# US 11,306,125 B2 · PCSK9 antagonists bicyclo-compounds

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- Number: US 11,306,125 B2
- Document ID: US11306125B2
- Status: Granted
- Kind: B2
- Application number: 17/253,815
- Filed: 2019-06-20
- Published: 2021-07-15
- Granted: 2022-04-19
- Earliest claimed: 2018-06-21
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: Yusheng Xiong; Thomas Joseph Tucker; Chengwei Wu; Elisabetta Bianchi; Danila Branca; Angela Dawn Kerekes; Abbas M. Walji; Hubert B. Josien; Fa-Xiang Ding; Hyewon Youm; Alessia Santoprete; Raffaele Ingenito
- Web page: https://patentgrep.com/patent/US11306125B2

## CPC

- A61P 3/06: Antihyperlipidemics
- C07K 7/56: the cyclisation not occurring through 2,4-diamino-butanoic acid
- C07D 487/18: Bridged systems
- C07D 498/22: in which the condensed system contains four or more hetero rings
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

Disclosed are compounds of Formula I, or a salt thereof cyclic polypeptide of Formula I: Formula I where A, B, E, R4, and R8 are as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula I or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions

## Claims

### Claim 1

A compound of the Formula I:
wherein:
R4 is: (a) linear, branched or cyclic alkyl of up to 6 carbon atoms; (b) —(CH2)x—R13B, wherein: x is 1-4, and R13B is —NH2 or —N+H3; (c) —(CH2)x—R13C, wherein: x is 1-4, and R13C is —N(R13D)2 or —N(R13D)3 wherein R13D is a linear or branched alkyl of up to 4 carbon atoms; (d) —CH2NH—C(O)—O—C(CH3)3; or
(e) —CH2—NH—C(O)—[(CH2)2—O—]y—(CH2)2—R13E, wherein, y is 1 to 4 and R13E is —NH2, —N+H3, or —N+(CH3)3;
R8 is a moiety of the formula:
wherein R8a is —H, or a linear, branched or cyclic alkyl of up to four carbon atoms;
A is (a) —CH2—; or
(b) a moiety of the formula:
wherein R3 is:
(i) linear, branched or cyclic alkyl of up to 6 carbon atoms;
(ii) —(CH2)z—R14A, wherein: z is 1-4, and R14A is —NH2 or —N+H3;
(iii) —(CH2)z—R14B, wherein: z is 1-4, and R14B is —N(CH3)2 or —N+(CH3)3; or
(iv) —CH2—NH—C(O)—[(CH2)y—O—]2—(CH2)2—R14C wherein, y′ is 1 to 6, and R14C is —NH2, —N+H3, or —N+(CH3)3;
B is:
(a) a moiety of the formula:
wherein:
R1 is —H or —NH—C(O)—CH3;
R2 is —H or —C(O)—R15A, wherein R15A is —NH2, —N+H3, or —N+(CH3)3; and
C1 is —CH2— or —(CH2)2—O—; or
(b) a moiety of the formula:
D is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
wherein R12 is —H or —CH3; and
E is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of claim 1 having the formula of Formula II:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R4 is:
(a) —CH3;
(b) —CH(CH3)2;
(c) —(CH2)x—R13b, wherein: x is 1-4, and R13b is —NH2 or —N+H3; (d) —CH2NH—C(O)—O—C(CH3)3; or (iv) —CH2—NH—C(O)—[(CH2)2—O—]2—(CH2)2—R13, wherein R13c is —NH2, —N+H3, or —N+(CH3)3.

### Claim 4 (depends on 2)

A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R8 is a moiety of the formula:
wherein R8b is —H, —CH3, or —C(CH3)3.

### Claim 5 (depends on 2)

A compound of claim 2, or a pharmaceutically acceptable salt thereof,
Wherein:
A is a moiety of the formula:
and
R3 is
(i) —CH3;
(ii) —CH(CH3)2;
(iii) —(CH2)z—R13a, wherein: z is 1-4, and R13a is —NH2 or —N+H3; or
(iv) —CH2—NH—C(O)—[(CH2)2—O—]2—(CH2)2—R13c, wherein R13c is —NH2, —N+H3, or —N+(CH3)3.

### Claim 6 (depends on 2)

A compound of claim 2 having the formula of Formula III:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A compound of claim 1 having the Formula IV:
wherein:
B2 is:
(a) a moiety of the formula:
or
(b) a moiety of the formula:
wherein:
R1 is —H or —NH—C(O)—CH3;
R2 is —H or —C(O)—R16A NH2 R16A is —NH2, —N+H3, —N(CH3)2, or —N+(CH3)3,
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

A compound of claim 1, which is selected from the group consisting of
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A composition comprising at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

### Claim 11 (depends on 10)

A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 10.

### Claim 12 (depends on 1)

A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 13 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in therapy.

### Claim 14 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for treating hypercholesterolemia.

### Claim 15 (depends on 1)

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