# US 10,246,468 B2 · BACE1 inhibitors

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- Number: US 10,246,468 B2
- Document ID: US10246468B2
- Status: Granted
- Kind: B2
- Application number: 15/735,890
- Filed: 2016-08-08
- Published: 2019-01-03
- Granted: 2019-04-02
- Earliest claimed: 2015-08-12
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Bjoern Bartels; Cosimo Dolente; Wolfgang Guba; Wolfgang Haap; Ulrike Obst Sander; Walter Vifian; Thomas Woltering
- Web page: https://patentgrep.com/patent/US10246468B2

## CPC

- C07D 513/04: Ortho-condensed systems
- 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
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a compound of formula I, having BACE1 inhibitory activity, their manufacture pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.

## Claims

### Claim 1

A compound of formula I,
wherein
n is 1, 2 or 3;
R1 is selected from the group consisting of
i) C1-6-alkyl and
ii) halogen-C1-6-alkyl;
R2 is selected from the group consisting of
i) C1-6-alkyl, and
ii) halogen-C1-6-alkyl;
or R1 and R2 form together with the C-atom they are attached to, a C3-6-cycloalkyl-, wherein the C3-6-cycloalkyl- is optionally substituted by one or more substituents selected from the group consisting of halogen and hydroxyl;
R3 is each independently selected from the group consisting of
i) hydrogen,
ii) C1-6-alkyl, and
iii) halogen;
R4 is each independently selected from the group consisting of
i) hydrogen,
ii) C1-4-alkyl, and
iii) halogen;
or wherein R3 and R4 together are —(CH2)m—, wherein m is 2, 3, 4 or 5,
R5 is hydrogen;
R6 is selected from the group consisting of
i) C1-6-alkyl, and
ii) halogen-C1-6-alkyl;
R7 is selected from the group consisting of
i) hydrogen, and
ii) halogen;
R8 is selected from the group consisting of
i) aryl,
ii) aryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-C1-6-alkyl, halogen-C1-6-alkoxy, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkynyl-C1-6-alkoxy, C2-6-alkynyl, C1-6-alkyl, COOR9, wherein R9 is H or C1-6-alkyl, CONR10R11, wherein R10 is H or C1-6-alkyl C3-6-cycloalkyl and R11 is H or C1-6-alkyl, C3-6-cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C1-6-alkyl and C1-6-alkoxy, C3-6-cycloalkyl-C1-6-alkoxy and C3-4-cycloalkyl-C1-6-alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C1-6-alkyl and C1-6-alkoxy;
iii) heteroaryl, and
iv) heteroaryl substituted by 1-4 substituents individually selected from amino, cyano, halogen, halogen-C1-6-alkyl, halogen-C1-6-alkoxy, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, C2-6-alkynyl-C1-6-alkoxy, C2-6-alkynyl, C1-6-alkyl, COOR9, wherein R9 is H or C1-6-alkyl, CONR10R11, wherein R10 is H or C1-6-alkyl C3-6-cycloalkyl and R11 is H or C1-6-alkyl, C3-6-cycloalkyl that is optionally substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C1-6-alkyl and C1-6-alkoxy, C3-6-cycloalkyl-C1-6-alkoxy and C3-6-cycloalkyl-C1-6-alkoxy, wherein the cycloalkyl unit is substituted by 1 to 4 substituents individually selected from the group consisting of halogen, cyano, C1-6-alkyl and C1-6-alkoxy;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein n, R1, R2, R3, R4, R5, R6, R7 and R8 are as described and when n=1, then the 5-ring has cis configuration.

### Claim 3 (depends on 1)

The compound according to claim 1, which is of formula Ia, wherein n, R1, R2, R3, R4, R5, R6, R7 and R8 are as described in claim 1

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R1 and R2 are methyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R3 and R4 are hydrogen.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R5 is hydrogen.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R6 is methyl.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R7 is F.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R8 is heteroaryl, substituted by 1-2 substituents individually selected from cyano, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl and C1-6-alkyl.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R8 is heteroaryl which is selected from pyridinyl, pyrazinyl, pyrimidyl or 1H-pyrazolyl, each substituted by 1-2 substituents individually selected from cyano, halogen, halogen-C1-6-alkoxy, halogen-C1-6-alkyl and C1-6-alkyl.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R8 is heteroaryl, substituted by 1-2 substituents individually selected from cyano and C1-6-alkyl.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R8 is phenyl substituted by 1-2 substituents individually selected from cyano, halogen and C1-6-alkyl.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein n is 1.

### Claim 14 (depends on 1)

The compound according to claim 1, selected from the group consisting of:
N-(3-((3aR,4R,8S)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-cyanopicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3,5-dichloropicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-2-chloro-4-cyanobenzamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(difluoromethoxy) picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)pyrazine-2-carboxamide,
N-(3-((3aS,4R8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-(trifluoromethyl)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-4-cyano-2-methylbenzamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5 (difluoromethoxy)-3-methylpicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2,3,3-tetrafluoropropoxy)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-(difluoromethoxy)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetra hydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(difluoromethoxy)pyrazine-2-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trim ethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-fluoropicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-chloropicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3,5-difluoropicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-methylpicolinamide,
N-(3-((3aS,4R8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-2-methylpyrimidine-5-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2,3,3-tetrafluoropropoxy) pyrazine-2-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3,5-dimethylpicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-methoxypicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-ethoxypicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-methoxy-3-methylpicolinamide, and
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-ethoxypyrazine-2-carboxamide,
or pharmaceutically acceptable salts thereof.

### Claim 15 (depends on 1)

The compound according to claim 1, selected from the group consisting of:
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trim ethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide,
N-(3-((3aR,4R,8S)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-cyanopicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3,5-dichloropicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-2-chloro-4-cyanobenzamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(difluoromethoxy)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-4-chloro-1-(difluoromethyl)-1H-pyrazole-3-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy) pyrazine-2-carboxamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-(trifluoromethyl) picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-4-cyano-2-methylbenzamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-(2,2,3,3-tetrafluoropropoxy) picolinamide,
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a4,7-tetra hydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-(difluoromethoxy)picolinamide, and
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide,
or pharmaceutically acceptable salts thereof.

### Claim 16 (depends on 1)

The compound according to claim 1, selected from the group consisting of:
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide and N-(3-((3aR,4R,8S)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide,
or pharmaceutically acceptable salts thereof.

### Claim 17 (depends on 1)

A method for treating diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits, comprising the step of administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a human being or animal in need thereof.

### Claim 18 (depends on 1)

A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 1)

A method for treating Alzheimer's Disease, comprising the step of administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a human being or animal in need thereof.