阅读说明：本技术 双环杂芳基衍生物 (Bicyclic heteroaryl derivatives ) 是由 哈萨内·拉特尼 珍妮弗·路易斯·卡特 于 2019-09-02 设计创作，主要内容包括：本发明提供了具有通式(I)的新型双环杂芳基化合物,其中R～1、Ar、n和m如本文所述,并且提供了包含所述化合物的组合物、生产所述化合物的方法以及使用所述化合物的方法。(The present invention provides novel bicyclic heteroaryl compounds having the general formula (I) wherein R 1 Ar, n and m are as described herein, and compositions comprising the compounds, methods of producing the compounds, and methods of using the compounds are provided.)

1. a compound of the formula (I),

wherein

R¹Is halogen, lower alkyl substituted by halogen, lower alkoxy, or lower alkoxy substituted by halogen,

and if n is 2 or 3, then R¹May be different;

m is 1 or 2;

n is 1,2 or 3;

ar is a six membered heteroaryl group selected from:

wherein

R²Is hydrogen, halogen, lower alkyl, halogenLower alkyl, or lower alkoxy substituted with an alkyl group;

R³is hydrogen or halogen;

or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is a compound of formula (Ia):

wherein R is¹M, n and Ar are as defined in claim 1.

3. The compound of formula (I) according to claim 1, wherein the compound of formula (I) is a compound of formula (Ib):

wherein R is¹M, n and Ar are as defined in claim 1.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein R¹Is halogen.

5. A compound of formula (I) according to any one of claims 1 to 4, wherein R¹Is fluorine or chlorine.

6. A compound of formula (I) according to any one of claims 1 to 5, wherein n is 2 or 3.

7. A compound of formula (I) according to any one of claims 1 to 6, wherein Ar is a six membered heteroaryl group selected from:

wherein

R²Is lower alkyl or lower alkoxy;

R³is hydrogen.

8. A compound of formula (I) according to any one of claims 1 to 7, wherein Ar is a six membered heteroaryl group selected from:

wherein

R²Is methyl or methoxy;

R³is hydrogen.

9. A compound of formula (I) according to any one of claims 1 to 3, wherein:

R¹is halogen;

m is 1 or 2;

n is 2 or 3;

ar is a six membered heteroaryl group selected from:

wherein

R²Is lower alkyl or lower alkoxy;

R³is hydrogen.

10. A compound of formula (I) according to any one of claims 1 to 3, wherein:

R¹is a fluorine or chlorine compound, and is,

m is 1 or 2;

n is 2 or 3;

ar is a six membered heteroaryl group selected from:

wherein

R²Is methyl or methoxy;

R³is hydrogen.

11. A compound according to any one of claims 1 to 10, selected from:

(9R) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] o]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] as]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(8R) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

or a pharmaceutically acceptable salt thereof.

12. A compound according to any one of claims 1 to 10, selected from:

(9R) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [ alpha ], [ alpha5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] as]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(8R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidine-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

or a pharmaceutically acceptable salt thereof.

13. A process for preparing a compound according to any one of claims 1 to 12, comprising reacting compound 5

The reaction with an amine 6 is carried out,

wherein Ar, R¹N and m are as defined in any one of claims 1 to 12,

to form said compound of formula (I) and, if desired, converting said compound obtained into a pharmaceutically acceptable salt thereof.

14. A compound according to any one of claims 1 to 12, produced according to the method of claim 13.

15. A compound according to any one of claims 1 to 12 and claim 14 for use as therapeutically active substance.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and claim 14 and a therapeutically inert carrier.

17. A compound according to any one of claims 1 to 12 and claim 14 for use in the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type, multi-infarct dementia, dementia pugilistica or down syndrome.

18. Use of a compound according to any one of claims 1 to 12 and claim 14 for the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type, multi-infarct dementia, dementia pugilistica or down syndrome.

19. Use of a compound according to any one of claims 1 to 12 and claim 14 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type, multi-infarct dementia, dementia pugilistica or down syndrome.

20. A method for the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type, multi-infarct dementia, dementia pugilistica or down syndrome, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 12 and claim 14.

21. The invention as hereinbefore described.

Technical Field

The present invention relates to bicyclic heteroaryl compounds useful as modulators of gamma-secretase, to processes for the production of said compounds, to pharmaceutical compositions comprising said compounds and to their use as medicaments for the therapeutic and/or prophylactic treatment of diseases associated with the deposition of beta-amyloid in the brain, such as alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica and down syndrome.

Background

Alzheimer's Disease (AD) is the most common cause of senile dementia. Pathologically, AD is characterized by amyloid deposits in extracellular plaques and intracellular neurofibrillary tangles of the brain. Amyloid plaques are composed primarily of the amyloid peptide (a β peptide), which is derived from β -Amyloid Precursor Protein (APP) through a series of proteolytic cleavage steps. Various forms of APP have been identified, with the most abundant being proteins of 695, 751 and 770 amino acids in length. They are all produced by differential splicing of a single gene. The a β peptide is derived from the same domain of APP.

A β peptides are produced by APP through the sequential action of two proteolytic enzymes, β -secretase and γ -secretase. The β -secretase enzyme first cleaves in the extracellular domain of APP outside the transmembrane domain (TM) to generate a C-terminal fragment of APP (CTF β) containing the TM and cytoplasmic domains. CTF β is a substrate for γ -secretase, and can be cleaved at several adjacent positions within the TM to produce the a β peptide and cytoplasmic fragments. Various proteolytic cleavages mediated by gamma-secretase produce a β peptides of different chain lengths, such as a β 38, a β 40 and a β 42. The latter is considered to be the more pathogenic amyloid peptide, since it forms neurotoxic aggregates very easily. The beta-secretase enzyme is a typical aspartyl protease.

Gamma-secretase is a high molecular weight complex consisting of four essential subunits: presenilin (PS, including PS1 and PS2), dystrophin (nicastrin), prepharyngeal deficient protein 1(APH-1), and presenilin enhancer 2 (PEN-2). Has published a resolution ofThe atomic structure of human gamma-secretase (X.Bai, C.Yan, G.Yang, P.Lu, D.Ma, L.Sun, R.Zhou)S.H.W.Scheres, Y.Shi, Nature,525(2015), 212-. Presenilins carry catalytic sites and represent a group of atypical aspartyl proteases that cleave their substrates within the TM and belong themselves to polyhedral membrane proteins. It is believed that the other essential components of the gamma-secretase, the flatting protein, and the products of the aph1 and pen-2 genes are responsible for the recognition and recruitment of substrates. The demonstrated substrates for γ -secretase are proteins of the APP and Notch receptor families, however, γ -secretase has loose substrate specificity and many other membrane proteins unrelated to APP and Notch are reported to be cleaved in vitro by γ -secretase.

Gamma-secretase activity is essential for the production of a β peptides. This has been demonstrated by genetic means (i.e., ablation of presenilin genes) as well as low molecular weight inhibitory compounds. According to the amyloid cascade hypothesis of AD, the production and deposition of a β is the ultimate cause of the disease. Thus, selective and effective inhibition of gamma-secretase is believed to be useful in the prevention and treatment of AD.

An alternative therapeutic approach is to modulate γ -secretase activity, which results in a selective reduction in a β 42 production. This will result in an increase in shorter a β isoforms (such as a β 38, a β 37 or other isoforms) that have no or reduced ability to aggregate or plaque form and no or reduced neurotoxicity. Compounds that modulate gamma-secretase activity include certain non-steroidal anti-inflammatory drugs (NSAIDs) and related analogs (Weggen et al, Nature, 414(2001) 212-.

Many documents describe recent knowledge about the regulation of gamma-secretase, such as the following publications:

morihara et al, J.neurochem.,83(2002),1009-12

Jantzen et al, J.neuroscience,22(2002),226-54

Takahashi et al, J.biol.chem.,278(2003),18644-70

Beher et al, j.biol.chem.,279(2004),43419-26

Lleo et al, Nature Med.,10(2004),1065-6

Kukar et al, Nature Med.,11(2005),545-50

Perretto et al, J.Med.chem.48(2005),5705-20

Clarke et al, J.biol.chem.,281(2006)31279-89

Stock et al, bioorg.Med.chem.Lett.,16(2006) 2219-2223

Narlawar et al, J.Med.chem.,49(2006)7588-91

Ebke et al, j.biol.chem.,286(2011)37181-86

Oehlich, Gijsen et al, J.Med.Chem.,54(2011), 669-

Li et al Biochemistry,52(2013),3197-

Hall et al, Progress in Med. chem.,53(2014)101-

Burswaich et al, J.Med.chem.,59 (2016).

Thus, modulation of γ -secretase activity is a promising therapeutic strategy for the treatment or prevention of diseases associated with the deposition of β -amyloid in the brain, such as alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica and down syndrome.

There is a need for novel compounds, formulations, treatments and therapies for treating diseases and disorders associated with the deposition of beta-amyloid in the brain. It is therefore an object of the present invention to provide compounds with improved therapeutic properties for the treatment or prevention or alleviation of such diseases and disorders.

Disclosure of Invention

A first object of the present invention is a compound of formula (I)

Wherein

R¹Is halogen, lower alkyl substituted by halogen, lower alkoxy, or lower alkoxy substituted by halogen,

and if n is 2 or 3, then R¹May be different;

m is 1 or 2;

n is 1,2 or 3;

ar is a six membered heteroaryl group selected from:

wherein

R²Is hydrogen, halogen, lower alkyl substituted by halogen, or lower alkoxy;

R³is hydrogen or halogen;

or a pharmaceutically acceptable salt thereof.

Another object of the present invention is a process for the preparation of a compound of formula (I) as described herein, which process comprises reacting compound 5

By reaction with amines 6

Wherein Ar, R¹N and m are as defined herein,

to form said compound of formula (I) and, if desired, converting said compound obtained into a pharmaceutically acceptable salt thereof.

Another object of the present invention is a compound of formula (I) as described herein, which is produced according to the process described above.

Another object of the present invention are compounds of formula (I) as described herein for use as therapeutically active substances.

Another object of the invention is a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

Another object of the present invention is a compound of formula (I) as described herein for use in the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or down syndrome.

Another object of the present invention is the use of a compound of formula (I) as described herein for the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica or down syndrome.

Another object of the present invention is the use of a compound of formula (I) as described herein for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica or down syndrome.

Another object of the invention is a method for the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica or down syndrome, which comprises administering an effective amount of a compound of formula (I) as described herein.

Detailed Description

The following definitions of general terms as used in the present specification apply when the terms in question appear alone or in combination with other groups.

The term "lower alkyl", alone or in combination with other groups, refers to a saturated straight or branched alkyl group having a single or multiple branches, wherein the alkyl group typically contains from 1 to 7 carbon atoms (C)_1-7Alkyl), such as methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, isobutyl (i-butyl), 2-butyl (sec-butyl), tert-butyl (t-butyl), isopentyl, 2-ethyl-propyl, 1, 2-dimethyl-propyl, and the like. Specific lower alkyl groups have 1 to 4 carbon atoms (C)_1-4-an alkyl group).

The term "lower alkyl substituted by halogen" refers to an alkyl group as defined above wherein at least one hydrogen atom is substituted by halogen, e.g.CF₃、CHF₂、CH₂F、CHFCF₃、CH₂CHF₂、CH₂CH₂F、CH₂C(CH₃)₂CF₃、CH₂CF₂CF₃、CH(CF₃)₂、CH₂CF₃、(CH₂)₂CF₃、(CH₂)₃CF₃、CH(CH₃)CF₃、CF₂CF₃And the like. Preferred groups are CF₃。

The term "alkoxy", alone or in combination, refers to a group of the formula "alkyl-O-", wherein the term "alkyl" has the previously given meaning, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Particular "alkoxy" groups are methoxy and tert-butoxy.

The term "lower alkoxy substituted by halogen" refers to a lower alkoxy group as defined above wherein at least one hydrogen atom is substituted by halogen.

The term "halogen" or "halo", used alone or in combination, refers to fluorine, chlorine, bromine or iodine, and particularly to fluorine, chlorine or bromine, more particularly to fluorine and chlorine. The term "halo" in combination with another group refers to said group substituted with at least one halogen, especially one to five halogens, especially one to four halogens (i.e. one, two, three or four halogens).

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, and which are not biologically or otherwise undesirable. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (particularly hydrochloric acid) and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine.

Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are salts of hydrochloric, hydrobromic, sulfuric, phosphoric and methanesulfonic acids.

As used herein, the term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a multifunctional compound for selective chemical reaction at another unprotected reactive site with which it is ordinarily associated in synthetic chemistry. The protecting group may be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxyl protecting groups. Specific protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Other specific protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in: protective Groups in Organic Chemistry,5 th edition, 2014, John Wiley & Sons, n.y., from t.w.greene and p.g.m.wutts.

The terms "asymmetric carbon atom" and "asymmetric center" refer to a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog specification, asymmetric carbon atoms may have either an "R" or "S" configuration.

The following abbreviations are used herein:

boc ═ tert-butoxycarbonyl, CAS RN ═ chemical abstracts accession number, DCM ═ dichloromethane, DIPEA ═ N, N-diisopropylethylamine, EtOAc ═ ethyl acetate, EtOH ═ ethanol, FCS ═ fetal calf serum, h ═ h, Hal ═ halogen, HPLC ═ high performance liquid chromatography, IMDM ═ iscoved Dulbecco medium, MeCN ═ acetonitrile, MeOH ═ methanol, Me ═ Me₂SO dimethyl sulfoxide (DMSO), min mL μ L, MS mass spectrum, NaOMe sodium methoxide, Na^tSodium BuO-tert-butoxide, nBuLi-n-butyllithium, NEt₃Triethylamine (TEA), NMP-N-methyl-2-pyrrolidone, OAc-acetoxy, Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium (0), p-TsOH ═ p-toluenesulfonic acid, R ═ any group, RT ═ room temperature, sat. aq. sol. ═ saturated aqueous solution, tBuXPhos ═ 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl, TEA ═ triethylamine, TFA ═ trifluoroacetic acid, THF ═ tetrahydrofuran, THP ═ trifluoroacetic acidTetrahydropyran.

Compounds of the invention

In a first aspect, the present invention provides a compound of formula (I)

Wherein

R¹Is halogen, lower alkyl substituted by halogen, lower alkoxy, or lower alkoxy substituted by halogen,

and if n is 2 or 3, then R¹May be different;

m is 1 or 2;

n is 1,2 or 3;

ar is a six membered heteroaryl group selected from:

wherein

R²Is hydrogen, halogen, lower alkyl substituted by halogen, or lower alkoxy;

R³is hydrogen or halogen;

or a pharmaceutically acceptable salt thereof.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein the compound of formula (I) is a compound of formula (Ia):

wherein R is¹M, n and Ar are as defined above.

In one embodiment, there is provided a compound of formula (I) as described herein, wherein the compound of formula (I) is a compound of formula (Ib):

wherein R is¹M, n and Ar are as defined above.

In one embodiment, R¹Is halogen.

In a preferred embodiment, R¹Is fluorine or chlorine.

In one embodiment, n is 2 or 3.

In a preferred embodiment, there is provided a compound of formula (I) as described herein, wherein Ar is a six membered heteroaryl group selected from

Wherein

R²Is lower alkyl or lower alkoxy;

R³is hydrogen.

In another preferred embodiment, there is provided a compound of formula (I) as described herein, wherein Ar is a six membered heteroaryl group selected from

Wherein

R²Is methyl or methoxy;

R³is hydrogen.

In another preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

R¹is halogen;

m is 1 or 2;

n is 2 or 3;

ar is a six membered heteroaryl group selected from:

wherein

R²Is lower alkyl or lower alkoxy;

R³is hydrogen.

In another preferred embodiment, there is provided a compound of formula (I) as described herein, wherein:

R¹is a fluorine or chlorine compound, and is,

m is 1 or 2;

n is 2 or 3;

ar is a six membered heteroaryl group selected from:

wherein

R²Is methyl or methoxy;

R³is hydrogen.

The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers such as racemates, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates, and the like.

In another preferred embodiment, there is provided a compound of formula (I) as described herein, selected from

(9R) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3-(6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] o]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1，4]Oxazazem-2-amine;

(9S) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1，4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1，4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] as]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(8R) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1，4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1，4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

or a pharmaceutically acceptable salt thereof.

In a more preferred embodiment, there is provided a compound of formula (I) as described herein, selected from

(9R) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1，4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] as]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(8R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(8S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrakisHydrogen- [1,2,4]]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

(9R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1，4]Oxazazem-2-amine;

(9S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amine;

or a pharmaceutically acceptable salt thereof.

Production method

A process for the production of a compound of formula (I) as described herein is also an object of the present invention.

The preparation of compounds of formula (I) as described herein may be carried out according to sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to perform the reaction and to purify the resulting product are known to those skilled in the art. Unless indicated to the contrary, the substituents and indices used in the following description of the methods have the meanings provided herein.

If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups which are unstable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups can be introduced prior to the critical step using methods well known in the art (e.g. "protective groups in Organic Chemistry" by T.W. Greene and P.G.M.Wuts, 3 rd edition, 1999, Wiley, New York). Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are t-butyloxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzoxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

If the starting materials or intermediates contain stereogenic centers, it is possible to obtain the compounds of formula (I) in the form of diastereomers or mixtures of enantiomers, which can be separated by methods well known in the art (e.g., chiral HPLC, chiral SFC, or chiral crystallization). Racemic compounds can be separated, for example, into their corresponding counterparts by separation of the diastereomeric salts, by crystallization with an optically pure acid, or by separation of the enantiomers by specific chromatography using chiral adsorbents or chiral eluents. Starting materials and intermediates containing stereogenic centers can likewise be isolated to provide diastereomerically/enantiomerically enriched starting materials and intermediates. The use of such diastereomer/enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (I) typically results in corresponding diastereomer/enantiomer-enriched compounds of formula (I).

One skilled in the art will recognize that the order of the reactions may vary depending on the reactivity and nature of the intermediates.

In more detail, the compounds of formula (I) can be produced by the methods described below, the methods described in the examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. Also, see, for example, the literature for reported reaction conditions that affect the reaction: comprehensive Organic Transformations A Guide to Functional Group Preparations, 2 nd edition, Richard C.Larock, John Wiley & Sons, New York, NY, 1999. It is convenient to carry out the reaction in the presence or absence of a solvent. There is no particular restriction as to the nature of the solvent used, as long as it has no adverse effect on the reaction or reagents involved and is at least to some extent soluble in the reagents. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. The above reaction can be conveniently carried out at a temperature ranging from-78 ℃ to reflux. The time required for the reaction can also vary widely depending on a number of factors, in particular the reaction temperature and the nature of the reagents. However, it usually takes from 0.5 hours to several days to obtain the intermediates and compounds. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps may be freely changed according to the starting materials and their corresponding reactivity.

If starting materials or intermediates are not commercially available or their synthesis is not reported in the literature, they can be prepared using existing methods of preparation similar to the close analogs or as outlined in the experimental section.

In one embodiment, the compounds of formula (I) as described herein may be prepared by: reacting compound 5

By reaction with amines 6

Wherein Ar, R¹N and m are as defined herein,

to form said compound of formula (I) and, if desired, converting said compound obtained into a pharmaceutically acceptable salt thereof.

In one embodiment, the process according to the invention can be carried out in the presence of a catalyst, such as palladium, optionally in the presence of a ligand, such as 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropylbiphenyl.

In another embodiment, the process according to the invention may further comprise a step of performing chiral separation to obtain the compounds of formula (Ia) and (Ib).

In one embodiment, formula (I) (wherein R is as described herein)¹N, m and Ar are as described herein) and intermediates thereof can be prepared following procedures analogous to those reported in the literature and/or, for example, the methods described in schemes 1 and 2, respectively.

Scheme 1

The preparation of the compound of formula (I) can be started by alkylation of 3, 5-dibromo-1H-1, 2, 4-triazole 2 with 2- (2-bromoethoxy) tetrahydropyran (if m is equal to 1) or 2- (3-bromopropoxy) tetrahydropyran (if m is equal to 2) as electrophile to give compound 3. Regioselective halolithiation with nBuLi followed by addition of an optionally substituted benzaldehyde derivative to give primary alcohols 4. Deprotection of primary alcohol 4 with pTsOH can be followed by intramolecular etherification with pTsOH at elevated temperatures to give intermediate 5. Finally, coupling of the Buchwald type with an amine 6 in the presence of palladium and a ligand gives the compounds of formula (I). Enantiomers can be separated by preparative chiral HPLC.

Intermediate 6 can be synthesized, for example, as shown in scheme 2 and/or similar to the methods described in the literature.

Scheme 2

N- [ (1S,5R,8S) -3-azabicyclo [3.2.1]Octane-8-yl]Coupling of tert-butyl carbamate 7(CAS847862-26-4) with heterocyclic halides of the formula Ar-X can be carried out with heating in a solvent such as ethanol or NMP in a base such as Et₃N, or using a metathesis reaction under catalytic conditions (e.g., palladium (0) or copper (II) catalysis) to provide intermediate 8. Deprotection with an acid, such as trifluoroacetic acid, affords amine 6. Heterocyclic halides are commercially available or well known in the literature and thus they can be prepared by methods known in the art.

In one aspect, the present invention provides a compound of formula (I) as described herein, produced according to any one of the methods described herein.

Pharmaceutical compositions and administrationBy using

Another object of the invention is a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments in the form of pharmaceutical preparations. The pharmaceutical preparations may be administered internally, such as orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (for example in the form of injections). Administration can also be effected topically, e.g., transdermally, or in the form of eye or ear drops.

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for the preparation of pharmaceutical preparations such as tablets, coated tablets, dragees, hard gelatine capsules, injections or topical preparations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such carriers for tablets, coated tablets, dragees and hard gelatine capsules.

Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance, however, no carriers are often required in soft gelatin capsules.

Suitable carriers for the preparation of solutions and syrups are, for example, water, alcohols, polyols, sucrose, glucose, invert sugar, vegetable oils and the like.

Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Suitable liquids for topical ophthalmic formulations are, for example, cyclodextrins, mannitol, or many other carriers and excipients known in the art.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. It may also contain other therapeutically valuable substances.

Objects of the present invention also include medicaments comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically inert carrier, and processes for their production, which comprise bringing one or more compounds of formula (I) and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits but will of course have to be adjusted to the individual requirements of each particular case. In general, in case of oral administration, a daily dose of about 0.1mg to 20mg per kg body weight, preferably 0.5mg to 4mg per kg body weight (e.g. about 300mg per person), preferably divided into 1-3 separate doses (which may consist of e.g. the same amount) should be suitable. In the case of topical administration, the formulation may contain 0.001% to 15% by weight of the drug, and the required dose may be between 0.1mg and 25mg, administered in a single dose per day or week, or in multiple doses (2 to 4 times) per day or week. It will be apparent, however, that if the display indicates an upper or lower limit given herein, that limit may be exceeded.

Preparation of pharmaceutical compositions comprising the Compounds of the invention

Tablet formulation (Wet granulation)

The production process comprises the following steps:

1. ingredients 1,2, 3 and 4 were mixed and granulated with purified water.

2. The granules were dried at 50 ℃.

3. The particles are passed through a suitable milling apparatus.

4. Adding ingredient 5 and mixing for three minutes; pressing on a suitable press.

Preparation of capsules

The production process comprises the following steps:

1. ingredients 1,2 and 3 were mixed in a suitable mixer for 30 minutes.

2. Ingredients 4 and 5 were added and mixed for 3 minutes.

3. Fill into suitable capsules.

Indications of

Another object of the present invention are compounds of formula (I) as described herein for use as therapeutically active substances.

As noted above, compounds of formula (I) and pharmaceutically acceptable salts thereof are useful as gamma secretase modulators.

In one aspect, the invention provides a compound of formula (I) as described herein for use in the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica or down syndrome.

In one embodiment, the present invention provides a compound of formula (I) as described herein for use in the therapeutic and/or prophylactic treatment of alzheimer's disease.

In another aspect, the invention provides the use of a compound of formula (I) as described herein for the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica or down syndrome.

In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the therapeutic and/or prophylactic treatment of alzheimer's disease.

In another aspect, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica or down syndrome.

In one embodiment, the present invention provides the use of a compound of formula (I) for the preparation of a medicament for the therapeutic and/or prophylactic treatment of alzheimer's disease.

In another aspect, the invention provides a method for the therapeutic and/or prophylactic treatment of alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis-dutch type (HCHWA-D), multi-infarct dementia, dementia pugilistica or down syndrome, comprising administering an effective amount of a compound of formula (I) as described herein.

In one embodiment, the present invention provides a method for the therapeutic and/or prophylactic treatment of alzheimer's disease, which comprises administering an effective amount of a compound of formula (I) as described herein.

Examples of the invention

The invention will be more fully understood by reference to the following examples. The claims, however, should not be viewed as limited in scope by the examples.

1)Preparation example

1.1)General of

The analysis method comprises the following steps: HPLC (method LCMS _ fastgradient)

-a column: agilent Zorbax Eclipse Plus C18 Rapid separation high throughput column, 2.1X 30mm, 1.8 μm, part number 959731-

-solvent a: 0.01% aqueous formic acid; solvent B: acetonitrile (MeCN)

-a gradient:

1.2)preparation of intermediates

1.2.1) intermediate of type 5, m ═ 1

Intermediate 5-1:

2-bromo-8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazine

Step 1: 2- (2-Bromoethoxy) tetrahydro-2H-pyran (10.0g,7.23ml,47.8mmol, Eq:1.00) and DIPEA (6.18g,8.35ml,47.8mmol, Eq:1.00) were added to a suspension of 3, 5-dibromo-1H-1, 2, 4-triazole (10.9g,47.8mmol, Eq:1.00) in MeCN (90ml) and stirred at 90 ℃ for 20H. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/heptane, increasing from 10/90 to 60/40) to give 3, 5-dibromo-1- (2-tetrahydropyran-2-yloxyethyl) -1,2, 4-triazole (12.08g, 33.7mmol, yield 70%) as a pale yellow oil. MS (ES +) m/z: 356.0[ (M + H)⁺]。

Step 2: n-BuLi (1.6M in hexane, 7.04ml, 11.3mmol, Eq:1.00) was added to a solution of 3, 5-dibromo-1- (2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) -1H-1,2, 4-triazole (4.00g,11.3mmol, Eq:1.00) in THF (100ml) at-78 ℃. The reaction mixture was stirred at-78 ℃ for 20min, then a solution of 2,3, 4-trifluorobenzaldehyde (1.80g,11.3mmol, Eq:1.00) in THF (30.0ml) was added. The solution was stirred at-78 ℃ for an additional 2 hours. The reaction temperature was gradually increased to RT, followed by addition of saturated NH₄Aqueous Cl (5.00ml) and the reaction was quenched. The reaction mixture was diluted with EtOAc (150ml) and washed with brine (2 × 50 ml). The organic phase is separated off and washed with Na₂SO₄Dried, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/heptane, ranging from 10/90 to 50/50) to yield [ 5-bromo-2- (2-tetrahydropyran-2-yl)Oxyethyl) -1,2, 4-triazol-3-yl]- (2,3, 4-trifluorophenyl) methanol (4.50g, 10.2mmol, 91% yield) as a pale yellow oil. MS (ES +) m/z: 436.1[ (M + H)⁺]。

Step 3: p-toluenesulfonic acid monohydrate (402mg,2.11mmol, Eq:0.20) was added to [ 5-bromo-2- (2-tetrahydropyran-2-yloxyethyl) -1,2, 4-triazol-3-yl]- (2,3, 4-trifluorophenyl) methanol (4.61g,10.6mmol, Eq:1.00) in MeOH (143 ml). The reaction mixture was stirred at RT for 2h and then concentrated in vacuo. The residue was dissolved in DCM (95.0ml) and saturated NaHCO was used₃The aqueous solution (50.0ml) was washed, and then the organic phase was separated and washed with Na₂SO₄Drying, concentrating and drying under vacuum to obtain 2- [ 3-bromo-5- [ hydroxy- (2,3, 4-trifluorophenyl) methyl]-1,2, 4-triazol-1-yl]Ethanol (3.42g, 8.45mmol, 80% yield) as a light yellow oil was used as is without purification. MS (ES +) m/z: 354.0[ (M + H)⁺]。

Step 4: p-toluenesulfonic acid monohydrate (1.85g,9.71mmol, Eq:1.00) was added to a solution of crude 2- (3-bromo-5- (hydroxy (2,3, 4-trifluorophenyl) methyl) -1H-1,2, 4-triazol-1-yl) ethan-1-ol (3.42g,9.71mmol, Eq:1.00) in xylene (140 ml). The solution was refluxed at 170 ℃ for 16 hours using a Dean-Stark apparatus to remove water. The reaction mixture was then cooled to RT. The residue was diluted with EtOAc (100mL) and saturated Na₂CO₃The aqueous solution (50.0ml) was washed. Separating the organic phase from Na₂SO₄Drying and purification by flash column chromatography on silica gel (eluent: EtOAc/heptane, ranging from 0/100 to 60/40) to give 2-bromo-8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2, 4-dihydro-5H- [1]Triazolo [5,1-c][1,4]Oxazine (1.37g, 4.06mmol, 42% yield) as an off-white solid. MS (ES +) m/z: 334.0[ (M + H)⁺]。

Intermediate 5-2:

2-bromo-8- (3-chloro-5-fluoro-phenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazines

Preparation of intermediate 5-1; but in the second step 3-chloro-5-fluoro-benzaldehyde was used to obtain the title product as a white solid. MS (ES +) m/z: 334.0[ (M + H)⁺]。

1.2.2) intermediate of type 5, m ═ 2

Intermediate 5-3:

2-bromo-9- (3-chloro-5-fluoro-phenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem

Step 1: 2- (3-Bromopropoxy) tetrahydro-2H-pyran (5.60g,4.25ml,25.1mmol, Eq:1.00) and DIPEA (3.24g,4.38ml,25.1mmol, Eq:1.00) were added to a suspension of 3, 5-dibromo-1H-1, 2, 4-triazole (5.69g,25.1mmol, Eq:1.00) in MeCN (50.0 ml). The reaction mixture was stirred at 90 ℃ for 3h, cooled to RT, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/heptane, increasing from 20/80 to 60/40) to give 3, 5-dibromo-1- (3-tetrahydropyran-2-yloxypropyl) -1,2, 4-triazole (7.50g, 19.7mmol, yield 79%) as a pale yellow oil.

Step 2: n-BuLi (1.6M in hexane, 4.04g, 5.94ml, 9.51mmol, Eq:1.00) was added to a solution of 3, 5-dibromo-1- (3-tetrahydropyran-2-yloxypropyl) -1,2, 4-triazole (3.50g,9.48mmol, Eq:1.00) in THF (110ml) at-78 ℃. The reaction mixture was stirred at-78 ℃ for 20min, then a solution of 3-chloro-5-fluorobenzaldehyde (1.50g,9.48mmol, Eq:1.00) in THF (25.0ml) was added and stirring continued at-78 ℃ for 1h, thenThe temperature was gradually increased to RT. Adding saturated NH₄Aqueous Cl (5.00ml), quench the reaction, then dilute the reaction mixture with EtOAc (100ml), wash with brine (2 × 100ml), then separate the organic phase and use Na₂SO₄Dried and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/heptane, ranging from 20/80 to 75/25) to yield [ 5-bromo-2- (3-tetrahydropyran-2-yloxypropyl) -1,2, 4-triazol-3-yl]- (3-chloro-5-fluorophenyl) methanol (1.94g, 4.28mmol, yield 45%) as a pale yellow oil. MS (ES +) m/z: 450.1[ (M + H)⁺]。

Step 3: p-toluenesulfonic acid monohydrate (164mg, 865. mu. mol, Eq:0.20) was added to [ 5-bromo-2- (3-tetrahydropyran-2-yloxypropyl) -1,2, 4-triazol-3-yl]- (3-chloro-5-fluorophenyl) methanol (1.94g,4.32mmol, Eq:1.00) in MeOH (60.0 ml). The reaction mixture was stirred at RT for 2h and then concentrated in vacuo. The residue was then dissolved in DCM (40.0ml) and saturated NaHCO was used₃The aqueous solution (50ml) was washed and the organic phase was then washed with Na₂SO₄Dried, concentrated and dried under vacuum to give 3- [ 3-bromo-5- [ (3-chloro-5-fluoro-phenyl) -hydroxy-methyl- ] -]-1,2, 4-triazol-1-yl]Propane-1-ol (1.48g, 3.73mmol, 86% yield) as a light yellow viscous oil was used as is without purification. MS (ES +) m/z: 366.0[ (M + H)⁺]。

Step 4: p-toluenesulfonic acid monohydrate (772mg,4.06mmol, Eq:1.00) was added to crude 3- [ 3-bromo-5- [ (3-chloro-5-fluoro-phenyl) -hydroxy-methyl]-1,2, 4-triazol-1-yl]Propane-1-ol (1.48g,4.06mmol, Eq:1.00) in xylene (60.0 ml). The solution was refluxed at 170 ℃ for 17h using a Dean-Stark apparatus to remove water. The reaction mixture was then cooled to RT, diluted with EtOAc (100ml), and saturated Na₂CO₃(50ml) was washed. The organic phase is separated off and washed with Na₂SO₄Dried and then concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/heptane, increasing from 20/80 to 80/20) to yield 2-bromo-9- (3-chloro-5-fluoro-phenyl) -5,6,7, 9-tetrahydro- [1,2,4]]Triazolo [5,1-c][1,4]Oxazazem(685mg, 1.96mmol, 48% yield) as a light brown solid. MS (ES +) m/z: 350.0[ (M + H)⁺]。

Intermediate 5-4:

2-bromo-9- (2, 3-difluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem

Preparation of 5-3 was analogous to the intermediate, but 2, 3-difluorobenzaldehyde was used in the second step to afford the title compound as a white solid. MS (ES +) m/z: 330.0/332.0[ (M + H)⁺]。

Intermediate 5-5:

2-bromo-9- (2, 4-difluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem

Preparation of 5-3 was analogous to the intermediate, but 2, 4-difluorobenzaldehyde was used in the second step to afford the title compound as a white solid. MS (ES +) m/z: 330.0[ (M + H)⁺]。

Intermediates 5 to 6:

2-bromo-9- (3, 5-difluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem

Preparation of 5-3 was analogous to the intermediate, but in the second step 3, 5-difluorobenzaldehyde was used to afford the title compound as a white solid. MS (ES +) m/z: 330.1[ (M + H)⁺]。

Intermediates 5 to 7:

2-bromo-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem

Preparation of 5-3 was analogous to the intermediate, but 2,3, 4-trifluorobenzaldehyde was used in the second step to afford the title compound as a white solid. MS (ES +) m/z: 350.1[ (M + H)⁺]。

1.2.3) intermediates of type 6

Intermediate 6-1:

(1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-amine

Step 1:in a sealed tube, N- [ (1R,5S,8S) -3-azabicyclo [3.2.1]]Octane-8-yl]Tert-butyl carbamate (500mg,2.21mmol) was dissolved in EtOH (10mL), followed by the addition of 4-chloro-6-methylpyrimidine (869mg,6.63mmol) and triethylamine (894mg,1.23mL,8.84mmol) in that order. The reaction mixture was stirred at 130 ℃ overnight. The crude reaction mixture was concentrated under vacuum. The residue was taken up in 20mL of CH₂Cl₂And 20mL of water. Using CH for organic phase₂Cl₂Extract (3X 20mL) with MgSO₄Dried and then concentrated under vacuum. The crude material was purified by flash column chromatography (0% to 100% EtOAc in heptane) to afford N- [ (1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [ 3.2.1%]Octane-8-yl]Tert-butyl carbamate as a yellow solid (496mg, 71% yield). MS (ES +) m/z: 319.2[ (M + H)⁺]。

Step 2:to N- [ (1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl](ii) CH of tert-butyl carbamate (260mg, 817. mu. mol)₂Cl₂To a light yellow solution (8mL) was added TFA (931mg, 629. mu.l, 8.17 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The crude material was purified by ion exchange column (Si-SCX-2, 10g, washed with MeOH and washed with MeOH (NH)₃2M) elution) to give (1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [ 3.2.1)]Octane-8-amine 6-1(195mg, 804. mu. mol, 98.5% yield), which was used in the next step without further purification. MS (ES +) m/z: 219.2[ (M + H)⁺]。

Intermediate 6-2:

(1R,5S,8S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1] octan-8-amine

Step 1:analogously to the preparation of intermediate 6-1 (step 1), starting from N- [ (1R,5S,8S) -3-azabicyclo [3.2.1]Octane-8-yl]Starting from tert-butyl carbamate (2.00g,8.84mmol) and 4-fluoro-2-methoxypyridine (1.12g,8.84mmol), in a sealed tube, with NMP as solvent and in the presence of DIPEA (2.28g,3.09mL,17.70mmol) at 140 ℃ N- [ (1R,5S,8S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]Tert-butyl carbamate (1.42g, 48%) as a white solid. MS (ES +) m/z: 334.3[ (M + H)⁺]。

Step 2:in analogy to the preparation of intermediate 6-1 (step 2), starting from N- [ (1R,5S,8S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2 ].1]Octane-8-yl]Tert-butyl carbamate (1.42g,4.26mmol) in CH₂Cl₂Starting with a solution, reaction in the presence of TFA (7.38g,5.0mL,15.2mmol) gave (1R,5S,8S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-amine 6-2(0.89g, 89%) as a white solid was used directly in the next step without further purification. MS (ES +) m/z: 234.2[ (M + H)⁺]。

Intermediate 6-3:

(1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-amine

Step 1:analogously to the preparation of intermediate 6-1 (step 1), starting from N- [ (1R,5S,8S) -3-azabicyclo [3.2.1]Octane-8-yl]Starting from tert-butyl carbamate (2.00g,8.84mmol) and 3, 5-dichloropyridazine (2.0g,13.4mmol), in a sealed tube, EtOH as solvent and in Et₃N (3.63g,5.0mL,35.9mmol) at 90 ℃ to yield N- [ (1R,5S,8S) -3- (6-chloropyridazin-4-yl) -3-azabicyclo [3.2.1]]Octane-8-yl]Tert-butyl carbamate (1.71g, 54%) as a white solid. MS (ES +) m/z: 339.2[ (M + H)⁺]。

Step 2:in a sealed tube to N- [ (1R,5S,8S) -3- (6-chloropyridazin-4-yl) -3-azabicyclo [3.2.1]]Octane-8-yl]To a solution of tert-butyl carbamate (963mg,2.70mmol) in MeOH (22mL) was added a solution of NaOMe in methanol (25%, 1.9mL,8.3 mmol). The reaction mixture was heated at 85 ℃ overnight. The reaction mixture was adsorbed on Isolute HM-N and N- [ (1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] was obtained by column chromatography]Octane-8-yl]Tert-butyl carbamate (362mg, 38%) as a white solid. MS (ES +) m/z: 335.2[ (M + H)⁺]。

And step 3:analogously to the preparation of intermediate 6-1 (step 2), starting from N- [ (1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] e]Octane-8-yl]Tert-butyl carbamate (0.93g,2.72mmol) in CH₂Cl₂Starting with a solution, reaction in the presence of TFA (1.12g,0.76mL,9.86mmol) gave (1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [ 3.2.1)]Octane-8-amine 6-3(225mg, 96%) as a white solid, which was used directly in the next step without further purification. MS (ES +) m/z: 235.2[ (M + H)⁺]。

Intermediate 6-4:

(1R,5S,8S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-amine

Following a preparation analogous to intermediates 6-1 and 6-2, starting from N- [ (1R,5S,8S) -3-azabicyclo [3.2.1]Octane-8-yl]Tert-butyl carbamate and 5-chloro-3-methyl-pyridazine gave the title compound 6-4 as a white solid. MS (ES +) m/z: 219.3[ (M + H)⁺]。

1.3)General procedure 1: buchwald coupling reaction

To a solution of intermediate 5(1mmol) in 2-Me-THF (10ml) in a sealed tube was added 1.1 equivalents of intermediate 6. The reaction mixture was degassed and NaOtBu (1.5eq.) was added at RT, stirring was continued for 15 minutes, then tBu-Xphos (0.06eq.) and Pd were added₂(dba)₃(0.03 eq.). The reaction mixture is heated at 60-80 ℃ until the reaction is complete (typically between 2 and 8 hours) and then concentrated under vacuum. Purification is performed using flash column chromatography or reverse phase preparative HPLC to give the desired product of formula 1.

Examples 1 and 2

(9R) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (2, 3-difluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-4 with (1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-3 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 32mg, MS (ES +) M/z 484.3[ (M + H)⁺](ii) a And 34mg, MS (ES +) M/z 484.3[ (M + H)⁺]。

Examples 3 and 4

(9R) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (2, 4-difluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-5 and (1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-3 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 37mg, MS (ES +) M/z 484.4[ (M + H)⁺](ii) a And 37mg, MS (ES +) M/z 484.4[ (M + H)⁺]。

Examples 5 and 6

(9R) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -9- (2, 3-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (2, 3-difluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-4 and (1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-1 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 37mg, MS (ES +) M/z 468.3[ (M + H)⁺](ii) a And 37mg, MS (ES +) M/z 468.3[ (M + H)⁺]。

Examples 7 and 9

(9R) -9- (3, 5-difluoro)Phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (3, 5-difluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-6 and (1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-1 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 150mg, MS (ES +) M/z 468.3[ (M + H)⁺](ii) a And 153mg, MS (ES +) M/z 468.3[ (M + H)⁺]。

Examples 8 and 10

(9R) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1，4]Oxazazem-2-amines

And

(9S) -9- (2, 4-difluorophenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (2, 4-difluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-5 and (1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-1 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 19.7mg, MS (ES +) M/z 468.3[ (M + H)⁺](ii) a And 18.3mg, MS (ES +) M/z 468.2[ (M + H)⁺]。

Examples 11 and 12

(9R) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] o]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -9- (3, 5-difluorophenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (3, 5-difluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-6 and (1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-3 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 17.3mg, MS (ES +) M/z 484.3[ (M + H)⁺](ii) a And 18.9mg, MS (ES +) M/z 484.3[ (M + H)⁺]。

Examples 13 and 14

(9R) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] S]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1，4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-7 and (1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-3 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 12.2mg, MS (ES +) M/z 502.3[ (M + H)⁺](ii) a And 16.9mg, MS (ES +) M/z 502.3[ (M + H)⁺]。

Examples 15 and 16

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetHydrogen- [1,2,4]]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

2-bromo-9- (3-chloro-5-fluoro-phenyl) -5,6,7, 9-tetrahydro- [1,2, 4-is accomplished using general procedure 1]Triazolo [5,1-c][1,4]Oxazazem5-3 and (1R,5S,8S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-4 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 102mg, MS (ES +) M/z 484.3[ (M + H)⁺](ii) a And 82.9mg, MS (ES +) M/z 484.3[ (M + H)⁺]。

Examples 17 and 18

(9R) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -N- [ (1R,5S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-7 and (1R,5S,8S) -3- (6-methylpyridazin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-4 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 17mg, MS (ES +) M/z 486.3[ (M + H)⁺](ii) a And 16mg, MS (ES +) M/z 486.3[ (M + H)⁺]。

Examples 19 and 20

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] as]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

2-bromo-9- (3-chloro-5-fluoro-phenyl) -5,6,7, 9-tetrahydro- [1,2, 4-is accomplished using general procedure 1]Triazolo [5,1-c][1，4]Oxazazem5-3 and (1R,5S,8S) -3- (6-methoxypyridazine-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-3 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 37mg, MS (ES +) M/z 500.3[ (M + H)⁺](ii) a And 40mg, MS (ES +) M/z 500.3[ (M + H)⁺]。

Examples 21 and 22

(8R) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

And

(8S) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

2-bromo-8- (3-chloro-5-fluoro-phenyl) -6, 8-dihydro-5H- [1,2,4 using general procedure 1]Triazolo [5,1-c][1，4]Oxazine 5-2 and (1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-3 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 39mg, MS (ES +) M/z 486.3[ (M + H)⁺](ii) a And 36mg, MS (ES +) M/z 486.3[ (M + H)⁺]。

Examples 23 and 24

(8R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

And

(8S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

General procedure 1 was used to complete 2-bromo-8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4]Triazolo [5,1-c][1,4]Oxazine 5-1 and (1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-1 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 21mg, MS (ES +) M/z 472.3[ (M + H)⁺](ii) a And 25mg, MS (ES +) M/z 472.3[ (M + H)⁺]。

Examples 25 and 26

(8R) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

And

(8S) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

2-bromo-8- (3-chloro-5-fluoro-phenyl) -6, 8-dihydro-5H- [1,2,4 using general procedure 1]Triazolo [5,1-c][1,4]Oxazine 5-2 and (1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-1 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 8mg, MS (ES +) M/z 470.2[ (M + H)⁺](ii) a And 9mg, MS (ES +) M/z 470.2[ (M + H)⁺]。

Examples 27 and 28

(8R) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

And

(8S) -N- [ (1R,5S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

General procedure 1 was used to complete 2-bromo-8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4]Triazolo [5,1-c][1,4]Oxazine 5-1 and (1R,5S,8S) -3- (6-methoxypyridazin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-3 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 26mg, MS (ES +) M/z 488.3[ (M + H)⁺](ii) a And 26mg, MS (ES +) M/z 488.3[ (M + H)⁺]。

Examples 29 and 30

(8R) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

And

(8S) -8- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

2-bromo-8- (3-chloro-5-fluoro-phenyl) -6, 8-dihydro-5H- [1,2,4 using general procedure 1]Triazolo [5,1-c][1，4]Oxazine 5-2 and (1R,5S,8S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-2 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 13mg, MS (ES +) M/z 486.3[ (M + H)⁺](ii) a And 14mg, MS (ES +) M/z 486.2[ (M + H)⁺]。

Examples 31 and 32

(8R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

And

(8S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1] octan-8-yl ] -8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4] triazolo [5,1-c ] [1,4] oxazin-2-amine

General procedure 1 was used to complete 2-bromo-8- (2,3, 4-trifluorophenyl) -6, 8-dihydro-5H- [1,2,4]Triazolo [5,1-c][1,4]Oxazine 5-1 and (1R,5S,8S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-2 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 19mg, MS (ES +) M/z 488.3[ (M + H)⁺](ii) a And 21mg, MS (ES +) M/z 488.3[ (M + H)⁺]。

Examples 33 and 34

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

2-bromo-9- (3-chloro-5-fluoro-phenyl) -5,6,7, 9-tetrahydro- [1,2, 4-is accomplished using general procedure 1]Triazolo [5,1-c][1,4]Oxazazem5-3 and (1R,5S,8S) -3- (6-methyl)Pyrimidin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-1 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 34mg, MS (ES +) M/z 484.3[ (M + H)⁺](ii) a And 33mg, MS (ES +) M/z 484.3[ (M + H)⁺]。

Examples 35 and 36

(9R) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -9- (3-chloro-5-fluoro-phenyl) -N- [ (1R,5S) -3- (2-methoxy-4-pyridinyl) -3-azabicyclo [3.2.1]Octane-8-yl]-5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

2-bromo-9- (3-chloro-5-fluoro-phenyl) -5,6,7, 9-tetrahydro- [1,2, 4-is accomplished using general procedure 1]Triazolo [5,1-c][1,4]Oxazazem5-3 and (1R,5S,8S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-2 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 26mg, MS (ES +) M/z:499.3[ (M + H)⁺](ii) a And 25mg, MS (ES +) M/z:499.3[ (M + H)⁺]。

Examples 37 and 38

(9R) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -N- [ (1R,5S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-7 and (1R,5S,8S) -3- (2-methoxy-4-pyridyl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-2 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 28.3mg, MS (ES +) M/z 501.3[ (M + H)⁺](ii) a And 26mg, MS (ES +) M/z 501.3[ (M + H)⁺]。

Examples 39 and 40

(9R) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

And

(9S) -N- [ (1R,5S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Octane-8-yl]-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem-2-amines

General procedure 1 was used to complete 2-bromo-9- (2,3, 4-trifluorophenyl) -5,6,7, 9-tetrahydro- [1,2,4]Triazolo [5,1-c][1,4]Oxazazem5-7 and (1R,5S,8S) -3- (6-methylpyrimidin-4-yl) -3-azabicyclo [3.2.1]Buchwald type coupling between octane-8-amine 6-1 followed by separation of the enantiomers using reverse phase chiral HPLC gave the title product as a white solid: 50mg, MS (ES +) M/z 486.3[ (M + H)⁺](ii) a And 41mg, MS (ES +) M/z 486.3[ (M + H)⁺]。

2)Biological examples

2.1) measurement procedure: cellular gamma-secretase assay

Human glioma H4 cells overexpressing human APP695 and carrying the Swedish double mutation (K595N/M596L) were plated at a density of 30,000 cells/well/100 μ L into IMDM (containing 10% FCS, 0.2mg/L hygromycin B) in 96-well plates and at 37 ℃ and 5% CO₂And (4) incubating.

3-4h after plating, the compound was diluted in medium and 50 μ L of this compound was added as a 1.5 fold concentrate to reach the final concentration. The compounds were incubated for 24 h. The final dose is typically in the range of 4 μ M to 0.0013 μ M, varying in half log steps, yielding an eight point dose response curve.

Only the vehicle and the appropriate control of the reference compound were used for this assay. Me₂The final concentration of SO was 0.4%.

At 37 ℃ and 5% CO₂After incubation, secreted Abeta 42 was quantitatively analyzed using the AlphaLisa assay kit (human amyloid beta 1-42 kit: catalog # AL203C, Perkin Elmer). Transfer 20 μ L of cell culture supernatant to assay plate. Then 10 μ L of a mixture of AlphaLisa-coupled capture antibody and biotinylated detection antibody was added and incubated at RT for 3h while gently shaking the assay plate. Further addingAfter 20 μ L of donor beads, assay plates were incubated for 30min at RT and shaken constantly in the dark. The assay plate was then read on a Paradigm AlphaLisa microplate reader using a built-in program with an excitation wavelength of 680nm and an emission wavelength of 570 nm. IC for inhibition of A.beta.42 secretion was then calculated from the measured signal by non-linear regression fit analysis using XLFit 5.3 software (from IDBS Co.)₅₀The value is obtained.

2.2) results

The following table shows the data for inhibition of a β 42 secretion by all compounds: