7 R 8 )
- compounds of formula li, Ij, Ik, Im, In and lo can be prepared following the procedures outlined in Scheme 4 below.
- one of the letter code, a,b,c or d represents a carbon atom, which is attached to the rest of the molecule via the substituent Y, and the other remaining letter codes are selected from N, CH and CR 10 , wherein R 10 represents chloro, to form a 6-membered heteroaryl or a heterocyclyl group R 1 as defined above.
- the compounds of formula li wherein X represents S0 2 CH 3 can be prepared (Scheme 4) by oxidation of a compound of formula Ih in the presence of a suitable oxidating reagent such as 3-chloroperbenzoic acid and in the presence of a suitable solvent such as DCM at a temperature between 0°C and RT.
- a suitable oxidating reagent such as 3-chloroperbenzoic acid
- a suitable solvent such as DCM
- the compounds of formula Ij can be prepared (Scheme 4) by an aromatic nucleophilic substitution of a compound of formula li with a commercially available or freshly prepared solution of sodium alkoxide of formula NaOR 11 , wherein R 11 represents (Ci-C 4 )alkyl, in the corresponding alcohol of formula HOR 11 , the reaction being carried out in the presence of a solvent such as the corresponding alcohol of formula HOR 11 or THF at a temperature between 0°C and 90°C.
- the compounds of formula Ik can be prepared (Scheme 4) by an aromatic nucleophilic substitution of a compound of formula li with an amine of formula HNR 11 R 12 , wherein R 11 represents (Ci-C 4 )alkyl and R 12 represents hydrogen or (Ci-C 4 )alkyl, optionally in the presence of a suitable base such as NEt 3 or DIPEA and heating in a suitable solvent such as H 2 0, THF, CH 3 CN or DMF at a temperature between RT and 120°C.
- a suitable base such as NEt 3 or DIPEA
- the compound of formula Im can be prepared (Scheme 4) by aromatic nucleophilic substitution of a compound of formula li with an aqueous sodium hydroxide solution and heating in a suitable solvent such as dioxane or THF at a temperature between RT and 100°C.
- the compound of formula In (or lo, respectively) can be prepared (Scheme 4) by alkylation of a compound of formula Im wherein Y represents NH (or Im wherein Y is different from NH, respectively) using a suitable alkylating reagent such as an alkyl iodide or bromide of formula R 13 -X, wherein R 13 represents (C 1 -C 4 )alkyl, in the presence of a suitable base such as Cs 2 C0 3 or potassium carbonate and carrying out the reaction in a suitable solvent such as DMF or THF at a temperature between RT and 45°C.
- a suitable alkylating reagent such as an alkyl iodide or bromide of formula R 13 -X, wherein R 13 represents (C 1 -C 4 )alkyl
- the compounds of formula Im can be prepared (Scheme 5) by cleavage of the protecting group (PG) in intermediates XXII or intermediates XXIII wherein PG represents a trimethylsilylethoxymethyl group by treatment with a tetrabutylammonium fluoride solution in THF and carrying out the reaction in a suitable solvent such as THF at a temperature between RT and 70°C.
- PG protecting group
- the compounds of formula Im can be prepared (Scheme 5) by cleavage of the protecting group (PG) in intermediates XXIII wherein PG represents a trimethylsilylethyl group by treatment with a suitable acid such as TFA and carrying out the reaction in a suitable solvent such as DCM at a temperature around RT.
- PG protecting group
- the compounds of formula XXV can be prepared (Scheme 6) by hydrolysis of a compound of formula XXIV using standard conditions such as those already described for the synthesis of the compounds of formula III and IV (Scheme 1 ).
- the compounds of formula Iq can be prepared (Scheme 6) by coupling an acid of formula XXV with ammonia as an ethanolic solution using standard amide coupling conditions such as an activation with isobutylchloroformate in the presence of a base such as 4- methylmorpholine and a suitable solvent such as DCM at a temperature between -70°C to RT.
- the compounds of formula Ir can be prepared (Scheme 6) by reduction of a compound of formula XXIV using a suitable reducing reagent such as diisobutylaluminum hydride, in the presence of a suitable solvent such as THF at a temperature around RT.
- a suitable reducing reagent such as diisobutylaluminum hydride
- intermediates of formula R 1 -X can be prepared following the procedures outlined in Scheme 7 below.
- one of the letter code, a,b,c or d represents a carbon atom bearing the halogen atom X
- the other remaining letter codes are selected from N, CH and CR 10 , wherein R 10 represents chloro, to form a 6-membered heteroaryl or a heterocyclyl group R 1 as defined above.
- the compounds of formula XXVII can be prepared (Scheme 7) by alkylation of a compound of formula XXVI using a suitable alkyl halide of formula R 14 -X wherein R 14 represents a (CrC 4 )alkyl or a (Ci-C 2 )alkoxy-(CrC 4 )alkyl group (or of formula PG-X wherein PG represents a tnmethylsilylethoxymethyl protecting group, respectively), in the presence of a suitable base such as potassium carbonate and carrying out the reaction in a suitable solvent such as acetone, CH 3 CN or DMF at a temperature between RT and 45°C.
- a suitable alkyl halide of formula R 14 -X wherein R 14 represents a (CrC 4 )alkyl or a (Ci-C 2 )alkoxy-(CrC 4 )alkyl group (or of formula PG-X wherein PG represents a tnmethylsilyleth
- the O-alkylated by-product of formula XXVIII can also be isolated.
- the compounds of formula XXVIII, wherein PG represents a trimethylsilylethyl protecting group can be prepared (Scheme 7) by an aromatic nucleophilic substitution of a compound of formula XXIX with a freshly prepared lithium 2- (trimethylsilyl)ethanolate (by treatment of 2-(trimethylsilyl)ethanol with n-butyllithium in THF at a temperature between -70°C and -30°C), the reaction being carried out in the presence of a suitable solvent such as THF at a temperature between -70°C and RT.
- a suitable solvent such as THF at a temperature between -70°C and RT.
- Scheme 7 synthesis of R 1 -X, wherein R 14 represents a (C ⁇ -C ⁇ alkyl or (Ci-Cg)alkoxy-(Ci- C ⁇ alkyl group and PG represents a trimethylsilylethoxymethyl or a trimethylsilylethyl protecting group
- the compounds of formula XXXII wherein R 15 represents trimethylsilyl or hydrogen can be prepared (Scheme 8) by cyanosilylation of a ketone of formula XXX using a suitable cyanation reagent such as trimethylsilylcyanide, in the presence of a lewis acid such as gold (III) chloride and carrying out the reaction in a suitable solvent such as DCM at a temperature around RT (Synthesis, 2008, 4, 507-510).
- the compounds of formula XXXII wherein R 15 represents (C 1 -C 4 )alkyl can be prepared (Scheme 8) by cyanation of a ketal of formula XXXI with a suitable cyanation reagent such as ferf-butyl isocyanide in the presence of a suitable lewis acid such as titanium tetrachloride and carrying out the reaction in a suitable solvent such as DCM at a temperature between -70°C and RT (Chemistry Lett., 1984, 937-940).
- the compounds of formula II wherein R 3 represents hydrogen and R 4 represents hydroxy or (Ci-C 4 )alkoxy, can be prepared (Scheme 8) by reduction of a compound of formula XXXII using a suitable reducing reagent such as lithium aluminum hydride, in the presence of a suitable solvent such as Et 2 0 or THF at a temperature between 0°C and RT. In those conditions, the consecutive hydrolysis of the possible trimethylsilyl group R 15 is observed.
- a suitable reducing reagent such as lithium aluminum hydride
- LC-MS Thermo Finnigan MSQ Surveyor MS with Agilent 1 100 Binary Pump and DAD.
- Eluents acidic conditions: A: H 2 0 + 0.04% TFA; B: CH 3 CN; gradient: 5% B ⁇ 95% B ; runtime: 1.5 min ; flow: 4.5 mL/min ; detection: UV/Vis + MS, t R is given in min.
- Atlantis column Waters Atlantis T3, 10 ⁇ , 30x75 mm
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 2.1 replacing intermediate 1.1 .
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 2.2 replacing intermediate 1.2.
- This compound was prepared using a method analogous to that of Example 2 (intermediate 2.1 ), intermediate 1.3 replacing intermediate 1.1 and 2-bromoethyl methyl ether replacing methyl iodide except that the reaction mixture was stirred for 3 days at RT and for 3 days at 70°C and that the crude was purified by CC (Hept/EtOAc 9/1 to 3/7).
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.1 ), 1 -bromo-2-fluorobenzene replacing iodobenzene.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 4.1 replacing intermediate 1.1 .
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 4.2 replacing intermediate 1.2.
- This compound was prepared using a method analogous to that of Example 2 (intermediate 2.1 ), intermediate 4.1 replacing intermediate 1.1 .
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .2), intermediate 5.1 replacing intermediate 1 .1 except that a 1 M solution of NaOH was used instead of lithium hydroxide in H 2 0.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 5.2 replacing intermediate 1.2.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.1 ), 2,4-difluoroiodobenzene replacing iodobenzene.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 6.1 replacing intermediate 1.1 .
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 6.2 replacing intermediate 1.2.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 7.1 replacing intermediate 1.1 .
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 7.2 replacing intermediate 1.2.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 8.1 replacing intermediate 1.1 .
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 8.2 replacing intermediate 1 .2, except that the crude was purified by preparative LC-MS using conditions I.
- This compound was prepared using a method analogous to that of Example 2 (intermediate 2.1 ), intermediate 8.1 replacing intermediate 1.1 except that the crude was purified by CC (Hept/EtOAc 1/0 to 0/1 ).
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .2), intermediate 9.1 replacing intermediate 1 .1 except that a 1 M solution of NaOH was used instead of lithium hydroxide in H 2 0.
- This compound was prepared using a method analogous to that of Example 1 , intermediate 1.1 , 2,4-dichloropyrimidine replacing iodobenzene.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 10.1 replacing intermediate 1.1.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 1 1 .1 replacing intermediate 1.1.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1.1 ), example 12 replacing intermediate 10.1 and the reaction mixture was stirred ON at 40°C.
- This compound was prepared using a method analogous to that of Example 10 (intermediate 10.3), intermediate 16.1 replacing intermediate 10.2 except that it was purified by preparative LC-MS using method III.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 1 1 .3 replacing intermediate 10.2 except that it was purified by preparative LC-MS using method III.
- This compound was prepared using a method analogous to that of Example 18 and was isolated as second regioisomer.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1 .1 ), ethyl iodide replacing methyl iodide except that the reaction mixture was stirred for 18h at RT.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 20.1 replacing intermediate 1 .1.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 20.3 replacing intermediate 10.2 except that it was purified by preparative LC-MS using method V.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1.1 ), propyl iodide replacing methyl iodide except that the reaction mixture was stirred for 18h at RT.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 22.1 replacing intermediate 1 .1.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 22.3 replacing intermediate 10.2 except that it was purified by preparative LC-MS using method V.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1 .1 ), isopropyl iodide replacing methyl iodide except that the reaction mixture was stirred for 18h at RT.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 24.1 replacing intermediate 1 .1.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 24.3 replacing intermediate 10.2 except that it was purified by preparative LC-MS using method V.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1.1 ), 1-iodo-2-methylpropane replacing methyl iodide except that the reaction mixture was stirred for 18h at RT and for 18h at 40°C.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .2), intermediate 26.1 replacing intermediate 1 .1 except that a 2M solution of NaOH was used instead of lithium hydroxide in H 2 0.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 26.3 replacing intermediate 10.2 except that it was purified by CC (EtOAc/MeOH 1/0 to 8/2).
- This compound was prepared using a method analogous to that of Example 12, intermediate 26.3 replacing intermediate 10.3 except that the reaction mixture was stirred for 45 min at 50°C.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1 .1 ), benzyl bromide replacing methyl iodide except that the reaction mixture was stirred for 18h at RT.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .2), intermediate 29.1 replacing intermediate 1 .1 except that a 2M solution of NaOH was used instead of lithium hydroxide in H 2 0.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 29.3 replacing intermediate 10.2 except that it was purified by CC (EtOAc/MeOH 1/0 to 8/2).
- This compound was prepared using a method analogous to that of Example 12, intermediate 29.3 replacing intermediate 10.3 except that the reaction mixture was stirred for 45 min at 50°C.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1 .1 ), 2-bromoethyl methyl ether replacing methyl iodide except that the reaction mixture was stirred for 18h at 40°C.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .2), intermediate 32.1 replacing intermediate 1 .1 except that a 2M solution of NaOH was used instead of lithium hydroxide in H 2 0.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 32.3 replacing intermediate 10.2 except that it was purified by CC (EtOAc/MeOH 1/0 to 8/2).
- This compound was prepared using a method analogous to that of Example 12, intermediate 32.3 replacing intermediate 10.3 except that the reaction mixture was stirred for 18h at 30°C.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1.1 ), iodomethylcyclopentane replacing methyl iodide except that the reaction mixture was stirred for 4 days at 40°C.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .2), intermediate 35.1 replacing intermediate 1 .1 except that a 2M solution of NaOH was used instead of lithium hydroxide in H 2 0.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 35.3 replacing intermediate 10.2 except that it was purified by CC (EtOAc/MeOH 1/0 to 8/2).
- This compound was prepared using a method analogous to that of Example 12, intermediate 35.3 replacing intermediate 10.3 except that the reaction mixture was stirred for 2h at 50°C.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1 .1 ), 2-bromoethyl phenyl ether replacing methyl iodide except that the reaction mixture was stirred for 3 days at RT.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .2), intermediate 38.1 replacing intermediate 1 .1 except that a 2M solution of NaOH was used instead of lithium hydroxide in H 2 0.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 38.3 replacing intermediate 10.2 except that it was purified by CC (EtOAc/MeOH 1/0 to 8/2).
- This compound was prepared using a method analogous to that of Example 12, intermediate 38.3 replacing intermediate 10.3 except that the reaction mixture was stirred for 18h at 30°C.
- This compound was prepared using a method analogous to that of Example 10 (intermediate 10.3), intermediate 1 1.2 replacing intermediate 10.2 and (R)-(-)-1- cyclohexylethylamine replacing 1 -aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), example 41 replacing intermediate 10.2 except that it was purified by preparative LC-MS using method V.
- This compound was prepared using a method analogous to that of Example 10 (intermediate 10.3), intermediate 1 1 .2 replacing intermediate 10.2 and L- cyclohexylglycinol replacing 1-aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 10 (intermediate 10.3), intermediate 1 1.2 replacing intermediate 10.2 and intermediate 45.2 replacing 1 -aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 45.3 replacing intermediate 10.2 except that the reaction mixture was stirred for 72h at 80°C and the crude was purified by preparative LC-MS using method I and then by CC (EtOAc/MeOH 1/0 to 1/1 ).
- This compound was prepared using a method analogous to that of Example 45 (intermediate 45.1 ), cyclooctanone replacing cycloheptanone except that the reaction mixture was stirred for 2h at RT.
- This compound was prepared using a method analogous to that of Example 45 (intermediate 45.2), intermediate 47.1 replacing intermediate 45.1 except that the reaction mixture was stirred for 2h at RT.
- This compound was prepared using a method analogous to that of Example 10 (intermediate 10.3), intermediate 1 1.2 replacing intermediate 10.2 and intermediate 47.2 replacing 1 -aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 47.3 replacing intermediate 10.2 except that the reaction mixture was stirred for 6h at 90°C and the crude was purified by preparative LC-MS using method I.
- This compound was prepared using a method analogous to that of Example 45 (intermediate 45.1 ), cyclopentanone replacing cycloheptanone except that the reaction mixture was stirred for 2h at RT and the desilylated product was isolated.
- This compound was prepared using a method analogous to that of Example 10 (intermediate 10.3), intermediate 1 1.2 replacing intermediate 10.2 and intermediate 49.2 replacing 1 -aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 49.3 replacing intermediate 10.2 except that the reaction mixture was stirred for 18h at 80°C and the crude was purified by preparative LC-MS using method IV.
- This compound was prepared using a method analogous to that of Example 10 (intermediate 10.3), intermediate 1 1.2 replacing intermediate 10.2 and intermediate 51 .2 replacing 1 -aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 51.3 replacing intermediate 10.2 except that the reaction mixture was stirred for 72h at 80°C and the crude was purified by preparative LC-MS using method VII.
- This compound was prepared using a method analogous to that of Example 10 (intermediate 10.3), intermediate 1 1 .2 replacing intermediate 10.2 and methyl 1- aminomethyl-cyclohexanecarboxylate replacing 1-aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 53.1 replacing intermediate 1.1.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 53.3 replacing intermediate 10.2 except that the reaction mixture was stirred for 72h at 80°C and the crude was purified by preparative LC-MS using method IV.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), example 55 replacing intermediate 10.2 except that the reaction mixture was stirred for 18h at 90°C and the crude was purified by preparative LC-MS using method III.
- This compound was prepared using a method analogous to that of Example 10 (intermediate 10.3), intermediate 1 1.2 replacing intermediate 10.2 and intermediate 57.2 replacing 1 -aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 57.3 replacing intermediate 10.2 except that the reaction mixture was stirred for 18h at 90°C and the crude was purified by preparative LC-MS using method IV.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.1 ), 4-chloro-2-methylthiopyrimidine replacing iodobenzene.
- This compound was prepared using a method analogous to that of Example (intermediate 1.2), intermediate 59.1 replacing intermediate 1.1.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .3), intermediate 59.2 replacing intermediate 1 .2 and (R)-(-)-1 - cyclohexylethylamine replacing 1 -aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .3), intermediate 59.2 replacing intermediate 1.2 and L-cyclohexylglycinol replacing 1 -aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1 .3), intermediate 59.2 replacing intermediate 1 .2 and intermediate 45.2 replacing 1 -aminomethyl-cyclohexanol hydrochloride.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.1 ), 2,4,6-trichloropyrimidine replacing iodobenzene.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1 .1 ), intermediate 62.1 replacing intermediate 10.1.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 62.2 replacing intermediate 1 .1. This compound was contaminated with 2-chloro-5-[(6-chloro-2-methoxy-pyrimidin-4-yl)-methyl-amino]-benzoic acid.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 62.3 replacing intermediate 1 .2.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 62.4 replacing intermediate 10.2 except that it was purified by preparative LC-MS using method V.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.1 ), 2,4,6-trichloropyrimidine replacing iodobenzene.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 65.2 replacing intermediate 1 .1.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 65.3 replacing intermediate 1.2.
- Example 66 (48 mg) was mixed with a 5.4 M solution of NaOMe in MeOH (0.196 ml.) and the reaction mixture was stirred ON at RT. It was quenched with H 2 0 and extracted with EtOAc. The organic phase was washed with a sat. solution of NaHC0 3 and brine, dried over MgS0 4 and concentrated in vacuo. The crude material was purified by CC (Hept/EtOAc 1/1 to 0/1 ) to give 32 mg of the titled compound as a white foam.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), example 66 replacing intermediate 10.2 except that it was purified by preparative LC-MS using method V.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.1 ), 2-chloropyrimidine replacing iodobenzene.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 69.1 replacing intermediate 1.1.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 69.2 replacing intermediate 1.2.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1 .1 ), intermediate 69.3 replacing intermediate 10.1.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1.1 ), intermediate 69.3 replacing intermediate 10.1 and 2-bromoethyl methyl ether replacing methyl iodide.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.1 ), 2-chloro-4-methylsulfanylpyrimidine replacing iodobenzene.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 72.1 replacing intermediate 1.1.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.3), intermediate 72.2 replacing intermediate 1.2.
- This compound was prepared using a method analogous to that of Example 1 1 (intermediate 1 1 .1 ), intermediate 72.3 replacing intermediate 10.1.
- This compound was prepared using a method analogous to that of Example 66, example 73 replacing intermediate 65.4.
- This compound was prepared using a method analogous to that of Example 67, intermediate 74.1 replacing example 66.
- This compound was prepared using a method analogous to that of Example 16 (intermediate 16.1 ), intermediate 74.1 replacing intermediate 10.2 except that the reaction mixture was stirred for 1 h at 45°C and that the crude was purified by preparative LC-MS using method V.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.1 ), 5-bromopyrimidine replacing iodobenzene.
- This compound was prepared using a method analogous to that of Example 1 (intermediate 1.2), intermediate 76.1 replacing intermediate 1.1.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Hospice & Palliative Care (AREA)
- Ophthalmology & Optometry (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020137024559A KR20140009374A (en) | 2011-02-22 | 2012-02-21 | Benzamide derivatives as p2x7 receptor antagonists |
CN201280009862XA CN103391923A (en) | 2011-02-22 | 2012-02-21 | Benzamide derivatives as p2x7 receptor antagonists |
CA2824415A CA2824415A1 (en) | 2011-02-22 | 2012-02-21 | Benzamide derivatives as p2x7 receptor antagonists |
US14/001,052 US20140073651A1 (en) | 2011-02-22 | 2012-02-21 | Benzamide derivatives as p2x7 receptor antagonists |
JP2013554962A JP2014513671A (en) | 2011-02-22 | 2012-02-21 | Benzamide derivatives as P2X7 receptor antagonists |
EP12709177.5A EP2678317A1 (en) | 2011-02-22 | 2012-02-21 | Benzamide derivatives as p2x7 receptor antagonists |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IB2011050728 | 2011-02-22 | ||
IBPCT/IB2011/050728 | 2011-02-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2012114268A1 true WO2012114268A1 (en) | 2012-08-30 |
Family
ID=45841546
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2012/050780 WO2012114268A1 (en) | 2011-02-22 | 2012-02-21 | Benzamide derivatives as p2x7 receptor antagonists |
Country Status (7)
Country | Link |
---|---|
US (1) | US20140073651A1 (en) |
EP (1) | EP2678317A1 (en) |
JP (1) | JP2014513671A (en) |
KR (1) | KR20140009374A (en) |
CN (1) | CN103391923A (en) |
CA (1) | CA2824415A1 (en) |
WO (1) | WO2012114268A1 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014097140A1 (en) | 2012-12-18 | 2014-06-26 | Actelion Pharmaceuticals Ltd | Indole carboxamide derivatives as p2x7 receptor antagonists |
CN104918946A (en) * | 2013-01-22 | 2015-09-16 | 埃科特莱茵药品有限公司 | Heterocyclic amide derivatives as p2x7 receptor antagonists |
CN104918617A (en) * | 2013-01-22 | 2015-09-16 | 埃科特莱茵药品有限公司 | Heterocyclic amide derivatives as p2x7 receptor antagonists |
US9221832B2 (en) | 2011-07-22 | 2015-12-29 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9409917B2 (en) | 2012-01-20 | 2016-08-09 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9718774B2 (en) | 2012-12-12 | 2017-08-01 | Idorsia Pharmaceuticals Ltd | Indole carboxamide derivatives as P2X7 receptor antagonist |
WO2020017587A1 (en) | 2018-07-19 | 2020-01-23 | 大日本住友製薬株式会社 | Pyridazinone derivative |
US10548877B2 (en) | 2016-03-11 | 2020-02-04 | Takeda Pharmaceutical Company Limited | Aromatic ring compound |
WO2020227159A2 (en) | 2019-05-03 | 2020-11-12 | Flagship Pioneering Innovations V, Inc. | Methods of modulating immune activity |
WO2021141041A1 (en) | 2020-01-07 | 2021-07-15 | 大日本住友製薬株式会社 | Therapeutic agent for tauopathies |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR200486683Y1 (en) | 2017-07-10 | 2018-06-21 | 주식회사 로스팅 파크 커피 컴퍼니 | Drip coffee machine |
WO2019073471A1 (en) * | 2017-10-09 | 2019-04-18 | Ramot At Tel-Aviv University Ltd. | Modulators of potassium ion and trpv1 channels and uses thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000061569A1 (en) * | 1999-04-09 | 2000-10-19 | Astrazeneca Ab | Adamantane derivatives |
WO2003042191A1 (en) | 2001-11-12 | 2003-05-22 | Pfizer Products Inc. | Benzamide and heteroarylamide as p2x7 receptor antagonists |
WO2004058270A1 (en) | 2002-12-31 | 2004-07-15 | Pfizer Products Inc. | 3-(3,5-dioxo-4,5-dihydro-3h-(1,2,4)triazin-2-yl)-benzamide derivatives as p2x7-inhibitors for the treatment of inflammatory diseases |
WO2004058731A1 (en) | 2002-12-31 | 2004-07-15 | Pfizer Products Inc. | Benzamide inhibitors of the p2x7 receptor |
WO2004099146A1 (en) | 2003-05-12 | 2004-11-18 | Pfizer Products Inc. | Benzamide inhibitors of the p2x7 receptor |
WO2005019182A1 (en) | 2003-08-20 | 2005-03-03 | Bayer Healthcare Ag | Pyrazolylmethylbenzamide derivatives as p2xt-receptor antagonists |
-
2012
- 2012-02-21 US US14/001,052 patent/US20140073651A1/en not_active Abandoned
- 2012-02-21 WO PCT/IB2012/050780 patent/WO2012114268A1/en active Application Filing
- 2012-02-21 EP EP12709177.5A patent/EP2678317A1/en not_active Withdrawn
- 2012-02-21 JP JP2013554962A patent/JP2014513671A/en active Pending
- 2012-02-21 CN CN201280009862XA patent/CN103391923A/en active Pending
- 2012-02-21 KR KR1020137024559A patent/KR20140009374A/en not_active Application Discontinuation
- 2012-02-21 CA CA2824415A patent/CA2824415A1/en not_active Abandoned
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000061569A1 (en) * | 1999-04-09 | 2000-10-19 | Astrazeneca Ab | Adamantane derivatives |
WO2003042191A1 (en) | 2001-11-12 | 2003-05-22 | Pfizer Products Inc. | Benzamide and heteroarylamide as p2x7 receptor antagonists |
WO2004058270A1 (en) | 2002-12-31 | 2004-07-15 | Pfizer Products Inc. | 3-(3,5-dioxo-4,5-dihydro-3h-(1,2,4)triazin-2-yl)-benzamide derivatives as p2x7-inhibitors for the treatment of inflammatory diseases |
WO2004058731A1 (en) | 2002-12-31 | 2004-07-15 | Pfizer Products Inc. | Benzamide inhibitors of the p2x7 receptor |
US20070281939A1 (en) * | 2002-12-31 | 2007-12-06 | Pfizer Inc. | Benzamide Inhibitors of The P2X7 Receptor |
WO2004099146A1 (en) | 2003-05-12 | 2004-11-18 | Pfizer Products Inc. | Benzamide inhibitors of the p2x7 receptor |
WO2005019182A1 (en) | 2003-08-20 | 2005-03-03 | Bayer Healthcare Ag | Pyrazolylmethylbenzamide derivatives as p2xt-receptor antagonists |
Non-Patent Citations (17)
Title |
---|
"Salt selection for basic drugs", INT. J. PHARM., vol. 33, 1986, pages 201 - 217 |
BARALDI P G ET AL: "Agonists and antagonists acting at P2X7 receptor", CURRENT TOPICS IN MEDICINAL CHEMISTRY, BENTHAM SCIENCE PUBLISHERS LTD, NETHERLANDS, vol. 4, no. 16, 1 January 2004 (2004-01-01), pages 1707 - 1717, XP008117103, ISSN: 1568-0266, DOI: 10.2174/1568026043387223 * |
CHEMISTRY LETT., 1984, pages 937 - 940 |
CHESSELL, I. P.; HATCHER, J. P. ET AL., PAIN, vol. 114, no. 3, 2005, pages 386 - 96 |
DEUCHARS, S. A.; ATKINSON, L. ET AL., J. NEUROSCI., vol. 21, no. 18, 2001, pages 7143 - 52 |
FERRARI, D.; CHIOZZI, P. ET AL., NEUROPHARMACOLOGY, vol. 36, no. 9, 1997, pages 1295 - 301 |
MARK FURBER, LILIAN ALCARAZ, JANICE E. BENT, ARMIN BEYERBACH, KEITH BOWERS, MARTIN BRADDOCK, MOYA V. CAFFREY: "Discovery of Potent and Selective Adamantane-Based Small-Molecule P2X7 Receptor Antagonists/Interleukin-1beta Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 50, 27 October 2007 (2007-10-27), pages 5882 - 5885, XP002678693, DOI: 10.1021/jm700949w * |
NORTH, R. A., PHYSIOL. REV., vol. 82, no. 4, 2002, pages 1013 - 67 |
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS, article "Pharmaceutical Manufacturing" |
SOLLE, M.; LABASI, J. ET AL., J. BIOL. CHEM., vol. 276, no. 1, 2001, pages 125 - 32 |
SPERLAGH, B.; KOFALVI, A. ET AL., J. NEUROCHEM., vol. 81, no. 6, 2002, pages 1196 - 211 |
SURPRENANT, A.; RASSENDREN, F. ET AL., SCIENCE, vol. 272, no. 5262, 1996, pages 735 - 8 |
SYNTHESIS, vol. 4, 2008, pages 507 - 510 |
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE |
VIRGINIO, C.; MACKENZIE, A. ET AL., J. PHYSIOL., vol. 519, 1999, pages 335 - 46 |
WILEY, J. S.; CHEN, J. R. ET AL., CIBA FOUND SYMP., vol. 198, 1996, pages 149 - 60,160-5 |
YU, Y.; UGAWA, S. ET AL., BRAIN. RES., vol. 1194, 2008, pages 45 - 55 |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9221832B2 (en) | 2011-07-22 | 2015-12-29 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9409917B2 (en) | 2012-01-20 | 2016-08-09 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9718774B2 (en) | 2012-12-12 | 2017-08-01 | Idorsia Pharmaceuticals Ltd | Indole carboxamide derivatives as P2X7 receptor antagonist |
WO2014097140A1 (en) | 2012-12-18 | 2014-06-26 | Actelion Pharmaceuticals Ltd | Indole carboxamide derivatives as p2x7 receptor antagonists |
US9556117B2 (en) | 2012-12-18 | 2017-01-31 | Actelion Pharmaceuticals Ltd. | Indole carboxamide derivatives as P2X7 receptor antagonists |
JP2016504995A (en) * | 2012-12-18 | 2016-02-18 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | Indole carboxamide derivatives as P2X7 receptor antagonists |
KR102232744B1 (en) | 2012-12-18 | 2021-03-26 | 이도르시아 파마슈티컬스 리미티드 | Indole carboxamide derivatives as p2x7 receptor antagonists |
KR20150095905A (en) * | 2012-12-18 | 2015-08-21 | 액테리온 파마슈티칼 리미티드 | Indole carboxamide derivatives as p2x7 receptor antagonists |
CN104918617B (en) * | 2013-01-22 | 2017-05-10 | 埃科特莱茵药品有限公司 | Heterocyclic amide derivatives as p2x7 receptor antagonists |
CN104918946A (en) * | 2013-01-22 | 2015-09-16 | 埃科特莱茵药品有限公司 | Heterocyclic amide derivatives as p2x7 receptor antagonists |
US9388198B2 (en) | 2013-01-22 | 2016-07-12 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US9388197B2 (en) | 2013-01-22 | 2016-07-12 | Actelion Pharmaceuticals Ltd. | Heterocyclic amide derivatives as P2X7 receptor antagonists |
CN104918617A (en) * | 2013-01-22 | 2015-09-16 | 埃科特莱茵药品有限公司 | Heterocyclic amide derivatives as p2x7 receptor antagonists |
JP2016510325A (en) * | 2013-01-22 | 2016-04-07 | アクテリオン ファーマシューティカルズ リミテッドActelion Pharmaceuticals Ltd | Heterocyclic amide derivatives as P2X7 receptor antagonists |
US10548877B2 (en) | 2016-03-11 | 2020-02-04 | Takeda Pharmaceutical Company Limited | Aromatic ring compound |
WO2020017587A1 (en) | 2018-07-19 | 2020-01-23 | 大日本住友製薬株式会社 | Pyridazinone derivative |
WO2020227159A2 (en) | 2019-05-03 | 2020-11-12 | Flagship Pioneering Innovations V, Inc. | Methods of modulating immune activity |
WO2021141041A1 (en) | 2020-01-07 | 2021-07-15 | 大日本住友製薬株式会社 | Therapeutic agent for tauopathies |
Also Published As
Publication number | Publication date |
---|---|
CN103391923A (en) | 2013-11-13 |
KR20140009374A (en) | 2014-01-22 |
EP2678317A1 (en) | 2014-01-01 |
JP2014513671A (en) | 2014-06-05 |
US20140073651A1 (en) | 2014-03-13 |
CA2824415A1 (en) | 2012-08-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2012114268A1 (en) | Benzamide derivatives as p2x7 receptor antagonists | |
AU2018371010B2 (en) | Sulfone pyridine alkyl amide-substituted heteroaryl compounds | |
EP2931717B1 (en) | Indole carboxamide derivatives as p2x7 receptor antagonists | |
JP5124471B2 (en) | Substituted bicyclic pyrimidone derivatives | |
EP2804865B1 (en) | Heterocyclic amide derivatives as p2x7 receptor antagonists | |
EP2755967A1 (en) | Heterocyclic compounds for the treatment of cystic fibrosis | |
SG184018A1 (en) | Pyridine and pyrazine derivative for the treatment of cf | |
WO2013160419A1 (en) | Novel compounds | |
US9556117B2 (en) | Indole carboxamide derivatives as P2X7 receptor antagonists | |
US8969389B2 (en) | Substituted 6-methylnicotinamides as mGluR5 positive allosteric modulators | |
KR20230004612A (en) | Substituted pyridines for the treatment of inflammatory diseases | |
CA2897459C (en) | Heterocyclic amide derivatives as p2x7 receptor antagonists | |
JP7043483B2 (en) | Bicyclic proline compound | |
US10752609B2 (en) | GSK-3 inhibitors | |
WO2019045006A1 (en) | Morphinan derivative | |
US20230265094A1 (en) | Ripk1 inhibitors and methods of use | |
CN117715898A (en) | Six-membered aryl or heteroaryl amide compound, composition and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12709177 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2824415 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012709177 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2013554962 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14001052 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 20137024559 Country of ref document: KR Kind code of ref document: A |