RU2017134379A - Формилированные n-гетероциклические производные в качестве ингибиторов fgfr4 - Google Patents

Формилированные n-гетероциклические производные в качестве ингибиторов fgfr4 Download PDF

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RU2017134379A
RU2017134379A RU2017134379A RU2017134379A RU2017134379A RU 2017134379 A RU2017134379 A RU 2017134379A RU 2017134379 A RU2017134379 A RU 2017134379A RU 2017134379 A RU2017134379 A RU 2017134379A RU 2017134379 A RU2017134379 A RU 2017134379A
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pyridin
cyano
methyl
methylurea
formyl
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Николь Бушманн
Робин Алек Фэрхерст
Паскаль Фюре
Томас КНЁПФЕЛЬ
Катрин Леблан
Роберт Мах
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Новартис Аг
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/4965—Non-condensed pyrazines
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Claims (60)

1. Соединение формулы (I) в свободной форме или в форме фармацевтически приемлемой соли
Figure 00000001
где
X представляет собой N или CH;
A представляет собой C(O) и B представляет собой NR5 или
A и B вместе образуют часть 5- или 6-членного ароматического кольца, где A представляет собой C и B представляет собой C или N;
R1 выбран из водорода, гидроксиС1-С3алкила, галогенС1-С3алкила, CO2H, CH2NR2R3, 5-членного ароматического гетероциклического кольца, содержащего по меньшей мере один гетероатом, выбранный из N, О или S, где кольцо необязательно замещено одним или более C1-C3алкилами;
R2 представляет собой C1-C3алкил и R3 представляет собой C(O)C1-C3алкил
или
R2 и R3 вместе с N, к которому они присоединены, образуют насыщенное 5- или 6-членное кольцо, необязательно содержащее один дополнительный гетероатом, выбранный из N, О или S, где это кольцо необязательно замещено одним или более R4;
R4 для каждого случая, независимо выбран из C1-C3алкила, C1-C3алкокси или два R4, присоединенные к одному и тому же углеродному атому, образуют оксогруппу;
R5 выбран из водорода, C1-C3алкила, C1-C3алкоксиC1-C3алкила, (CH2)0-1-R6;
R6 представляет собой 4-, 5- или 6-членное насыщенное гетероциклическое кольцо, содержащее по меньшей мере один гетероатом, выбранный из N, O или S;
R7 выбран из циано, галогенС1-С3алкила;
R8 выбран из водорода, NR9R10, C1-C6алкокси;
R9 представляет собой водород;
R10 выбран из C1-C6алкила, гидроксиC1-C6алкила, C1-C4алкоксиC1-C6алкила.
2. Соединение по п.1 формулы (Ia) в свободной форме или в форме фармацевтически приемлемой соли
Figure 00000002
3. Соединение по п.1 формулы (Ib) в свободной форме или в форме фармацевтически приемлемой соли
Figure 00000003
где n равно 0 или 1;
B представляет собой C или N;
D, E, F, G каждый независимо выбран из CH или N, при условии, что, когда n равно 0, по меньшей мере один из B, E, F или G представляет собой N.
4. Соединение по любому из пп.1-3 в свободной форме или в форме фармацевтически приемлемой соли, где X предствляет собой CH.
5. Соединение по п.1 в свободной форме или в форме фармацевтически приемлемой соли, которое выбрано из
6-((2-(6-формилпиридин-2-ил)фенил)амино)никотинонитрила;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-(6-формилпиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-(6-формилпиридин-2-ил)-1-(2-метоксиэтил)мочевины;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-(6-формилпиридин-2-ил)-1-((тетрагидрофуран-3-ил)метил)мочевины;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-(6-формил-5-(гидроксиметил)пиридин-2-ил)-1-((тетрагидрофуран-3-ил)метил)мочевины;
3-(5-циано-4-изопропоксипиридин-2-ил)-1-(7-гидрокси-5-оксо-5,7-дигидрофуро[3,4-b]пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-(7-гидрокси-5-оксо-5,7-дигидрофуро[3,4-b]пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-этил-1-(6-формил-5-(1-метил-1H-пиразол-4-ил)пиридин-2-ил)мочевины;
3-(5-циано-4-(изопропиламино)пиридин-2-ил)-1-этил-1-(6-формил-5-(1-метил-1H-пиразол-4-ил)пиридин-2-ил)мочевины;
3-(5-циано-4-изопропоксипиридин-2-ил)-1-этил-1-(6-формил-5-(1-метил-1H-пиразол-4-ил)пиридин-2-ил)мочевины;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-(6-формил-5-(1-метил-1H-пиразол-4-ил)пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-(изопропиламино)пиридин-2-ил)-1-(6-формил-5-(1-метил-1H-пиразол-4-ил)пиридин-2-ил)-1-метилмочевины;
N-((6-(3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-метилуреидо)-2-формилпиридин-3-ил)метил)-N-метилацетамида;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-(5-(дифторметил)-6-формилпиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-изопропоксипиридин-2-ил)-1-(6-формил-5-((4-метилпиперазин-1-ил)метил)пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-изопропоксипиридин-2-ил)-1-(5-(дифторметил)-6-формилпиридин-2-ил)-1-метилмочевины;
3-(5-цианопиридин-2-ил)-1-(6-формил-5-((2-оксопирролидин-1-ил)метил)пиридин-2-ил)-1-метилмочевины3-(5-цианопиридин-2-ил)-1-(6-формил-5-((2-оксопирролидин-1-ил)метил)пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-(6-формил-5-((2-оксопирролидин-1-ил)метил)пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-изопропоксипиридин-2-ил)-1-(6-формил-5-((4-метил-2-оксопиперазин-1-ил)метил)пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-((2-гидрокси-2-метилпропил)амино)пиридин-2-ил)-1-(6-формил-5-(1-метил-1H-пиразол-4-ил)пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-изопропоксипиридин-2-ил)-1-(6-формил-5-((2-оксопирролидин-1-ил)метил)пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-((2-метоксиэтил)амино)пиридин-2-ил)-1-(6-формил-5-((4-метил-2-оксопиперазин-1-ил)метил)пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-изопропоксипиридин-2-ил)-1-(6-формил-5-(1-метил-1H-пиразол-4-ил)пиридин-2-ил)-1-метилмочевины;
3-(5-циано-4-изопропоксипиридин-2-ил)-1-(6-формил-5-((3-метоксипирролидин-1-ил)метил)пиридин-2-ил)-1-метилмочевины;
6-(2-((4-((2-метоксиэтил)амино)-5-(трифторметил)пиридин-2-ил)амино)-1H-имидазол-1-ил)-3-(1-метил-1H-пиразол-4-ил)пиколинальдегида;
6-(5-((4-((2-метоксиэтил)амино)-5-(трифторметил)пиридин-2-ил)амино)-1H-пиразол-1-ил)-3-(1-метил-1H-пиразол-4-ил)пиколинальдегида;
3-(5-циано-4-изопропоксипиридин-2-ил)-1-(6-формил-5-(пирролидин-1-илметил)пиридин-2-ил)-1-метилмочевины и
1-(5-циано-4-изопропоксипиридин-2-ил)-3-(4-формилпиримидин-2-ил)мочевины.
6. Фармацевтическая композиция, содержащая терапевтически эффективное количество соединения по любому из пп.1-5 или его фармацевтически приемлемой соли и один или несколько фармацевтически приемлемых носителей.
7. Комбинация, содержащая терапевтически эффективное количество соединения по любому из пп.1-5 или его фармацевтически приемлемой соли и одно или несколько терапевтически активных средств.
8. Соединение по любому из пп.1-5 или его фармацевтически приемлемая соль для применения в качестве лекарственного средства.
9. Соединение по любому из пп.1-5 или его фармацевтически приемлемая соль для применения при лечении рака.
10. Соединение по п.9 или его фармацевтически приемлемая соль, где рак выбран из рака печени, рака молочной железы, глиобластомы, рака предстательной железы, рабдомиосаркомы, рака желудка, рака яичников, рака легких, рака толстой кишки.
11. Применение соединения по любому из пп.1-6 или его фармацевтически приемлемой соли в изготовлении лекарственного средства для лечения рака.
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CN107840842A (zh) 2016-09-19 2018-03-27 北京天诚医药科技有限公司 炔代杂环化合物、其制备方法及其在医药学上的应用
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EP3444275A1 (en) 2017-08-16 2019-02-20 Exiris S.r.l. Monoclonal antibody anti-fgfr4
CN109745321B (zh) * 2017-11-08 2022-04-29 上海翰森生物医药科技有限公司 包含fgfr4抑制剂的药物组合物
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US20190105309A1 (en) 2019-04-11
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