PCSK9 antagonist compounds
Disclosed are compounds of Formula A, or a pharmaceutically acceptable salt thereof: where A, X, R 1 , and R 2 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.
1. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of 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 ]—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 ]—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 method of claim 1 , wherein the compound has a 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 ] t —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 ] t —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.
3. The method of claim 2 ,
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 selected from:
(a) H,
(b) C 1-6 alkyl, and
(c) —(CR 2 ) z —NR b —C(O)R 10 ;
R 2 is selected from:
(a) C 1-6 alkyl, and
(b) —(CR 2 ) z —NR b —C(O)R 10 ;
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)— 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 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 ) g —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 , and —C 11-20 alkyl-C(O)NR—(CR d 2 ) 2 H;
R 20 is independently selected from
a) —(CR a 2 ) t O(CR a 2 ) n O—(CR a 2 ) t —,
b) —(CR a 2 ) t O(CR a 2 ) n O—(CR a 2 ) t —NRC(O)—,
c) —(CR a 2 ) t O(CR a 2 ) n —NRC(O)—(CR a 2 ) n O(CR a 2 ) n O—,
d) —(CR a 2 ) t —NRC(O) —(CR a 2 ) n O(CR a 2 ) n O—(CR a 2 ) t —,
e) —(CR a 2 ) t O(CR a 2 ) n O—,
f) —(CR a 2 ) t —O—(CR a 2 ) n O(CR a 2 ) n O—(CR a 2 ) t —,
A is C 2-6 alkyl;
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 or 2;
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. The method of claim 3 , where the compound has the structure of Formula IA:
or a pharmaceutically acceptable salt thereof.
5. The method of claim 3 , wherein the compound has the structure of Formula II:
wherein
R 1 is —(CR 2 ) z —NR b —C(O)R 10 ,
or a pharmaceutically acceptable salt thereof.
6. The method of claim 3 , wherein the compound has the structure of Formula IIA:
wherein
R 2 is —(CR 2 ) z —NR b —C(O)R 10 ,
or a pharmaceutically acceptable salt thereof.
7. The method of claim 2 , wherein R 6 is
(CR a 2 ) x NRC(O)—,
or a pharmaceutically acceptable salt thereof.
8. The method of claim 2 , wherein R 10 is selected from
a) —R 6 —R 20 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 12 ,
b) —R 20 —N + (CH 3 ) 2 —(R 6 ) m —(R 20 ) n —(R 6 ) q —R 12 ,
c) —(R 20 ) n —(R 6 ) m —R 12 ,
d) —R 5 —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) m —R 12 ,
e) —(R 20 ) n —N + (CH 3 ) 2 —(R 20 ) n —(R 6 ) q —R 12 ,
f) —(R 20 ) n —N + (CH 3 ) 2 —(R 6 ) q —R 12 , and
g) —(R 20 ) n —(R 6 ) m —R 20 —N + (CH 3 ) 2 —(R 20 ) s —(R 6 ) q —R 12 ,
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the compound is selected from the group consisting of:
Ex
No
Structure
Ex-1*
Ex-2*
Ex-3*
Ex-4*
Ex-5*
Ex-6*
Ex-7*
Ex-8*
Ex-9*
Ex- 10*
Ex- 11*
Ex- 12*
Ex- 13*
Ex- 14*
Ex- 15*
Ex- 16*
Ex- 17*
Ex-18
Ex- 19*
Ex- 20*
Ex- 21*
Ex- 22*
Ex- 23*
Ex-24
Ex- 25*
Ex- 26*
Ex- 27*
Ex- 28*
Ex- 29*
Ex- 30*
Ex31*
Ex- 32*
Ex- 33*
Ex- 34*
Ex- 35*
Ex- 36*
Ex- 37*
Ex- 38*
Ex- 39*
Ex- 40*
Ex-41
Ex-42
Ex- 43*
Ex- 44*
Ex- 45*
Ex- 46*
Ex- 47*
Ex- 48*
Ex- 49*
Ex- 50*
Ex- 51*
Ex- 52*
Ex- 53*
Ex- 54*
Ex- 55*
Ex- 56*
Ex- 57*
Ex- 58*
Ex- 59*
Ex- 60*
Ex- 61*
Ex- 62*
Ex- 63*
Ex- 64*
Ex-65
Ex-66
Ex-67
Ex-68
wherein A − is a pharmaceutically acceptable counter ion,
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the compound is selected from the group consisting of:
Ex No
Structure
Ex-2
Ex-4
Ex-8
Ex-9
Ex-10
Ex-22
Ex-34
Ex-44
Ex-48
Ex-49
Ex-58
or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 , wherein the compound is selected from the group consisting of:
Ex
No
Structure
Ex-4
Ex-8
Ex-9
Ex-10
Ex-22
Ex-34
Ex-48
Ex-49
or a pharmaceutically acceptable salt thereof.
12. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof or freebase form thereof, and at least one pharmaceutically acceptable excipient.
13. The method of claim 1 , wherein the compound has the structure:
wherein A− is a pharmaceutically acceptable counter ion,
or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the compound is:
15. The method of claim 1 , wherein the compound has the structure:
wherein A− is a pharmaceutically acceptable counter ion,
or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 , wherein the compound is:
17. The method of claim 1 , wherein the compound has the structure:
wherein A− is a pharmaceutically acceptable counter ion,
or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , wherein the compound is: