RU2018123698A - Полициклические антагонисты tlr7/8 и их применение в лечении иммунных расстройств - Google Patents
Полициклические антагонисты tlr7/8 и их применение в лечении иммунных расстройств Download PDFInfo
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- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 title claims 3
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- 150000001875 compounds Chemical class 0.000 claims 19
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- 125000005842 heteroatom Chemical group 0.000 claims 6
- 229910052757 nitrogen Inorganic materials 0.000 claims 6
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- 125000003118 aryl group Chemical group 0.000 claims 4
- 229910052736 halogen Inorganic materials 0.000 claims 4
- 150000002367 halogens Chemical class 0.000 claims 4
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- 125000001072 heteroaryl group Chemical group 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
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- 125000002098 pyridazinyl group Chemical group 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
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- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical group C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims 1
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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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Claims (47)
1. Соединение формулы I,
или его фармацевтически приемлемая соль, где:
Кольцо A представляет собой арил или гетероарил, содержащий 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждый из которых необязательно замещен;
Кольцо B представляет собой арил или гетероарил, содержащий 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждый из которых необязательно замещен;
R1 отсутствует или представляет собой -H, -CHF2, -CF3, -OMe или -CN;
каждый R2 независимо представляет собой -H, -R, галоген, -галогеналкил, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R или -N(R)2;
каждый R3 независимо представляет собой -H, -R, галоген, -галогеналкил, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R или -N(R)2;
X представляет собой C(R4)2, O, NR4, S, S(R4) или S(R4)2;
каждый R4 независимо представляет собой -H, -R, галоген, -галогеналкил, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R или -N(R)2;
каждый R5 независимо представляет собой -H, -R, галоген, -галогеналкил, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R или -N(R)2;
каждый R независимо представляет собой водород, C1-6 алифатическую группу, C3-10 арил, 3-8 членное насыщенное или частично ненасыщенное карбоциклическое кольцо, 3-7 членное гетероциклическое кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы, или 5-6 членное моноциклическое гетероарильное кольцо, содержащее 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждая из этих групп необязательно замещена; или
две R группы на одном и том же атоме взяты вместе с атомом, к которому они присоединены, с образованием C3-10 арила, 3-8-членного насыщенного или частично ненасыщенного карбоциклического кольца, 3-7-членного гетероциклического кольца, содержащего 1-4 гетероатома, независимо выбранных из азота, кислорода или серы, или 5-6-членного моноциклического гетероарильного кольца, содержащего 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждое из которых необязательно замещено;
k имеет значение 0 или 1;
n имеет значение 0, 1 или 2;
p имеет значение 0, 1 или 2;
r имеет значение 0, 1 или 2; и
t имеет значение 0, 1 или 2.
2. Соединение по п. 1, где кольцо A представляет собой фенил, пиридил, пиримидинил, пиразинил, пиридазинил или триазинил; каждый из которых необязательно замещен.
3. Соединение по любому из предшествующих пунктов, где кольцо A представляет собой
4. Соединение по любому из предшествующих пунктов, где кольцо A представляет собой
5. Соединение по любому из предшествующих пунктов, где кольцо B представляет собой фенил, пиридил, пиримидинил, пиразинил, пиридазинил, триазинил, пиррол, имидазол, изоксазол, оксазол или тиазол; каждый из которых необязательно замещен.
6. Соединение по любому из предшествующих пунктов, где кольцо B представляет собой
7. Соединение по любому из предшествующих пунктов, где кольцо B представляет собой
8. Соединение по любому из предшествующих пунктов, где X представляет собой CH2.
9. Соединение по любому из предшествующих пунктов, где X представляет собой O.
10. Соединение по любому из предшествующих пунктов, где каждый R4 независимо представляет собой -H, C1-6 алифатическую группу, -OR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R или -N(R)2; каждая из этих групп необязательно замещена.
11. Соединение по любому из предшествующих пунктов, где каждый R4 независимо представляет собой -H, C1-6 алифатическую группу, -C(O)N(R)2, -NRC(O)R или -N(R)2; каждая из этих групп необязательно замещена.
12. Соединение по п. 1, формулы I-h
или его фармацевтически приемлемая соль.
13. Соединение по п. 1, формулы I-J
или его фармацевтически приемлемая соль.
14. Соединение по п. 1, формулы I-m
или его фармацевтически приемлемая соль.
15. Соединение по любому из предшествующих пунктов, выбранное из Таблицы 1.
16. Фармацевтическая композиция, включающая соединение по любому из пп. 1-15 и фармацевтически приемлемый адъювант, носитель или наполнитель.
17. Способ ингибирования активности TLR7/8 или его мутанта у пациента или в биологическом образце, включающий стадию введения указанному пациенту или контактирование указанного биологического образца с соединением по любому из пп. 1-15 или его физиологически приемлемой солью.
18. Способ лечения TLR7/8-опосредованного расстройства у пациента, нуждающегося в этом, включающий стадию введения указанному пациенту соединения по любому из пп. 1-15 или его физиологически приемлемой соли.
19. Способ по п. 18, где расстройство выбрано из ревматоидного артрита, псориатического артрита, остеоартрита, системной красной волчанки, волчаночного нефрита, анкилозирующего спондилита, остеопороза, системного склероза, рассеянного склероза, псориаза, диабета I типа, диабета II типа, воспалительного заболевания кишечника (болезнь Крона и язвенный колит), гипериммуноглобулинемии D и синдрома периодической лихорадки, криопирин-ассоциированных периодических синдромов, синдрома Шницлера, системного ювенильного идиопатического артрита, болезни Стилла, развившейся у взрослых, подагры, псевдоподагры, синдрома SAPHO, болезни Кастлемана, сепсиса, инсульта, атеросклероза, глютеновой болезни, DIRA (дефицит антагониста IL-1 рецептора), болезни Альцгеймера, болезни Паркинсона и рака.
20. Способ лечения рака у субъекта, включающий стадию введения указанному субъекту соединения по п. 1 или его физиологически приемлемой соли.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562268765P | 2015-12-17 | 2015-12-17 | |
| US62/268,765 | 2015-12-17 | ||
| US201662353603P | 2016-06-23 | 2016-06-23 | |
| US62/353,603 | 2016-06-23 | ||
| PCT/US2016/067112 WO2017106607A1 (en) | 2015-12-17 | 2016-12-16 | Polycyclic tlr7/8 antagonists and use thereof in the treatment of immune disorders |
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| Application Number | Title | Priority Date | Filing Date |
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| RU2022129070A Division RU2022129070A (ru) | 2015-12-17 | 2016-12-16 | Полициклические антагонисты tlr7/8 и их применение в лечении иммунных расстройств |
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| RU2018123698A true RU2018123698A (ru) | 2020-01-17 |
| RU2018123698A3 RU2018123698A3 (ru) | 2020-04-02 |
| RU2783748C2 RU2783748C2 (ru) | 2022-11-16 |
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