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RU2018130876A - Замещенные пиридиновые и пиразиновые соединения в качестве ингибиторов pde4 - Google Patents

Замещенные пиридиновые и пиразиновые соединения в качестве ингибиторов pde4 Download PDF

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Publication number
RU2018130876A
RU2018130876A RU2018130876A RU2018130876A RU2018130876A RU 2018130876 A RU2018130876 A RU 2018130876A RU 2018130876 A RU2018130876 A RU 2018130876A RU 2018130876 A RU2018130876 A RU 2018130876A RU 2018130876 A RU2018130876 A RU 2018130876A
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RU
Russia
Prior art keywords
methyl
chlorophenyl
methoxypyridin
group
pyrimidin
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RU2018130876A
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English (en)
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RU2802185C2 (ru
RU2018130876A3 (ru
Inventor
Венкатая БОЛЛУ
Джеймс БРАЙТЕНБУХЕР
Алан КАПЛАН
Роберт ЛЕМУС
Эндрю ЛИНДСТРОМ
Трой ВИКЕРС
Марк Е. УИЛСОН
Джеймс ЗАРФ
Майкл И. ВАЙНХАУС
Original Assignee
Дарт Нейросайенс (Кайман) Лтд.
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Publication of RU2018130876A publication Critical patent/RU2018130876A/ru
Publication of RU2018130876A3 publication Critical patent/RU2018130876A3/ru
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    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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Claims (124)

1. Фармацевтическая композиция, содержащая соединение Формулы (I):
Figure 00000001
где Z представляет собой СН или N;
i) где если Z представляет собой СН, то
R1 выбран из группы, состоящей из: -Н и -C1-3алкила;
Y представляет собой -C(Ra)2-, где каждый Ra независимо выбран из группы, состоящей из: -Н, -F, -СН3, -ОН и -N(Rb)2;
R2 выбран из группы, состоящей из:
A) фенила, незамещенного или замещенного одним заместителем Rc, где Rc независимо выбран из группы, состоящей из: галогена, -CN, -CO2Rb, -CONH2, -SO2CH3, -C(Rb)2OH, -CH2NH2, -CH2CONH2, -СН2СO2С1-3алкила, -NHCONH2, -NHCONH-оксетана, -CONH-оксетана,
Figure 00000002
B) шестичленного моноциклического гетероароматического кольца, содержащего один или два атома азота, незамещенного или замещенного одним или двумя заместителями, каждый из которых независимо выбран из группы, состоящей из: галогена, -C1-3алкила, -C1-3галогеналкила, -CN, -ОН, -C(Rb)2OH, -CH2NH2, -C(Rb)2CN, -C(Rb)2CONH2, -OCH2CONH2, -OC1-3алкила, -OCH2C(Rb)2OH, -ОСН2циклопропила, -OC1-3галогеналкила, -CO2H, -CON(Rb)2, -N(Rb)2, -NHCH2CF3, -NHCH(CH3)2, -NHCH2CH2N(CH3)2, -NHCH2CH2OH, -NН-циклопропила, -NHCOCH3, морфолинила, пирролидин-3-ола и азетидин-3-ола;
C) пятичленного моноциклического гетероароматического кольца, содержащего два, три или четыре атома азота, незамещенного или замещенного одним или двумя заместителями, каждый из которых независимо выбран из группы, состоящей из галогена, -C1-3алкила, -C1-3галогеналкила, -C(Rb)2OH, -N(Rb)2, -NO2, -CN, -CH2CN, -OC1-3алкила, -СН2ОСН3, -СН2СН2ОН, -CH2NH2, -CH2CONH2, -СO2C1-3алкила, -СO2Н, -CONH2, -NHCOCH3 и циклопропила; и
D) пяти- или шестичленного кольца, выбранного из: 1,2-дигидропиридин-2-она, тиазола или 1,2-оксазола, незамещенного или замещенного одним или двумя заместителями, каждый из которых независимо выбран из группы, состоящей из -СН3 и -NH2;
R3 представляет собой фенил или пиридин, каждый из которых замещен одним или двумя заместителями, каждый из которых независимо выбран из группы, состоящей из: -галогена, -C1-3алкила, -ОC1-3алкила, -О-циклопропила, -О-оксетана, -C1-3галогеналкила, -OC1-3галогеналкила, -CN, -СН2ОН, -SO2CH3 и -N(СН3)2;
R4 выбран из группы, состоящей из -C1-3алкила и -C1-3галогеналкила; и
каждый Rb представляет собой -Н или -СН3;
ii) где если Z представляет собой N, то:
R1 представляет собой -Н;
Y представляет собой -СН2-;
R2 выбран из группы, состоящей из:
A) фенила, замещенного одним или двумя заместителями Rd, где каждый Rd независимо выбран из группы, состоящей из: -CN, -CONH2 и -СO2C1-3алкила;
B) шестичленного моноциклического гетероароматического кольца, содержащего один или два атома азота, незамещенного или замещенного заместителем, выбранным из группы, состоящей из: -CN, -ОC1-3алкила, -CONH2, -NHCH2CH2OH, -N(Rb)2 и -NH-циклопропила;
C) пятичленного моноциклического гетероароматического кольца, содержащего два или три атома азота, незамещенного или замещенного одним или двумя заместителями, каждый из которых независимо выбран из группы, состоящей из -C1-3алкила, -C1-3галогеналкила, -CH2ORb, -N(Rb)2, -NO2, -СО2СН3, -CO2N(Rb)2 или циклопропила; и
D) 1,2-оксазола, необязательно замещенного одним или двумя заместителями Rb;
R3 представляет собой фенил, замещенный одним или двумя заместителями, каждый из которых независимо выбран из группы, состоящей из: -Cl, -ОC1-3алкила или -ОC1-3галогеналкила;
R4 представляет собой -C1-3алкил; и
каждый Rb независимо выбран из -Н или -СН3;
и фармацевтически приемлемое вспомогательное вещество.
2. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
5-({6-[3-(Дифторметокси)фенил]-5-этоксипиразин-2-ил}метил)пиримидин-2-карбонитрила;
2-Хлор-5-{[5-(3-хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидина;
{2-[(5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-ил)амино]этил}диметиламина;
2-Метокси-3-(6-метоксипиридин-2-ил)-5-(1Н-1,2,4-триазол-1-илметил)пиридина;
2-Метокси-3-(3-метилфенил)-5-(1Н-1,2,4-триазол-1-илметил)пиридина;
2-Метокси-3-(5-метилпиридин-3-ил)-5-(1Н-1,2,4-триазол-1-илметил)пиридина;
2-Метокси-3-(2-метилпиридин-4-ил)-5-(1Н-1,2,4-триазол-1-илметил)пиридина;
{3-[2-Метокси-5-(1Н-1,2,4-триазол-1-илметил)пиридин-3-ил]фенил}метанола;
3-(3-Метансульфонилфенил)-2-метокси-5-(1Н-1,2,4-триазол-1-илметил)пиридина;
2-Метокси-3-(4-метилпиридин-2-ил)-5-(1Н-1,2,4-триазол-1-илметил)пиридина; и
2-Метокси-3-(6-метилпиридин-2-ил)-5-(1Н-1,2,4-триазол-1-илметил)пиридина.
3. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
2-(Дифторметокси)-3-(3-метилфенил)-5-(1Н-1,2,4-триазол-1-илметил)пиридина;
5-({6-[3-(Дифторметокси)фенил]-5-этоксипиразин-2-ил}метил)пиримидин-2-карбоксамида;
[5-(3-Хлорфенил)-6-метоксипиридин-3-ил](4-фторфенил)метанола;
1-[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]-1-(4-фторфенил)этан-1-ола;
[5-(3-Хлорфенил)-6-метоксипиридин-3-ил](5-фторпиридин-2-ил)метанола;
{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил](4-фторфенил)метил}(метил)амина;
[5-(3-Хлорфенил)-6-метоксипиридин-3-ил](4-фторфенил)метанамина;
{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил](4-фторфенил)метил}диметиламина;
3-(3-Хлорфенил)-5-[фтор(4-фторфенил)метил]-2-метоксипиридина; и
4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}бензойной кислоты.
4. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
5-{[6-(3-Хлорфенил)-5-метоксипиразин-2-ил]метил}пиримидин-2-карбонитрила;
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-карбоновой кислоты;
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-карбоксамида;
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-амина;
(4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)мочевины;
4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}бензамида;
3-(3-Хлорфенил)-2-(дифторметокси)-5-(1Н-пиразол-4-илметил)пиридина;
5-{[6-(Дифторметокси)-5-(3-метоксифенил)пиридин-3-ил]метил}пиримидин-2-амина;
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиридин-2-амина; и
1-(4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)-3-(оксетан-3-ил)мочевины.
5. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
3-(3-Хлорфенил)-2-метокси-5-[(6-метоксипиридин-3-ил)метил]пиридина;
5-{[5-(3-Хлорфенил)-6-(дифторметокси)пиридин-3-ил]метил}пиридин-2-амина;
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}-N,N-диметилпиридин-2-амина;
5-{[5-(3-Хлорфенил)-6-(дифторметокси)пиридин-3-ил]метил}пиримидин-2-карбонитрила;
5-{[5-(3-Хлорфенил)-6-(дифторметокси)пиридин-3-ил]метил}-1,3-тиазол-2-амина;
(2-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)метанола;
5-{[5-(3-Фторфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-амина;
5-{[5-(3-Фторфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-карбонитрила;
5-{[5-(3-Хлорфенил)-6-этоксипиридин-3-ил]метил}пиримидин-2-амина; и
5-{[5-(3-Хлорфенил)-6-(пропан-2-илокси)пиридин-3-ил]метил}пиримидин-2-амина.
6. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
5-{[6-(Дифторметокси)-5-[3-(пропан-2-илокси)фенил]пиридин-3-ил]метил}пиримидин-2-амина;
5-{[6-(Дифторметокси)-5-[3-(оксетан-3-илокси)фенил]пиридин-3-ил]метил}пиримидин-2-амина;
N-(5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-ил)ацетамида;
3-(3-Хлорфенил)-2-(дифторметокси)-5-[(4-метансульфонилфенил)метил]пиридина;
5-{[6-(Дифторметокси)-5-(2-метоксипиридин-4-ил)пиридин-3-ил]метил}пиримидин-2-амина;
5-({5-[2-(Дифторметокси)пиридин-4-ил]-6-метоксипиридин-3-ил}метил)пиримидин-2-амина;
2-[5-({5-[3-(Дифторметокси)фенил]-6-метоксипиридин-3-ил}метил)пиримидин-2-ил]пропан-2-ола;
3-(3-Хлорфенил)-2-метокси-5-{[6-(трифторметил)пиридин-3-ил]метил}пиридина;
3-(3-Хлорфенил)-2-(дифторметокси)-5-{[6-(пропан-2-илокси)пиридин-3-ил]метил}пиридина; и
3-(3-Хлорфенил)-2-(дифторметокси)-5-[(6-пропоксипиридин-3-ил)метил]пиридина.
7. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}-1-метил-1,2-дигидропиридин-2-она;
3-(3-Хлорфенил)-2-метокси-5-(пиридин-4-илметил)пиридина;
5-{[5-(3-Хлорфенил)-6-(дифторметокси)пиридин-3-ил]метил}пиридин-2-карбоновой кислоты;
3-(3-Хлорфенил)-2-метокси-5-[(2-метоксипиримидин-5-ил)метил]пиразина;
5-{[6-(3-Хлорфенил)-5-метоксипиразин-2-ил]метил}-N-метилпиримидин-2-амина;
5-{[6-(3-Хлорфенил)-5-метоксипиразин-2-ил]метил}-N-циклопропилпиримидин-2-амина;
3-(3-Хлорфенил)-2-метокси-5-[(1-метил-1Н-пиразол-4-ил)метил]пиразина;
(4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)метанамина;
4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиридин-2-амина;
3-(3-Хлорфенил)-5-[(2,6-диметилпиридин-4-ил)метил]-2-метоксипиридина; и
4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиридин-2-карбонитрила.
8. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}бензойной кислоты;
4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}бензамида;
(4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)мочевины;
1-(4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)-3-(оксетан-3-ил)мочевины; и
(4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)метанамина.
9. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-амина;
(4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)мочевины;
5-({6-[3-(Дифторметокси)фенил]-5-(3-метоксифенил)пиридин-3-ил}метил)пиримидин-2-амина;
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-карбоксамида; и
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-карбоновой кислоты.
10. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиримидин-2-амина.
11. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)мочевины.
12. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
5-{[6-(Дифторметокси)-5-(3-метоксифенил)пиридин-3-ил]метил}пиримидин-2-амина.
13. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиридин-2-карбоксамида.
14. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
5-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}пиридин-2-карбоновой кислоты.
15. Композиция по п. 1, где соединение Формулы (I) выбрано из группы, состоящей из:
4-{[5-(3-Хлорфенил)-6-метоксипиридин-3-ил]метил}фенил)метанамина.
16. Способ лечения заболевания, расстройства или медицинского состояния, опосредованного ферментативной активностью PDE4, включающий введение субъекту, нуждающемуся в таком лечении, эффективного количества композиции по любому из п.п. 1-15.
17. Способ лечения заболевания, расстройства или медицинского состояния, опосредованного ферментом PDE4, включающий введение субъекту, нуждающемуся в таком лечении, эффективного количества композиции по любому из пп. 1-15.
18. Применение композиции по любому из пп. 1-15 в способе лечения неврологического расстройства, включающего введение субъекту, нуждающемуся в таком лечении, эффективного количества указанной композиции.
19. Применение по п. 18, отличающееся тем, что неврологическое расстройство выбрано из группы, состоящей из расстройства центральной нервной системы (ЦНС), психиатрического расстройства, расстройства личности, расстройства, связанного с употреблением химических соединений, диссоциативного расстройства, расстройства пищевого поведения, расстройства сна, нарушения развития, нейродегенеративного расстройства, травматического расстройства, болевого расстройства и когнитивного расстройства.
20. Применение композиции по любому из пп. 1-15 в способе лечения периферического расстройства, включающего введение субъекту, нуждающемуся в таком лечении, эффективного количества композиции по любому из пп. 1-15.
21. Применение по п. 20, где периферическое расстройство выбрано из группы, состоящей из воспалительной болезни кишечника; ревматоидного артрита, хронической обструктивной болезни легких (COPD), астмы, аллергического ринита, легочной артериальной гипертензии; болезней почек; аллергических кожных заболеваний и псориаза.
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