ES2615749T3 - Aminoquinazolinas como inhibidores de quinasa - Google Patents
Aminoquinazolinas como inhibidores de quinasa Download PDFInfo
- Publication number
- ES2615749T3 ES2615749T3 ES12824263.3T ES12824263T ES2615749T3 ES 2615749 T3 ES2615749 T3 ES 2615749T3 ES 12824263 T ES12824263 T ES 12824263T ES 2615749 T3 ES2615749 T3 ES 2615749T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- alkoxy
- benzo
- thiazol
- ferc
- 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.)
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- 229940043355 kinase inhibitor Drugs 0.000 title description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 4
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical class C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 title description 2
- -1 halo (C1-C6) alkyl Chemical group 0.000 claims abstract description 310
- 150000001875 compounds Chemical class 0.000 claims abstract description 226
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 159
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 136
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 134
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 124
- 150000003839 salts Chemical class 0.000 claims abstract description 113
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 109
- 150000002367 halogens Chemical class 0.000 claims abstract description 108
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 76
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 75
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 62
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 62
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 59
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 51
- 125000001424 substituent group Chemical group 0.000 claims abstract description 46
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 37
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 33
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 31
- 125000005843 halogen group Chemical group 0.000 claims abstract description 30
- 125000003118 aryl group Chemical group 0.000 claims abstract description 28
- 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 28
- 125000004429 atom Chemical group 0.000 claims abstract description 27
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 27
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 27
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 23
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 21
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 21
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 20
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims abstract description 19
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 18
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 14
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 13
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 12
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 11
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 10
- 125000005019 carboxyalkenyl group Chemical group 0.000 claims abstract description 8
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 7
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims abstract description 6
- 125000005159 cyanoalkoxy group Chemical group 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims description 66
- UJZYHMZRXGNDFB-UHFFFAOYSA-N 1,3-benzothiazol-5-amine Chemical compound NC1=CC=C2SC=NC2=C1 UJZYHMZRXGNDFB-UHFFFAOYSA-N 0.000 claims description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 55
- 102100022502 Receptor-interacting serine/threonine-protein kinase 2 Human genes 0.000 claims description 48
- 101001109137 Homo sapiens Receptor-interacting serine/threonine-protein kinase 2 Proteins 0.000 claims description 37
- 208000035475 disorder Diseases 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 27
- 201000010099 disease Diseases 0.000 claims description 27
- 238000011282 treatment Methods 0.000 claims description 27
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 24
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 24
- 125000005605 benzo group Chemical group 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 230000001404 mediated effect Effects 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 125000006536 (C1-C2)alkoxy group Chemical group 0.000 claims description 10
- 208000009766 Blau syndrome Diseases 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- BWDCBBZUYJDNJZ-UHFFFAOYSA-N quinazolin-7-ol Chemical compound C1=NC=NC2=CC(O)=CC=C21 BWDCBBZUYJDNJZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 8
- LKFXYYLRIUSARI-UHFFFAOYSA-N 1,3-thiazol-5-amine Chemical compound NC1=CN=CS1 LKFXYYLRIUSARI-UHFFFAOYSA-N 0.000 claims description 8
- 208000011231 Crohn disease Diseases 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 201000000306 sarcoidosis Diseases 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 7
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 7
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 7
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 7
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 7
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 210000000056 organ Anatomy 0.000 claims description 6
- 208000004930 Fatty Liver Diseases 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- 201000004624 Dermatitis Diseases 0.000 claims description 4
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 4
- 208000006673 asthma Diseases 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Substances CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 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 4
- MZLFZLVSRDZFFJ-UHFFFAOYSA-N 2-[4-(1,3-benzothiazol-5-ylamino)-7-methoxyquinazolin-6-yl]sulfonylethanol Chemical compound C1=C2SC=NC2=CC(NC=2N=CN=C3C=C(C(=CC3=2)S(=O)(=O)CCO)OC)=C1 MZLFZLVSRDZFFJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000006016 2-bromoethoxy group Chemical group 0.000 claims description 3
- LBQKGPAQEOLBBE-UHFFFAOYSA-N 4-(1,3-benzothiazol-5-ylamino)-7-methoxy-n,n-dimethylquinazoline-6-sulfonamide Chemical compound C1=C2SC=NC2=CC(NC=2N=CN=C3C=C(C(=CC3=2)S(=O)(=O)N(C)C)OC)=C1 LBQKGPAQEOLBBE-UHFFFAOYSA-N 0.000 claims description 3
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 3
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- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 206010069351 acute lung injury Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
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- ZUJRYXRSXABIAY-UHFFFAOYSA-N 1-[4-(1,3-benzothiazol-5-ylamino)-7-methoxyquinazolin-6-yl]sulfonylpyrrolidin-3-ol Chemical compound COC1=CC2=NC=NC(NC=3C=C4N=CSC4=CC=3)=C2C=C1S(=O)(=O)N1CCC(O)C1 ZUJRYXRSXABIAY-UHFFFAOYSA-N 0.000 claims description 2
- NOUORWQORZAMEI-UHFFFAOYSA-N 1-[4-[4-(1,3-benzothiazol-5-ylamino)-7-methoxyquinazolin-6-yl]sulfonylpiperazin-1-yl]ethanone Chemical compound COC1=CC2=NC=NC(NC=3C=C4N=CSC4=CC=3)=C2C=C1S(=O)(=O)N1CCN(C(C)=O)CC1 NOUORWQORZAMEI-UHFFFAOYSA-N 0.000 claims description 2
- UHDOJINBFLDQJM-UHFFFAOYSA-N 2-[4-(1,3-benzothiazol-5-ylamino)-6-tert-butylsulfonylquinazolin-7-yl]oxyethanol Chemical compound C1=C2SC=NC2=CC(NC2=C3C=C(C(=CC3=NC=N2)OCCO)S(=O)(=O)C(C)(C)C)=C1 UHDOJINBFLDQJM-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- ZGYAVKPNQOUSLY-UHFFFAOYSA-N 4-(1,3-benzothiazol-5-ylamino)-7-methoxy-n-propan-2-ylquinazoline-6-sulfonamide Chemical compound C1=C2SC=NC2=CC(NC=2N=CN=C3C=C(C(=CC3=2)S(=O)(=O)NC(C)C)OC)=C1 ZGYAVKPNQOUSLY-UHFFFAOYSA-N 0.000 claims description 2
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- 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 2
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 2
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- 108060006633 protein kinase Proteins 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
- 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 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- 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 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
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- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
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- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 1
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- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-FIBGUPNXSA-N trideuteriomethanethiol Chemical compound [2H]C([2H])([2H])S LSDPWZHWYPCBBB-FIBGUPNXSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- 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
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- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
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- 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
- A61P11/06—Antiasthmatics
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- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
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| TWI592417B (zh) | 2012-09-13 | 2017-07-21 | 葛蘭素史克智慧財產發展有限公司 | 胺基喹唑啉激酶抑制劑之前藥 |
| AR092530A1 (es) | 2012-09-13 | 2015-04-22 | Glaxosmithkline Llc | Compuesto de amino-quinolina, composicion farmaceutica que lo comprende y uso de dicho compuesto para la preparacion de un medicamento |
| JP6301374B2 (ja) | 2013-02-21 | 2018-03-28 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ | キナーゼ阻害剤としてのキナゾリン類 |
| CN105228625A (zh) * | 2013-03-15 | 2016-01-06 | 昂科迪塞恩股份有限公司 | 大环rip2激酶抑制剂 |
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| TWI730959B (zh) | 2015-05-19 | 2021-06-21 | 英商葛蘭素史克智慧財產發展有限公司 | 作為激酶抑制劑之雜環醯胺 |
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| CN109311867A (zh) * | 2016-04-20 | 2019-02-05 | 葛兰素史克知识产权开发有限公司 | 包含ripk2抑制剂的共轭物 |
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| WO2020043122A1 (zh) * | 2018-08-28 | 2020-03-05 | 南京明德新药研发有限公司 | 作为rip2激酶抑制剂的喹唑啉类衍生物 |
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