PCSK9 antagonist compounds

Patent metadata

Field	Value
Publication number	US-11484565-B2
Application number	US-202017005686-A
Country	US
Kind code	B2
Filing date	Aug 28, 2020
Priority date	Aug 30, 2019
Publication date	Nov 1, 2022
Grant date	Nov 1, 2022

Abstract

Disclosed are compounds of Formula A, or a pharmaceutically acceptable salt thereof:where A, X, R1, and R2 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.

First claim

What is claimed is:

1. A compound of Formula A:

wherein:
X is H, F, Cl, or Br;
R is independently selected from H or C 1-6 alkyl;
R a is independently selected from H, —CR 2 —S(O) 2 OR 9 , 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 1 is selected from:
(a) —H,
(b) C 1-6 alkyl,
(c) —(CR 2 ) z —NR b —C(O)R 10 , and
(d) —(CR 2 ) z —NR—C(O)—(CR 2 ) z [O(CR 2 ) n ] r —N + (CH 3 ) 3 ;

R 2 is selected from:
(a) —H,
(b) C 1-6 alkyl,
(c) —(CR 2 ) z —NR b —C(O)R 10 , and
(d) —(CR 2 ) z —NR—C(O)—(CR 2 ) z [O(CR 2 ) n ] r —N + (CH 3 ) 3 ;

provided that at least one of R 1 and R 2 is —(CR 2 ) z —NR b —C(O)R 10 ;
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 —;

A is selected from C 2-6 alkyl or C 2-6 alkenyl;
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. The compound of claim 1 having the structure of Formula I:

wherein:
X is H, F, Cl, or Br;
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 1 is selected from:
(a) —H,
(b) C 1-6 alkyl,
(c) —(CR 2 ) z —NR b —C(O)R 10 , and
(d) —(CR 2 ) z —NR—C(O)—(CR 2 ) z [O(CR 2 ) n ] r —N + (CH 3 ) 3 ;

R 2 is selected from:
(a) —H,
(b) C 1-6 alkyl,
(c) —(CR 2 ) z —NR b —C(O)R 10 , and
(d) —(CR 2 ) z —NR—C(O)—(CR 2 ) z [O(CR 2 ) n ] r —N + (CH 3 ) 3 ;

provided that at least one of R 1 and R 2 is —(CR 2 ) z —NR b —C(O)R 10 ;
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 ) q —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 —;

A is selected from C 2-6 alkyl or C 2-6 alkenyl;
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. The compound according to claim 2 of Formula I, wherein
X is F;
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 1 is

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Josien Hubert
• Walji Abbas
• Wood Harold B
• Ding Fa-Xiang
• Liu Jian
• Tucker Thomas Joseph
• Lo Michael Man-Chu
• Guo Liangqin

Classifications

• C07K9/006

  the peptide sequence being part of a ring structure · CPC title

• A61K38/12 Primary

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61P3/06 Primary

  Antihyperlipidemics · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• A61K47/542

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title