Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase

• US 10,421,756 B2
• Filed: 07/05/2016
• Issued: 09/24/2019
• Est. Priority Date: 07/06/2015
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Rodin Therapeutics, Inc. (Alkermes Incorporated)
• Inventors: Jefson, Martin R., Lowe, III, John A., Dey, Fabian, Bergmann, Andreas, Schoop, Andreas
• Primary Examiner(s): Habte, Kahsay
• Application Number:
  US15/741,609
• Publication Number:
  US 20180194760A1
• Time in Patent Office: 1,176 Days
• Field of Search: 514256
• 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 471/08 Bridged systems
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/08 Bridged systems
• CPC Class Codes: C07D 491/08 Bridged systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

This invention provides compounds that are inhibitors of HDAC2. The compounds (e.g., compounds according to Formula (I) or any one of Compounds 100-175) accordingly are useful for treating, alleviating, or preventing a condition in a subject such as a neurological disorder, memory or cognitive function disorder or impairment, extinction learning disorder, fungal disease or infection, inflammatory disease, hematological disease, or neoplastic disease, or for improving memory or treating, alleviating, or preventing memory loss or impairment.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein R¹ is selected from:

6,7-dihydrothiazolo[5,4-c]pyridin-2-yl,

4,5,6,7-tetrahydrothiazolo[4,5-c]pyridin-2-yl,

4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl,

2-oxa-8-azaspiro[4.5]decan-8-yl,

1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl,

2,8-diazaspiro[4.5]decan-8-yl,

2,8-diazaspiro[4.5]decan-2-yl,

hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,

5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl,

5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl,

2-oxa-7-azaspiro[3.5]nonan-7-yl,

5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl,

octahydro-5H-pyrrolo[3,4-c]pyridin-5-yl,

5-oxa-2-azaspiro[3.5]nonan-2-yl,

5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl,

8-oxa-2-azaspiro[4.5]decan-2-yl,

7-oxa-2-azaspiro[3.5]nonan-2-yl,

2,7-diazaspiro[3.5]nonan-2-yl,

2,7-diazaspiro[3.5]nonan-7-yl,

2,7-diazaspiro[4.4]nonan-2-yl

octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl,

3,8-diazabicyclo[3.2.1]octan-3-yl,

3,8-diazabicyclo[3.2.1]octan-8-yl,

3,8-diazabicyclo[3.2.1]octan-8-yl,

2,5-diazabicyclo[2.2.1]heptan-2-yl,

8-oxa-3-azabicyclo[3.2.1]octan-3-yl,

5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-yl,

6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl,

5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl,

2-oxa-6-azaspiro[3.4]octan-6-yl,

2-oxa-6-azaspiro[3.3]heptan-6-yl, and

2,6-diazaspiro[3.4]octan-6-yl, wherein R¹ is optionally substituted with up to 4 independently selected substituents.

3. The compound of claim 2, wherein R¹ is selected from:

4. The compound of claim 3, wherein R¹ is selected from:

5. The compound of claim 4, wherein R¹ is selected from:

6. The compound of claim 5, wherein R² is selected from para-substituted phenyl, pyridinyl, furanyl, 1H-Pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, isothiazolyl, 5,6-dihydro-4H-Pyrrolol[1,2-b]pyrazolyl, pyridazinyl, and pyrimidinyl, and wherein R² is optionally additionally substituted.

7. The compound of claim 6, wherein R² is selected from 4-fluorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-difluromethoxyphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 3,4,5-trifluorophenyl, 2-fluoro-4-trifluoromethylphenyl, 2-methyl-4-fluorophenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5-trifluoromethylpyridin-2-yl, 6-methoxypyridin-3-yl, 6-methylpyridin-3-yl, 6-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2-fluoropyridin-4-yl, furan-2-yl, 5-methylfuran-2-yl, 5-chlorofuran-2-yl, furan-3-yl, 5-methylfuran-3-yl, 5-chlorofuran-3-yl, 1H-pyrazol-4-yl, 1-ethyl-1H-Pyrazol-4-yl, 1-methyl-1H-Pyrazol-4-yl, 1-cyclobutyl-1H-pyrazol-4-yl, 1,5-dimethyl-1H-pyrazol-4-yl, 2-methylthiazol-5-yl, 3-methylisoxazol-5-yl, 2-methyloxazoly-5-yl, 3-methylisothiazol-5-yl, 5,6-dihydro-4H-Pyrrolol[1,2-b]pyrazol-3-yl, 6-methylpyridazin-4-yl, 6-methylpyridazin-3-yl, and pyrimidin-3-yl.

8. The compound of claim 7, wherein R² is selected from 4-fluorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-difluromethoxyphenyl, 4-cyanophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl, and 1 -methyl- 1H-Pyrazol-4-yl.

9. The compound of claim 8, wherein R² is selected from 4-fluorophenyl, 4-methoxyphenyl, 4-difluromethoxyphenyl, pyridin-4-yl, furan-2-yl, and furan-3-yl.

10. The compound of claim 1, wherein the compound is selected from:

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

and a pharmaceutically acceptable carrier.

12. A method of treating a condition in a subject selected from

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, Fragile X, Lewy body dementia, vascular dementia, frontotemporal dementia, ADHD, dyslexia, bipolar disorder and social, cognitive and learning disorders associated with autism, traumatic head injury, 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, or Parkinson'"'"'s disease;

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

c. a neoplastic disease; and

d. an extinction learning disorder selected from fear extinction and post-traumatic stress disorder, comprising administering to the subject in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

13. The method of claim 12, wherein the condition is Alzheimer'"'"'s disease, Huntington'"'"'s disease, frontotemporal dementia, Freidreich'"'"'s ataxia, post-traumatic stress disorder (PTSD), Parkinson'"'"'s disease, or substance dependence recovery.