RU2503681C2 - New condensed derivative of aminodihydrothiazine - Google Patents

New condensed derivative of aminodihydrothiazine Download PDF

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RU2503681C2
RU2503681C2 RU2011117341/04A RU2011117341A RU2503681C2 RU 2503681 C2 RU2503681 C2 RU 2503681C2 RU 2011117341/04 A RU2011117341/04 A RU 2011117341/04A RU 2011117341 A RU2011117341 A RU 2011117341A RU 2503681 C2 RU2503681 C2 RU 2503681C2
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thia
hexahydro
oxa
amino
carboxamide
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RU2011117341/04A
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RU2011117341A (en
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Такафуми МОТОКИ
Кунитоси ТАКЕДА
Йоити КИТА
Мамору Такаиси
Юити СУЗУКИ
Тасуку ИСИДА
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Эйсай Ар Энд Ди Менеджмент Ко., Лтд.
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Priority claimed from PCT/JP2009/066728 external-priority patent/WO2010038686A1/en
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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Abstract

FIELD: biotechnologies.
SUBSTANCE: invention refers to new compounds represented with common formula (I) to its pharmaceutically acceptable salts that have inhibiting activity in relation to products of amyloid β-protein (Aβ42) or decomposition with ferment of beta-site of amyloid-β (BACE1) precursor. In general formula
Figure 00000259
, circle A represents aryl chosen from phenyl, which can be replaced with substitutes with number of 1 to 3, which have been chosen from a group of substitutes α, 5-6-membered heteroalkyl with sulphur atom as heteroatom that can have 1 to 3 substitutes chosen from a group of substitutes α, or 9-10-membered benzo-condensed heterocyclic group having 2 atoms of oxygen in heterocyclic part of the above group, which can be replaced with substitutes with number of 1 to 3, which have been chosen from the group of substitutes α, L means ordinary bond, -NRLCO- (in which RL means hydrogen atom) or -NRLCO-C1-6alkyl (in which RL means hydrogen atom). Circle B represents 5-6-membered heteroaryl or saturated heterocyclic group with 1-3 heteroatoms in a cycle, which have been chosen from a group of hydrogen, oxygen or sulphur atoms, each of which can have 1 to 3 substitutes chosen from the group of substitutes α, or 9-10-membered benzo-condensed group having 2 oxygen atoms in heterocyclic part of the above group, X means methylene that can have 1 to 2 substitutes chosen from the group of substitutes α, Y means methylene that can have 1 to 2 substitutes chosen from the group of substitutes α, and Z means oxygen atom. The rest substitutes are specified in the claim.
EFFECT: compounds can be used for treatment of neurodegenerative diseases caused with Aβ presented with Alzheimer disease as a typical case.
9 cl, 13 dwg, 12 tbl, 88 ex

Description

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Claims (9)

1. Соединение, представленное формулой (I):
Figure 00000258

или его фармацевтически приемлемая соль, в которой
Кольцо А представляет собой арил, выбранный из фенила, который может быть замещен заместителями числом от 1 до 3, выбранными из Группы заместителей α, 5-6-членный гетероарил с атомом серы в качестве гетероатома, который может иметь от 1 до 3 заместителей, выбранных из Группы заместителей α, или 9-10-членную бензо-конденсированную гетероциклическую группу, имеющую 2 атома кислорода в гетероциклической части указанной группы, которая может быть замещен заместителями числом от 1 до 3, выбранными из Группы заместителей α,
L обозначает простую связь, -NRLCO- (в которой RL обозначает атом водорода) или - NRLCO-C1-6алкил (в которой RL обозначает атом водорода),
Кольцо B представляет собой 5-6-членную гетероарильную или насыщенную гетероциклическую группу с 1-3 гетероатомами в цикле, выбранными из группы атомов водорода, кислорода или серы, каждая из которых может иметь от 1 до 3 заместителей, выбранных из Группы заместителей α, или 9-10-членную бензо-конденсированную гетероциклическую группу, имеющую 2 атома кислорода в гетероциклической части указанной группы,
X обозначает метилен, который может иметь от 1 до 2 заместителей, выбранных из Группы заместителей α,
Y обозначает метилен, который может иметь от 1 до 2 заместителей, выбранных из Группы заместителей α,
Z обозначает атом кислорода,
R1, R2, R5 и R6 обозначают атомы водорода, и
R3 и R4 обозначают независимо атом водорода, атом галогена, C1-6 алкил, который может иметь от 1 до 3 заместителей, выбранных из Группы заместителей α, или C1-6алкокси, который может иметь от 1 до 3 заместителей, выбранных из Группы заместителей α,
[Группа заместителей α: атом водорода, атом галогена, гидроксильная группа, нитрогруппа, цианогруппа, C1-6алкокси, которая может иметь от 1 до 3 заместителей, выбранных из Группы заместителей β, и C1-6 алкил, который может иметь от 1 до 3 заместителей, выбранных из Группы заместителей β,
Группа заместителей β: атом галогена, гидроксильная группа и метокси].1. The compound represented by formula (I):
Figure 00000258

or its pharmaceutically acceptable salt, in which
Ring A is aryl selected from phenyl, which may be substituted with 1 to 3 substituents selected from Substituent Group α, a 5-6 membered heteroaryl with a sulfur atom as a hetero atom, which may have 1 to 3 substituents selected from the substituent group α, or a 9-10 membered benzo-fused heterocyclic group having 2 oxygen atoms in the heterocyclic part of the indicated group, which may be substituted by substituents from 1 to 3 selected from the group of substituents α,
L represents a single bond, -NR L CO- (wherein R L represents a hydrogen atom), or - NR L CO-C 1-6 alkyl (wherein R L represents a hydrogen atom),
Ring B is a 5-6 membered heteroaryl or saturated heterocyclic group with 1-3 heteroatoms in the ring selected from the group of hydrogen, oxygen or sulfur atoms, each of which may have 1 to 3 substituents selected from Substituent Group α, or A 9-10 membered benzo-fused heterocyclic group having 2 oxygen atoms in the heterocyclic part of said group,
X is methylene, which may have 1 to 2 substituents selected from Substituent Group α,
Y is methylene, which may have 1 to 2 substituents selected from Substituent Group α,
Z is an oxygen atom,
R 1 , R 2 , R 5 and R 6 are hydrogen atoms, and
R 3 and R 4 independently represent a hydrogen atom, a halogen atom, C 1-6 alkyl, which may have 1 to 3 substituents selected from Substituent Group α, or C 1-6 alkoxy, which may have 1 to 3 substituents, selected from the substituent group α,
[Substituent Group α: hydrogen atom, halogen atom, hydroxyl group, nitro group, cyano group, C 1-6 alkoxy, which may have 1 to 3 substituents selected from Substituent Group β, and C 1-6 alkyl, which may have from 1 to 3 substituents selected from Substituent Group β,
Substituent group β: halogen atom, hydroxyl group and methoxy]. 2. Соединение по п.1 или его фармацевтически приемлемая соль, в котором L обозначает -NRLCO- (в которой RL обозначает атом водорода).2. The compound according to claim 1 or its pharmaceutically acceptable salt, in which L is —NR L CO— (in which R L is a hydrogen atom). 3. Соединение по п.1 или его фармацевтически приемлемая соль, в котором заместители, выбранные из Группы заместителей α, представляют собой атом водорода, цианогруппу, атом галогена, метокси, который может иметь от 1 до 3 заместителей, выбранных из Группы заместителей β, или метил, который может иметь от 1 до 3 заместителей, выбранных из Группы заместителей β.3. The compound according to claim 1 or its pharmaceutically acceptable salt, in which the substituents selected from the group of substituents α, represent a hydrogen atom, a cyano group, a halogen atom, methoxy, which may have from 1 to 3 substituents selected from the group of substituents β, or methyl, which may have 1 to 3 substituents selected from Substituent Group β. 4. Соединение по п.1 или его фармацевтически приемлемая соль, причем соединение выбрано из следующих соединений:
1) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
2) N-[3-((8S*,8aR*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-фторметоксипиразин-2-карбоксамид,
3) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиразин-2-карбоксамид,
4) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-трифторметоксифенил]-5-цианопиридин-2-карбоксамид,
5) N-[3-((8S*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-трифторметоксифенил]-5-хлорпиридин-2-карбоксамид,
6) N-[3-((4aR*,6S*,8aS*)-2-амино-6-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-хлорпиридин-2-карбоксамид,
7) N-[3-((4aR*,6S*,8aS*)-2-амино-6-метил-4,4a,5,6,8,8a-гексагидро-7-окса-3--тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
8) N-[3-((4aR*,6S*,8aS*)-2-амино-6-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-трифторметилпиридин-2-карбоксамид,
9) N-[3-((4aR*,6S*,8aS*)-2-амино-6-метил-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиразин-2-карбоксамид,
10) N-[3-((4aR*,6S*,8aS*)-2-амино-6-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-фторметоксипиразин-2-карбоксамид,
11) N-[3-((4aR*,6R*,8aS*)-2-амино-6-метоксиметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
12) N-[3-((4aR*,6R*,8aS*)-2-амино-6-метоксиметил-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметилпиразин-2-карбоксамид,
13) N-[3-((4aR*,6R*,8aS*)-2-амино-6-метоксиметил-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-хлорпиридин-2-карбоксамид,
14) N-[3-((4aR*,6R*,8aS*)-2-амино-6-метоксиметил-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-фторметоксипиразин-2-карбоксамид,
15) N-[3-((4aR*,6R*,8aS*)-2-амино-6-метоксиметил-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиразин-2-карбоксамид,
16) N-[3-((4aS,5S,8aS)-2-амино-5-фтор-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
17) N-[3-((4aS,5S,8aS)-2-амино-5-фтор-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметилпиразин-2-карбоксамид,
18) N-[3-((4aS,5S,8aS)-2-амино-5-фтор-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-хлорпиридин-2-карбоксамид,
19) N-[3-((4aS,5S,8aS)-2-амино-5-фтор-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-трифторметилпиридин-2-карбоксамид,
20) N-[3-((4aS,5S,8aS)-2-амино-5-фтор-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиридин-2-карбоксамид,
21) N-[3-((4aS,5S,8aS)-2-амино-5-фтор-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-фторметоксипиразин-2-карбоксамид,
22) N-[3-((4aS,5S,8aS)-2-амино-5-фтор-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиразин-2-карбоксамид,
23) N-[3-((4aR*,5R*,8aR*)-2-амино-5-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-хлорпиридин-2-карбоксамид,
24) N-[3-((4aR*,5S*,8aS*)-2-амино-5-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
25) N-[3-((4aR*,5S*,8aS*)-2-амино-5-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиразин-2-карбоксамид,
26) N-[3-((4aR*,5R*,8aS*)-2-амино-5-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-хлорпиридин-2-карбоксамид,
27) N-[3-((4aR*,5R*,8aS*)-2-амино-5-метил-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-l-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
28) N-[3-((4aR*,5R*,8aS*)-2-амино-5-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиразин-2-карбоксамид,
29) N-[3-((4aR*,5R*,8aS*)-2-амино-5-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметилпиразин-2-карбоксамид,
30) N-[3-((4aS*,5R*,8aS*)-2-амино-5-метокси-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
31) N-[3-((2R*,4aR*,8aS*)-2-амино-4-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
32) N-[3-((2R*,4aR*,8aS*)-2-амино-4-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметилпиразин-2-карбоксамид,
33) N-[3-((4aR,6R,8aS)-2-амино-6-гидроксиметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-хлорпиридин-2-карбоксамид,
34) N-[3-((4aR,6R,8aS)-2-амино-6-гидроксиметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
35) N-[3-((4aR*,6R*,8aS*)-2-амино-6-трифторметил-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
36) N-[3-((4aR*,6R*,8aS*)-2-амино-6-трифторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиразин-2-карбоксамид,
37) N-[3-((4aR*,6R*,8aS*)-2-амино-6-трифторметил-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-фторпиридин-2-карбоксамид,
38) N-[3-((4aR*,6R*,8aS*)-2-амино-6-трифторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-пиридин-2-карбоксамид,
39) N-[3-((4aR*,6R*,8aS*)-2-амино-6-трифторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-фторметоксипиразин-2-карбоксамид,
40) N-[3-((4aR*,6R*,8aS*)-2-амино-6-трифторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-пиримидин-4-карбоксамид,
41) N-[3-((4aR*,6R*,8aS*)-2-амино-6-трифторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-3,5-дифторпиридин-2-карбоксамид,
42) N-[3-((4aR*,6R*,8aS*)-2-амино-6-трифторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиридин-2-карбоксамид,
43) N-[3-((4aR*,6R*,8aS*)-2-амино-6-трифторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметилпиразин-2-карбоксамид,
44) N-[3-((4aR,6R,8aS)-2-амино-6-фторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-цианопиридин-2-карбоксамид,
45) N-[3-((4aR,6R,8aS)-2-амино-6-фторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-хлорпиридин-2-карбоксамид,
46) N-[3-((4aR,6R,8aS)-2-амино-6-фторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-трифторметилпиридин-2-карбоксамид,
47) N-[3-((4aR,6R,8aS)-2-амино-6-фторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-фторметоксипиразин-2-карбоксамид,
48) N-[3-((4aR,6R,8aS)-2-амино-6-фторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметилпиразин-2-карбоксамид,
49) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-хлорпиридин-2-карбоксамид,
50) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-бромпиридин-2-карбоксамид,
51) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-3,5-дифторпиридин-2-карбоксамид,
52) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-3,5-дихлорпиридин-2-карбоксамид,
53) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-фторпиридин-2-карбоксамид,
54) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-3,5-дибромпиридин-2-карбоксамид,
55) N-[3-((4aR*,8aS*)-2-амино-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-1-азанафталин-8a-ил)-4-фторфенил]-5-трифторметилпиридин-2-карбоксамид,
56) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметилпиридин-2-карбоксамид,
57) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметилпиразин-2-карбоксамид,
58) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-дифторметоксипиридин-2-карбоксамид,
59) (±)-(4aR*,6R*,8aS*)-8а-[2-фтор-5-(2-фторпиридин-3-ил)фенил]-6-трифторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-2-иламин,
60) (4aR,6R,8aS)-8а-[2-фтор-5-(2-фторпиридин-3-ил)фенил]-6-фторметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-2-иламин,
61) (±)-(4aR*,8aS*)-8а-[2-фтор-5-(2-фторпиридин-3-ил)фенил]-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1 -азанафталин-2-иламин,
62)(±)-(4аR*,8аS*)-8а-(2-фтор-5-пиримидин-5-илфенил)-4,4а,5,6,8,8а-гексагидро-7-окса-3 -тиа-1 -азанафталин-2-иламин,
63)(±)-(4аR*,8аS*)-8а-[5-(5-хлорпиридин-3-ил)-2-фторфенил]-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-!-азанафталин-2-иламин,
64) М-[5-((4аR*,8аS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)тиофен-3-ил]-5-цианопиридин-2-карбоксамид,
65) (±)-(4аR*,8аS*)-8а-[4-(2-фторпиридин-3-ил)-тиофен-2-ил]-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1 -азанафталин-2-иламин,
66) (4аR,6R,8аS)-8а-[2-фтор-5-(2-фторпиридин-3-ил)фенил]-6-бензилоксиметил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-2-иламин,
67) (±)-N-[7-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-2,2-дифторбензо[1,3]диоксол-5-ил]-5-цианопиридин-2-карбоксамид,
68) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-5-(2-метоксиэтокси)-пиразин-2-карбоксамид,
69) N-[3-((4aR*,8aS*)-2-амино-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-2-метилтиазол-4-карбоксамид,
70) N-[3-((4aR*,5R*,8aS*)-2-амино-5-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-2,5-диметилфуран-3-карбоксамид,
71) N-[3-((4aR*,5R*,8aS*)-2-амино-5-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-4-метил-[1,2,3]тиадиазол-5-карбоксамид,
72) N-[3-((4aR*,5R*,8aS*)-2-амино-5-метил-4,4a,5,6,8,8a-гексагидро-7-окса-3-тиа-l-азанафталин-8а-ил)-4-фторфенил]-3-пиперидин-1-илпропионамид и
73) N-[3-((4aR*,5R*,8aS*)-2-амино-5-метил-4,4а,5,6,8,8а-гексагидро-7-окса-3-тиа-1-азанафталин-8а-ил)-4-фторфенил]-2-метилоксазол-4-карбоксамид,
или его фармацевтически приемлемая соль.4. The compound according to claim 1 or its pharmaceutically acceptable salt, and the compound is selected from the following compounds:
1) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
2) N- [3 - ((8S *, 8aR *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-fluoromethoxypyrazine-2-carboxamide,
3) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-difluoromethoxypyrazine-2-carboxamide,
4) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-trifluoromethoxyphenyl] -5-cyanopyridin-2-carboxamide,
5) N- [3 - ((8S *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-trifluoromethoxyphenyl] -5-chloropyridin-2-carboxamide,
6) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-chloropyridin-2-carboxamide,
7) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3 - thia 1-azanaphthalen-8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
8) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide,
9) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethoxypyrazine-2-carboxamide,
10) N- [3 - ((4aR *, 6S *, 8aS *) - 2-amino-6-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-fluoromethoxypyrazine-2-carboxamide,
11) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
12) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethylpyrazine-2-carboxamide,
13) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-chloropyridin-2-carboxamide,
14) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-fluoromethoxypyrazine-2-carboxamide,
15) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-methoxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethoxypyrazine-2-carboxamide,
16) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
17) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-difluoromethylpyrazine-2-carboxamide,
18) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4а, 5,6,8,8а-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-chloropyridin-2-carboxamide,
19) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide,
20) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-difluoromethoxypyridine-2-carboxamide,
21) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-fluoromethoxypyrazine-2-carboxamide,
22) N- [3 - ((4aS, 5S, 8aS) -2-amino-5-fluoro-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-difluoromethoxypyrazine-2-carboxamide,
23) N- [3 - ((4aR *, 5R *, 8aR *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-chloropyridin-2-carboxamide,
24) N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
25) N- [3 - ((4aR *, 5S *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethoxypyrazine-2-carboxamide,
26) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-chloropyridin-2-carboxamide,
27) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-l -azanaphthalen-8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
28) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethoxypyrazine-2-carboxamide,
29) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethylpyrazine-2-carboxamide,
30) N- [3 - ((4aS *, 5R *, 8aS *) - 2-amino-5-methoxy-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
31) N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
32) N- [3 - ((2R *, 4aR *, 8aS *) - 2-amino-4-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethylpyrazine-2-carboxamide,
33) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-chloropyridin-2-carboxamide,
34) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-hydroxymethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
35) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
36) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethoxypyrazine-2-carboxamide,
37) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-fluoropyridin-2-carboxamide,
38) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalene-8a-yl) -4-fluorophenyl] pyridine-2-carboxamide,
39) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-fluoromethoxypyrazine-2-carboxamide,
40) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] pyrimidine-4-carboxamide,
41) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -3,5-difluoropyridin-2-carboxamide,
42) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethoxypyridin-2-carboxamide,
43) N- [3 - ((4aR *, 6R *, 8aS *) - 2-amino-6-trifluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -5-difluoromethylpyrazine-2-carboxamide,
44) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-cyanopyridin-2-carboxamide,
45) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-chloropyridin-2-carboxamide,
46) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide,
47) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-fluoromethoxypyrazine-2-carboxamide,
48) N- [3 - ((4aR, 6R, 8aS) -2-amino-6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -4-fluorophenyl] -5-difluoromethylpyrazine-2-carboxamide,
49) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-chloropyridin-2-carboxamide,
50) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-bromopyridin-2-carboxamide,
51) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -3,5-difluoropyridin-2-carboxamide,
52) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -3,5-dichloropyridin-2-carboxamide,
53) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-fluoropyridin-2-carboxamide,
54) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -3,5-dibromopyridin-2-carboxamide,
55) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-trifluoromethylpyridin-2-carboxamide,
56) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-difluoromethylpyridin-2-carboxamide,
57) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-difluoromethylpyrazine-2-carboxamide,
58) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5-difluoromethoxypyridine-2-carboxamide,
59) (±) - (4aR *, 6R *, 8aS *) - 8- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-trifluoromethyl-4,4a, 5,6, 8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-ylamine,
60) (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-fluoromethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-thia-1-azanaphthalen-2-ylamine,
61) (±) - (4aR *, 8aS *) - 8- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-thia-1-azanaphthalen-2-ylamine,
62) (±) - (4aR *, 8aS *) - 8- (2-fluoro-5-pyrimidin-5-ylphenyl) -4,4a, 5,6,8,8a-hexahydro-7-oxa-3 - thia-1-azanaphthalen-2-ylamine,
63) (±) - (4aR *, 8aS *) - 8- [5- (5-chloropyridin-3-yl) -2-fluorophenyl] -4,4a, 5,6,8,8a-hexahydro-7- oxa-3-thia -! - azanaphthalene-2-ylamine,
64) M- [5 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) thiophen-3-yl] -5-cyanopyridin-2-carboxamide,
65) (±) - (4aR *, 8aS *) - 8- [4- (2-fluoropyridin-3-yl) -thiophen-2-yl] -4,4a, 5,6,8,8a-hexahydro 7-oxa-3-thia-1-azanaphthalen-2-ylamine,
66) (4aR, 6R, 8aS) -8a- [2-fluoro-5- (2-fluoropyridin-3-yl) phenyl] -6-benzyloxymethyl-4,4a, 5,6,8,8a-hexahydro-7 -oxa-3-thia-1-azanaphthalen-2-ylamine,
67) (±) -N- [7 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene- 8a-yl) -2,2-difluorobenzo [1,3] dioxol-5-yl] -5-cyanopyridin-2-carboxamide,
68) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -5- (2-methoxyethoxy) pyrazine-2-carboxamide,
69) N- [3 - ((4aR *, 8aS *) - 2-amino-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalene-8a-yl) -4-fluorophenyl] -2-methylthiazole-4-carboxamide,
70) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -2,5-dimethylfuran-3-carboxamide,
71) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -4-methyl- [1,2,3] thiadiazole-5-carboxamide,
72) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-l -azanaphthalen-8a-yl) -4-fluorophenyl] -3-piperidin-1-ylpropionamide and
73) N- [3 - ((4aR *, 5R *, 8aS *) - 2-amino-5-methyl-4,4a, 5,6,8,8a-hexahydro-7-oxa-3-thia-1 -azanaphthalen-8a-yl) -4-fluorophenyl] -2-methyloxazole-4-carboxamide,
or a pharmaceutically acceptable salt thereof. 5. Фармацевтическая композиция, имеющая свойства ингибитора продукции амилоидного β-белка (Aβ42) или расщепления ферментом бета-сайта предшественника амилоида-β (ВАСЕ1), включающая в качестве активного ингредиента соединение по п.1 или его фармацевтически приемлемую соль.5. A pharmaceutical composition having the properties of an inhibitor of amyloid β-protein production (Aβ42) or enzyme cleavage of the beta site of amyloid-β precursor (BACE1), comprising, as an active ingredient, the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 6. Фармацевтическая композиция по п.5 для ингибирования продукции амилоидного β-белка.6. The pharmaceutical composition according to claim 5 for inhibiting the production of amyloid β-protein. 7. Фармацевтическая композиция по п.5 для ингибирования расщепления ферментом 1 бета-сайта предшественника амилоида-β (ВАСЕ1).7. The pharmaceutical composition of claim 5 for inhibiting enzyme 1 cleavage of the beta site of amyloid-β precursor (BACE1). 8. Фармацевтическая композиция по любому из пп.5-7 для лечения нейродегенеративного заболевания.8. The pharmaceutical composition according to any one of claims 5 to 7 for the treatment of a neurodegenerative disease. 9. Фармацевтическая композиция по п.8, причем нейродегенеративное заболевание представляет собой деменцию типа болезни Альцгеймера или синдром Дауна. 9. The pharmaceutical composition of claim 8, wherein the neurodegenerative disease is dementia such as Alzheimer's disease or Down syndrome.
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US5665718A (en) * 1994-03-16 1997-09-09 Hoffmann-La Roche Inc. Imidazodiazepines
RU2175316C2 (en) * 1995-12-20 2001-10-27 Ф. Хоффманн-Ля Рош Аг Aryl-s(o)n-substituted carboxylic-hydroxamic acids and method of their synthesis
US20040019215A1 (en) * 2002-03-19 2004-01-29 Kolb Hartmuth C. Large scale synthesis of 1,2,4- and 1,3,4-oxadiazole carboxylates
EP1841426A1 (en) * 2005-01-19 2007-10-10 Merck & Co., Inc. Tertiary carbinamines having substituted heterocycles, which are active as inhibitors of beta-secretase, for the treatment of alzheimer's disease
WO2009091016A1 (en) * 2008-01-18 2009-07-23 Eisai R & D Management Co., Ltd. Condensed aminodihydrothiazine derivative

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US5665718A (en) * 1994-03-16 1997-09-09 Hoffmann-La Roche Inc. Imidazodiazepines
RU2175316C2 (en) * 1995-12-20 2001-10-27 Ф. Хоффманн-Ля Рош Аг Aryl-s(o)n-substituted carboxylic-hydroxamic acids and method of their synthesis
US20040019215A1 (en) * 2002-03-19 2004-01-29 Kolb Hartmuth C. Large scale synthesis of 1,2,4- and 1,3,4-oxadiazole carboxylates
EP1841426A1 (en) * 2005-01-19 2007-10-10 Merck & Co., Inc. Tertiary carbinamines having substituted heterocycles, which are active as inhibitors of beta-secretase, for the treatment of alzheimer's disease
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