# US 11,078,196 B2 · Heteroaryl amides as inhibitors of protein aggregation

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- Number: US 11,078,196 B2
- Document ID: US11078196B2
- Status: Granted
- Kind: B2
- Application number: 16/438,348
- Filed: 2019-06-11
- Published: 2019-10-10
- Granted: 2021-08-03
- Earliest claimed: 2014-01-29
- Assignees: UCB Biophama SRL
- Applicants: UCB Biopharma SRL
- Inventors: Wolfgang Wrasidlo; Emily M. Stocking
- Web page: https://patentgrep.com/patent/US11078196B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to certain heteroaryl amide compounds, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia, fronto-temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, and multiple system atrophy, and cancer and melanoma.

## Claims

### Claim 1

A compound of Formula (I):
wherein
R1 is H, halo, C1-4alkyl, or —CF3;
R2 is —CF3 or C1-4alkyl unsubstituted or substituted with halo or —CF3;
A is a 5-membered heteroaryl ring with two or three heteroatom ring atoms selected from the group consisting of N, O, and S, and wherein the 5-membered heteroaryl ring is attached to
and Y via two non-adjacent carbon ring atoms;
Y is absent or is C1-4alkylene;
where when Y is absent, R3 and R4 taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl ring, unsubstituted or substituted with C1-4alkyl; and
when Y is C1-4alkylene, R3 and R4 taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl ring, unsubstituted or substituted with C1-4alkyl; or R3 and Y taken together with the nitrogen to which R3 is attached form a monocyclic heterocycloalkyl ring, and R4 is H or C1-4alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H, fluoro, chloro, bromo, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H or fluoro.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —CF3, or is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl, each unsubstituted or substituted with fluoro, chloro, bromo, or —CF3.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is —CF3 or is C1-4alkyl optionally substituted with halo or —CF3.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is C3-4alkyl, unsubstituted or substituted with fluoro or —CF3.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is butyl.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is propyl substituted with —CF3.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is in an “R” stereochemical configuration.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is in an “S” stereochemical configuration.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl ring with two heteroatom ring atoms.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a 5-membered heteroaryl ring with two non-adjacent heteroatom ring atoms.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is thiazole, thiadiazole, oxazole, imidazole, or triazole.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is thiadiazole.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is thiazole.

### Claim 16 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is absent.

### Claim 17 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is —CH2—, —CH2CH2—, —CH(CH3)—, —(CH2)3—, —C(CH3)2—, —(CH2)4—, —CH((CH2)2CH3)—, —CH(CH(CH3)2), —CH(CH2CH3)CH2—, —CH(CH3)CH(CH3)—, —CH(CH3)(CH2)2—, or —CH2CH(CH3)CH2—.

### Claim 18 (depends on 17)

The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein Y is —CH2—, —CH2CH2—, or —CH(CH3)—.

### Claim 19 (depends on 17)

The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein Y is —CH2CH2—.

### Claim 20 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 are taken together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl ring, unsubstituted or substituted with C1-4alkyl.

### Claim 21 (depends on 20)

The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 taken together with the nitrogen to which they are attached form azetidine, pyrrolidine, piperidine, azepine, piperazine, morpholine, thiomorpholine, or 1,1-dioxo-thiomorpholine, each unsubstituted or substituted with C1-4alkyl.

### Claim 22 (depends on 20)

The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 taken together with the nitrogen to which they are attached form pyrrolidine, unsubstituted or substituted with C1-4alkyl.

### Claim 23 (depends on 20)

The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 taken together with the nitrogen to which they are attached form morpholine, unsubstituted or substituted with C1-4alkyl.

### Claim 24 (depends on 20)

The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 taken together with the nitrogen to which they are attached form piperazine, unsubstituted or substituted with C1-4alkyl.

### Claim 25 (depends on 20)

The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R3 and R4 taken together with the nitrogen to which they are attached form piperazine or 4-methyl-piperazine.

### Claim 26 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is C1-4alkylene, and R3 and Y taken together with the nitrogen to which R3 is attached form a monocyclic heterocycloalkyl ring, and R4 is H or C1-4alkyl.

### Claim 27 (depends on 26)

The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein Y and R3 taken together with the nitrogen to which R3 is attached form pyrrolidine or piperidine.

### Claim 28 (depends on 26)

The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein R4 is H or methyl.

### Claim 29 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H, R2 is C1-4alkyl, A is thiazole, Y is absent or is ethylene, and R3 and R4 taken together with the nitrogen to which they are attached form N-methylpiperazine.

### Claim 30

A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 31

A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 32 (depends on 1)

A pharmaceutical composition comprising (a) at least one compound or pharmaceutically acceptable salt thereof according to claim 1, and (b) a pharmaceutically acceptable excipient.

### Claim 33 (depends on 32)

The pharmaceutical composition of claim 32, wherein R2 is substantially in an “R” stereochemical configuration.

### Claim 34 (depends on 32)

The pharmaceutical composition of claim 32, wherein R2 is substantially in an “S” stereochemical configuration.

### Claim 35 (depends on 1)

A method of treating a disease or medical condition associated with protein aggregation, comprising administering to a subject in need of such treatment an effective amount of at least one compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the disease or medical condition associated with protein aggregation is Alzheimer's disease, Parkinson's disease, fronto-temporal dementia, dementia with Lewy bodies (Lewy body disease), Parkinson's disease with dementia, multiple system atrophy, amyotrophic lateral sclerosis, Huntington's disease, or melanoma.

### Claim 36 (depends on 1)

A method of interfering with the accumulation of protein or peptide aggregates in a cell, or preventing, slowing, reversing, or inhibiting protein or peptide aggregation in a cell, comprising contacting the cell with an effective amount of at least one compound or pharmaceutically acceptable salt according to claim 1, wherein the contacting is in vitro ex vivo or in vivo.

### Claim 37 (depends on 32)

A method of interfering with the accumulation of protein or peptide aggregates in a cell, or preventing, slowing, reversing, or inhibiting protein or peptide aggregation in a cell, comprising contacting the cell with an effective amount of a pharmaceutical composition according to claim 32, wherein the contacting is in vitro, ex vivo, or in vivo.