RU2019100295A - Соединения и композиции для подавления активности shp2 - Google Patents

Соединения и композиции для подавления активности shp2 Download PDF

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RU2019100295A
RU2019100295A RU2019100295A RU2019100295A RU2019100295A RU 2019100295 A RU2019100295 A RU 2019100295A RU 2019100295 A RU2019100295 A RU 2019100295A RU 2019100295 A RU2019100295 A RU 2019100295A RU 2019100295 A RU2019100295 A RU 2019100295A
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methyl
decan
azaspiro
hydrogen
amino
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RU2019100295A
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RU2019100295A3 (ru
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Чжолян Чэнь
Хорхе Гарсия Фортанет
Раджеш Карки
Мэттью Дж. Ламарш
Диути Маджумдар
Лоренс Блас Перес
Мартин Сендцик
Трой Дуглас Смит
Фань Ян
Бин Юй
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Новартис Аг
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Claims (65)

1. Соединение, выбранное из формул I и II:
Figure 00000001
в которых:
R1 выбирают из:
Figure 00000002
R2 и R3 вместе с атомом азота, к которому присоединены оба R2 и R3, образуют кольцо, выбранное из пиперидинила, пиперазинила, 2-окса-8-азаспиро[4.5]декан-8-ила, 8-азаспиро[4.5]декан-8-ила и пирролидинила; где указанные пирролидинил, пиперазинил, 2-окса-8-азаспиро[4.5]декан-8-ил, 8-азаспиро[4.5]декан-8-ил или пиперидинил не замещены или замещены 1-3 группами, независимо выбранными из аминогруппы, метила, этила, амино-метила, метил-аминогруппы, гидроксила, цианогруппы, фтор-метила, фтора и ((((5-метил-2-оксо-1,3-диоксол-4-ил)метокси)карбонил)амино)метила;
R4 выбран из гидроксила, C1-3алкоксигруппы и OC(O)C1-3алкила;
R5 выбран из Н и метила;
R6 выбран из водорода, метила и фенила;
R7 выбран из водорода, метила, этила, фенила и бензила;
R8 выбран из водорода и метила;
Y1 выбран из N и CH;
Y2 выбран из N и CH;
Y3 выбран из NН и CH2;
Y4 выбран из N и CH;
Y5 выбран из N и CH; или его фармацевтически приемлемая соль.
2. Соединение по п. 1, характеризующееся формулой II:
Figure 00000003
в которой:
R1 выбирают из:
Figure 00000004
R2 и R3 вместе с атомом азота, к которому присоединены оба R2 и R3, образуют кольцо, выбранное из пиперидинила, пиперазинила, 2-окса-8-азаспиро[4.5]декан-8-ила, 8-азаспиро[4.5]декан-8-ила и пирролидинила; где указанные пирролидинил, пиперазинил, 2-окса-8-азаспиро[4.5]декан-8-ил, 8-азаспиро[4.5]декан-8-ил или пиперидинил не замещены или замещены 1-3 группами, независимо выбранными из аминогруппы, метила, этила, амино-метила, метил-аминогруппы, гидроксила, цианогруппы, фтор-метила, фтора и ((((5-метил-2-оксо-1,3-диоксол-4-ил)метокси)карбонил)амино)метила;
R4 выбран из гидроксила;
R5 выбран из Н и метила;
R6 выбран из водорода, метила и фенила;
R7 выбран из водорода, метила, этила, фенила и бензила;
R8 выбран из водорода и метила;
Y1 выбран из N и CH;
Y2 выбран из N и CH;
Y3 выбран из NН и CH2;
Y4 выбран из N и CH;
Y5 выбран из N и CH; или его фармацевтически приемлемая соль.
3. Соединение по п. 2 или его фармацевтически приемлемая соль, в котором:
R1 выбирают из:
Figure 00000005
R4 выбран из гидроксила;
R5 выбран из Н и метила;
R6 выбран из водорода, метила и фенила;
R7 выбран из водорода, метила, этила, фенила и бензила;
R8 выбран из водорода и метила;
Y4 выбран из N и CH; и
Y5 выбран из N и CH.
4. Соединение по п. 3 или его фармацевтически приемлемая соль, выбранное из:
Figure 00000006
;
Figure 00000007
;
Figure 00000008
;
Figure 00000009
;
Figure 00000010
;
Figure 00000011
;
Figure 00000012
;
Figure 00000013
;
Figure 00000014
и
Figure 00000015
.
5. Соединение по п. 1, характеризующееся формулой I:
Figure 00000016
в котором:
R1 выбирают из:
Figure 00000017
R2 и R3 вместе с атомом азота, к которому присоединены оба R2 и R3, образуют кольцо, выбранное из пиперидинила, пиперазинила, 2-окса-8-азаспиро[4.5]декан-8-ила, 8-азаспиро[4.5]декан-8-ила и пирролидинила; где указанные пирролидинил, пиперазинил, 2-окса-8-азаспиро[4.5]декан-8-ил, 8-азаспиро[4.5]декан-8-ил или пиперидинил незамещены или замещены 1-3 группами, независимо выбранными из аминогруппы, метила, этила, амино-метила, метил-аминогруппы, гидроксила, цианогруппы, фтор-метила, фтора и ((((5-метил-2-оксо-1,3-диоксол-4-ил)метокси)карбонил)амино)метила;
R4 выбран из гидроксила;
R5 выбран из Н и метила;
R6 выбран из водорода, метила и фенила;
R7 выбран из водорода, метила, этила, фенила и бензила;
R8 выбран из водорода и метила;
Y1 выбран из N и CH;
Y2 выбран из N и CH;
Y3 выбран из NН и CH2;
Y4 выбран из N и CH;
Y5 выбран из N и CH; или его фармацевтически приемлемая соль.
6. Соединение по п. 5 или его фармацевтически приемлемая соль, выбранное из:
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
;
Figure 00000033
;
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
;
Figure 00000065
;
Figure 00000066
;
Figure 00000067
;
Figure 00000068
и
Figure 00000069
.
7. Фармацевтическая композиция, содержащая соединение по п. 1 или его фармацевтически приемлемую соль и по меньшей мере один фармацевтически приемлемый носитель.
8. Способ лечения, включающий в себя введение соединения по п. 1 или его фармацевтически приемлемой соли лицу, нуждающемуся в таком лечении, в эффективном количестве для профилактики или терапевтического лечения заболевания или расстройства, опосредованного активностью SHP2.
9. Способ по п. 8, где заболевание или расстройство, опосредованное активностью SHP2, выбрано из синдрома Нунан, синдрома Leopard, ювенильных миеломоноцитарных лейкозов, нейробластомы, меланомы, острого миелоидного лейкоза, рака молочной железы, рака пищевода, рака легкого, рака толстой кишки, рака головы, нейробластомы, плоскоклеточной карциномы головы и шеи, карциномы желудка, анапластической крупноклеточной лимфомы и глиобластомы.
RU2019100295A 2016-06-14 2017-06-12 Соединения и композиции для подавления активности shp2 RU2744988C2 (ru)

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