IP Library › Granted Patent US 11,484,565

Granted Patent B2

US 11,484,565 · App. 17/005,686 · Granted Nov 1, 2022

PCSK9 antagonist compounds

Inventors: Hubert Josien (Jersey City, NJ); Abbas Walji (Lansdale, PA); Harold B. Wood (Westfield, NJ); Fa-Xiang Ding (Staten Island, NY); Jian Liu (Edison, NJ); Thomas Joseph Tucker (North Wales, PA); Michael Man-Chu Lo (Bedminster, NJ); Liangqin Guo (Monroe, NJ)

Assignee: MERCK SHARP & DOHME LLC

A61K38/12 A61P3/06 C07K9/006

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Quick Facts

Patent No.: US 11,484,565
App. No.: 17/005,686
Granted: Nov 1, 2022
Kind: B2

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Abstract

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.

Claims (318)

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,

(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,

(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,

(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,

(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 selected from:

(a) —H,

(b) C 1-6 alkyl,

R 2 is selected from:

(a) —H,

(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)—, —(CR a 2 ) n O(CR a 2 ) q 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 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.

4. The compound of claim 3 having the structure of Formula IA

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3 having 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 compound of claim 3 having 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 compound according to claim 2 of Formula I, wherein R 6 is

—(CR a 2 ) x NRC(O)—,

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 2 of Formula I, 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 compound of claim 1 , which is selected from the group consisting of:

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 compound according to claim 1 , 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 compound according to claim 10 , selected from the group consisting of:

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 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 compound having the structure:

wherein A − is a pharmaceutically acceptable counter ion,

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13 , wherein the compound is:

15. The compound having the structure:

wherein A − is a pharmaceutically acceptable counter ion,

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 , wherein the compound is:

17. The compound having the structure:

wherein A − is a pharmaceutically acceptable counter ion,

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 , wherein the compound is:

Assignments (2)

MERGER Recorded Jun 3, 2022

From: MERCK SHARP & DOHME CORP.

To: MERCK SHARP & DOHME LLC

Reel/Frame 060098/0222 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 8, 2021

From: JOSIEN, HUBERT; WALJI, ABBAS; WOOD, HAROLD B.; DING, FA-XIANG; LIU, JIAN; TUCKER, THOMAS JOSEPH; MAN-CHU LO, MICHAEL; GUO, LIANGQIN

To: MERCK SHARP & DOHME CORP.

Reel/Frame 056792/0554 →

Continuity (3)

Provisional Application 62950690 · Dec 19, 2019

Provisional Application 62894286 · Aug 30, 2019

Related Publication 20210069288A1 · Mar 11, 2021

Cited By (2)

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