# US 2021/0276977 A1 · Bicyclic inhibitors of histone deacetylase

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- Number: US 2021/0276977 A1
- Document ID: US20210276977A1
- Status: Published application
- Kind: A1
- Application number: 17/260,192
- Filed: 2019-07-12
- Published: 2021-09-09
- Earliest claimed: 2018-07-13
- Assignees: Alkermes, Inc.
- Applicants: Alkermes, Inc.
- Inventors: Nathan Oliver Fuller; John A. Lowe, III
- Web page: https://patentgrep.com/patent/US20210276977A1

## CPC

- C07D 401/14: containing three or more hetero rings
- 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 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are compounds of Formula I and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with histone deacetylases (HDAC).

## Claims

### Claim 1

A compound having the Formula I:
or a pharmaceutically acceptable salt thereof, wherein
ring A is phenyl or thiopheneyl;
X is (CRaRb)t, O, or NR5;
q is 0, 1, or 2;
t is 1, 2, or 3;
R1 is phenyl or heteroaryl, each of which are optionally substituted with 1 to 3 groups selected from Rc;
R2 is halo, (C1-C4)alkyl, (C1-C4)alkoxy, or OH;
R3 is hydrogen or halo;
R4 is halo when ring A is phenyl and R4 is hydrogen when ring A is thiopheneyl;
R5 is hydrogen, (C1-C4)alkyl, or (C1-C4)alkylO(C1-C4)alkyl;
Ra and Rb are each independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, or halo; and
Rc is halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkylO(C1-C4)alkyl, (C1-C4)alkylNH(C1-C4)alkyl, (C1-C4)alkylN((C1-C4)alkyl)2, —(C1-C4)alkylheteroaryl, or —(C1-C4)alkylheterocyclyl, wherein said heteroaryl and heterocyclyl are each optionally and independently substituted with 1 to 3 groups selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is of the Formula II or IIa:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is of the Formula III or IIIa:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound is of the Formula IV or IVa:
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R3 is halo.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R3 is fluoro.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R3 is hydrogen.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R4 is fluoro.

### Claim 9 (depends on 1)

The compound of claim 1, wherein X is (CRaRb)t.

### Claim 10 (depends on 1)

The compound of claim 1, wherein Ra is hydrogen, (C1-C4)alkyl, or halo; and Rb is hydrogen or halo.

### Claim 11 (depends on 1)

The compound of claim 1, wherein Ra is hydrogen, methyl, or fluoro; and Rb is hydrogen or fluoro.

### Claim 12 (depends on 1)

The compound of claim 1, wherein Ra is hydrogen and Rb is halo.

### Claim 13 (depends on 12)

The compound of claim 12, wherein Rb is fluoro.

### Claim 14 (depends on 1)

The compound of claim 1, wherein Ra is halo and Rb is halo.

### Claim 15 (depends on 14)

The compound of claim 14, wherein Ra and Rb are each fluoro.

### Claim 16 (depends on 1)

The compound of claim 1, wherein t is 1 or 2.

### Claim 17 (depends on 1)

The compound of claim 1, wherein the compound of the Formula V or Va:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The compound of claim 1, wherein the compound of the Formula VI or VIa:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

The compound of claim 1, wherein R1 is heteroaryl optionally substituted with 1 to 2 groups selected from Rc.

### Claim 20 (depends on 1)

The compound of claim 1, wherein R1 is pyrimidinyl, pyridinyl, imidazopyridinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, or thiadiazolyl, each of which is optionally substituted with 1 to 2 groups selected from Rc.

### Claim 21 (depends on 1)

The compound of claim 1, wherein Rc is halo, halo(C1-C4)alkyl, (C1-C4)alkyl, or (C1-C4)alkylO(C1-C4)alkyl.

### Claim 22 (depends on 1)

The compound of claim 1, wherein Rc is fluoro, CF3, methyl, or CH2OCH3.

### Claim 23 (depends on 1)

The compound of claim 1, wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 1)

The compound of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

### Claim 26 (depends on 1)

A method of inhibiting HD AC activity in a subject comprising the step of administering to the subject in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 1)

A method of treating a condition in a subject selected from a neurological disorder, memory or cognitive function disorder or impairment, extinction learning disorder, 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, or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 27)

The method of claim 27, wherein the condition is:
a. a cognitive function disorder or impairment associated with Alzheimer's disease, posterior cortical atrophy, normal-pressure hydrocephalus, Huntington's disease, seizure induced memory loss, schizophrenia, Rubinstein Taybi syndrome, Rett Syndrome, depression, Fragile X, Lewy body dementia, stroke, vascular dementia, vascular cognitive impairment (VCI), Binswanger's Disease, fronto-temporal lobar degeneration (FTLD), ADHD, dyslexia, major depressive disorder, bipolar disorder and social, cognitive and learning disorders associated with autism, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), multiple sclerosis (MS), 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; or
e. hearing loss or a hearing disorder; or
f. fibrotic diseases, such as pulmonary fibrosis, renal fibrosis, cardiac fibrosis, and scleroderma; or
g. bone pain in patients with cancer; or
h. neuropathic pain.

### Claim 29 (depends on 28)

The method of claim 28, wherein the condition is Alzheimer's disease, Huntington's disease, frontotemporal dementia, Friedreich's ataxia, post-traumatic stress disorder (PTSD), Parkinson's disease, or substance dependence recovery.

### Claim 30 (depends on 27)

The method of claim 27, wherein the condition is selected from Alzheimer's disease, Huntington's disease, fronto-temporal lobar degeneration, Friedreich's ataxia, post-traumatic stress disorder, Parkinson's disease, Parkinson's disease dementia, substance dependence recovery, memory or cognitive function disorder or impairment, neurological disorder with synaptic pathology, disorder of learning distinction, psychiatric disorders, cognitive function or impairment associated with Alzheimer's disease, Lewy body dementia, schizophrenia, Rubinstein Taybi syndrome, Rett Syndrome, Fragile X, multiple sclerosis, age associated memory impairment, age related cognitive decline, and social, cognitive and learning disorders associated with autism.