RU2331642C2 - Новые ингибиторы киназ - Google Patents

Новые ингибиторы киназ Download PDF

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RU2331642C2
RU2331642C2 RU2005104422/04A RU2005104422A RU2331642C2 RU 2331642 C2 RU2331642 C2 RU 2331642C2 RU 2005104422/04 A RU2005104422/04 A RU 2005104422/04A RU 2005104422 A RU2005104422 A RU 2005104422A RU 2331642 C2 RU2331642 C2 RU 2331642C2
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yloxy
methyl
indol
fluoro
methylpyrrolo
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Раджив БХАЙД (US)
Раджив БХАЙД
Жен-Вей КАЙ (US)
Жен-Вей КАЙ
Лиганг КИАН (US)
Лиганг КИАН
Стефани БАРБОСА (US)
Стефани БАРБОСА
Луис ЛОМБАРДО (US)
Луис ЛОМБАРДО
Джеффри РОБЛ (US)
Джеффри РОБЛ
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Бристол-Маерс Сквибб Компани
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Abstract

Описываются новые пирроло[2,1-f][1,2,4]триазины общей формулы I
Figure 00000001
где Z означает О или N при условии, что когда Z означает О, R41 отсутствует, а когда Z означает N, R41 означает водород; Y отсутствует; Х означает О, NHCO2 или отсутствует; R1 и R6 означают водород; R3 означает низший алкил; R42 означает радикал формулы
Figure 00000002
где R43 означает водород или фтор; R44 означает метил или водород; R2 означает водород или низший алкил, возможно одно- или многократно замещенный; если Х отсутствует, R2 означает 1,3,4-оксадиазолил, замещенный галоидалкилом, при условии, что R2 не может означать водород, если Х означает -NHCO2-, конкретные представители данного ряда, фармацевтические композиции, их содержащие, способы лечения пролиферативных заболеваний и рака. 10 н. и 1 з.п. ф-лы, 5 табл., 1 ил.

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Claims (11)

1. Пирроло[2,1-f][1,2,4]триазины общей формулы I
Figure 00000077
где Z означает О или N, при условии, что когда Z означает О, R41 отсутствует, а когда Z означает N, R41 означает водород;
Y отсутствует;
Х означает О, NHCO2 или отсутствует;
R1 и R6 означают водород;
R3 означает низший алкил;
R42 означает радикал формулы
Figure 00000078
где R43 означает водород или фтор;
R44 означает метил или водород;
R2 означает водород или низший алкил, возможно одно- или многократно замещенный гидрокси, низшим алкокси, галоидом, амино, ди(низший)алкиламино, моно(низший) алкиламино, (низший) алкокси (низший) алкокси, циклопропилом, оксиранилом, метансульфонилом, метансульфонамидом, метилсульфанилом, метансульфинилом, диэтиловым эфиром фосфоновой кислоты, оксо, пирролидин-2-оном, пиперидинилом, 1,2,3- или 1,2,4-триазолилом, морфолино, имидазолилом, который сам может быть замещен низшим алкилом, 1,1-диоксотиоморфолино, пиридинилокси, тиазолилом, который сам может быть замещен низшим алкилом, ди(низший)алкиламиносульфониламино,
моно(низший)алкиламиносульфониламино, формамидной группой, низшим алканоилом, в свою очередь, замещенным амино или ди(низший)алкиламиногруппой; причем если Х отсутствует, R2 означает 1,3,4-оксадиазолил, замещенный галоген (низшим) алкилом, при условии, что R2 не может обозначать водород, если Х обозначает NHCO2, их энантиомеры, диастереомеры или фармацевтически приемлемые соли.
2. Соединение по п.1, отличающееся тем, что Х обозначает кислород; R2 обозначает замещенный алкил и R43 обозначает фтор.
3. Соединение, выбранное из группы, включающей
4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-ол,
1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-4-(аминосульфонил)аминобутан-2-ол,
N-{3-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-2-гидроксипропил}-метансульфонамид,
(2S)-3-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропан-1,2-диол,
(2R)-3-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропан-1,2-диол,
(2R)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропан-2-ол,
(2S)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропан-2-ол,
(2R)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-3-метоксипропан-2-ол,
(2S)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-3-метоксипропан-2-ол,
2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-этанол,
N-{2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-этил}-метансульфонамид,
(2R)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-4-метансульфонилбутан-2-ол,
(2S)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-4-метансульфонилбутан-2-ол,
5-Метил-4-(2-метил-1Н-индол-5-илокси)-6-(3-пиперидин-1-илпропокси)-пирроло[2,1-f][1,2,4]триазин,
4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метил-6-(2-пиперидин-4-илэтокси)-пирроло[2,1-f][1,2,4]триазин,
4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метил-6-(3-пиридин-4-илпропокси)-пирроло[2,1-f][1,2,4]триазин,
{1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илоксиметил]-3-метансульфонилпропил}-диметиламин, 71
2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-1-метилэтиламин,
{2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-1-метилэтил}-метиламин,
4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метил-6-(морфолин-2-илметокси)-пирроло[2,1-f][1,2,4]триазин,
[2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]]-1-метилэтиловый эфир [(1R),2S]-2-диметиламинопропионовой кислоты,
[2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]]-1-метилэтиловый эфир [(1R),2S]-2-амино-4-метилпентановой кислоты,
2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-1][1,2,4]триазин-6-илокси]-1-метилэтиловый эфир [(1R),2S]-2-аминопропионовой кислоты,
4-(4-Фтор-2-метил-1Н-индол-5-илокси)-6-(3-метансульфонилпропокси)-5-метилпирроло[2,1-f][1,2,4]триазин и
N-{3-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропил}-метансульфонамид.
4. Соединение, выбранное из группы, включающей
4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-ол,
(2S)-3-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропан-1,2-диол,
(2R)-3-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропан-1,2-диол,
(2R)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропан-2-ол,
(2S)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропан-2-ол,
(2R)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-3-метоксипропан-2-ол,
(2S)-1-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-3-метоксипропан-2-ол,
5-Метил-4-(2-метил-1Н-индол-5-илокси)-6-(3-пиперидин-1-илпропокси)-пирроло[2,1-f][1,2,4]триазин,
4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метил-6-(2-пиперидин-4-илэтокси)-пирроло[2,1-f][1,2,4]триазин,
2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-1-метилэтиламин,
[2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]]-1-метилэтиловый эфир [(1R),2S]-2-диметиламинопропионовой кислоты,
[2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]]-1-метилэтиловый эфир [(1R),2S]-2-амино-4-метилпентановой кислоты,
2-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-1-метилэтиловый эфир [(1R),2S]-2-аминопропионовой кислоты,
4-(4-Фтор-2-метил-1Н-индол-5-илокси)-6-(3-метансульфонилпропокси)-5-метилпирроло[2,1-f][1,2,4]триазин и
N-{3-[4-(4-Фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]-пропил}-метансульфонамид.
5. (2R)-1-(4-(4-фтор-2-метил-1Н-индол-5-илокси)-5-метилпирроло[2,1-f][1,2,4]триазин-6-илокси]пропан-2-ол.
6. Фармацевтическая композиция для лечения пролиферативных заболеваний, содержащая, по меньшей мере, одно из соединений по п.1, и фармацевтически приемлемый носитель.
7. Фармацевтическая композиция для лечения пролиферативных заболеваний, содержащая, по меньшей мере, одно из соединений по п.3 и фармацевтически приемлемый носитель.
8. Фармацевтическая композиция для лечения пролиферативных заболеваний, содержащая, по меньшей мере, одно из соединений по п.4 и фармацевтически приемлемый носитель для него.
9. Фармацевтическая композиция для лечения пролиферативных заболеваний, содержащая соединение по п.5 и фармацевтически приемлемый носитель для него.
10. Способ лечения пролиферативных заболеваний, заключающийся во введении нуждающемуся в этом млекопитающему терапевтически эффективного количества композиции по п.9.
11. Способ лечения рака, заключающийся во введении нуждающемуся в этом млекопитающему терапевтически эффективного количества композиции по п.9.
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