IP Library › Granted Patent US 12,577,259

Granted Patent B2

US 12,577,259 · App. 17/757,622 · Granted Mar 17, 2026

PCSK9 antagonist compounds

Inventors: Hubert Josien (Jersey City, NJ); Jian Liu (Edison, NJ); Thomas Joseph Tucker (North Wales, PA); Abbas M. Walji (Lansdale, PA); Harold B. Wood (Westfield, NJ)

Assignee: MERCK SHARP & DOHME LLC

C07D498/22 C07K7/64

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Quick Facts

Patent No.: US 12,577,259
App. No.: 17/757,622
Granted: Mar 17, 2026
Kind: B2

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Abstract

Disclosed are compounds of Formula (I), or a pharmaceutically acceptable salt thereof: (I) wherein A, A 1 , A 2 , R 1 , R 2 and R 3 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 (211)

1 . A compound of Formula I

wherein:

A is C 2-6 alkyl;

A 1 is

A 2 is —(CR 2 ) n X(CR 2 ) n —;

X is O or CR 2 ;

R is independently selected from H or C 1-6 alkyl;

R a is independently selected from H or —C(O)OR 9 ;

R b is independently selected from H, C 1-6 alkyl, or C 1-6 alkyl-N + (CH 3 ) 2 ;

R d is independently selected from H or —C(O)OR 9 ;

R x is triazolyl;

R 1 is H;

R 2 is selected from

—(CR 2 ) z —NR b —C(O)R 10 ;

R 3 is F;

R 4 is

R 5 is independently selected from —(CR a 2 ) x —, —(CR a 2 ) x O(CR a 2 ) x —, and C 1-8 alkyl;

R 6 is independently selected from —(CR a 2 ) x NRC(O)—, —(CR 2 ) x NRS(O) 2 —, and —(CR a 2 ) n O(CR a 2 ) q NRC(O)—;

R 9 is independently selected from H or C 1-6 alkyl;

R 10 is independently selected from:

a) —(R 5 —N + (CH 3 ) 2 —R 6 ) u —(R 20 ) n —(R 6 ) m —R 12 ,

b) —(R 20 ) n —(R 6 ) m —R 5 —N + (CH 3 ) 2 —R 6 —R 12 ,

c) —(R 20 ) n —R 5 —N + (CH 3 ) 2 —(R 20 ) s —(R 6 ) q —R 12 ,

d) —R 6 —R 20 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 12 ,

e) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —(R 20 ) n —(R 6 ) q —R 12 ,

f) —(R 20 ) n —(R 6 ) m —R 12 ,

g) —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 5 —[NRC(O)—R 5 ] q ,

h) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —R 5 ,

i) —R 5 —N + (CH 3 ) 2 —(R 20 ) n (R 6 ) m —R 5 ,

j) —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 12 ,

k) —(R 20 ) n —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 ,

l) —R 6 —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 ,

m) —(R 20 ) n —N + (CH 3 ) 2 —(R 6 ) q —R 12 ,

n) —(R 20 ) n —(R 6 ) m —R 20 —N + (CH 3 ) 2 —(R 20 ) s —(R 6 ) q —R 12 ,

o) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —R 4 ,

p) —(R 20 ) n —N + (CH 3 ) 2 —(R 6 ) q —(R 20 ) n —(R 6 ) m —R 12 ,

q) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —(R 20 ) n —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 ,

r) —R 5 —N + (CH 3 ) 2 —(R 6 ) m —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 , and

s) —CR b 2 —(R 20 ) n —(R 6 ) m —R 12 ;

R 12 is independently selected from —C 11-20 alkyl-R d , —(CR 2 ) x —O—(CR 2 ) x —R d , —C 11-20 alkyl-C(O)NR—(CR d 2 ) 2 H, and C 2-16 alkenyl;

R 20 is independently selected from

a) —(CR a 2 ) t O(CR a 2 ) q O—(CR a 2 ) t —,

b) —(CR a 2 ) t O(CR a 2 ) q O—(CR a 2 ) t —NRC(O)—,

c) —(CR a 2 ) t O(CR a 2 ) q —NRC(O)—(CR a 2 ) n O(CR a 2 ) n O—,

d) —(CR a 2 ) t —NRC(O)—(CR a 2 ) q O(CR a 2 ) q O—(CR a 2 ) t —,

e) —(CR a 2 ) t O(CR a 2 ) q O—(CR a 2 ) t —, and

f) —(CR a 2 ) t —O—(CR a 2 ) q O(CR a 2 ) q O—(CR a 2 ) t —;

m is independently selected from 0, 1, 2, 3 or 4;

n is independently selected from 1, 2 or 3;

q is independently selected from 1, 2, 3 or 4;

r is independently selected from 0, 1, 2, 3 or 4;

s is independently selected from 0, 1, 2 or 3;

t is independently selected from 0, 1, 2 or 3;

u is 1 or 2;

x is independently selected from 1, 2, 3, 4, 5, 6, 7, or 8;

z is independently selected from 1, 2, 3, 4, 5 or 6;

or a pharmaceutically acceptable salt of any thereof.

2 . A compound of Formula I:

wherein:

A is selected from C 2-6 alkyl or —(CR 2 ) n R x (CR 2 ) n —;

A 1 is

A 2 is —(CR 2 ) n X(CR 2 ) n ;

X is O or CR 2 ;

R is independently selected from H or C 1-6 alkyl;

Ra is independently selected from H or —C(O)OR 9 ;

R 6 is independently selected from H, C 1-6 alkyl, or C 1-6 alkyl-N + (CH 3 ) 2 ;

R x is triazolyl;

R d is independently selected from H or —C(O)OR 9 ;

R 1 is H;

R 2 is selected from:

(a) —(CR 2 ) z —NR b —C(O)R 10 , and

(b) —(CR 2 ) z —NR—C(O)—(CR 2 ) z [O(CR 2 ) n ] r —N + (CH 3 ) 3 ;

R 3 is F;

R 4 is

R 5 is independently selected from —(CR a 2 ) x —, —(CR a 2 ) x O(CR a 2 ) x —, and C 1-8 alkyl;

R 6 is independently selected from —(CR a 2 ) x NRC(O)—, —(CR 2 ) x NRS(O) 2 —, and —(CR a 2 ) n O(CR a 2 ) q NRC(O)—;

R 9 is independently selected from H or C 1-6 alkyl;

R 10 is independently selected from:

a) —(R 5 —N + (CH 3 ) 2 —R 6 ) u —(R 20 ) n —(R 6 ) m —R 12 ,

b) —(R 20 ) n —(R 6 ) m —R 5 —N + (CH 3 ) 2 —R 6 —R 12 ,

c) —(R 20 ) n — R 5 —N + (CH 3 ) 2 —(R 20 ), —(R 6 ) q —R 12 ,

d) —R 6 —R 20 —N + (CH 3 ) 2 —(R 20 ) n (R 6 ) m —R 12 ,

e) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —(R 20 ) n —(R 6 ) q —R 12 ,

f) —(R 20 ) n —(R 6 ) m —R 12 ,

g) —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 5 —[NRC(O)—R 5 ] q ,

h) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —R 5 ,

i) —R 5 —N + (CH 3 ) 2 —(R 20 ) n (R 6 ) m —R 5 ,

j) —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 12 ,

k) —(R 20 ) n —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 ,

l) —R 6 —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 ,

m) —(R 20 ) n —N + (CH 3 ) 2 —(R 6 ) q —R 12 ,

n) —(R 20 ) n —(R 6 ) m —R 20 —N + (CH 3 ) 2 —(R 20 ), (R 6 ) q —R 12 ,

o) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —R 4 ,

p) —(R 20 ) n —N + (CH 3 ) 2 —(R 6 ) q —(R 20 ) n —(R 6 ) m —R 12 ,

q) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —(R 20 ) n —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 ,

r) —R 5 —N + (CH 3 ) 2 —(R 6 ) m —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 , and

s) —CR b 2 —(R 20 ) n (R 6 ) m —R 12 ;

R 12 is independently selected from —C 11-20 alkyl-R d , —(CR 2 ) x —O—(CR 2 ) x —R d , —C 11-20 alkyl-C(O)NR—(CR d 2 ) 2 H, and C 2-16 alkenyl;

R 20 is independently selected from

a) —(CR a 2 ) t O(CR a 2 ) q O—(CR a 2 ) t —,

b) —(CR a 2 ) t O(CR a 2 ) q O—(CR a 2 ) t —NRC(O)—,

c) —(CR a 2 ) t O(CR a 2 ) q —NRC(O)—(CR a 2 ) n O(CR a 2 ) n O—,

d) —(CR a 2 ) t —NRC(O)—(CR a 2 ) q O(CR a 2 ) q O—(CR a 2 ) t —,

e) —(CR a 2 ) t O(CR a 2 ) q O—(CR a 2 ) t —, and

f) —(CR a 2 ) t —O—(CR a 2 ) q O(CR a 2 ) q O—(CR a 2 ) t —;

m is independently selected from 0, 1, 2, 3 or 4;

n is independently selected from 1, 2 or 3;

q is independently selected from 1, 2, 3 or 4;

r is independently selected from 0, 1, 2, 3 or 4;

s is independently selected from 0, 1, 2 or 3;

t is independently selected from 0, 1, 2 or 3;

u is 1 or 2;

x is independently selected from 1, 2, 3, 4, 5, 6, 7, or 8;

z is independently selected from 1, 2, 3, 4, 5 or 6;

or a pharmaceutically acceptable salt of any thereof.

3 . A compound of Formula I:

wherein:

A is C 2-6 alkyl;

A 1 is

A 2 is —(CR 2 ) n NRC(O)(CR 2 ) n —;

R is independently selected from H or C 1-6 alkyl;

R a is independently selected from H or —C(O)OR 9 ;

R b is independently selected from H, C 1-6 alkyl, or C 1-6 alkyl-N + (CH 3 ) 2 ;

R x is triazolyl;

R d is independently selected from H or —C(O)OR 9 ;

R 1 is selected from:

(a) —(CR 2 ) z —R x —(CR 2 ) z NR 2 ,

(b) —(CR 2 ) z —R x —(CR 2 ) z NR—C(O)—(CR 2 ) z [O(CR 2 ) n ] r —N + (CH 3 ) 3 , and

R 2 is selected from:

(a) —(CR 2 ) z —NR b —C(O)R 10 , and

(b) —(CR 2 ) z —NR—C(O)—(CR 2 ) z [O(CR 2 ) n ] r —N + (CH 3 ) 3 ;

R 3 is F;

R 4 is

R 5 is independently selected from —(CR a 2 ) x —, —(CR a 2 ) x O(CR a 2 ) x —, and C 1-8 alkyl;

R 6 is independently selected from —(CR a 2 ) x NRC(O)—, —(CR 2 ) x NRS(O) 2 —, and —(CR a 2 ) n O(CR a 2 ) q NRC(O)—;

R 9 is independently selected from H or C 1-6 alkyl;

R 10 is independently selected from:

a) —(R 5 —N + (CH 3 ) 2 —R 6 ) u —(R 20 ) n —(R 6 ) m —R 12 ,

b) —(R 20 ) n —(R 6 ) m —R 5 —N + (CH 3 ) 2 —R 6 —R 12 ,

c) —(R 20 ) n —R 5 —N + (CH 3 ) 2 —(R 20 ) s —(R 6 ) q —R 12

d) —R 6 —R 20 —N + (CH 3 ) 2 —(R 20 ) n (R 6 ) m —R 12 ,

e) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —(R 20 ) n —(R 6 ) q —R 12 ,

f) —(R 20 ) n —(R 6 ) m —R 12 ,

g) —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 5 —[NRC(O)—R 5 ] q ,

h) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —R 5 ,

i) —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 5 ,

j) —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 12 ,

k) —(R 20 ) n —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12

l) —R 6 —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12

m) —(R 20 ) n —N + (CH 3 ) 2 —(R 6 ) q —R 12 ,

n) —(R 20 ) n —(R 6 ) m —R 20 —N + (CH 3 ) 2 —(R 20 ) s —(R 6 ) q —R 12

o) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —R 4 ,

p) —(R 20 ) n —N + (CH 3 ) 2 —(R 6 ) q —(R 20 ) n (R 6 ) m —R 12 ,

q) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —(R 20 ) n —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 ,

r) —R 5 —N + (CH 3 ) 2 —(R 6 ) m —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 , and

s) —CR b 2 —(R 20 ) n (R 6 ) m —R 12 ;

R 12 is independently selected from —C 11-20 alkyl-R d , —(CR 2 ) x —O—(CR 2 ) x —R d , —C 11-20 alkyl-C(O)NR—(CR d 2 ) 2 H, and C 2-16 alkenyl;

R 20 is independently selected from

a) —(CR a 2 ) t O(CR a 2 ) q O—(CR a 2 ) t —,

b) —(CR a 2 ) t O(CR a 2 ) q O—(CR a 2 ) t —NRC(O)—,

c) —(CR a 2 ) t O(CR a 2 ) q —NRC(O)—(CR a 2 ) n O(CR a 2 ) n O—,

d) —(CR a 2 ) t —NRC(O)—(CR a 2 ) q O(CR a 2 ) q O—(CR a 2 ) t —,

e) —(CR a 2 ) t O(CR a 2 ) q O—(CR a 2 ) t —, and

f) —(CR a 2 ) t —O—(CR a 2 ) q O(CR a 2 ) q O—(CR a 2 ) t —;

m is independently selected from 0, 1, 2, 3 or 4;

n is independently selected from 1, 2 or 3;

q is independently selected from 1, 2, 3 or 4;

r is independently selected from 0, 1, 2, 3 or 4;

s is independently selected from 0, 1, 2 or 3;

t is independently selected from 0, 1, 2 or 3;

u is 1 or 2;

x is independently selected from 1, 2, 3, 4, 5, 6, 7, or 8;

z is independently selected from 1, 2, 3, 4, 5 or 6;

or a pharmaceutically acceptable salt of any thereof.

4 . A compound selected from the group consisting of:

10*

11*

12*

and

13*

wherein A − is a pharmaceutically acceptable counter ion,

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 4 , selected from the group consisting of:

or any other pharmaceutically acceptable salt thereof.

6 . The compound of claim 5 , selected from the group consisting of:

or any other pharmaceutically acceptable salt thereof.

7 . The compound of claim 4 , which is selected from the group consisting of:

wherein A − is a pharmaceutically acceptable counter ion,

or a pharmaceutically acceptable salt thereof.

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

9 . A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 8 .

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

11 . A composition comprising at least one compound of claim 4 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

12 . A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 11 .

13 . A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4 .

14 . A composition comprising at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

15 . A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 14 .

16 . A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2 .

17 . A composition comprising at least one compound of claim 3 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

18 . A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 17 .

19 . A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 3 .

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 22, 2022

From: JOSIEN, HUBERT; TUCKER, THOMAS JOSEPH; WALJI, ABBAS M.; WOOD, HAROLD B.

To: MERCK SHARP & DOHME CORP.

Reel/Frame 061179/0361 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 22, 2022

From: LIU, JIAN

To: MERCK SHARP & DOHME CORP.

Reel/Frame 061180/0421 →

MERGER Recorded Sep 22, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 061183/0596 →

Continuity (2)

Provisional Application 62951802 · Dec 20, 2019

Related Publication 20230144324A1 · May 11, 2023

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