BICYCLIC INHIBITORS OF HISTONE DEACETYLASE

• US 20180215759A1
• Filed: 03/23/2018
• Published: 08/02/2018
• Est. Priority Date: 01/11/2017
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Rodin Therapeutics, Inc. (Alkermes Incorporated)
• Inventors: Fuller, Nathan Oliver, Lowe, III, John A.
• Granted Patent: US 10,519,149 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• 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: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Provided herein are compounds and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of conditions associated with inhibition of HDAC (e.g., HDAC2).

Claims

1. A compound of the formula:

2. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

4. A method of treating a condition in a subject selected from a neurological disorder, memory or cognitive function disorder or impairment, disorder of learning extinction, fungal disease or infection, inflammatory disease, hematological disease, psychiatric disorders, and neoplastic disease, comprising administering to the subject in need thereof an effective amount the compound of claim 1.

5. The method of claim 4, wherein the condition is:

a. a cognitive function disorder or impairment associated with Alzheimer'"'"'s disease, Huntington'"'"'s disease, seizure induced memory loss, schizophrenia, Rubinstein Taybi syndrome, Rett Syndrome, depression, Fragile X, Lewy body dementia, vascular dementia, fronto-temporal lobar degeneration (FTLD), ADHD, dyslexia, bipolar disorder and social, cognitive and learning disorders associated with autism, traumatic head injury, traumatic brain injury (TBI), multiple sclerosis, attention deficit disorder, anxiety disorder, conditioned fear response, panic disorder, obsessive compulsive disorder, posttraumatic stress disorder (PTSD), phobia, social anxiety disorder, substance dependence recovery, Age Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), ataxia, Parkinson'"'"'s disease, or Parkinson'"'"'s disease dementia;

or

b. a hematological disease selected from acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, myelodysplastic syndromes, and sickle cell anemia;

or

c. a neoplastic disease;

or

d. a disorder of learning extinction selected from fear extinction and post-traumatic stress disorder.

6. The method of claim 5, wherein the condition is Alzheimer'"'"'s disease, Huntington'"'"'s disease, fronto-temporal lobar degeneration (FTLD) Friedreich'"'"'s ataxia, post-traumatic stress disorder (PTSD), Parkinson'"'"'s disease, or substance dependence recovery.

3. (canceled)

7. A method of treating a condition in a subject selected from a neurological disorder, memory or cognitive function disorder or impairment, neurological disorder with synaptic pathology, disorder of learning extinction, fungal disease or infection, inflammatory disease, hematological disease, psychiatric disorders, and neoplastic disease, comprising administering to the subject in need thereof an effective amount a compound of the Formula:

8. The method of claim 7, wherein the condition is:

a. a cognitive function disorder or impairment associated with Alzheimer'"'"'s disease, Huntington'"'"'s disease, seizure induced memory loss, schizophrenia, Rubinstein Taybi syndrome, Rett Syndrome, depression, Fragile X, Lewy body dementia, vascular dementia, fronto-temporal lobar degeneration (FTLD), ADHD, dyslexia, bipolar disorder and social, cognitive and learning disorders associated with autism, traumatic head injury, traumatic brain injury (TBI), multiple sclerosis, attention deficit disorder, anxiety disorder, conditioned fear response, panic disorder, obsessive compulsive disorder, posttraumatic stress disorder (PTSD), phobia, social anxiety disorder, substance dependence recovery, Age Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), ataxia, Parkinson'"'"'s disease, or Parkinson'"'"'s disease dementia;

or

b. a hematological disease selected from acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, myelodysplastic syndromes, and sickle cell anemia;

or

c. a neoplastic disease;

or

d. a disorder of learning extinction selected from fear extinction and post-traumatic stress disorder.

9. The method of claim 8, wherein the condition is Alzheimer'"'"'s disease, Huntington'"'"'s disease, fronto-temporal lobar degeneration (FTLD), Friedreich'"'"'s ataxia, post-traumatic stress disorder (PTSD), Parkinson'"'"'s disease, or substance dependence recovery.