EA025436B1 - Аминохиназолины в качестве ингибиторов киназ - Google Patents

Info

Publication number

EA025436B1

EA025436B1 EA201490474A EA201490474A EA025436B1 EA 025436 B1 EA025436 B1 EA 025436B1 EA 201490474 A EA201490474 A EA 201490474A EA 201490474 A EA201490474 A EA 201490474A EA 025436 B1 EA025436 B1 EA 025436B1

Authority

EA

Eurasian Patent Office

Prior art keywords

benzo

thiazol

tert

alkoxy

butylsulfonyl

Prior art date

2011-08-18

Links

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• Global Dossier
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• 229940043355 kinase inhibitor Drugs 0.000 title description 3
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 3
• CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical class C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 231
• -1 halo (C1-C4) alkyl Chemical group 0.000 claims description 358
• 125000005605 benzo group Chemical group 0.000 claims description 215
• 229910052736 halogen Inorganic materials 0.000 claims description 139
• 150000003839 salts Chemical class 0.000 claims description 118
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 113
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 92
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 89
• LKFXYYLRIUSARI-UHFFFAOYSA-N 1,3-thiazol-5-amine Chemical compound NC1=CN=CS1 LKFXYYLRIUSARI-UHFFFAOYSA-N 0.000 claims description 81
• 150000002367 halogens Chemical class 0.000 claims description 80
• 125000003545 alkoxy group Chemical group 0.000 claims description 64
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 60
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
• 125000001072 heteroaryl group Chemical group 0.000 claims description 47
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 45
• 125000001424 substituent group Chemical group 0.000 claims description 40
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 39
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
• 239000000460 chlorine Substances 0.000 claims description 34
• 238000011282 treatment Methods 0.000 claims description 32
• 239000012634 fragment Substances 0.000 claims description 31
• 108091000080 Phosphotransferase Proteins 0.000 claims description 30
• 102000020233 phosphotransferase Human genes 0.000 claims description 30
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 30
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 29
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
• 125000006536 (C1-C2)alkoxy group Chemical group 0.000 claims description 23
• 125000000217 alkyl group Chemical group 0.000 claims description 22
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 22
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 22
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
• 201000010099 disease Diseases 0.000 claims description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims description 20
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 20
• 229910052757 nitrogen Inorganic materials 0.000 claims description 19
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
• 125000005842 heteroatom Chemical group 0.000 claims description 17
• 230000001404 mediated effect Effects 0.000 claims description 17
• 125000005843 halogen group Chemical group 0.000 claims description 16
• 125000002619 bicyclic group Chemical group 0.000 claims description 14
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 14
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 12
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 11
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 239000001301 oxygen Substances 0.000 claims description 11
• 125000004076 pyridyl group Chemical group 0.000 claims description 10
• 229940124530 sulfonamide Drugs 0.000 claims description 10
• 239000011593 sulfur Substances 0.000 claims description 10
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
• 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 8
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• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 8
• XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
• 238000006467 substitution reaction Methods 0.000 claims description 8
• 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 8
• NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 7
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
• 230000005764 inhibitory process Effects 0.000 claims description 7
• 201000000306 sarcoidosis Diseases 0.000 claims description 7
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• 206010046851 Uveitis Diseases 0.000 claims description 5
• 229960000074 biopharmaceutical Drugs 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
• SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 4
• NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
• 108010008165 Etanercept Proteins 0.000 claims description 4
• 206010037660 Pyrexia Diseases 0.000 claims description 4
• 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
• 239000003246 corticosteroid Substances 0.000 claims description 4
• 229960001334 corticosteroids Drugs 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 210000000056 organ Anatomy 0.000 claims description 4
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 3
• HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 claims description 3
• 108090000426 Caspase-1 Proteins 0.000 claims description 3
• 201000004624 Dermatitis Diseases 0.000 claims description 3
• 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 3
• 206010003246 arthritis Diseases 0.000 claims description 3
• 208000006673 asthma Diseases 0.000 claims description 3
• 125000000062 cyclohexylmethoxy group Chemical group [H]C([H])(O*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• 239000003814 drug Substances 0.000 claims description 3
• 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 3
• ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Substances CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 3
• 229960000485 methotrexate Drugs 0.000 claims description 3
• 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 3
• 229960004618 prednisone Drugs 0.000 claims description 3
• XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 claims description 3
• AHJBHKTZBNAQDR-UHFFFAOYSA-N quinazoline-6-sulfonamide Chemical compound N1=CN=CC2=CC(S(=O)(=O)N)=CC=C21 AHJBHKTZBNAQDR-UHFFFAOYSA-N 0.000 claims description 3
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
• IYZUIOQTKXSNLZ-UHFFFAOYSA-N 2-[4-(1,3-benzothiazol-5-ylamino)quinazolin-6-yl]sulfonylethanol Chemical compound C1=C2SC=NC2=CC(NC2=NC=NC3=CC=C(C=C32)S(=O)(=O)CCO)=C1 IYZUIOQTKXSNLZ-UHFFFAOYSA-N 0.000 claims description 2
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 2
• 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 2
• 208000007082 Alcoholic Fatty Liver Diseases 0.000 claims description 2
• UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 claims description 2
• ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
• 206010063837 Reperfusion injury Diseases 0.000 claims description 2
• 206010069351 acute lung injury Diseases 0.000 claims description 2
• 229960002964 adalimumab Drugs 0.000 claims description 2
• 208000026594 alcoholic fatty liver disease Diseases 0.000 claims description 2
• 229940073621 enbrel Drugs 0.000 claims description 2
• 229960000403 etanercept Drugs 0.000 claims description 2
• 229960001743 golimumab Drugs 0.000 claims description 2
• 229940048921 humira Drugs 0.000 claims description 2
• CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 2
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• 208000028774 intestinal disease Diseases 0.000 claims description 2
• 230000000302 ischemic effect Effects 0.000 claims description 2
• 210000004072 lung Anatomy 0.000 claims description 2
• KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 claims description 2
• 229960004963 mesalazine Drugs 0.000 claims description 2
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• NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 claims description 2
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• NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 claims description 2
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• 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims 1
• KKJKRBWPKJJGTO-UHFFFAOYSA-N 2-(4,5-dimethyl-1H-pyrazol-3-yl)quinazolin-4-amine Chemical compound CC=1C(=NNC=1C)C1=NC2=CC=CC=C2C(=N1)N KKJKRBWPKJJGTO-UHFFFAOYSA-N 0.000 claims 1
• QFXIIWGIPTWHOU-UHFFFAOYSA-N 2-[4-[(4,5-dimethyl-1h-pyrazol-3-yl)amino]-7-methoxyquinazolin-6-yl]sulfonylethanol Chemical compound C=12C=C(S(=O)(=O)CCO)C(OC)=CC2=NC=NC=1NC1=NNC(C)=C1C QFXIIWGIPTWHOU-UHFFFAOYSA-N 0.000 claims 1
• 125000006012 2-chloroethoxy group Chemical group 0.000 claims 1
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• 238000000034 method Methods 0.000 abstract description 35
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