# US 2023/0407285 A1 · Pcsk9 inhibitors and methods of use thereof

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- Number: US 2023/0407285 A1
- Document ID: US20230407285A1
- Status: Published application
- Kind: A1
- Application number: 18/159,270
- Filed: 2023-01-25
- Published: 2023-12-21
- Earliest claimed: 2019-01-18
- Assignees: AstraZeneca AB
- Applicants: AstraZeneca AB
- Inventors: Michael H. Serrano-Wu; Brian K. Hubbard; Virendar Kaushik; Doug Daniels
- Web page: https://patentgrep.com/patent/US20230407285A1

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- C12N 9/6424: {Serine endopeptidases (3.4.21)}
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/06: Antihyperlipidemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C12N 9/0012: {acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7)}
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention relates to a novel inhibitor pharmacophore of PCSK9 and heteroaryl compounds that bind the PCSK9 protein.

## Claims

### Claim 1

A compound or pharmaceutically acceptable salt thereof, wherein the compound contacts PCSK9 and binds to a binding pocket defined by amino acid residues Val589 and Ser636 of human PCSK9.

### Claim 2 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is an allosteric inhibitor.

### Claim at position 3

-5. (canceled)

### Claim 6 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof comprises an H-bond acceptor/donor group having two H-bond acceptor moieties and one H-bond donor moiety disposed to donate an H-bond to and accept an H-bond from the backbone amide functionality of residue Val589, and accept an H-bond from the hydroxymethyl sidechain of Ser636 of human PCSK9.

### Claim 7 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof comprises an H-bond acceptor/donor group having two H-bond donor moieties and one H-bond acceptor moiety disposed to donate an H-bond to and accept an H-bond from the backbone amide functionality of residue Val589, and donate an H-bond to the hydroxymethyl sidechain of Ser636 of human PCSK9.

### Claim 8 (depends on 6)

The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein the compound or pharmaceutically acceptable salt thereof comprises a pyrimidinyl ring and the two H-bond acceptor moieties are the two nitrogen atoms present on the pyrimidinyl ring.

### Claim 9 (depends on 8)

The compound or pharmaceutically acceptable salt thereof according to claim 8, wherein the compound or pharmaceutically acceptable salt thereof comprises a 2-NH-pyrimidinyl moiety and the one H-bond donor moiety is the amino hydrogen atom.

### Claim 10 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof further comprises one or more of:
a) an H-bond acceptor moiety disposed to bind with amino acid residues Ser642, His643 or Val 644,
b) an H-bond donor moiety disposed to bind with amino acid residue Ala637 or Thr641, and
c) a cation-pi stacking interaction moiety disposed to bind with amino acid residue Arg495 or His591,
wherein the H-bond acceptor/donor group is bound to amino acid residues Val589 and Ser636 of human PC SK9.

### Claim 11 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof further comprises an H-bond acceptor moiety disposed to bind with amino acid residue Glu612.

### Claim 12 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof interacts with at least one residue in the M2 C-terminal domain and at least one residue in the M3 C-terminal domain.

### Claim 13 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof further interacts with at least one residue in the M1 C-terminal domain.

### Claim 14 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof interacts with at least one residue in the M1 C-terminal domain and at least one residue in the M3 C-terminal domain.

### Claim 15 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof interacts with at least one residue in the M1 C-terminal domain and at least one residue in the M2 C-terminal domain.

### Claim 16 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof interacts with a pocket in PCSK9 between amino acid residues 558-590 in the M2 C-terminal domain and amino acids residues 631-650 in the M3 C-terminal domain.

### Claim 17 (depends on 1)

The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof interacts with at least one residue in beta strand 3 and beta strand 5 of the M2 C-terminal domain and beta strand 3 and beta strand 4 of the M3 C-terminal domain.

### Claim 18 (depends on 17)

The compound or pharmaceutically acceptable salt thereof according to claim 17, wherein the compound or pharmaceutically acceptable salt thereof interacts with a pocket in PCSK9 created between amino acid residues 558-566 in beta strand 3 of the M2 C-terminal domain and amino acids residues 587-590 in beta strand 5 of the M2 C-terminal domain.

### Claim 19 (depends on 18)

The compound or pharmaceutically acceptable salt thereof according to claim 18, wherein the compound or pharmaceutically acceptable salt thereof interacts with a pocket in PCSK9 created between amino acid residues 631-637 in beta strand 3 of the M3 C-terminal domain and amino acids residues 644-650 in beta strand 4 of the M3 C-terminal domain.

### Claim at position 18

-72. (canceled)

### Claim 73 (depends on 1)

A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients.

### Claim 74 (depends on 11)

The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein the compound or pharmaceutically acceptable salt thereof has one H-bond acceptor moiety disposed to bind with amino acid residue Ser642, one H-bond acceptor moiety disposed to bind with amino acid residue Val644, and one H-bond donor moiety disposed to bind with amino acid residue Ala637.

### Claim 75

(canceled)

### Claim 76 (depends on 11)

The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein the compound or pharmaceutically acceptable salt thereof has one H-bond donor moiety disposed to bind with amino acid residue Ala637, and one cation-pi stacking interaction moiety disposed to bind with amino acid Arg495.

### Claim 77

(canceled)

### Claim 78 (depends on 11)

The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein the compound or pharmaceutically acceptable salt thereof has one H-bond donor moiety disposed to bind with amino acid residue Ala637, one H-bond donor moiety disposed to bind with amino acid residue Thr641, one H-bond acceptor moiety disposed to bind with amino acid residue His643, one cation-pi stacking interaction moiety disposed to bind with amino acid residue Arg495, and cation-pi stacking interaction moiety disposed to bind with amino acid residue His591.

### Claim 79

(canceled)

### Claim 79 (depends on 78)

The claim 78, wherein the compound is

### Claim 80 (depends on 11)

The compound or pharmaceutically acceptable salt thereof according to claim 11, wherein the compound or pharmaceutically acceptable salt thereof has one H-bond donor moiety disposed to bind with amino acid residue Ala637, one H-bond acceptor moiety disposed to bind with amino acid residue Val644, and one cation-pi stacking interaction moiety disposed to bind with amino acid 591.

### Claim 80 (depends on 10)

The claim 10, wherein the inhibitor has one H-bond donor moiety disposed to bind with amino acid residue Ala637, one H-bond acceptor moiety disposed to bind with amino acid residue Val644, and one cation-pi stacking interaction moiety disposed to bind with amino acid 591.

### Claim 81

(canceled)

### Claim 81 (depends on 80)

The claim 80, wherein the compound is