CA2980159A1 - Substituted tricyclic heterocyclic compounds - Google Patents
Substituted tricyclic heterocyclic compounds Download PDFInfo
- Publication number
- CA2980159A1 CA2980159A1 CA2980159A CA2980159A CA2980159A1 CA 2980159 A1 CA2980159 A1 CA 2980159A1 CA 2980159 A CA2980159 A CA 2980159A CA 2980159 A CA2980159 A CA 2980159A CA 2980159 A1 CA2980159 A1 CA 2980159A1
- Authority
- CA
- Canada
- Prior art keywords
- zero
- substituted
- alkyl
- phenyl
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- 150000002391 heterocyclic compounds Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 301
- 150000003839 salts Chemical class 0.000 claims abstract description 100
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 17
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 14
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 88
- 125000003118 aryl group Chemical group 0.000 claims description 81
- -1 -OH Chemical group 0.000 claims description 69
- 125000000623 heterocyclic group Chemical group 0.000 claims description 56
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000002950 monocyclic group Chemical group 0.000 claims description 32
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 30
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 229910052731 fluorine Inorganic materials 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 24
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 13
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000005605 benzo group Chemical group 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 4
- 201000005569 Gout Diseases 0.000 claims description 4
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 4
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 102000003298 tumor necrosis factor receptor Human genes 0.000 claims description 4
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 3
- 208000023328 Basedow disease Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 206010016207 Familial Mediterranean fever Diseases 0.000 claims description 3
- 208000015023 Graves' disease Diseases 0.000 claims description 3
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 3
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 2
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 2
- 208000024908 graft versus host disease Diseases 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 208000004296 neuralgia Diseases 0.000 claims description 2
- 208000021722 neuropathic pain Diseases 0.000 claims description 2
- 230000000737 periodic effect Effects 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 208000020408 systemic-onset juvenile idiopathic arthritis Diseases 0.000 claims description 2
- MWYJODZWNRUGPZ-HXUWFJFHSA-N (3R)-3-(2,5-dimethylphenyl)-11-(6-methoxypyridin-3-yl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraene Chemical compound CC1=C(C=C(C=C1)C)[C@H]1CCC2=NC=3C(=NC(=CC=3)C=3C=NC(=CC=3)OC)N21 MWYJODZWNRUGPZ-HXUWFJFHSA-N 0.000 claims 2
- XIPXRVHFDSSFBE-AREMUKBSSA-N (3R)-3-(2,5-dimethylphenyl)-11-[4-(4-methylpiperazin-1-yl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraene Chemical compound CC1=C(C=C(C=C1)C)[C@H]1CCC2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)N3CCN(CC3)C)N21 XIPXRVHFDSSFBE-AREMUKBSSA-N 0.000 claims 2
- FUMXWCXIKLKMMQ-UHFFFAOYSA-N 11-[4-(2-hydroxypropan-2-yl)phenyl]-3-(2-methoxyphenyl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound OC(C)(C)C1=CC=C(C=C1)C1=CC=C2C(=N1)N1C(=N2)C(CC1C1=C(C=CC=C1)OC)O FUMXWCXIKLKMMQ-UHFFFAOYSA-N 0.000 claims 2
- WCJSZPKAHIGHSP-UHFFFAOYSA-N 11-[4-(2-hydroxypropan-2-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound OC(C)(C)C1=CC=C(C=C1)C1=CC=C2C(=N1)N1C(=N2)C(CC1C1=C(C=CC=C1)C(F)(F)F)O WCJSZPKAHIGHSP-UHFFFAOYSA-N 0.000 claims 2
- JBBNVIMXSSPSFU-UHFFFAOYSA-N 11-[4-(2-hydroxypropan-2-yl)phenyl]-3-[2-methyl-5-(trifluoromethyl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound OC(C)(C)C1=CC=C(C=C1)C1=CC=C2C(=N1)N1C(=N2)C(CC1C1=C(C=CC(=C1)C(F)(F)F)C)O JBBNVIMXSSPSFU-UHFFFAOYSA-N 0.000 claims 2
- CCYYYKOUISBKNQ-HSZRJFAPSA-N 2-[4-[(3R)-3-(2,5-dimethylphenyl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound CC1=C(C=C(C=C1)C)[C@H]1CCC2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21 CCYYYKOUISBKNQ-HSZRJFAPSA-N 0.000 claims 2
- UJQIXEYIQCDDAB-UHFFFAOYSA-N 2-[4-[3-(2-cyclopropylphenyl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound C1(CC1)C1=C(C=CC=C1)C1CCC2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21 UJQIXEYIQCDDAB-UHFFFAOYSA-N 0.000 claims 2
- DCQCGNMFCGZMGL-UHFFFAOYSA-N 2-[4-[3-(2-cyclopropylphenyl)-5-fluoro-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound C1(CC1)C1=C(C=CC=C1)C1CC(C2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21)F DCQCGNMFCGZMGL-UHFFFAOYSA-N 0.000 claims 2
- BVWMDSRUMHZQQY-UHFFFAOYSA-N 2-[4-[3-(2-methoxyphenyl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound COC1=C(C=CC=C1)C1CCC2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21 BVWMDSRUMHZQQY-UHFFFAOYSA-N 0.000 claims 2
- HTWJGCUKEIUWNB-UHFFFAOYSA-N 2-[4-[3-[2-(difluoromethoxy)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound FC(OC1=C(C=CC=C1)C1CCC2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21)F HTWJGCUKEIUWNB-UHFFFAOYSA-N 0.000 claims 2
- FXWYBCDCDHAQFS-UHFFFAOYSA-N 2-[4-[3-[2-(difluoromethoxy)phenyl]-5-fluoro-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound FC(OC1=C(C=CC=C1)C1CC(C2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21)F)F FXWYBCDCDHAQFS-UHFFFAOYSA-N 0.000 claims 2
- XLDXEBXBEVPCDQ-UHFFFAOYSA-N 2-[4-[3-[2-(trifluoromethyl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound FC(C1=C(C=CC=C1)C1CCC2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21)(F)F XLDXEBXBEVPCDQ-UHFFFAOYSA-N 0.000 claims 2
- LWOODTYOEVZSQK-UHFFFAOYSA-N 2-[4-[3-[2-fluoro-6-(trifluoromethyl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound FC1=C(C(=CC=C1)C(F)(F)F)C1CCC2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21 LWOODTYOEVZSQK-UHFFFAOYSA-N 0.000 claims 2
- DVPPBWSHROBBFJ-UHFFFAOYSA-N 2-[4-[3-[5-fluoro-2-(trifluoromethyl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound FC=1C=CC(=C(C=1)C1CCC2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21)C(F)(F)F DVPPBWSHROBBFJ-UHFFFAOYSA-N 0.000 claims 2
- RROYCRUUWHVBCL-UHFFFAOYSA-N 2-[4-[5-[3-(2-methoxyphenyl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]pyrimidin-2-yl]piperazin-1-yl]acetic acid Chemical compound COC1=C(C=CC=C1)C1CCC2=NC=3C(=NC(=CC=3)C=3C=NC(=NC=3)N3CCN(CC3)CC(=O)O)N21 RROYCRUUWHVBCL-UHFFFAOYSA-N 0.000 claims 2
- MQHNRCXLKUUPKQ-UHFFFAOYSA-N 2-[4-[5-fluoro-3-[2-(trifluoromethoxy)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound FC1CC(N2C1=NC=1C2=NC(=CC=1)C1=CC=C(C=C1)C(C)(C)O)C1=C(C=CC=C1)OC(F)(F)F MQHNRCXLKUUPKQ-UHFFFAOYSA-N 0.000 claims 2
- AQHQIKSWRGMNJB-UHFFFAOYSA-N 2-[4-[5-fluoro-3-[2-(trifluoromethyl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound FC1CC(N2C1=NC=1C2=NC(=CC=1)C1=CC=C(C=C1)C(C)(C)O)C1=C(C=CC=C1)C(F)(F)F AQHQIKSWRGMNJB-UHFFFAOYSA-N 0.000 claims 2
- NJCVMGATHWOLKA-UHFFFAOYSA-N 2-[4-[5-fluoro-3-[2-fluoro-6-(trifluoromethyl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]phenyl]propan-2-ol Chemical compound FC1CC(N2C1=NC=1C2=NC(=CC=1)C1=CC=C(C=C1)C(C)(C)O)C1=C(C=CC=C1C(F)(F)F)F NJCVMGATHWOLKA-UHFFFAOYSA-N 0.000 claims 2
- LMLGUPLXAVIXKY-UHFFFAOYSA-N 2-[5-[3-(2,5-dimethylphenyl)-5-fluoro-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]pyrimidin-2-yl]propan-2-ol Chemical compound CC1=C(C=C(C=C1)C)C1CC(C2=NC=3C(=NC(=CC=3)C=3C=NC(=NC=3)C(C)(C)O)N21)F LMLGUPLXAVIXKY-UHFFFAOYSA-N 0.000 claims 2
- XEPMXXAHTTXNFI-UHFFFAOYSA-N 2-[5-[3-[2-(difluoromethoxy)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC(OC1=C(C=CC=C1)C1CCC2=NC=3C(=NC(=CC=3)C=3C=NC(=NC=3)C(C)(C)O)N21)F XEPMXXAHTTXNFI-UHFFFAOYSA-N 0.000 claims 2
- BIICWYBWGDLGDM-UHFFFAOYSA-N 2-[5-[3-[2-(difluoromethoxy)phenyl]-5-fluoro-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC(OC1=C(C=CC=C1)C1CC(C2=NC=3C(=NC(=CC=3)C=3C=NC(=NC=3)C(C)(C)O)N21)F)F BIICWYBWGDLGDM-UHFFFAOYSA-N 0.000 claims 2
- YOCDSSXWILGVBW-UHFFFAOYSA-N 2-[5-[3-[5-methyl-2-(trifluoromethyl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-11-yl]pyrimidin-2-yl]propan-2-ol Chemical compound CC1=CC=C(C(=C1)C1CCC2=NC3=CC=C(N=C3N12)C1=CN=C(N=C1)C(C)(C)O)C(F)(F)F YOCDSSXWILGVBW-UHFFFAOYSA-N 0.000 claims 2
- RLIVIHIZSSNDJL-UHFFFAOYSA-N 3-(2,5-dimethylphenyl)-11-(2-morpholin-4-ylpyrimidin-5-yl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound CC1=C(C=C(C=C1)C)C1CC(C2=NC=3C(=NC(=CC=3)C=3C=NC(=NC=3)N3CCOCC3)N21)O RLIVIHIZSSNDJL-UHFFFAOYSA-N 0.000 claims 2
- PAMLATFAJUQAAY-UHFFFAOYSA-N 3-(2,5-dimethylphenyl)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound CC1=C(C=C(C=C1)C)C1CC(C2=NC=3C(=NC(=CC=3)C=3C=NC(=NC=3)C(C)(C)O)N21)O PAMLATFAJUQAAY-UHFFFAOYSA-N 0.000 claims 2
- HFVDAIWVGPDAOQ-UHFFFAOYSA-N 3-(2,5-dimethylphenyl)-11-[4-(2-hydroxypropan-2-yl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound CC1=C(C=C(C=C1)C)C1CC(C2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21)O HFVDAIWVGPDAOQ-UHFFFAOYSA-N 0.000 claims 2
- CQPPZDGXQLWBLL-UHFFFAOYSA-N 3-(2-cyclopropylphenyl)-11-[4-(2-hydroxypropan-2-yl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound C1(CC1)C1=C(C=CC=C1)C1CC(C2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21)O CQPPZDGXQLWBLL-UHFFFAOYSA-N 0.000 claims 2
- FSBFKKBPTYESEH-UHFFFAOYSA-N 3-[2,5-bis(trifluoromethyl)phenyl]-11-[4-(2-hydroxypropan-2-yl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound FC(C1=C(C=C(C=C1)C(F)(F)F)C1CC(C2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21)O)(F)F FSBFKKBPTYESEH-UHFFFAOYSA-N 0.000 claims 2
- GDEUQKWVQBGMPO-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-11-(1-methylpyrazol-4-yl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraene Chemical compound FC(OC1=C(C=CC=C1)C1CCC2=NC=3C(=NC(=CC=3)C=3C=NN(C=3)C)N21)F GDEUQKWVQBGMPO-UHFFFAOYSA-N 0.000 claims 2
- UCDQWLXDJQLDLC-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-11-(2-morpholin-4-ylpyrimidin-5-yl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound FC(OC1=C(C=CC=C1)C1CC(C2=NC=3C(=NC(=CC=3)C=3C=NC(=NC=3)N3CCOCC3)N21)O)F UCDQWLXDJQLDLC-UHFFFAOYSA-N 0.000 claims 2
- YWGVUJDGXZCYRX-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-11-(6-methoxypyridin-3-yl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraene Chemical compound FC(OC1=C(C=CC=C1)C1CCC2=NC=3C(=NC(=CC=3)C=3C=NC(=CC=3)OC)N21)F YWGVUJDGXZCYRX-UHFFFAOYSA-N 0.000 claims 2
- JIZHFNUDERURSW-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound FC(OC1=C(C=CC=C1)C1CC(C2=NC=3C(=NC(=CC=3)C=3C=NC(=NC=3)C(C)(C)O)N21)O)F JIZHFNUDERURSW-UHFFFAOYSA-N 0.000 claims 2
- HWQNCQBWUJAXRI-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-11-[4-(2-hydroxypropan-2-yl)phenyl]-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraen-5-ol Chemical compound FC(OC1=C(C=CC=C1)C1CC(C2=NC=3C(=NC(=CC=3)C3=CC=C(C=C3)C(C)(C)O)N21)O)F HWQNCQBWUJAXRI-UHFFFAOYSA-N 0.000 claims 2
- VEHLTTOIHVWYNM-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-5-fluoro-11-(1-methylpyrazol-4-yl)-2,7,12-triazatricyclo[6.4.0.02,6]dodeca-1(8),6,9,11-tetraene Chemical compound FC(OC1=C(C=CC=C1)C1CC(C2=NC=3C(=NC(=CC=3)C=3C=NN(C=3)C)N21)F)F VEHLTTOIHVWYNM-UHFFFAOYSA-N 0.000 claims 2
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Classifications
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- 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]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
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)
- Medicinal Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Epidemiology (AREA)
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| US201562134769P | 2015-03-18 | 2015-03-18 | |
| US62/134,769 | 2015-03-18 | ||
| PCT/US2016/022737 WO2016149436A1 (en) | 2015-03-18 | 2016-03-17 | Substituted tricyclic heterocyclic compounds |
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| CA2980159A1 true CA2980159A1 (en) | 2016-09-22 |
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| SG (1) | SG11201707469WA (enExample) |
| WO (1) | WO2016149436A1 (enExample) |
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| EA201792054A1 (ru) | 2015-03-18 | 2018-01-31 | Бристол-Майерс Сквибб Компани | Гетероциклические соединения, применимые в качестве ингибиторов tnf |
| MX2017011433A (es) | 2015-03-18 | 2017-11-10 | Bristol Myers Squibb Co | Compuestos heterociclicos triciclicos utiles como inhibidores del factor de necrosis tumoral (tnf). |
| TW201710257A (zh) | 2015-04-17 | 2017-03-16 | 艾伯維有限公司 | Ｔｎｆ信號傳遞之三環調節劑 |
| TW201706258A (zh) | 2015-04-17 | 2017-02-16 | 艾伯維有限公司 | 作為ｔｎｆ信號傳遞調節劑之吲唑酮 |
| WO2016168638A1 (en) | 2015-04-17 | 2016-10-20 | Abbvie Inc. | Indazolones as modulators of tnf signaling |
| GB201510758D0 (en) | 2015-06-18 | 2015-08-05 | Ucb Biopharma Sprl | Novel TNFa structure for use in therapy |
| KR102679517B1 (ko) | 2015-08-03 | 2024-06-27 | 브리스톨-마이어스 스큅 컴퍼니 | Tnf 알파의 조정제로서 유용한 시클릭 화합물 |
| GB201621907D0 (en) | 2016-12-21 | 2017-02-01 | Ucb Biopharma Sprl And Sanofi | Antibody epitope |
| WO2018167176A1 (en) | 2017-03-15 | 2018-09-20 | Ucb Biopharma Sprl | Fused pentacyclic imidazole derivatives as modulators of tnf activity |
Family Cites Families (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6038397B2 (ja) * | 1980-03-06 | 1985-08-31 | エスエス製薬株式会社 | チアジノイミダゾ−ル誘導体及びその製造法 |
| CA2281927C (en) | 1997-02-25 | 2004-01-27 | Christopher J. Michejda | Substituted benzimidazoles as non-nucleoside inhibitors of reverse transcriptase |
| ES2254238T3 (es) * | 1999-10-27 | 2006-06-16 | Novartis Ag | Compuestos de tiazol e imidazo(4,5-b)piridina y su uso farmaceutico. |
| US7601846B2 (en) | 2001-06-26 | 2009-10-13 | The Regents Of The University Of California | Compounds having activity as inhibitors of apoptosis |
| TW200306822A (en) | 2002-01-31 | 2003-12-01 | Daiichi Seiyaku Co | Imidazo[1, 2-a]pyridine derivative |
| WO2004050035A2 (en) | 2002-12-03 | 2004-06-17 | Isis Pharmaceuticals, Inc. | Benzimidazoles and analogs thereof as antivirals |
| US20050124638A1 (en) | 2003-12-08 | 2005-06-09 | Swayze Eric E. | Benzimidazoles and analogs thereof as antivirals |
| ATE538120T1 (de) * | 2007-06-26 | 2012-01-15 | Sanofi Sa | Regioselektive, metallkatalysierte synthese annelierter benzimidazole und azabenzimidazole |
| FR2919610B1 (fr) * | 2007-08-02 | 2009-10-16 | Sanofi Aventis Sa | Derives de n-heteroaryl-carboxamides tricycliques,leur preparation et leur application en therapeutique |
| WO2009045174A1 (en) | 2007-10-05 | 2009-04-09 | S*Bio Pte Ltd | 2-morpholinylpurines as inhibitors of pi3k |
| JP2009227599A (ja) | 2008-03-21 | 2009-10-08 | Daiichi Sankyo Co Ltd | イミダゾピリダジン誘導体 |
| CN101717397B (zh) | 2008-10-09 | 2012-11-28 | 中国科学院上海药物研究所 | 一类取代吡啶并[2',1':2,3]咪唑并[4,5-c]异喹啉酮类化合物及其合成方法和用途,以及包含该类化合物的药物组合物 |
| BRPI0922565A2 (pt) * | 2008-12-19 | 2015-12-15 | Bristol Myers Squibb Co | compostos de carbazol carboxamida úteis como inibidores de cinase |
| US8691187B2 (en) | 2009-03-23 | 2014-04-08 | Eli Lilly And Company | Imaging agents for detecting neurological disorders |
| CA2756137C (en) | 2009-03-23 | 2015-11-24 | Siemens Medical Solutions Usa, Inc. | Imaging agents for detecting neurological disorders |
| WO2012148550A1 (en) | 2011-02-25 | 2012-11-01 | Myrexis, Inc. | Prodrugs of therapeutic compounds |
| EP2527344A1 (en) | 2011-05-25 | 2012-11-28 | Almirall, S.A. | Pyridin-2(1H)-one derivatives useful as medicaments for the treatment of myeloproliferative disorders, transplant rejection, immune-mediated and inflammatory diseases |
| US9550737B2 (en) * | 2012-06-11 | 2017-01-24 | Ucb Biopharma Sprl | TNF -α modulating benzimidazoles |
| GB201212513D0 (en) | 2012-07-13 | 2012-08-29 | Ucb Pharma Sa | Therapeutic agents |
| BR112015000675B1 (pt) | 2012-07-13 | 2022-07-12 | UCB Biopharma SRL | Derivados de imidazopiridina como moduladores da atividade de tnf |
| GB201321743D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
| GB201321742D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
| GB201321738D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic Agents |
| GB201321739D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
| GB201321744D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
| GB201321737D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic Agents |
| GB201321746D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
| GB201321741D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
| CN105814022B (zh) | 2013-12-09 | 2018-09-28 | Ucb生物制药私人有限公司 | 作为tnf活性调节剂的稠合的二环杂芳族衍生物 |
| GB201321735D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic Agents |
| GB201321745D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
| US9920052B2 (en) | 2013-12-09 | 2018-03-20 | Ucb Biopharma Sprl | Imidazopyridine derivatives as modulators of TNF activity |
| RS61884B1 (sr) | 2014-10-06 | 2021-06-30 | Signal Pharm Llc | Supstituisana aminopurinska jedinjenja, kompozicije koje ih sadrže i postupci za lečenje u kojima se koriste |
| MX2017011433A (es) | 2015-03-18 | 2017-11-10 | Bristol Myers Squibb Co | Compuestos heterociclicos triciclicos utiles como inhibidores del factor de necrosis tumoral (tnf). |
| EA201792054A1 (ru) | 2015-03-18 | 2018-01-31 | Бристол-Майерс Сквибб Компани | Гетероциклические соединения, применимые в качестве ингибиторов tnf |
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| JP2018508553A (ja) | 2018-03-29 |
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| WO2016149436A1 (en) | 2016-09-22 |
| IL254424A0 (en) | 2017-11-30 |
| BR112017019773A2 (pt) | 2018-05-15 |
| KR20170129810A (ko) | 2017-11-27 |
| EP3271360A1 (en) | 2018-01-24 |
| EA201792034A1 (ru) | 2018-03-30 |
| EP3271360B1 (en) | 2020-04-22 |
| KR102654709B1 (ko) | 2024-04-03 |
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| ES2797805T3 (es) | 2020-12-03 |
| US20180111936A1 (en) | 2018-04-26 |
| US10189840B2 (en) | 2019-01-29 |
| SG11201707469WA (en) | 2017-10-30 |
| JP6793657B2 (ja) | 2020-12-02 |
| AU2016233288A1 (en) | 2017-11-09 |
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