N-[2-(2-amino-6,6-disubstituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl)-1,3-thiazol-4-yl]amides

Patent metadata

Field	Value
Publication number	US-9751895-B2
Application number	US-201615272501-A
Country	US
Kind code	B2
Filing date	Sep 22, 2016
Priority date	Sep 24, 2015
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

Abstract

The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I,

and the variables R 1 , R 2 and R 3 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

First claim

We claim:

1. The compound of of Formula la

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer;
wherein
R 1 is a C 5-9 bicycloalkyl; and
R 2 and R 3 are each independently selected from C 1-6 alkyl or C 3 - 7 cycloalkyl; wherein the C 1-6 alkyl is optionally substituted with one to three fluoro or C 1-3 alkoxy; or R 2 and R 3 taken together with the carbon to which they are attached form a C 3-6 cycloalkyl ring or a 4-to 6-membered heterocycloalkyl ring, each of which is optionally and independently substituted with one to three fluoro, C 1-3 alkyl or C 1 - 3 alkoxy.

2. The compound according to claim 1 wherein
R 1 is bicyclo[1.1.1]pentan-1-yl or bicyclo[1.1.1]pentan-2-yl; and
R 2 and R 3 are each independently methyl or ethyl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

3. The compound according to claim 2 wherein R 1 is bicyclo[1.1.1]pentan-1-yl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

4. The compound according to claim 2 wherein R 1 is bicyclo[1.1.11]pentan-2-yl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

5. The compound according to claim 2 selected from the group consisting of:
N-{2-[(4aR,8aR)-2-amino-6,6-dimethyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4yl}bicyclo[1.1.1]pentane-1-carboxamide;
N-{2-[(4aR,6S,8aR)-2-amino-6-ethyl-6-methyl-4,4a,5,6-tetrahydropyrano[3,4-d[]1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}bicyclo[1.1.1]pentane-2-carboxamide;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

6. The compound of claim 5 which is N-{2-[(4aR,8aR)-2-amino-6,6-dimethyl-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}bicyclo[1.1.1]pentane-1-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

7. The compound of claim 5 which is N-{2-[(4aR,6S,8aR)-2-amino-6-ethyl-6-methyl-4,4a,5,6-tetrahydropyrano[3,4d][1,3]thiazin-8a(8H)-yl]-1,3-thiazol-4-yl}bicyclo[1.1.1]pentane-2-carboxamide; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer, and a pharmaceutically acceptable vehicle, diluent or carrier.

9. A method for treating Alzheimer's disease, treating Type 2 diabetes, of inhibiting production of amyloid-β protein or of inhibiting beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in a patient, the method comprising administering a therapeutically effective amount of a compound according to claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer, to a patient in need of treatment of Alzheimer's disease, treatment of Type 2 diabetes, inhibition of production of amyloid-β protein or inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1).

10. The method of claim 9 wherein Alzheimer's disease is treated.

11. The method of claim 9 wherein Type 2 diabetes is treated.

12. The method of claim 9 wherein the production of amyloid-β protein is inhibited.

13. The method of claim 9 wherein beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is inhibited.

Assignees

• Pfizer

Inventors

• Brodney Michael Aaron
• Butler Christopher Ryan
• Zhang Lei
• O'Neill Brian Thomas
• Verhoest Patrick Robert
• Mikochik Peter Justin
• Murray John Charles
• Hou Xinjun

Classifications

• C07D513/10

  Spiro-condensed systems · CPC title

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D513/20

  Spiro-condensed systems · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title