# US 11,440,915 B2 · Triazolo-azepine derivatives

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- Number: US 11,440,915 B2
- Document ID: US11440915B2
- Status: Granted
- Kind: B2
- Application number: 16/954,996
- Filed: 2018-12-17
- Published: 2020-10-08
- Granted: 2022-09-13
- Earliest claimed: 2017-12-18
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Bjoern Bartels; Xinlan Aloise Ford Cook; Hasane Ratni; Michael Reutlinger; Walter Vifian
- Web page: https://patentgrep.com/patent/US11440915B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/4858: {Organic compounds}
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- 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: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds of formula (I), wherein R is hydrogen or halogen, wherein R may be different if n=2 or 3; n is 1, 2 or 3; (II) is a disubstituted bicyclo[1,1,1]pentane or bicyclo[2,2,2]octane as defined below: (III) or (IV); or to a pharmaceutically active acid addition salt thereof, to a racemic mixture or to its corresponding enantiomer and/or an optical isomer and/or stereoisomer thereof. The compounds may be used for the 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.

## Claims

### Claim 1

A compound of formula I
wherein:
R is hydrogen or halogen, wherein R may be different if n=2 or 3;
n is 1, 2 or 3; and
is a disubstituted bicyclo[1,1,1]pentane or bicyclo[2,2,2]octane selected from:
or a pharmaceutically acceptable acid addition salt thereof, or a racemic mixture or its corresponding enantiomer, or stereoisomer thereof.

### Claim 2 (depends on 1)

A compound according to claim 1,
wherein
or a pharmaceutically acceptable acid addition salt thereof, or a racemic mixture or its corresponding enantiomer, or stereoisomer thereof.

### Claim 3 (depends on 1)

A compound of claim 1,
wherein
or a pharmaceutically acceptable acid addition salt thereof, or a racemic mixture or its corresponding enantiomer, or stereoisomer thereof.

### Claim 4 (depends on 2)

A compound of claim 2, selected from the group consisting of:
(9R)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9S)-9-(3-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9R)-9-(4-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9S)-9-(4-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9R)-9-(4-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9S)-9-(4-chlorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9R)-9-(3-chloro-5-fluoro-phenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9S)-9-(3-chloro-5-fluoro-phenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9R)-9-(3,4-difluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9S)-9-(3,4-difluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9R)-9-(2-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9S)-9-(2-fluorophenyl)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9R)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, or
(9S)-N-[3-(4-methylimidazol-1-yl)-1-bicyclo[1.1.1]pentanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine.

### Claim 5 (depends on 3)

A compound of claim 3, selected from the group consisting of:
(9R)-9-(3-chloro-5-fluoro-phenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9S)-9-(3-chloro-5-fluoro-phenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9R)-9-(3,4-difluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9S)-9-(3,4-difluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9R)-9-(2-fluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9S)-9-(2-fluorophenyl)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine,
(9R)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine, or
(9S)-N-[4-(4-methylimidazol-1-yl)-1-bicyclo[2.2.2]octanyl]-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-amine.

### Claim 6 (depends on 1)

A pharmaceutical preparation containing one or more compounds of claim 1 and pharmaceutically acceptable excipients.

### Claim 7 (depends on 4)

A pharmaceutical preparation containing one or more compounds of claim 4 and pharmaceutically acceptable excipients.

### Claim 8 (depends on 5)

A pharmaceutical preparation containing one or more compounds of claim 5 and pharmaceutically acceptable excipients.

### Claim 9 (depends on 1)

A method of treating Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome, which method comprises administering to an adult an effective amount of a compound as defined in claim 1.

### Claim 10 (depends on 4)

A method of treating Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome, which method comprises administering to an adult an effective amount of a compound as defined in claim 4.

### Claim 11 (depends on 5)

A method of treating Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome, which method comprises administering to an adult an effective amount of a compound as defined in claim 5.

### Claim 12 (depends on 1)

A process for preparing a compound of formula I of claim 1, which process comprises:
a) reacting a compound of formula 7
with a compound of formula 8
to form a compound of formula I
and, optionally, converting the compound into a pharmaceutically acceptable acid addition salt;
or
b) Cyclizing a compound of formula 14
in the presence of KI and K2CO3 to form a compound of formula I
and, optionally, converting the compound into a pharmaceutically acceptable acid addition salt.

### Claim 13 (depends on 12)

A compound prepared by the process of claim 12.