# US 9,751,895 B2 · 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

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- Number: US 9,751,895 B2
- Document ID: US9751895B2
- Status: Granted
- Kind: B2
- Application number: 15/272,501
- Filed: 2016-09-22
- Published: 2017-03-30
- Granted: 2017-09-05
- Earliest claimed: 2015-09-24
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: Michael Aaron Brodney; Christopher Ryan Butler; Lei Zhang; Brian Thomas O'Neill; Patrick Robert Verhoest; Peter Justin Mikochik; John Charles Murray; Xinjun Hou
- Web page: https://patentgrep.com/patent/US9751895B2

## CPC

- C07D 513/04: Ortho-condensed systems
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 25/28: 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
- C07D 513/10: Spiro-condensed systems
- C07D 513/20: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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 R1, R2 and R3 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

## Claims

### Claim 1

The compound of of Formula la
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer;
wherein
R1 is a C5-9bicycloalkyl; and
R2 and R3 are each independently selected from C1-6alkyl or C3-7cycloalkyl; wherein the C1-6alkyl is optionally substituted with one to three fluoro or C1-3alkoxy; or R2 and R3 taken together with the carbon to which they are attached form a C3-6cycloalkyl ring or a 4-to 6-membered heterocycloalkyl ring, each of which is optionally and independently substituted with one to three fluoro, C1-3alkyl or C1-3alkoxy.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein
R1 is bicyclo[1.1.1]pentan-1-yl or bicyclo[1.1.1]pentan-2-yl; and
R2 and R3 are each independently methyl or ethyl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

### Claim 3 (depends on 2)

The compound according to claim 2 wherein R1 is bicyclo[1.1.1]pentan-1-yl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

### Claim 4 (depends on 2)

The compound according to claim 2 wherein R1 is bicyclo[1.1.11]pentan-2-yl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

### Claim 5 (depends on 2)

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.

### Claim 6 (depends on 5)

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.

### Claim 7 (depends on 5)

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.

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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).

### Claim 10 (depends on 9)

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

### Claim 11 (depends on 9)

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

### Claim 12 (depends on 9)

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

### Claim 13 (depends on 9)

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