RU2019111188A - Кетоновые ингибиторы лизин-специфичного гингипаина - Google Patents

Кетоновые ингибиторы лизин-специфичного гингипаина Download PDF

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RU2019111188A
RU2019111188A RU2019111188A RU2019111188A RU2019111188A RU 2019111188 A RU2019111188 A RU 2019111188A RU 2019111188 A RU2019111188 A RU 2019111188A RU 2019111188 A RU2019111188 A RU 2019111188A RU 2019111188 A RU2019111188 A RU 2019111188A
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pharmaceutically acceptable
acceptable salt
compound according
disease
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RU2019111188A
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RU2019111188A3 (ru
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Андрей В. Конради
Роберт А. мл. Галеммо
Стефен С. ДОМИНИ
Кейси С. ЛИНЧ
Лесли Дж. ХОЛСИНГЕР
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Кортексим, Инк.
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    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Claims (98)

1. Соединение формулы I
Figure 00000001
или его фармацевтически приемлемая соль, где
А выбран из группы, состоящей из -CH2- и -О-;
каждый из R1a и R1b независимо выбран из группы, состоящей из водорода, C1-4 алкила и защитной группы аминогруппы;
каждый из R2a и R2b независимо выбран из группы, состоящей из водорода, галогена, C1-4 галогеналкила и C1-4 галогеналкокси;
R3 выбран из группы, состоящей из C3-8 циклоалкила, C3-8 алкила, 3-12-членного гетероциклила, C6-10 арила, 5-12-членного гетероарила и репортерного фрагмента, где R3 является необязательно замещенным одним или более R3а заместителями;
каждый R3а независимо выбран из группы, состоящей из галогена, -CN, -NO2, -N3, -ОН, C1-4 алкила, C1-4 галогеналкила, C1-4 алкокси, С1-4 галогеналкокси, -N(Rc)2, -N+(Rb)3, -(CH2)kC(O)Rb, -NRc(CH2)uC(O)Rb, -O(CH2)uC(O)Rb, -(CH2)kCONRcRc, -(CH2)kNRcC(O)Rb, -NRc(CH2)uCONRcRc, -NRc(CH2)uNRcC-(O)Rb, -O(CH2)uCONRcRc, -O(CH2)uNRcC(O)Rb и необязательно замещенного триазолила;
каждый Rb независимо выбран из группы, состоящей из C1-4 алкила, C1-4 галогеналкила и C1-4 дейтероалкила;
каждый Rc независимо выбран из группы, состоящей из водорода и C1-8 алкила;
каждый подстрочный индекс k независимо выбран из 0, 1, 2, 3, 4, 5 и 6;
каждый подстрочный индекс u независимо выбран из 1, 2, 3, 4, 5 и 6;
R4 выбран из группы, состоящей из водорода и С1-4 алкила;
R5 выбран из группы, состоящей из -CH2R5a, -CHS(O)(R5b)2 и С1-6 галогеналкила;
R5а выбран из группы, состоящей из -O-R6, -S-R7, -SO-R7 -SО2-R7, -N(R8)2, 5-12-членного гетероарила и 3-12-членного гетероциклила,
где 5-12-членный гетероарил является необязательно замещенным одним или более заместителями, независимо выбранными из группы, состоящей из галогена, С1-3 алкила и C1-3 галогеналкила, и
3-12-членный гетероциклил является необязательно замещенным одним или более заместителями, независимо выбранными из группы, состоящей из оксо, галогена, С1-3 алкила и С1-3 галогеналкила;
каждый R5b независимо выбран из C1-6 алкила;
R6 и R7 выбраны из группы, состоящей из фенила, C1-6 алкила, C1-6 галогеналкила и 5-12-членного гетероарила,
где фенил является замещенным 1-5 атомами галогена, и
где 5-12-членный гетероарил является необязательно замещенным одним или более атомами галогена, С1-3 алкилами или С1-3 галогеналкилами;
каждый R8 независимо выбран из C1-6 алкила; и
R5 необязательно содержит гасящий фрагмент R9;
при условии, что R5 не является 2,3,5,6-тетрафторфеноксиметилом.
2. Соединение по п.1 или его фармацевтически приемлемая соль, где R3 выбран из группы, состоящей из C3-8 циклоалкила, C3-8 алкила, С6-10 арила, 5-12-членного гетероарила и 3-12-членного гетероциклила, каждый из которых является необязательно замещенным одним или более R3а заместителями.
3. Соединение по п.1 или 2, или его фармацевтически приемлемая соль, где R3 выбран из группы, состоящей из циклопентила и фенила, каждый из которых является необязательно замещенным одним или более R3а заместителями.
4. Соединение по п.2 или 3, или его фармацевтически приемлемая соль, где каждый R3a независимо выбран из группы, состоящей из галогена, -N3, C1-4 алкила, C1-4 галогеналкила, C1-4 алкокси, C1-4 галогеналкокси, -N(Rc)2, -N+(Rb)3 и -NRcC(O)Rb.
5. Соединение по п.1 или его фармацевтически приемлемая соль, где R3 представляет собой циклопентил.
6. Соединение по п.1 или 2, или его фармацевтически приемлемая соль, где R3 представляет С3-8 алкил, замещенный C1-4 алкокси.
7. Соединение по п.6 или его фармацевтически приемлемая соль, где R3 представляет собой метоксипропил.
8. Соединение по п.5 или его фармацевтически приемлемая соль, структура которого соответствует формуле Iа
Figure 00000002
9. Соединение по п.8 или его фармацевтически приемлемая соли, где R4 представляет собой водород.
10. Соединение по п.9 или его фармацевтически приемлемая соль, где R5a представляет собой -O-фенил, где фенил является замещенным 1-5 атомами галогена.
11. Соединение по п.10 или его фармацевтически приемлемая соль, где каждый атом галогена в R5a независимо выбран из группы, состоящей из F и Cl.
12. Соединение по п.11 или его фармацевтически приемлемая соль где R5 выбран из группы, состоящей из 2,3,6-трифторфенокси, 2,3,5-трифторфенокси, 2,3-дифторфенокси, 2,5-дифторфенокси, 2,6-дифторфенокси, 3,5-дифторфенокси, 2-фторфенокси и 3-фторфенокси.
13. Соединение по любому из пп. 1-4, 6 и 7 или его фармацевтически приемлемая соль, структура которого соответствует формуле Iа
Figure 00000003
14. Соединение по любому из пп. 1-4, 6, 7 и 13 или его фармацевтический приемлемая соли, где R4 представляет собой водород.
15. Соединение по п.13 или 14, или его фармацевтически приемлемая соль, где R5а представляет собой -О-фенил, где фенил является замещенным 1-5 атомами галогена.
16. Соединение по п.15 или его фармацевтически приемлемая соль, где каждый атом галогена в R5а независимо выбран из группы, состоящей из F и Cl.
17. Соединение по п.16 или его фармацевтически приемлемая соль, где каждый атом галогена в R5а представляет собой F.
18. Соединение по любому из пп. 1-4, 6, 7 и 13-17 или его фармацевтически приемлемая соль, где R5а выбран из группы, состоящей из 2,3,6-трифторфенокси, 2,3,5-трифторфенокси, 2,3,4-трифторфенокси, 3,4,5-трифторфенокси, 2,3-дифторфенокси, 2,4-дифторфенокси, 2,5-дифторфенокси, 2,6-дифторфенокси, 3,4-дифторфенокси, 3,5-дифторфенокси, 2-фторфенокси, 3-фторфенокси и 4-фторфенокси.
19. Соединение по п.18 или его фармацевтически приемлемая соль, где R5 выбран из группы, состоящей из 2,3,6-трифторфенокси, 2,3,5-трифторфенокси, 2,3-дифторфенокси, 2,5-дифторфенокси, 2,6-дифторфенокси, 3,5-дифторфенокси, 2-фторфенокси и 3-фторфенокси.
20. Соединение по п.18 или его фармацевтический приемлемая соль, где R5а выбран из группы, состоящей из 2,3,6-трифторфенокси и 2,6-дифторфенокси.
21. Соединение по п.13 или 14. или его фармацевтически приемлемая соль, где R5 представляет собой -CH2R5a, R5a представляет собой -O-R6, и R6 представляет собой C1-6 галогеналкил.
22. Соединение по п.21 или его фармацевтически приемлемая соль, где R6 выбран из группы, состоящей из трифторэтила и гексафторпропила.
23. Соединение по п.13 или 14, или его фармацевтически приемлемая соль, где R5 представляет собой -CH2R5a, R5a представляет собой -O-R6, и R6 представляет собой 5-12-членный гетероарил, который является необязательно замещенным одним или более заместителями, независимо выбранными из группы, состоящей из галогена и C1-3 алкила.
24. Соединение по п.23, где R6 выбран из группы, состоящей из изоксазолила и пиридинила.
25. Соединение по п.13 или 14, или его фармацевтически приемлемая соль, где R5а выбран из группы, состоящей из -N(R8)2, 5-12-членного гетероарила и 3-12-членного гетероциклила, где
5-12-членный гетероарил является необязательно замещенным одним или более заместителями, независимо выбранными из группы, состоящей из галогена, C1-3 алкила и C1-3 галогеналкила, и
3-12-членный гетероциклил является необязательно замещенным одним или более заместителями, независимо выбранными из группы, состоящей из оксо, галогена, C1-3 алкила и C1-3 галогеналкила.
26. Соединение по п.25 или его фармацевтический приемлемая соль, где R5а выбран из группы, состоящей из тетразолила и оксопиримидинила.
27. Соединение по п.13 или 14, или его фармацевтически приемлемая соль, где
R5 выбран из группы, состоящей из -CH2R5a и -CHS(O)(R5b)2,
R5а выбран из группы, состоящей из -S-R7 и -S-(O)2R7, и
R7 выбран из группы, состоящей из C1-6 алкила, C1-6 галогеналкила, 5-12-членного гетероарила и 3-12-членного гетероциклила.
28. Соединение по п.27 или его фармацевтически приемлемая соль, где R5 представляет собой -CH2R5a, R5a выбран из группы, состоящей из -S-R7 и -S-(O)2R7, и R7 представляет собой C1-6 алкил.
29. Соединение по п.27 или его фармацевтически приемлемая соль, где R5 представляет собой -CH2R5а, R5а представляет собой -SR7, и R7 выбран из группы, состоящей из 5-12-членного гетероарила и 3-12-членного гетероциклила.
30. Соединение по п.29 или его фармацевтически приемлемая соль, где R7 выбран из группы, состоящей из изоксазолила, пиридинила и пиримидинила.
31. Соединение по п.27, где R5 представляет собой -CHS(O)(R5b)2.
32. Соединение по п.13 или 14, где R5 представляет собой C1-6 галогеналкил.
33. Соединение по п.32, где R5 представляет дифторметил.
34. Соединение по п.1 или его фармацевтически приемлемая соль, которое выбрано из группы, состоящей из
Figure 00000004
Figure 00000005
Figure 00000006
Figure 00000007
35. Соединение по п.1 или его фармацевтически приемлемая соль, которое выбрано из группы, состоящей из
Figure 00000008
Figure 00000009
Figure 00000010
Figure 00000011
36. Фармацевтическая композиция, содержащая соединение по любому из пп. 1-35 или его фармацевтически приемлемую соль и фармацевтически приемлемый эксципиент.
37. Способ лечения заболевания или состояния, связанного с P. gingivalis инфекцией, включающий введение пациенту эффективного количества соединения по любому из пп. 1-35 или его фармацевтически приемлемой соли или эффективного количества композиции по п.36.
38. Способ по п.37, в котором заболевание или состояние выбрано из группы, состоящей из нарушения мозговой деятельности, заболевания пародонта, диабета, сердечно-сосудистого заболевания, артрита, ревматоидного артрита, остеоартрита, инфекционного артрита, псориатического артрита, повышенного риска преждевременных родов, пневмонии, рака, заболевания почек, заболевания печени, поражения сетчатки и глаукомы.
39. Способ по п.38, в котором заболевание или состояние представляет собой нарушение мозговой деятельности.
40. Способ по п.39, в котором нарушение мозговой деятельности выбрано из группы, состоящей из болезни Альцгеймера, синдрома Дауна, эпилепсии, аутизма, болезни Паркинсона, эссенциального тремора, фронто-темпоральной деменции, прогрессирующего надъядерного паралича, бокового амиотрофического склероза, болезни Гантингтона, рассеянного склероза, умеренного когнитивного нарушения, возрастного нарушения памяти, хронической травматической энцефалопатии, инсульта, нарушения мозгового кровообращения, болезни телец Леви, множественной системной атрофии, шизофрении и депрессии.
41. Способ по п.40, в котором нарушение мозговой деятельности представляет собой болезнь Альцгеймера.
42. Способ по п.41, дополнительно включающий введение пациенту одного или нескольких активных агентов, выбранных из группы, состоящей из ингибитора холинэстеразы, модулятора серотонина, модулятора NMDA, терапевтического средства Αβ-направленного действия, терапевтического средства АпоЕ-направленного действия, терапевтического средства микроглия-направленного действия, терапевтического средства действия, направленного на гематоэнцефалический барьер, терапевтического средства тау-направленного действия, терапевтического средства комплемент-направленного действия и противовоспалительного терапевтического средства.
43. Способ по п.38, в котором заболевание или состояние представляет собой заболевание пародонта.
44. Способ по п.38, в котором заболевание или состояние представляет собой заболевание печени.
45. Способ по п.44, в котором заболевание печени представляет собой неалкогольный стеатогепатит.
46. Способ по п.38, где заболевание или состояние представляет собой поражение сетчатки.
47. Способ по п.46, в котором поражение сетчатки представляет собой возрастную макулярную дегенерацию.
48. Способ по п.38, в котором заболевание или состояние представляет собой рак.
49. Способ по п.48, в котором рак выбран из группы, состоящей из рака ротовой полости, рака молочной железы, рака поджелудочной железы и мультиформной глиобластомы.
50. Способ по п.38, в котором заболевание или состояние представляет собой повышенный риск преждевременных родов.
51. Способ по п.38, в котором заболевание или состояние представляет собой артрит.
52. Способ по п.51, в котором артрит представляет собой ревматоидный артрит или остеоартрит.
53. Способ по п.38, в котором заболевание или состояние представляет собой сердечно-сосудистое заболевание.
54. Способ по п.38, в котором заболевание или состояние представляет собой диабет.
55. Способ по любому из пп. 37-54, в котором соединение вводят пациенту в течение по меньшей мере одного месяца.
56. Способ по п.55, в котором соединение вводят пациенту в течение по меньшей мере одного года.
57. Способ по п.55, в котором соединение вводят пациенту в течение по меньшей мере 10 лет.
58. Способ по п.55, в котором соединение вводят пациенту в течение по меньшей мере 60 лет.
59. Способ по любому из пп. 37-58, в котором пациент представляет собой человека, собаку или кошку.
60. Способ по п.59, в котором пациент представляет собой человека.
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