ES2828696T3 - Compuestos cíclicos útiles como moduladores de TNF alfa - Google Patents
Compuestos cíclicos útiles como moduladores de TNF alfa Download PDFInfo
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- ES2828696T3 ES2828696T3 ES16748045T ES16748045T ES2828696T3 ES 2828696 T3 ES2828696 T3 ES 2828696T3 ES 16748045 T ES16748045 T ES 16748045T ES 16748045 T ES16748045 T ES 16748045T ES 2828696 T3 ES2828696 T3 ES 2828696T3
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- zero
- alkyl
- substituted
- heterocyclyl
- crgrg
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- 150000001923 cyclic compounds Chemical class 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 298
- 150000001875 compounds Chemical class 0.000 claims abstract description 282
- -1 -OH Chemical group 0.000 claims abstract description 203
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 180
- 125000003118 aryl group Chemical group 0.000 claims abstract description 136
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 104
- 125000002950 monocyclic group Chemical group 0.000 claims abstract description 95
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 87
- 150000003839 salts Chemical class 0.000 claims abstract description 75
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 61
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 57
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 45
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 39
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 34
- 125000004452 carbocyclyl group Chemical group 0.000 claims abstract description 33
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 33
- 125000005843 halogen group Chemical group 0.000 claims abstract description 33
- 125000003709 fluoroalkyl group Chemical group 0.000 claims abstract description 31
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 24
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 24
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract description 22
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 20
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 15
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 14
- 125000005605 benzo group Chemical group 0.000 claims abstract description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 12
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 10
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims abstract description 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 8
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims abstract description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004429 atom Chemical group 0.000 claims abstract description 7
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 6
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims abstract description 6
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims abstract description 6
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 125000006574 non-aromatic ring group Chemical group 0.000 claims abstract description 6
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims abstract description 5
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims abstract description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 4
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract 2
- 239000000203 mixture Substances 0.000 claims description 67
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 22
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 19
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 19
- 208000023275 Autoimmune disease Diseases 0.000 claims description 18
- 208000027866 inflammatory disease Diseases 0.000 claims description 16
- 230000002757 inflammatory effect Effects 0.000 claims description 13
- JPFAOFJABONAJB-VHSZZVNMSA-N 2-[5-[(3R,4R,6S)-11-fluoro-3-(2-phenoxyphenyl)-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC=1C(=CC2=C(N=C3N2[C@H]([C@H]2[C@@H]3C2)C2=C(C=CC=C2)OC2=CC=CC=C2)C=1)C=1C=NC(=NC=1)C(C)(C)O JPFAOFJABONAJB-VHSZZVNMSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- VNALVOZUSICTIH-UHFFFAOYSA-N 6,9-diazatricyclo[4.3.0.02,4]nona-1(9),2,4,7-tetraene Chemical compound N1=C2N(C=C1)C=C1C2=C1 VNALVOZUSICTIH-UHFFFAOYSA-N 0.000 claims description 10
- DSEWTWHQTAWRCR-VWKPWSFCSA-N 2-[5-[(3S,4R,6S)-3-[2-(difluoromethoxy)phenyl]-11-fluoro-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC(OC1=C(C=CC=C1)[C@@H]1[C@H]2[C@@H](C=3N1C1=C(N=3)C=C(C(=C1)C=1C=NC(=NC=1)C(C)(C)O)F)C2)F DSEWTWHQTAWRCR-VWKPWSFCSA-N 0.000 claims description 9
- SBZJQXFOZICKET-UHFFFAOYSA-N N1C=2N(C=C1C(=O)N)C=CC=2 Chemical compound N1C=2N(C=C1C(=O)N)C=CC=2 SBZJQXFOZICKET-UHFFFAOYSA-N 0.000 claims description 9
- DSEWTWHQTAWRCR-XFQAVAEZSA-N 2-[5-[(3R,4R,6S)-3-[2-(difluoromethoxy)phenyl]-11-fluoro-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC(OC1=C(C=CC=C1)[C@H]1[C@H]2[C@@H](C=3N1C1=C(N=3)C=C(C(=C1)C=1C=NC(=NC=1)C(C)(C)O)F)C2)F DSEWTWHQTAWRCR-XFQAVAEZSA-N 0.000 claims description 8
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- JIQGOPATCHHCIY-JVAFGIKQSA-N 2-[5-[(3R,4R,6S)-11-fluoro-3-[2-(2-fluorophenoxy)phenyl]-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC=1C(=CC2=C(N=C3N2[C@H]([C@H]2[C@@H]3C2)C2=C(C=CC=C2)OC2=C(C=CC=C2)F)C=1)C=1C=NC(=NC=1)C(C)(C)O JIQGOPATCHHCIY-JVAFGIKQSA-N 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- JPFAOFJABONAJB-XXAUWVGASA-N 2-[5-[(3R,4S,6R)-11-fluoro-3-(2-phenoxyphenyl)-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC=1C(=CC2=C(N=C3N2[C@H]([C@@H]2[C@H]3C2)C2=C(C=CC=C2)OC2=CC=CC=C2)C=1)C=1C=NC(=NC=1)C(C)(C)O JPFAOFJABONAJB-XXAUWVGASA-N 0.000 claims description 6
- ZEUSMNCNQXELPK-JWZKTCGFSA-N 2-[5-[(3R,4S,6R)-11-fluoro-3-(2-phenylmethoxyphenyl)-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound C(C1=CC=CC=C1)OC1=C(C=CC=C1)[C@H]1[C@@H]2[C@H](C=3N1C1=C(N=3)C=C(C(=C1)C=1C=NC(=NC=1)C(C)(C)O)F)C2 ZEUSMNCNQXELPK-JWZKTCGFSA-N 0.000 claims description 6
- DDDWRDSBPPTAAS-UHFFFAOYSA-N 4-(6-methoxypyridin-3-yl)-15-phenyl-1,8,12-triazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraene Chemical compound COC1=CC=C(C=N1)C1=CC2=C(N=C3N2C(C2C3CNC2)C2=CC=CC=C2)C=C1 DDDWRDSBPPTAAS-UHFFFAOYSA-N 0.000 claims description 6
- QIJWWKSMZROLSE-JKSBSHDWSA-N 5-[(3R,4S,6R)-3-[2-(difluoromethoxy)phenyl]-11-fluoro-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyridine-2-carbonitrile Chemical compound FC(OC1=C(C=CC=C1)[C@H]1[C@@H]2[C@H](C=3N1C1=C(N=3)C=C(C(=C1)C=1C=CC(=NC=1)C#N)F)C2)F QIJWWKSMZROLSE-JKSBSHDWSA-N 0.000 claims description 6
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 6
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- ZMXXUTYAIDYCHN-TYBLODHISA-N 1-[(10R,14S,15S)-4-(6-methoxypyridin-3-yl)-15-phenyl-1,8,12-triazatetracyclo[7.6.0.02,7.010,14]pentadeca-2(7),3,5,8-tetraen-12-yl]ethanone Chemical compound COC1=CC=C(C=N1)C1=CC2=C(N=C3N2[C@@H]([C@H]2[C@@H]3CN(C2)C(C)=O)C2=CC=CC=C2)C=C1 ZMXXUTYAIDYCHN-TYBLODHISA-N 0.000 claims description 4
- KPSZBWZVNHDONM-MFEFFIJZSA-N 2-[5-[(3R,4S,6R)-3-[2-(difluoromethoxy)phenyl]-11-fluoro-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyridin-2-yl]propan-2-ol Chemical compound FC(OC1=C(C=CC=C1)[C@H]1[C@@H]2[C@H](C=3N1C1=C(N=3)C=C(C(=C1)C=1C=CC(=NC=1)C(C)(C)O)F)C2)F KPSZBWZVNHDONM-MFEFFIJZSA-N 0.000 claims description 4
- 201000005569 Gout Diseases 0.000 claims description 4
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- QMLWSAXEQSBAAQ-UHFFFAOYSA-N oxetan-3-ol Chemical compound OC1COC1 QMLWSAXEQSBAAQ-UHFFFAOYSA-N 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
- SMBWSTQAPWTKBN-VHSZZVNMSA-N 2-[5-[(3R,4R,6S)-11-fluoro-3-[2-(pyridin-4-ylmethoxy)phenyl]-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC=1C(=CC2=C(N=C3N2[C@H]([C@H]2[C@@H]3C2)C2=C(C=CC=C2)OCC2=CC=NC=C2)C=1)C=1C=NC(=NC=1)C(C)(C)O SMBWSTQAPWTKBN-VHSZZVNMSA-N 0.000 claims description 3
- DSEWTWHQTAWRCR-UHFFFAOYSA-N 2-[5-[3-[2-(difluoromethoxy)phenyl]-11-fluoro-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound CC(C)(C1=NC=C(C=N1)C2=CC3=C(C=C2F)N=C4N3C(C5C4C5)C6=CC=CC=C6OC(F)F)O DSEWTWHQTAWRCR-UHFFFAOYSA-N 0.000 claims description 3
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- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
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- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
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- 125000004655 dihydropyridinyl group Chemical group N1(CC=CC=C1)* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
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- JIQGOPATCHHCIY-IOKPGSKQSA-N 2-[5-[(3S,4R,6S)-11-fluoro-3-[2-(2-fluorophenoxy)phenyl]-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC=1C(=CC2=C(N=C3N2[C@@H]([C@H]2[C@@H]3C2)C2=C(C=CC=C2)OC2=C(C=CC=C2)F)C=1)C=1C=NC(=NC=1)C(C)(C)O JIQGOPATCHHCIY-IOKPGSKQSA-N 0.000 claims 2
- KNIBARYIKQDQLT-IEGUWTFLSA-N 4-[5-[(3S,4R,6S)-3-[2-(difluoromethoxy)phenyl]-11-fluoro-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]pyrimidin-2-yl]morpholine Chemical compound FC(OC1=C(C=CC=C1)[C@@H]1[C@H]2[C@@H](C=3N1C1=C(N=3)C=C(C(=C1)C=1C=NC(=NC=1)N1CCOCC1)F)C2)F KNIBARYIKQDQLT-IEGUWTFLSA-N 0.000 claims 2
- UYWCYWQJCZVXOE-DMPWYTOCSA-N 5-[(3R,4S,6R)-3-[2-(difluoromethoxy)phenyl]-11-fluoro-2,8-diazatetracyclo[7.4.0.02,7.04,6]trideca-1(9),7,10,12-tetraen-12-yl]-N-methylpyridine-2-carboxamide Chemical compound FC(OC1=C(C=CC=C1)[C@H]1[C@@H]2[C@H](C=3N1C1=C(N=3)C=C(C(=C1)C=1C=CC(=NC=1)C(=O)NC)F)C2)F UYWCYWQJCZVXOE-DMPWYTOCSA-N 0.000 claims 2
- NACQRCDPSHHQPT-UHFFFAOYSA-N 8-(6-methoxypyridin-3-yl)-11-phenyl-4,4a,11,11a-tetrahydro-1H-isoindolo[2,1-a]benzimidazole Chemical compound COc1ccc(cn1)-c1ccc2nc3C4CC=CCC4C(c4ccccc4)n3c2c1 NACQRCDPSHHQPT-UHFFFAOYSA-N 0.000 claims 2
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims 2
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A—HUMAN NECESSITIES
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
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- C—CHEMISTRY; METALLURGY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
Landscapes
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- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
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|---|---|---|---|
| US201562200415P | 2015-08-03 | 2015-08-03 | |
| PCT/US2016/045104 WO2017023902A1 (en) | 2015-08-03 | 2016-08-02 | Cyclic compounds useful as modulators of tnf alpha |
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| ES2828696T3 true ES2828696T3 (es) | 2021-05-27 |
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| ES16748045T Active ES2828696T3 (es) | 2015-08-03 | 2016-08-02 | Compuestos cíclicos útiles como moduladores de TNF alfa |
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| AR104293A1 (es) | 2015-04-17 | 2017-07-12 | Abbvie Inc | Indazolonas como moduladores de la señalización de tnf |
| US9856253B2 (en) | 2015-04-17 | 2018-01-02 | Abbvie, Inc. | Tricyclic modulators of TNF signaling |
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| EP3331889A1 (en) | 2018-06-13 |
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| CA2994703A1 (en) | 2017-02-09 |
| AU2016301215A1 (en) | 2018-03-22 |
| IL257159A (en) | 2018-03-29 |
| JP6811233B2 (ja) | 2021-01-13 |
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