# US 11,298,345 B2 · Compounds that modulates AMPA receptor function

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,298,345 B2
- Document ID: US11298345B2
- Status: Granted
- Kind: B2
- Application number: 16/970,394
- Filed: 2019-03-01
- Published: 2021-04-22
- Granted: 2022-04-12
- Earliest claimed: 2018-03-01
- Assignees: University College Cardiff Consultants Limited
- Applicants: University College Cardiff Consultants Limited
- Inventors: Simon Ward; Paul Beswick; Lewis Pennicott; Tristan Reuillon; Irina Chuckowree; Carolina Villalonga-Barber; Roderick Alan Porter
- Web page: https://patentgrep.com/patent/US11298345B2

## CPC

- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- 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 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/14: containing three or more hetero rings
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 413/10: linked by a carbon chain containing aromatic rings
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides compounds of the formula (I): (I) wherein A1, A2, R2, R4, B1, B2, X, X1, n, a and b are as defined are defined in the specification, to pharmaceutical compositions comprising the compounds and the compounds for use as medicaments. The compounds potentiate AMPA receptor function and are expected to be useful in the treatment of central nervous system disorders, for example in the treatment of depressive disorders, mood disorders and cognitive dysfunction associated with neuropsychiatric disorders such as schizophrenia.

## Claims

### Claim 1

A compound of the formula (I), or a pharmaceutically acceptable salt thereof:
A1 is N or CR1;
A2 is N or CR3;
and wherein only a single one of A1 and A2 may be N;
R1 is selected from the group consisting of: H, CN, C1-4 alkyl, C1-4 haloalkyl, C3-4 cycloalkyl, —C1-4 alkyl-ORA1 and —C(O)NRA1RB1;
R2 is selected from the group consisting of: H, CN, C1-4 alkyl, C1-4 haloalkyl, C3-4 cycloalkyl, —C1-4 alkyl-ORA2 and —C(O)NRA2RB2;
R3 is selected from H, C1-4 alkyl, C1-4 haloalkyl, C3-4 cycloalkyl, —C1-4 alkyl-OH and —C(O)NRA3RB3;
each X is independently H or F, provided at least one X is F;
B1 and B2 are independently CH or N;
R4 is halo;
X1 is O or CH2;
RA1, RB1, RA2, RB2, RA3 and RB3 are each independently selected from: H and C1-4 alkyl;
a is an integer selected from 0, 1 or 2;
b is an integer selected from 0, 1 or 2;
a+b is 0, 1, 2 or 3; and
n is 0, 1 or 2;
with the following provisos:
R1, R2 and R3 are not all H;
when A1 is N, at least one of R2 and R3 is C1-4 alkyl or C1-4 haloalkyl;
when A2 is N, at least one of R1 and R2 is C1-4 alkyl or C1-4 haloalkyl;
when A1 is CR1, R1 is —CH2OH and B1 is N, then R2 is not H; and
when A1 is CR1, R1 is —CN and B2 is N, then R2 is not H.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the group —CX3 is —CF3.

### Claim 3 (depends on 1)

The compound of claim 1, wherein B2 is CH.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the group of the formula:
is selected from:

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is of the formula (III), or a pharmaceutically acceptable salt thereof:

### Claim 6 (depends on 1)

The compound of claim 1, wherein n is 0.

### Claim 7 (depends on 1)

The compound of claim 1, wherein B1 is N.

### Claim 8 (depends on 1)

The compound of claim 1, wherein B1 is CH.

### Claim 9 (depends on 1)

The compound of claim 1, wherein A1 is N or CR1 and R1 is selected from the group consisting of: H, CN, C1-3 alkyl, C1-3 fluoroalkyl, —C1-3 alkyl-OH, —C1-3 alkyl-OMe, —C(O)NH2; —C(O)NHMe and —C(O)N(Me)2.

### Claim 10 (depends on 1)

The compound of claim 1, wherein A1 is CR1 and R1 is CN.

### Claim 11 (depends on 1)

The compound of claim 1, wherein R2 is selected from the group consisting of: H, C1-3 alkyl, C1-3 fluoroalkyl, —C1-3 alkyl-OH and —C1-3 alkyl-OMe.

### Claim 12 (depends on 1)

The compound of claim 1, wherein A2 is N or CR3 and R3 is selected from the group consisting of: H, C1-3 fluoroalkyl and —C1-3 alkyl-OH.

### Claim 13 (depends on 1)

The compound of claim 1, wherein A2 is CH.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the group of the formula:
is selected from the group consisting of:

### Claim 15 (depends on 1)

The compound of claim 1, wherein the group of the formula:
is selected from the group consisting of:

### Claim 16 (depends on 1)

The compound of claim 1, selected from:

### Claim 17 (depends on 1)

A pharmaceutical formulation comprising a compound of claim 1, and a pharmaceutically acceptable excipient.

### Claim 18

A compound selected from a compound of the formula (XII) or (XIII), or a pharmaceutically acceptable salt thereof:
wherein
A2 is N or CR3;
B1 and B2 are independently CH or N;
R4 is halo;
each is independently H or F, provided at least one X is F;
X1 is O or CH2;
a is an integer selected from 0, 1 or 2;
b is an integer selected from 0, 1 or 2;
a+b is 0, 1, 2, or 3, and
n is 0, 1 or 2.

### Claim 19 (depends on 1)

A method for treating a condition which is modulated by an AMPA receptor in a subject in need thereof, the method comprising administering an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to said subject.

### Claim 20 (depends on 1)

A method for treating a condition selected from a depressive disorder, a mood disorder, cognitive dysfunction, a psychotic disorder, a bipolar disorder, attention-deficit hyperactivity disorder, a neurodegenerative disorder, a neurodevelopmental disorder, a motor neuron disease, ataxia, respiratory depression and a hearing disorder in a subject in need thereof, the method comprising administering an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to said subject.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the condition is cognitive dysfunction associated with a neurological or neuropsychiatric disorder.

### Claim 22 (depends on 20)

The method according to claim 20, wherein the condition is cognitive dysfunction associated with schizophrenia.

### Claim 23 (depends on 20)

The method according to claim 20, wherein the compound is co-administered to a subject with an additional therapeutic agent.