RU2020117684A - Ингибиторы irak4 и варианты их применения - Google Patents

Ингибиторы irak4 и варианты их применения Download PDF

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RU2020117684A
RU2020117684A RU2020117684A RU2020117684A RU2020117684A RU 2020117684 A RU2020117684 A RU 2020117684A RU 2020117684 A RU2020117684 A RU 2020117684A RU 2020117684 A RU2020117684 A RU 2020117684A RU 2020117684 A RU2020117684 A RU 2020117684A
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Иинонг XИЕ
Лее Е. БAБИСС
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Синблиa Тхерaпеутикс, Инк.
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Claims (67)

1. Соединение, представленное формулой:
Figure 00000001
, или его фармацевтически приемлемая соль;
где пунктирная линия указывает на наличие или отсутствие ковалентной связи;
А является группой, представляющей собой необязательно замещенный сочлененный бициклический гетероарил, группой, представляющей собой необязательно замещенный нафтил, или группой, представляющей собой необязательно замещенный сочлененный трициклический гетероарил, где А содержит заместитель R1;
L представляет собой прямую ковалентную связь, необязательно замещенную С1-3Н2-6Х0-1 или X, где X представляет собой О, S, SO, SO2 или NH;
D представляет собой необязательно замещенное гетероциклическое кольцо или необязательно замещенную сочлененную или спиробициклическую группу;
R1 представляет собой Н, -NRARB, -ORA, -O-RA-O-RB, -O-RA-O-RB-O-RC, -C(O)NRARB или -SRA;
R2 представляет собой H, -C(O)- или прямую ковалентную связь с R1; и
RA, RB, RC и RD независимо представляют собой Н или С1-12- гидрокарбил.
2. Соединение по п. 1, где R1 и L присоединены к А так, что 4 атома кольца в А непосредственно соединяют R1 с L.
3. Соединение по пп. 1, 2, где A-L представляет собой A-OC(RA)(RB)-, A-N(RC)C(RA)(RB)-, A-S(O)0-2C(RA)(RB)-,
Figure 00000002
или A-C(RA)(RB)C(RC)(RD)-, A-N(RC)-, A-S(O)0-2, или L представляет собой прямую ковалентную связь.
4. Соединение по пп. 1-3, где А выбран из группы, состоящей из необязательно замещенного 2-оксо-2,3-дигидро-1Н-имидазо[4,5-g]изохинолин-4-ил, необязательно замещенного изохинолинила, необязательно замещенного 1,3-диоксо-2,3-дигидро-1Н-пирроло[3,4-g]изохинолинила, необязательно замещенного 3-имино-2-оксо-2,3-дигидро-1Н-пирроло[2,3-g]изохинолинила или необязательно замещенного 3-(гидроксиимино)-2-оксо-2,3-дигидро-1Н-пирроло[2,3-g] изохинолинила, необязательно замещенного индолила, необязательно замещенного бензоимидазолила, необязательно замещенного 1Н-имидазо[1,2-а]индолила, необязательно замещенного нафто[2,3-b]тиофенила, необязательно замещенного тиазоло[3,2-а]индолила, необязательно замещенного 1Н-бензо[f]индолила, необязательно замещенного 2-оксо-1,2-дигидробензо[g]хиноксалинила, необязательно замещенного 2-оксо-1,2,3,4-тетрагидробензо[g]хиноксалинила, необязательно замещенного нафто[2,3-b]фуранила, необязательно замещенного оксазоло[3,2-а]индолила, необязательно замещенного 3Н-имидазо[4,5-с]изохинолин-2-амина, необязательно замещенного тиазоло[5,4-с]изохинолин-2-амина, необязательно замещенного оксазоло[5,4-с]изохинолин-2-амина, необязательно замещенного хинолона, необязательно замещенного б-карбамоил-7-метоксиизохинолин-1-ила, 6-карбамоил-7-метоксиизохинолин-1-ила, необязательно замещенного 6-карбамоил-7-метокси-4-(проп-1-ин-1-ил)изохинолин-1-ила, и 6-карбамоил-7-метокси-4-(проп-1-ин-1-ил)изохинолин-1-ил; или А содержит необязательно замещенное ароматическое полностью углеродное кольцо, которое имеет заместитель R1.
5. Соединение по пп. 1-4, где А замещен заместителями, выбранными из группы, состоящей из -OC(O)NH2, -C(O)NH2, -C(O)NHOH, -C(O)NHS(O)2CH3, -C(O)NHCN, -OH, -C(O)CHF2, -NHC(O)CH3, -NH2, -C(S)NH2, -SC(O)NH2, -OC(S)NH2, -NHC(S)NH2, -C(O)SH, -NHC(=NCH3)NH2, -NHC(O)SCH3, -NHC(O)OCH3, -C≡C-CH3-, -Br, и -CN.
6. Соединение по пп. 1-5, где D выбран из группы, состоящей из необязательно замещенного 5-оксопирролидинила, необязательно замещенного 2-оксооксазолидинила, необязательно замещенного 2-оксоимидазолидинила, необязательно замещенного октагидроциклопента[с]пирролила, необязательно замещенного азетидинила, необязательно замещенного 4-оксогексагидропирроло[3,4-с]пиррол-2(1Н)-ила, необязательно замещенного пиперидина, необязательно замещенного циклопентана, необязательно замещенного пиперазина, необязательно замещенного 1Н-1,2,3-триазола, необязательно замещенного 2-окса-8-азаспиро[4,5]декана, необязательно замещенного пирролидина, необязательно замещенного 5-оксопирролидин-2-ила, необязательно замещенного 3-этил-5-оксопирролидин-2-ила, 3-этил-5-оксопирролидин-2-ил, необязательно замещенного 3-аминопиперидин-1-ила, и 3-аминопиперидин-1-ила.
7. Соединение по пп. 1-6, где D замещен заместителями, выбранными из группы, состоящей из -NH2, -ОН, -СН3, -СН2СН3, -СН2СН2СН3, и -CH2NH2; или заместители как -СН3, так и -CH2NH2 при одном и том же атоме С кольца.
8. Соединение по любому из предыдущих пунктов, где L выбран из группы, состоящей из -O-СН2- -NH-CH2- и связи.
9. Соединение по любому из предыдущих пунктов, где L представляет собой связь, и атом N кольца в кольце D непосредственно присоединен к кольцу А.
10. Соединение по любому из предыдущих пунктов, где присутствует ковалентная связь между R1 и R2, и R1-R2 выбран из группы, состоящей из -ОСН2СН2ОСН2-, -ОСН2СН2ОСН2СН2-, -ОСН2СН2ОСН2СН2ОСН2-, -OCH2CH2OCH2C(О)-.
11. Соединение по любому из предыдущих пунктов или его фармацевтически приемлемая соль, где соединение включает:
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
или
Figure 00000029
где каждая структура является необязательно замещенной.
12. Соединение по любому из предыдущих пунктов, или его фармацевтически приемлемая соль, где соединение включает:
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
или
Figure 00000048
где каждая структура необязательно замещена.
13. Соединение по любому из предыдущих пунктов, где соединение представляет собой R-энантиомер, S-энантиомер или единственный диастереомер.
14. Фармацевтическая композиция, содержащая соединение по любому из пп. 1-13, или его фармацевтически приемлемую соль, или таутомер указанного соединения, или указанную соль и фармацевтически приемлемый носитель, разбавитель или носитель.
15. Соединение по любому из пп. 1-13 или его фармацевтически приемлемая соль, или его таутомер для использования в лечении рака, аутоиммунных заболеваний, воспалительных заболеваний, аутовоспалительных состояний, связанных с нарушениями, опосредованными IRAK4, у млекопитающего.
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