# US 11,897,868 B2 · Heterocyclic inhibitors of PCSK9

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

- Number: US 11,897,868 B2
- Document ID: US11897868B2
- Status: Granted
- Kind: B2
- Application number: 17/363,721
- Filed: 2021-06-30
- Published: 2022-01-06
- Granted: 2024-02-13
- Earliest claimed: 2017-03-17
- Assignees: Cardio Therapeutics Pty Ltd
- Applicants: Cardio Therapeutics Pty Ltd
- Inventors: Herbert Treutlein; Jun Zeng; Ian Dixon; Ian James; James T. Palmer
- Web page: https://patentgrep.com/patent/US11897868B2

## CPC

- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07D 233/61: with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

This application relates to chemical compounds which may act as inhibitors of, or which may otherwise modulate the activity of, PCSK9, or a pharmaceutically acceptable salt, solvate, prodrug or polymorph thereof, and to compositions and formulations comprising such compounds, and methods of using and making such compounds. Compounds include compounds of Formula (I): wherein A, D and Q are described herein.

## Claims

### Claim 1

A method for reducing LDL-C in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound according to Formula (1):
or a pharmaceutically acceptable salt thereof, wherein
A is an optionally substituted 5-membered heteroaryl ring, wherein the substituent is a methyl group;
Q is selected from the group consisting of optionally substituted: C2-C6 alkenyl, C2-C6 haloalkenyl, C1-C6 alkyloxy, C2-C6 alkenyloxy, C1-C6 alkylamino, C2-C6 alkenylamino, C2-C6 alkenylcarboxy, C1-C6 haloalkoxy, C2-C6 haloalkenyloxy, C1-C6 hydroxyalkyl, C2-C6 hydroxyalkenyl, C1-C6 alkylcarboxyamide, C2-C6 alkenylcarboxyamide, C1-C6 alkylsulfanyl, C2-C6 alkenylsulfenyl, C1-C6 alkylsulfenyl, C2-C6 alkenylsulfenyl, C1-C6 alkylsulfonyl, C2-C6 alkenylsulfenyl, C1-C6 alkylsulfonylamino, C2-C6 alkenylsulfonylamino, C4-C7 heterocyclyl, (C1-C3 alkyl)C3-C7 heterocyclyl, (C1-C3 alkyl)C3-C7 cycloalkyl and C3-C7 cycloalkyl;
wherein D is
wherein G is selected from the group consisting of —NR1C(O)—, —C(O)NR1—, —S(O)2NR1—, and —NR1S(O)2—;
wherein R1 is H or methyl and R2 is H,
or wherein G is —NR1C(O)— and R1 and R2, together with the atoms between them, form an optionally substituted C3-C6 heterocyclic ring, thereby creating a bicyclic or tricyclic ring; and
wherein X1 is CR3 and X2 is N, or X1 is N and X2 is CR3, or both X1 and X2 are CR3;
wherein R3 is H, C1-C2 alkyl, C1-C2 hydroxyalkyl, C1-C2 alkoxy or C1-C2 alkylamino; and
wherein Y1 is H or methyl and Y2 is
or Y2 is H or methyl and Y1 is
or both Y1 and Y2 are independently selected from H or methyl;
wherein L is selected from the group consisting of —O—, —NH—, —C(O)—, —NH(CH2)m—, C1-C3 alkoxy, C1-C3 alkylamino;
where m is 1 or 2; and
wherein
is optionally substituted aryl or optionally substituted heteroaryl with the proviso that
named relative to the position of attachment to L, is not pyrazolopyridinyl, ortho-substituted pyridine, 4-pyrimidinyl or imidazole; and
wherein R4 is H, NHC(O)CH3, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

### Claim 2 (depends on 1)

A method according to claim 1 further comprising administering a statin.

### Claim 3 (depends on 1)

The method according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein A is selected from

### Claim 4 (depends on 3)

The method according to claim 3, or a pharmaceutically acceptable salt thereof,
wherein A is

### Claim 5 (depends on 1)

The method according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein G is —NR1C(O)—.

### Claim 6 (depends on 5)

The method according to claim 5, or a pharmaceutically acceptable salt thereof,
wherein R1 is H.

### Claim 7 (depends on 1)

The method according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein Y2 is H or methyl and Y1 is

### Claim 8 (depends on 1)

The method according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein
is optionally substituted aryl.

### Claim 9 (depends on 1)

The method according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein
is optionally substituted heteroaryl wherein the heteroaryl group is optionally substituted 2-pyrimidinyl, wherein 2-pyrimidinyl refers to the position of attachment to L.

### Claim 10 (depends on 1)

The method according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein
is optionally substituted heteroaryl wherein the heteroaryl group is an optionally substituted bicyclic heteroaryl group.

### Claim 11 (depends on 1)

The method according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein Q is optionally substituted C4-C7 heterocyclyl or optionally substituted (C1-C3 alkyl)C3-C7 heterocyclyl.

### Claim 12 (depends on 11)

The method to claim 11, or a pharmaceutically acceptable salt thereof,
wherein the optionally substituted C4-C7 heterocyclyl or optionally substituted (C1-C3 alkyl)C3-C7 heterocyclyl is selected from the group consisting of optionally substituted morpholino, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted 4-methyl piperazinyl, optionally substituted 4-(C3 alkoxy)piperazinyl, optionally substituted (C1-C3 alkyl)(amino-substituted piperidinyl), optionally substituted (C1-C3 alkyl)(hydroxy-substituted piperidinyl), optionally substituted (C1-C3 alkyl)piperidinyl, and
wherein n is 1-2.

### Claim 13 (depends on 1)

The method according to claim 1, or a pharmaceutically acceptable salt thereof,
wherein L is —O— or —NH—.

### Claim 14 (depends on 1)

A method according to claim 1 wherein the compound is
A is
D is
G is —NR1C(O)—;
R1 is H;
R2 is H;
Y2 is H or methyl;
Y1 is
is selected from group consisting of optionally substituted aryl, optionally substituted 2-pyrimidinyl, or optionally substituted isoquinolinyl; wherein 2-pyrimidinyl refers to the position of attachment to L,
or a pharmaceutically acceptable salt thereof.

### Claim 15

A method for reducing LDL-C in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 15)

A method of claim 15 wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 15)

A method of claim 15 wherein the compound is:
or a pharmaceutically acceptable salt thereof.