RU2012138257A - Замещенные пирролидин-2-карбоксамиды - Google Patents

Замещенные пирролидин-2-карбоксамиды Download PDF

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RU2012138257A
RU2012138257A RU2012138257/04A RU2012138257A RU2012138257A RU 2012138257 A RU2012138257 A RU 2012138257A RU 2012138257/04 A RU2012138257/04 A RU 2012138257/04A RU 2012138257 A RU2012138257 A RU 2012138257A RU 2012138257 A RU2012138257 A RU 2012138257A
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fluorophenyl
chloro
dimethylpropyl
carbonyl
amino
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Дейвид Джозеф БАРТКОВИЦ
Синьцзи Чу
Цинцзи Дин
Нань ЯН
Цзиньцзунь ЛЮ
Тина Морган РОСС
Цзин ЧЖАН
Чжумин ЧЖАН
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Ф.Хоффманн-Ля Рош Аг
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Abstract

1. Соединение, выбранное из группы, включающейхиральный трет-бутиловый эфир [2-(4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-фенил)-этил]-карбаминовой кислоты,рац-трет-бутиловый эфир (4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-бензил)-карбаминовой кислоты,этиловый эфир 1-(4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-фенил)-пиперидин-4-карбоновой кислоты,1-(4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-фенил)-пиперидин-4-карбоновую кислоту,рац-трет-бутиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-4-метилпиперидин-1-карбоновой кислоты,метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-трифторметоксибензойной кислоты,4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-трифторметоксибензойную кислоту,метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-метоксибензойной кислоты,метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циапо-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-фторбензойной кислоты,метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-хлорбензойной кислоты,4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметил�

Claims (9)

1. Соединение, выбранное из группы, включающей
хиральный трет-бутиловый эфир [2-(4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-фенил)-этил]-карбаминовой кислоты,
рац-трет-бутиловый эфир (4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-бензил)-карбаминовой кислоты,
этиловый эфир 1-(4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-фенил)-пиперидин-4-карбоновой кислоты,
1-(4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-фенил)-пиперидин-4-карбоновую кислоту,
рац-трет-бутиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-4-метилпиперидин-1-карбоновой кислоты,
метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-трифторметоксибензойной кислоты,
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-трифторметоксибензойную кислоту,
метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-метоксибензойной кислоты,
метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циапо-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-фторбензойной кислоты,
метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-хлорбензойной кислоты,
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-хлорбензойную кислоту,
метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-2,5-дифторбензойной кислоты,
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-2,5-дифторбензойную кислоту,
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-2,6-дифторбензойную кислоту,
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-гидроксибензойную кислоту,
метиловый эфир 4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-2-фтор-5-метоксибензойной кислоты,
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-2-фтор-5-метоксибензойную кислоту,
рац-4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-2-этоксибензойную кислоту,
5-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-пиразин-2-карбоновую кислоту,
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-метоксибензойную кислоту, и
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-2-трифторметилбензойную кислоту, и
их фармацевтически приемлемые соли.
2. Соединение по п.1
Figure 00000001
рац-4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-2-этоксибензойная кислота.
3. Соединение по п.1
Figure 00000002
5-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-пиразин-2-карбоновая кислота.
4. Соединение по п.1
Figure 00000003
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-3-метоксибензойная кислота.
5. Соединение по п.1
Figure 00000004
4-{[(2R,3S,4R,5S)-4-(4-хлор-2-фторфенил)-3-(3-хлор-2-фторфенил)-4-циано-5-(2,2-диметилпропил)-пирролидин-2-карбонил]-амино}-2-трифторметилбензойная кислота.
6. Фармацевтический препарат, содержащий соединение по любому из пп.1-5 вместе с фармацевтически приемлемыми инертными наполнителями или носителями.
7. Соединение по любому из пп.1-5, предназначенное для применения в качестве лекарственного средства.
8. Соединение по любому из пп.1-5, предназначенное для применения в качестве лекарственного средства, предназначенного для лечения рака, предпочтительно солидных опухолей, более предпочтительно опухолей молочной железы, толстой кишки, легких и предстательной железы.
9. Применение соединения по любому из пп.1-5 для приготовления лекарственного средства, предназначенного для лечения рака, предпочтительно солидных опухолей, более предпочтительно.
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