4-amino-6-phenyl-5,6-dihydroimidazo[1,5-A]pyrazine derivatives as inhibitors of beta-secretase (BACE)

• US 9,580,433 B2
• Filed: 06/12/2014
• Issued: 02/28/2017
• Est. Priority Date: 06/12/2013
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Oehlrich, Daniel, Gijsen, Henricus Jacobus Maria, Surkyn, Michel
• Primary Examiner(s): Davis, Brian J
• Application Number:
  US14/897,378
• Publication Number:
  US 20160115170A1
• Time in Patent Office: 992 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: 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
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention relates to novel 5,6-dihydroimidazo[1,5-a]pyrazinyl 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

1. A compound of Formula (I)

2. The compound according to claim 1, or a stereoisomeric form thereof, wherein:

R is selected from the group consisting of hydrogen;

halo;

—

CN;

C_1-4alkyl optionally substituted with one or more substituents each independently selected from halo, —

CN and C_1-4alkyloxy; and

C_1-4alkyloxy optionally substituted with one or more substituents each independently selected from halo and C_1-4alkyloxy;

R¹ is selected from the group consisting of hydrogen;

halo; and

C_1-4alkyl;

R² is selected from the group consisting of C_1-4alkyl optionally substituted with one or more substituents each independently selected from fluoro, and C_1-4alkyloxy; and

C_3-7cycloalkyl;

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);

3. The compound according to claim 1, or a stereoisomeric form thereof, wherein:

R is selected from the group consisting of hydrogen;

—

CN; and

—

(CH₂)_m—

NR^x(C═

O)R^y, wherein m is an integer selected from the group consisting of 0 and 1, R^x is hydrogen and R^y is C_1-4alkyl;

R¹ is selected from the group consisting of hydrogen;

C_1-4alkyl substituted with one or more halo substituents; and

—

C_1-4alkyl(C_3-7cycloalkyl);

R² is C_1-4alkyl optionally substituted with one or more substituents each independently selected from fluoro;

R³ is halo;

n is 1;

R⁴ is (a);

4. The compound according to claim 1, wherein R¹ is hydrogen or halo.

5. The compound according to claim 1, wherein R² is C_1-4alkyl.

6. The compound according to claim 1, wherein R⁴ is

7. The compound of claim 1, having the configuration shown in Formula (I′

)

8. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier.

9. A process for preparing a pharmaceutical composition as defined in claim 8, characterized in that the pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound.

10. 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 diffuse 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.

11. 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.

12. 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 diffuse 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 pharmaceutical composition as defined in claim 8.

13. 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 8.

14. A method of treating a disease or condition selected from the group consisting of 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.

15. 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 8.