RU2016119519A - Соединения гетероарила в качестве ингибиторов btk и их применение - Google Patents

Соединения гетероарила в качестве ингибиторов btk и их применение Download PDF

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RU2016119519A
RU2016119519A RU2016119519A RU2016119519A RU2016119519A RU 2016119519 A RU2016119519 A RU 2016119519A RU 2016119519 A RU2016119519 A RU 2016119519A RU 2016119519 A RU2016119519 A RU 2016119519A RU 2016119519 A RU2016119519 A RU 2016119519A
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compound
nitrogen
nrc
sulfur
oxygen
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RU2016119519A
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RU2703301C2 (ru
RU2016119519A3 (ru
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Хой Цю
Ричард Д. Колдвелл
Константин Неагу
Игорь Мочалкин
Лесли Лю-Буджалски
Рейналдо ДЖОУНС
Девон ТАТЕ
Тереза Л. Джонсон
Анна ГАРДБЕРГ
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Мерк Патент Гмбх
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    • 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
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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Claims (51)

1. Соединение формулы I,
Figure 00000001
или его фармацевтически приемлемая соль, где:
кольцо A представляет собой 6-членное гетероарильное кольцо, содержащее 1 или 2 азота, выбранное из пиридина, пиразина, пиридазина и пиримидина;
R2 выбирают из -R, галогена, -галоалкила, -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;
R3 выбирают из -R, галогена, -галоалкила, -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;
где, по меньшей мере, один из R2 или R3 представляет собой -C(O)N(R)2 или CN;
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; каждое из которых необязательно замещено; или
две R группы на одном и том же атоме, взятые вместе с атомом, к которому они присоединены, образуют 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; каждый из которых необязательно замещен;
L представляет собой двухвалентную группу, выбранную из C1-6 алифатической группы, 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, и 5-6-членного моноциклического гетероарильного кольца, содержащего 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждый из которых необязательно замещен; или L представляет собой двухвалентную группу, выбранную из C1-6 алифатического-C3-10 арила, C1-6 алифатического-3-8-членного насыщенного или частично ненасыщенного карбоциклического кольца, C1-6 алифатического-3-7-членного гетероциклического кольца, содержащего 1-4 гетероатома, независимо выбранных из азота, кислорода или серы, и C1-6 алифатического-5-6-членного моноциклического гетероарильного кольца, содержащего 1-4 гетероатома, независимо выбранных из азота, кислорода или серы; каждый из которых необязательно замещен;
Y представляет собой O, S, SO2, SO, C(O), CO2, C(O)N(R), -NRC(O), -NRC(O)N(R), -NRSO2 или N(R); или Y отсутствует;
R1 представляет собой 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; каждый из которых необязательно замещен;
X представляет собой O, S, SO2, SO, C(O), CO2, C(O)N(R), -NRC(O), -NRC(O)N(R), -NRSO2 или N(R); или X отсутствует; и
R4 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; каждое из которых необязательно замещено; или
X-R4 отсутствует.
2. Соединение по п. 1, где R2 представляет собой водород, галоген, -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 и R3 представляет собой водород, галоген, -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; где по меньшей мере, один из R2 или R3 представляет собой -C(O)N(R)2.
3. Соединение по п. 1, где L представляет собой
Figure 00000002
Figure 00000003
Figure 00000004
4. Соединение по п. 1, где Y представляет собой
Figure 00000005
;
и R1 представляет собой
Figure 00000006
.
5. Соединение по п. 1, где X представляет собой O, C(O)NH, -NHC(O), NH или N(Me); или X отсутствует.
6. Соединение по п. 1, где R4 представляет собой водород, метилом,
Figure 00000007
Figure 00000008
Figure 00000009
Figure 00000010
Figure 00000011
7. Соединение по п. 1, где X-R4 отсутствует.
8. Соединение по п. 1, формулы I-a1
Figure 00000012
I-a1;
или его фармацевтически приемлемая соль.
9. Соединение по п. 8, где R2 представляет собой -C(O)NH2, и R3 отсутствует.
10. Соединение по п. 8, где X представляет собой O, и R4 представляет собой
Figure 00000013
; или X представляет собой NH; и R4 представляет собой
Figure 00000014
.
11. Соединение по п. 1 формулы I-c1:
Figure 00000015
I-c1;
или его фармацевтически приемлемая соль.
12. Соединение по п. 11, где R2 представляет собой -C(O)NH2, и R3 отсутствует.
13. Соединение по п. 11, где X представляет собой O, и R4 представляет собой
Figure 00000013
.
14. Соединение по п. 1, выбранное из таблицы 1.
15. Фармацевтическая композиция, содержащая соединение по п. 1 и фармацевтически приемлемый адъювант, носитель или наполнитель.
16. Способ ингибирования активности BTK или ее мутанта у пациента или в биологическом образце, включающий стадию введения указанному пациенту или контакта указанного биологического образца с соединением по пункту 1 или его физиологически приемлемой солью.
17. Способ лечения опосредованного BTK расстройства у пациента, нуждающегося в таковом, включающий стадию введения указанному пациенту соединения по п. 1.
18. Способ лечения волчанки у пациента, включающий стадию введения указанному пациенту соединения по п. 1 или его физиологически приемлемой соли.
19. Применение соединения по п. 1 или его физиологически приемлемых солей для производства лекарственного средства для профилактического или терапевтического лечения опосредованного BTK расстройства.
20. Способ производства соединения формулы I по п. 1, включающий стадии:
взаимодействия соединения формулы (II):
Figure 00000016
,
где X, X1 и X2 такие, как определены в п. 1;
с соединением с получением соединения формулы I:
Figure 00000001
,
где X, R1, R2, R3, R4, L и Y такие, как определены в п.1.
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