RU2019101613A - Низкомолекулярные модуляторы пантотенаткиназ - Google Patents

Низкомолекулярные модуляторы пантотенаткиназ Download PDF

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RU2019101613A
RU2019101613A RU2019101613A RU2019101613A RU2019101613A RU 2019101613 A RU2019101613 A RU 2019101613A RU 2019101613 A RU2019101613 A RU 2019101613A RU 2019101613 A RU2019101613 A RU 2019101613A RU 2019101613 A RU2019101613 A RU 2019101613A
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acyclic
alkyl
cyclopropyl
halogen
cyclobutyl
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Лалит Кумар ШАРМА
Ричард Э. ЛИ
Чарльз О. РОК
Сюзан ЯКОВСКИ
Ми Кюйн ЮНЬ
Читра СУБРАМАНИАН
Цзюй ЛЮ
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Ст. Джуд Чилдрен'З Рисерч Хоспитал
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Claims (63)

1. Соединение, имеющее структуру, представленную формулой:
Figure 00000001
,
где A выбран из O, CO, CH2, CF2, NH, N(CH3) и CH(OH);
где Q1 представляет собой CH; и где R2 выбран из –SCH3, C1-C8 ациклического алкила, C1-C8 ациклического алкенила, C1-C8 моногалогеналкила, C1-C8 полигалогеналкила, C1-C8 алкоксигалогеналкила, циклопропила, циклобутила и оксетена, причем циклопропил, циклобутил и оксетен необязательно замещены 1, 2 или 3 группами, независимо выбранными из –OH, C1-C4 алкила и C1-C4 алкокси; или
где Q1 представляет собой N; и R2 выбран из галогена, –SCH3, C1-C8 ациклического алкила, C1-C8 ациклического алкенила, C1-C8 моногалогеналкила, C1-C8 полигалогеналкила, C1-C8 алкоксигалогеналкила, циклопропила, циклобутила и оксетена, причем циклопропил, циклобутил и оксетен необязательно замещены 1, 2 или 3 группами, независимо выбранными из –OH, C1-C4 алкила и C1-C4 алкокси;
где Q2 представляет собой структуру, выбранную из:
Figure 00000002
,
Figure 00000003
,
Figure 00000004
Figure 00000005
,
Figure 00000006
,
Figure 00000007
,
Figure 00000008
,
Figure 00000009
,
Figure 00000010
,
Figure 00000011
,
Figure 00000012
,
Figure 00000013
,
Figure 00000014
,
Figure 00000015
,
Figure 00000016
,
Figure 00000017
,
Figure 00000018
,
Figure 00000019
,
Figure 00000020
,
Figure 00000021
,
Figure 00000022
,
Figure 00000023
,
Figure 00000024
,
Figure 00000025
,
Figure 00000026
,
Figure 00000027
,
Figure 00000028
,
Figure 00000029
,
Figure 00000030
,
Figure 00000031
,
Figure 00000032
 и
Figure 00000033
;
где каждый из R3a и R3b независимо выбран из водорода, галогена, −OH, C1-C4 алкокси и C1-C4 алкила; и
где R4 выбран из водорода, галогена, –CN, SO2NH2, SO2CH3, SO2CF3 и NO2,
или его фармацевтически приемлемая соль.
2. Соединение по п. 1, в котором Q1 представляет собой CH и R2 выбран из C1-C8 ациклического алкила, C1-C8 ациклического алкенила, C1-C8 моногалогеналкила, C1-C8 полигалогеналкила и циклопропила; или где Q1 представляет собой N и R2 выбран из галогена, C1-C8 ациклического алкила, C1-C8 ациклического алкенила, C1-C8 моногалогеналкила, C1-C8 полигалогеналкила и циклопропила; и где Q2 представляет собой структуру, выбранную из:
Figure 00000002
,
Figure 00000003
,
Figure 00000004
Figure 00000005
,
Figure 00000006
,
Figure 00000007
,
Figure 00000008
,
Figure 00000009
,
Figure 00000010
,
Figure 00000011
,
Figure 00000012
,
Figure 00000013
,
Figure 00000014
,
Figure 00000015
,
Figure 00000016
,
Figure 00000017
,
Figure 00000018
,
Figure 00000019
,
Figure 00000020
,
Figure 00000021
,
Figure 00000022
,
Figure 00000023
,
Figure 00000024
,
Figure 00000025
,
Figure 00000026
,
Figure 00000027
,
Figure 00000028
,
Figure 00000029
 и
Figure 00000030
.
3. Соединение по п. 1, в котором Q2 представляет собой структуру, выбранную из:
Figure 00000034
,
Figure 00000035
,
Figure 00000036
,
Figure 00000037
,
Figure 00000038
,
Figure 00000039
,
Figure 00000040
,
Figure 00000041
,
Figure 00000042
,
Figure 00000043
,
Figure 00000044
,
Figure 00000045
,
Figure 00000046
,
Figure 00000047
,
Figure 00000048
,
Figure 00000049
,
Figure 00000050
,
Figure 00000051
,
Figure 00000052
,
Figure 00000053
,
Figure 00000054
,
Figure 00000055
,
Figure 00000056
,
Figure 00000057
,
Figure 00000058
,
Figure 00000059
,
Figure 00000060
,
Figure 00000061
,
Figure 00000062
,
Figure 00000063
,
Figure 00000064
, и
Figure 00000065
.
4. Соединение по п. 1, в котором Q2 представляет собой структуру, выбранную из:
Figure 00000066
,
Figure 00000067
,
Figure 00000068
,
Figure 00000069
,
Figure 00000070
,
Figure 00000071
,
Figure 00000040
,
Figure 00000072
,
Figure 00000073
,
Figure 00000074
,
Figure 00000075
,
Figure 00000076
,
Figure 00000077
,
Figure 00000078
,
Figure 00000079
,
Figure 00000080
,
Figure 00000081
,
Figure 00000082
,
Figure 00000083
,
Figure 00000084
,
Figure 00000085
,
Figure 00000086
,
Figure 00000087
,
Figure 00000088
,
Figure 00000089
,
Figure 00000090
,
Figure 00000091
,
Figure 00000092
,
Figure 00000093
,
Figure 00000094
,
Figure 00000095
 и
Figure 00000096
.
5. Соединение по п. 1, имеющее структуру, представленную формулой:
Figure 00000097
,
или его фармацевтически приемлемая соль.
6. Соединение по п. 1, имеющее структуру, представленную формулой:
Figure 00000098
,
или его фармацевтически приемлемая соль.
7. Соединение по п. 1, выбранное из:
Figure 00000099
,
Figure 00000100
,
Figure 00000101
 и
Figure 00000102
.
или его фармацевтически приемлемая соль.
8. Соединение по п. 1, выбранное из:
Figure 00000103
,
Figure 00000104
,
Figure 00000105
,
Figure 00000106
,
Figure 00000107
, и
Figure 00000108
.
9. Соединение по п. 1, представляющее собой:
Figure 00000109
.
10. Соединение, имеющее структуру, представленную формулой:
Figure 00000110
,
где Q2 представляет собой структуру, выбранную из:
Figure 00000002
,
Figure 00000003
,
Figure 00000004
,
Figure 00000005
,
Figure 00000006
,
Figure 00000007
,
Figure 00000008
,
Figure 00000009
,
Figure 00000010
,
Figure 00000011
,
Figure 00000012
,
Figure 00000013
,
Figure 00000014
,
Figure 00000015
,
Figure 00000016
,
Figure 00000017
,
Figure 00000018
,
Figure 00000019
,
Figure 00000020
,
Figure 00000021
,
Figure 00000023
,
Figure 00000024
,
Figure 00000025
,
Figure 00000111
,
Figure 00000027
,
Figure 00000028
 и
Figure 00000029
;
где Z выбран из O(C=O), CF2CO, COCH2, CH2CO,
Figure 00000112
, CO, CH2SO2, SO2, NHCO, N(CH3)CO и CH(OH)CO;
где Ar1 выбран из арила и гетероарила и замещен 1, 2 или 3 группами, независимо выбранными из галогена, –NO2, –CN, –OH, –SH, –NH2, C1-C8 ациклического алкила, C1-C8 ациклического алкенила, C1-C8 гидроксиалкила, C1-C8 моногалогеналкила, C1-C8 полигалогеналкила, C1-C8 алкокси, C1-C8 моногалогеналкокси, C1-C8 полигалогеналкокси, C1-C8 ациклического алкиламино, (C1-C8)(C1-C8) диалкиламино, –CO(C1-C8 ациклического алкила) и циклопропила, циклобутила и оксетена, причем циклопропил, циклобутил и оксетен необязательно замещены 1, 2 или 3 группами, независимо выбранными из –OH, C1-C4 алкила и C1-C4 алкокси; и
где Ar3 представляет собой структуру, выбранную из:
Figure 00000113
 и
Figure 00000114
;
где R5, в случае наличия, выбран из CN, галогена, –NO2, SO2NH2 и SO2CH3,
при условии, что если R5 представляет собой CN и Z представляет собой CO, то Ar1 не замещен C1-C8 моногалогеналкилом или C1-C8 полигалогеналкилом;
при условии, что если R5 представляет собой галоген, то Ar1 выбран из 5- и 6-членного гетероарила и Z не может быть CO,
или его фармацевтически приемлемая соль.
11. Соединение по п. 10, в котором Ar1 выбран из арила и гетероарила и замещен 1, 2 или 3 группами, независимо выбранными из галогена, –NO2, –CN, –OH, –SH, –NH2, C1-C8 ациклического алкила, C1-C8 ациклического алкенила, C1-C8 гидроксиалкила, C1-C8 моногалогеналкила, C1-C8 полигалогеналкила, C1-C8 алкокси, C1-C8 моногалогеналкокси, C1-C8 полигалогеналкокси, C1-C8 ациклического алкиламино, (C1-C8)(C1-C8) диалкиламино, –CO(C1-C8 ациклического алкила) и циклопропила.
12. Соединение по п. 10, в котором Ar3 представляет собой:
Figure 00000113
.
13. Соединение по п. 10, в котором R5 представляет собой CN.
14. Соединение по п.10, в котором R5 представляет собой –Cl.
15. Соединение по п.10, в котором R5 выбран из галогена, –NO2, SO2NH2 и SO2CH3.
16. Соединение по п.10, представляющее собой:
Figure 00000115
,
или его фармацевтически приемлемая соль.
17. Способ лечения расстройства, связанного с активностью пантотенаткиназы, у субъекта, включающий введение субъекту эффективного количества по меньшей мере одного соединения, имеющего структуру, представленную формулой:
Figure 00000001
,
где A выбран из O, CO, CH2, CF2, NH, N(CH3) и CH(OH);
где Q1 представляет собой CH; и где R2 выбран из –SCH3, C1-C8 ациклического алкила, C1-C8 ациклического алкенила, C1-C8 моногалогеналкила, C1-C8 полигалогеналкила, C1-C8 алкоксигалогеналкила, циклопропила, циклобутила и оксетена, причем циклопропил, циклобутил и оксетен необязательно замещены 1, 2 или 3 группами, независимо выбранными из –OH, C1-C4 алкила и C1-C4 алкокси; или
где Q1 представляет собой N; и где R2 выбран из галогена, –SCH3, C1-C8 ациклического алкила, C1-C8 ациклического алкенила, C1-C8 моногалогеналкила, C1-C8 полигалогеналкила, C1-C8 алкоксигалогеналкила, циклопропила, циклобутила и оксетена, причем циклопропил, циклобутил и оксетен необязательно замещены 1, 2 или 3 группами, независимо выбранными из –OH, C1-C4 алкила и C1-C4 алкокси;
где Q2 представляет собой структуру, выбранную из:
Figure 00000002
,
Figure 00000003
,
Figure 00000004
Figure 00000005
,
Figure 00000006
,
Figure 00000007
,
Figure 00000008
,
Figure 00000009
,
Figure 00000010
,
Figure 00000011
,
Figure 00000012
,
Figure 00000013
,
Figure 00000014
,
Figure 00000015
,
Figure 00000016
,
Figure 00000017
,
Figure 00000018
,
Figure 00000019
,
Figure 00000020
,
Figure 00000021
,
Figure 00000022
,
Figure 00000023
,
Figure 00000024
,
Figure 00000025
,
Figure 00000026
,
Figure 00000027
,
Figure 00000028
,
Figure 00000029
,
Figure 00000030
,
Figure 00000031
,
Figure 00000032
 и
Figure 00000033
;
где каждый из R3a и R3b независимо выбран из водорода, галогена, −OH, C1-C4 алкокси и C1-C4 алкила; и
где R4 выбран из водорода, галогена, –CN, SO2NH2, SO2CH3, SO2CF3 и NO2,
или его фармацевтически приемлемой соли.
18. Способ по п. 17, в котором расстройство, связанное с активностью пантотенаткиназы, связано с нарушением регуляции и/или повышением уровня кофермента А, что приводит к гипергликемии.
19. Способ по п. 17, в котором расстройство, связанное с активностью пантотенаткиназы, связано с дефицитом пантотенаткиназы или кофермента А, что приводит к нейродегенерации.
20. Способ по п. 17, в котором расстройство, связанное с активностью пантотенаткиназы, выбрано из PKAN (пантотенаткиназа-ассоциированной нейродегенерации) и диабета.
RU2019101613A 2016-06-23 2017-06-23 Низкомолекулярные модуляторы пантотенаткиназ RU2764652C2 (ru)

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