BR112015020264B1 - derivados de piridinil e piridinil fundida triazolona, composição farmacêutica, combinação e usos dos mesmos - Google Patents

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Publication number

BR112015020264B1

BR112015020264B1 BR112015020264-0A BR112015020264A BR112015020264B1 BR 112015020264 B1 BR112015020264 B1 BR 112015020264B1 BR 112015020264 A BR112015020264 A BR 112015020264A BR 112015020264 B1 BR112015020264 B1 BR 112015020264B1

Authority

BR

Brazil

Prior art keywords

triazole

tautomer

compound

pharmaceutically acceptable

isoquinolin

Prior art date

2013-03-11

Links

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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
• 125000004076 pyridyl group Chemical group 0.000 title description 6
• DKHMDUDREAVQOQ-UHFFFAOYSA-N 5-pyridin-2-yltriazol-4-one Chemical compound O=C1N=NN=C1C1=CC=CC=N1 DKHMDUDREAVQOQ-UHFFFAOYSA-N 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 380
• 150000003839 salts Chemical class 0.000 claims abstract description 87
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 69
• 208000035475 disorder Diseases 0.000 claims abstract description 36
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 20
• 201000011510 cancer Diseases 0.000 claims abstract description 13
• 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 8
• 208000027866 inflammatory disease Diseases 0.000 claims abstract description 7
• 208000010216 atopic IgE responsiveness Diseases 0.000 claims abstract description 5
• 230000003211 malignant effect Effects 0.000 claims abstract description 5
• 230000002062 proliferating effect Effects 0.000 claims abstract description 5
• -1 R10 Chemical group 0.000 claims description 209
• 125000005843 halogen group Chemical group 0.000 claims description 113
• 125000001424 substituent group Chemical group 0.000 claims description 110
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 98
• 229910052739 hydrogen Inorganic materials 0.000 claims description 93
• 239000001257 hydrogen Substances 0.000 claims description 93
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 75
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 73
• 125000004432 carbon atom Chemical group C* 0.000 claims description 64
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 59
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 53
• 125000003386 piperidinyl group Chemical group 0.000 claims description 51
• 229910052757 nitrogen Inorganic materials 0.000 claims description 45
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 32
• 201000010099 disease Diseases 0.000 claims description 32
• 239000003814 drug Substances 0.000 claims description 23
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 20
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
• 229940079593 drug Drugs 0.000 claims description 17
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
• 125000004043 oxo group Chemical group O=* 0.000 claims description 15
• 125000000623 heterocyclic group Chemical group 0.000 claims description 13
• 239000000460 chlorine Substances 0.000 claims description 12
• 229910052801 chlorine Inorganic materials 0.000 claims description 12
• 125000001072 heteroaryl group Chemical group 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
• 239000011737 fluorine Substances 0.000 claims description 11
• 229910052731 fluorine Inorganic materials 0.000 claims description 11
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• 230000005764 inhibitory process Effects 0.000 claims description 10
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
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• VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 8
• 239000005977 Ethylene Substances 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• 125000000217 alkyl group Chemical group 0.000 claims description 8
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• FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 5
• 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 5
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• HIMUHMBGRATXMK-LBPRGKRZSA-N 5-[1-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C=C)CC[C@@H]1OC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 HIMUHMBGRATXMK-LBPRGKRZSA-N 0.000 claims description 4
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• OUXQVZPHPUFGSB-LBPRGKRZSA-N 5-[7-chloro-1-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C12=CC(Cl)=CC=C2C=C(C=2NC(=O)NN=2)N=C1O[C@H]1CCN(C(=O)C=C)C1 OUXQVZPHPUFGSB-LBPRGKRZSA-N 0.000 claims description 3
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• UHOLIIZPKLSUEZ-NSHDSACASA-N 5-[8-[[(3s)-1-prop-2-enoylpyrrolidin-3-yl]amino]-1,7-naphthyridin-6-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C=C)CC[C@@H]1NC1=NC(C=2NC(=O)NN=2)=CC2=CC=CN=C12 UHOLIIZPKLSUEZ-NSHDSACASA-N 0.000 claims description 3
• KLOPMWUFPGQSEQ-NSHDSACASA-N 5-[8-chloro-1-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C=12C(Cl)=CC=CC2=CC(C=2NC(=O)NN=2)=NC=1O[C@H]1CCN(C(=O)C=C)C1 KLOPMWUFPGQSEQ-NSHDSACASA-N 0.000 claims description 3
• WIWSEHXQQRGARM-NSHDSACASA-N 5-[8-fluoro-1-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C=12C(F)=CC=CC2=CC(C=2NC(=O)NN=2)=NC=1O[C@H]1CCN(C(=O)C=C)C1 WIWSEHXQQRGARM-NSHDSACASA-N 0.000 claims description 3
• XQNSUCSTZWTOOI-NSHDSACASA-N 5-[8-fluoro-1-[[(3s)-1-prop-2-enoylpyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C=12C(F)=CC=CC2=CC(C=2NC(=O)NN=2)=NC=1N[C@H]1CCN(C(=O)C=C)C1 XQNSUCSTZWTOOI-NSHDSACASA-N 0.000 claims description 3
• 201000001320 Atherosclerosis Diseases 0.000 claims description 3
• 208000009137 Behcet syndrome Diseases 0.000 claims description 3
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
• 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
• 208000005777 Lupus Nephritis Diseases 0.000 claims description 3
• RDAUVLJFXVQEQM-UHFFFAOYSA-N N-[1-[3-(5-oxo-1,2,4-triazolidin-3-yl)isoquinolin-1-yl]pyrrolidin-3-yl]prop-2-enamide Chemical compound C=CC(=O)NC1CCN(C1)c1nc(cc2ccccc12)C1NNC(=O)N1 RDAUVLJFXVQEQM-UHFFFAOYSA-N 0.000 claims description 3
• 201000011152 Pemphigus Diseases 0.000 claims description 3
• 201000004681 Psoriasis Diseases 0.000 claims description 3
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
• 201000010105 allergic rhinitis Diseases 0.000 claims description 3
• 201000008937 atopic dermatitis Diseases 0.000 claims description 3
• 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 3
• 208000010125 myocardial infarction Diseases 0.000 claims description 3
• 201000001976 pemphigus vulgaris Diseases 0.000 claims description 3
• ZXTHQQJBDSNNOS-CYBMUJFWSA-N 5-[1-[(3r)-1-(2-methylprop-2-enoyl)pyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C(=C)C)CC[C@H]1OC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 ZXTHQQJBDSNNOS-CYBMUJFWSA-N 0.000 claims description 2
• HIMUHMBGRATXMK-GFCCVEGCSA-N 5-[1-[(3r)-1-prop-2-enoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C=C)CC[C@H]1OC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 HIMUHMBGRATXMK-GFCCVEGCSA-N 0.000 claims description 2
• ZXTHQQJBDSNNOS-ZDUSSCGKSA-N 5-[1-[(3s)-1-(2-methylprop-2-enoyl)pyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C(=C)C)CC[C@@H]1OC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 ZXTHQQJBDSNNOS-ZDUSSCGKSA-N 0.000 claims description 2
• UKIVMPXDGIAZID-PXTSUWAFSA-N 5-[1-[(3s)-1-[(e)-4-(dimethylamino)but-2-enoyl]pyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)/C=C/CN(C)C)CC[C@@H]1OC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 UKIVMPXDGIAZID-PXTSUWAFSA-N 0.000 claims description 2
• YFGTVWDQSBQMBM-LBPRGKRZSA-N 5-[1-[(3s)-1-acetylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C)CC[C@@H]1OC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 YFGTVWDQSBQMBM-LBPRGKRZSA-N 0.000 claims description 2
• KYZPCEHHHGJVOX-ZDUSSCGKSA-N 5-[1-[(3s)-1-prop-2-enoylpiperidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C=C)CCC[C@@H]1OC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 KYZPCEHHHGJVOX-ZDUSSCGKSA-N 0.000 claims description 2
• HTXPJYDZXSMZTC-LBPRGKRZSA-N 5-[1-[(3s)-1-propanoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)CC)CC[C@@H]1OC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 HTXPJYDZXSMZTC-LBPRGKRZSA-N 0.000 claims description 2
• LJWJTZQRGMIPDK-ZDUSSCGKSA-N 5-[1-[[(2s)-1-prop-2-enoylpyrrolidin-2-yl]methoxy]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C=CC(=O)N1CCC[C@H]1COC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 LJWJTZQRGMIPDK-ZDUSSCGKSA-N 0.000 claims description 2
• UTDUWAWPKONJGQ-NSHDSACASA-N 5-[1-[[(3s)-1-(2-chloroacetyl)pyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)CCl)CC[C@@H]1NC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 UTDUWAWPKONJGQ-NSHDSACASA-N 0.000 claims description 2
• OQVAZKQKTNVHRQ-ZDUSSCGKSA-N 5-[1-[[(3s)-1-(2-methylprop-2-enoyl)pyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C(=C)C)CC[C@@H]1NC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 OQVAZKQKTNVHRQ-ZDUSSCGKSA-N 0.000 claims description 2
• CYMOLUOXIMMCFW-NDRDAGNVSA-N 5-[1-[[(3s)-1-[(e)-but-2-enoyl]pyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)/C=C/C)CC[C@@H]1NC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 CYMOLUOXIMMCFW-NDRDAGNVSA-N 0.000 claims description 2
• LJHLTVPJMRHWGZ-ZDUSSCGKSA-N 5-[1-[methyl-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound N=1C(C=2NC(=O)NN=2)=CC2=CC=CC=C2C=1N(C)[C@H]1CCN(C(=O)C=C)C1 LJHLTVPJMRHWGZ-ZDUSSCGKSA-N 0.000 claims description 2
• SLIKOFJPQARPAU-JTQLQIEISA-N 5-[4-methyl-6-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxypyridin-2-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound N=1C(C=2NC(=O)NN=2)=CC(C)=CC=1O[C@H]1CCN(C(=O)C=C)C1 SLIKOFJPQARPAU-JTQLQIEISA-N 0.000 claims description 2
• RITRWFUHKPESFH-VIFPVBQESA-N 5-[6-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxypyridin-2-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C=C)CC[C@@H]1OC1=CC=CC(C=2NC(=O)NN=2)=N1 RITRWFUHKPESFH-VIFPVBQESA-N 0.000 claims description 2
• MTCIVWJQXPPNAS-LBPRGKRZSA-N 5-[7-fluoro-1-[(3s)-1-prop-2-enoylpyrrolidin-3-yl]oxyisoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C12=CC(F)=CC=C2C=C(C=2NC(=O)NN=2)N=C1O[C@H]1CCN(C(=O)C=C)C1 MTCIVWJQXPPNAS-LBPRGKRZSA-N 0.000 claims description 2
• FLDYREMAARAHTJ-LBPRGKRZSA-N 5-[8-methoxy-1-[[(3s)-1-prop-2-enoylpyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C=12C(OC)=CC=CC2=CC(C=2NC(=O)NN=2)=NC=1N[C@H]1CCN(C(=O)C=C)C1 FLDYREMAARAHTJ-LBPRGKRZSA-N 0.000 claims description 2
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• 150000002431 hydrogen Chemical group 0.000 claims 14
• MIJKWXXKYTVHGR-LBPRGKRZSA-N 5-[1-[[(3s)-1-prop-2-enoylpyrrolidin-3-yl]amino]isoquinolin-3-yl]-1,2-dihydro-1,2,4-triazol-3-one Chemical compound C1N(C(=O)C=C)CC[C@@H]1NC1=NC(C=2NC(=O)NN=2)=CC2=CC=CC=C12 MIJKWXXKYTVHGR-LBPRGKRZSA-N 0.000 claims 2
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