# US 9,751,886 B2 · 4-amino-6-phenyl-6,7-dihydro[1,2,3]triazolo[1,5-A]pyrazine derivatives as inhibitors of beta-secretase (BACE)

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- Number: US 9,751,886 B2
- Document ID: US9751886B2
- Status: Granted
- Kind: B2
- Application number: 14/897,396
- Filed: 2014-06-12
- Published: 2016-05-12
- Granted: 2017-09-05
- Earliest claimed: 2013-06-12
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Daniel Oehlrich; Henricus Jacobus Maria Gijsen
- Web page: https://patentgrep.com/patent/US9751886B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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 novel 6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6-yl derivatives as inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE, in particular BACE1 and/or BACE2 (wherein BACE1, is also known as Asp2, or memapsin2 and BACE2 is also known as Asp1, Memapsin 1 or DRAP). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention and treatment of disorders in which beta-secretase is involved, such as Alzheimer's disease (AD), mild cognitive impairment, senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, dementia associated with beta-amyloid, age-related macular degeneration, type 2 diabetes and other metabolic disorders.

## Claims

### Claim 1

A compound of Formula (I)
or a stereoisomeric form thereof, wherein:
R1 is selected from the group consisting of hydrogen; halo; and C1-4alkyl;
R2 is selected from the group consisting of C1-4alkyl optionally substituted with one or more substituents each independently selected from fluoro and C1-4alkyloxy; and
C3-7 cycloalkyl;
R3 is in each instance an independently selected halo substituent;
n is an integer selected from 1 and 2;
R4 is selected from (a) and (b):
wherein R5 and R6 are each independently selected from the group consisting of aryl and heteroaryl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of halo, —CN, C1-4alkyl optionally substituted with one or more halo substituents, and C1-4alkyloxy optionally substituted with one or more halo substituents;
wherein aryl is phenyl;
wherein heteroaryl is a 5-membered aromatic heterocycle selected from the group consisting of oxazole and pyrazole; or is a 6-membered aromatic heterocycle selected from the group consisting of pyridinyl, pyrimidinyl and pyrazinyl;
or a pharmaceutically acceptable addition salt or a solvate thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is hydrogen or halo.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R2 is C1-4alkyl or C1-4alkyl substituted with one or more fluoro substituents.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R4 is
wherein R5 is heteroaryl, optionally substituted with one or more substituents each independently selected from the group consisting of halo, —CN, C1-4alkyl optionally substituted with one or more halo substituents, and C1-4alkyloxy optionally substituted with one or more halo substituents;
wherein heteroaryl is a 5-membered aromatic heterocycle selected from oxazole and pyrazole; or is a 6-membered aromatic heterocycle selected from the group consisting of pyridinyl, pyrimidinyl and pyrazinyl.

### Claim 5 (depends on 1)

The compound of claim 1, having the configuration shown in Formula (I′)
wherein Ar is

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 7 (depends on 6)

A process for preparing a pharmaceutical composition as defined in claim 6, characterized in that the pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound.

### Claim 8 (depends on 1)

A method of treating a disorder selected from the group consisting of Alzheimer's Disease (AD), mild cognitive impairment (MCI), memory impairment, senility, dementia, dementia with Lewy bodies, dementia with progressive nuclear palsy, dementia with Cortico-basal degeneration, mixed dementia with Alzheimer's and vascular type, Alzheimer's disorder with difuse Lewy Body disease, amyloid angiopathy, cerebral amyloid angiopathy, multi-infarct dementia, Down's syndrome, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, senile dementia of the Alzheimer's type, vascular dementia, dementia due to HIV disease, dementia due to head trauma, dementia due to Huntington's disease, dementia due to Pick's disease, dementia due to Creutzfeldt-Jakob disease, frontotemporal dementia, dementia pugilistica, dementia associated with beta-amyloid, amyloidosis of the brain and other organs (age and non-age related), Dutch type of hereditary cerebral haemorrhage with amyloidosis, traumatic brain injury (TBI), temporal lobe epilepsy (TLE), hypoxia, ischemia, disruptions in cerebral metabolism, age-related macular degeneration, type 2 diabetes and other metabolic disorders, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), arterial thrombosis, autoimmune/inflammatory diseases, breast cancer, myocardial infarction, stroke, hypertension, dermatomyositis, prion disease (Creutzfeld-Jakob disease), gastrointestinal diseases, Glioblastoma multiforme, Graves' Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasctitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whippel's Disease and Wilson's Disease, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound as defined in claim 1.

### Claim 9 (depends on 1)

A method of treating a disease or condition selected from the group consisting of neurocognitive disorder due to Alzheimer's disease, neurocognitive disorder due to traumatic brain injury, neurocognitive disorder due to Lewy body disease, neurocognitive disorder due to Parkinson's disease, vascular neurocognitive disorder and type 2 diabetes, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1.

### Claim 10 (depends on 6)

A method of treating a disorder selected from the group consisting of Alzheimer's Disease (AD), mild cognitive impairment (MCI), memory impairment, senility, dementia, dementia with Lewy bodies, dementia with progressive nuclear palsy, dementia with Cortico-basal degeneration, mixed dementia with Alzheimer's and vascular type, Alzheimer's disorder with difuse Lewy Body disease, amyloid angiopathy, cerebral amyloid angiopathy, multi-infarct dementia, Down's syndrome, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, senile dementia of the Alzheimer's type, vascular dementia, dementia due to HIV disease, dementia due to head trauma, dementia due to Huntington's disease, dementia due to Pick's disease, dementia due to Creutzfeldt-Jakob disease, frontotemporal dementia, dementia pugilistica, dementia associated with beta-amyloid, amyloidosis of the brain and other organs (age and non-age related), Dutch type of hereditary cerebral haemorrhage with amyloidosis, traumatic brain injury (TBI), temporal lobe epilepsy (TLE), hypoxia, ischemia, disruptions in cerebral metabolism, age-related macular degeneration, type 2 diabetes and other metabolic disorders, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), arterial thrombosis, autoimmune/inflammatory diseases, breast cancer, myocardial infarction, stroke, hypertension, dermatomyositis, prion disease (Creutzfeld-Jakob disease), gastrointestinal diseases, Glioblastoma multiforme, Graves' Disease, Huntington's Disease, inclusion body myositis (IBM), inflammatory reactions, Kaposi Sarcoma, Kostmann Disease, lupus erythematosus, macrophagic myofasctitis, juvenile idiopathic arthritis, granulomatous arthritis, malignant melanoma, multiple myeloma, rheumatoid arthritis, Sjogren syndrome, SpinoCerebellar Ataxia 1, SpinoCerebellar Ataxia 7, Whippel's Disease and Wilson's Disease, comprising administering to the subject in need thereof, a therapeutically effective amount of a pharmaceutical composition as defined in claim 6.

### Claim 11 (depends on 6)

A method of treating a disease or condition selected from the group consisting of neurocognitive disorder due to Alzheimer's disease, neurocognitive disorder due to traumatic brain injury, neurocognitive disorder due to Lewy body disease, neurocognitive disorder due to Parkinson's disease, vascular neurocognitive disorder and type 2 diabetes, comprising administering to a subject in need thereof, a therapeutically effective amount of a pharmaceutical composition according to claim 6.

### Claim 12 (depends on 1)

A method of treating a disease or condition selected from the group consisting of mild cognitive impairment (MCI), senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, vascular dementia, dementia due to head trauma and dementia associated with beta-amyloid, comprising administering to the subject in need thereof a therapeutically effective amount of a compound as defined in claim 1.

### Claim 13 (depends on 6)

A method of treating a disease or condition selected from the group consisting of mild cognitive impairment (MCI), senility, dementia, dementia with Lewy bodies, Down's syndrome, dementia associated with Parkinson's disease, dementia of the Alzheimer's type, vascular dementia, dementia due to head trauma, and dementia associated with beta-amyloid, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as defined in claim 6.