# US 11,306,066 B2 · 4H-pyran compounds as insulin-regulated aminopeptidase (IRAP) inhibitors

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- Number: US 11,306,066 B2
- Document ID: US11306066B2
- Status: Granted
- Kind: B2
- Application number: 15/572,554
- Filed: 2016-05-06
- Published: 2018-06-21
- Granted: 2022-04-19
- Earliest claimed: 2015-05-08
- Assignees: Monash University
- Applicants: Monash University; The Florey Institute of Neuroscience and Mental Health; St. Vincent's Institute of Medical Research
- Inventors: Siew Yeen Chai; Philip Thompson; Simon Mountford; Michael W. Parker
- Web page: https://patentgrep.com/patent/US11306066B2

## CPC

- C07D 309/32: having two double bonds between ring members or between ring members and non-ring members
- 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 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 407/10: linked by a carbon chain containing aromatic rings
- C07D 409/10: linked by a carbon chain containing aromatic rings
- C07D 493/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure relates generally, but not exclusively, to compounds and their use in therapy, to compositions and agents comprising said compounds, to methods of treatment using said compounds, and their use in the manufacture of medicaments. The disclosure further relates to inhibitors of IRAP and their use in the treatment or prevention of Alzheimer's disease and the treatment and prevention of memory and cognitive disorders.

## Claims

### Claim 1

A compound of Formula (I),
wherein
A is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, which is substituted by at least one of CO2H or a carboxylic acid isostere,
wherein the carboxylic isostere is selected from —SO3H, —SO2NH2, —SO2NHR, —PO2H2, —PO2HR, —SH, —NHCOH, —CONH2, —CONHR, —CONH(O)H, —CONH(O)R, —CONHNHSO2H, —CONHNHSO2R, —COHNSO2—H, —COHNSO2R and —CONH—CN, where R is selected from alkyl, phenyl and benzyl; and carbocyclic and heterocyclic groups selected from:
and wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl may be further optionally substituted by one or more substituents;
RA and RB are independently selected from hydrogen, alkyl and acyl, and wherein at least one of RA and RB is hydrogen;
R1 is selected from CN and CO2RC;
R2 is selected from CO2RC and acyl;
R3 is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, each of which maybe optionally substituted;
RC is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, each of which may be optionally substituted,
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein one of RA and RB is hydrogen and the other is alkyl or acyl.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein RA and RB are independently selected from alkyl and acyl.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R2 and R3 together form a 5-6-membered saturated keto-carbocyclic ring:
wherein n is 1 or 2;
and which ring may be optionally substituted one or more times by C1-6alkyl; or
R2 and R3 together form a 5-membered lactone ring (a) or a 6-membered lactone ring (b)
wherein is an optional double bond and R′ is alkyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein A is selected from phenyl and pyridinyl.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein A is phenyl.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein RA and RB are both hydrogen.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R1 is selected from CN, CO2C1-6alkyl, CO2C1-6alkenyl, CO2C1-6alkynyl, CO2phenyl, CO2 (CH2)1-6phenyl, CO25-6-membered heteroaryl, CO2 (CH2)1-6-5-6-membered heteroaryl, CO2C3-6cycloalkyl, and CO2 (CH2)1-6C3-6cycloalkyl.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R2 is selected from CO2C1-6alkyl, CO2C1-6alkenyl, CO2C1-6 alkynyl, CO2phenyl, CO2(CH2)1-6phenyl, CO25-6-membered CO2heteroaryl, CO2(CH2)1-6-5-6-membered heteroaryl, CO2C3-6cycloalkyl, CO2(CH2)1-6C3-6cycloalkyl, C(O)C1-6alkyl, C(O)C1-6alkenyl, C(O)C1-6alkynyl, C(O)phenyl, C(O)(CH2)1-6phenyl, C(O)5-6-membered heteroaryl, C(O)(CH2)1-6-5-6-membered heteroaryl, C(O)C3-6cycloalkyl, or C(O)(CH2)1-6C3-6cycloalkyl, each of which may be optionally substituted.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R3 is alkyl.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R2 is selected from CO2RC and acyl; and
R3 is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, each of which may be optionally substituted.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R1 is selected from CN, CO2C1-6alkyl, CO2C1-6alkenyl, CO2C1-6alkynyl, CO2phenyl, CO2 (CH2)1-6phenyl, CO25-6-membered heteroaryl, CO2 (CH2)1-6-5-6-membered heteroaryl, CO2C3-6cycloalkyl, and CO2 (CH2)1-6C3-6cycloalkyl;
R2 is selected from CO2C1-6alkyl, CO2C1-6alkenyl, CO2C1-6alkynyl, CO2phenyl, CO2(CH2)1-6phenyl, CO25-6-membered CO2heteroaryl, CO2(CH2)1-6-5-6-membered heteroaryl, CO2C3-6cycloalkyl, CO2(CH2)1-6C3-6cycloalkyl, C(O)C1-6alkyl, C(O)C1-6alkenyl, C(O)C1-6alkynyl, C(O)phenyl, C(O)(CH2)1-6phenyl, C(O)5-6-membered heteroaryl, C(O)(CH2)1-6-5-6-membered heteroaryl, C(O)C3-6cycloalkyl, or C(O)(CH2)1-6C3-6cycloalkyl, each of which may be optionally substituted; and
R3 is alkyl.

### Claim 13 (depends on 1)

A compound according to claim 1, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 14

A composition comprising a compound of Formula (I),
wherein
A is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, which is substituted by at least one of CO2H or a carboxylic acid isostere, wherein the carboxylic isostere is selected from —SO3H, —SO2NH2, —SO2NHR, —PO2H2, —PO2HR, —SH, —NHCOH, —CONH2, —CONHR, —CONH(O)H, —CONH(O)R, —CONHNHSO2H, —CONHNHSO2R, —COHNSO2—H, —COHNSO2R and —CONH—CN, where R is selected from alkyl, phenyl and benzyl; and carbocyclic and heterocyclic groups selected from:
and wherein said phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl may be further optionally substituted by one or more substituents;
RA and RB are independently selected from hydrogen, alkyl and acyl, and wherein at least one of RA and RB is hydrogen;
R1 is selected from CN and CO2RC;
R2 is selected from CO2RC and acyl;
R3 is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, each of which maybe optionally substituted;
RC is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, each of which may be optionally substituted,
or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable additive.

### Claim 15 (depends on 14)

The composition according to claim 14, wherein A is selected from phenyl and pyridinyl.

### Claim 16 (depends on 14)

The composition according to claim 14, wherein A is phenyl.

### Claim 17 (depends on 14)

The composition according to claim 14, wherein RA and RB are both hydrogen.

### Claim 18 (depends on 14)

The composition according to claim 14, wherein R1 is selected from CN, CO2C1-6alkyl, CO2C1-6alkenyl, CO2C1-6alkynyl, CO2phenyl, CO2 (CH2)1-6phenyl, CO25-6-membered heteroaryl, CO2 (CH2)1-6-5-6-membered heteroaryl, CO2C3-6cycloalkyl, and CO2 (CH2)1-6C3-6cycloalkyl.

### Claim 19 (depends on 14)

The composition according to claim 14, wherein R2 is selected from CO2C1-6alkyl, CO2C1-6alkenyl, CO2C1-6alkynyl, CO2phenyl, CO2(CH2)1-6phenyl, CO25-6-membered CO2heteroaryl, CO2(CH2)1-6-5-6-membered heteroaryl, CO2C3-6cycloalkyl, CO2(CH2)1-6C3-6cycloalkyl, C(O)C1-6alkyl, C(O)C1-6alkenyl, C(O)C1-6alkynyl, C(O)phenyl, C(O)(CH2)1-6phenyl, C(O)5-6-membered heteroaryl, C(O)(CH2)1-6-5-6-membered heteroaryl, C(O)C3-6cycloalkyl, or C(O)(CH2)1-6C3-6cycloalkyl, each of which may be optionally substituted.

### Claim 20 (depends on 14)

The composition according to claim 14, wherein R3 is alkyl.

### Claim 21 (depends on 1)

A method of treating or preventing memory loss or impairment or improving cognition and/or memory in a subject in need thereof comprising administering to said subject a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined in claim 1.

### Claim 22 (depends on 1)

A method of treating or preventing Alzheimer's Disease in a subject in need thereof comprising administering to said subject a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or prodrug thereof, as defined in claim 1.

### Claim 23 (depends on 14)

The composition according to claim 14 wherein R2 is selected from CO2RC and acyl; and
R3 is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, each of which may be optionally substituted.

### Claim 24 (depends on 14)

The composition according to claim 14, wherein R1 is selected from CN, CO2C1-6alkyl, CO2C1-6alkenyl, CO2C1-6alkynyl, CO2phenyl, CO2 (CH2)1-6phenyl, CO25-6-membered heteroaryl, CO2 (CH2)1-6-5-6-membered heteroaryl, CO2C3-6cycloalkyl, and CO2 (CH2)1-6C3-6cycloalkyl;
R2 is selected from CO2C1-6alkyl, CO2C1-6alkenyl, CO2C1-6alkynyl, CO2phenyl, CO2(CH2)1-6phenyl, CO25-6-membered CO2heteroaryl, CO2(CH2)1-6-5-6-membered heteroaryl, CO2C3-6cycloalkyl, CO2(CH2)1-6C3-6cycloalkyl, C(O)C1-6alkyl, C(O)C1-6alkenyl, C(O)C1-6alkynyl, C(O)phenyl, C(O)(CH2)1-6phenyl, C(O)5-6-membered heteroaryl, C(O)(CH2)1-6-5-6-membered heteroaryl, C(O)C3-6cycloalkyl, or C(O)(CH2)1-6C3-6cycloalkyl, each of which may be optionally substituted; and
R3 is alkyl.

### Claim 25 (depends on 14)

A composition according to claim 14, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.