PCSK9 antagonist compounds

Patent metadata

Field	Value
Publication number	US-11427616-B2
Application number	US-201916446940-A
Country	US
Kind code	B2
Filing date	Jun 20, 2019
Priority date	Jun 21, 2018
Publication date	Aug 30, 2022
Grant date	Aug 30, 2022

Abstract

Disclosed are compounds of Formula I, or a salt thereof:where A, B, D, X, R1, R2 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.

First claim

What is claimed is:

1. A compound of Formula I:

wherein:
X is H, F, Cl or Br;
R 1 is selected from:
(a) —H; or
(b) —(CH 2 ) z —R 14A , wherein: z is 1-6, and R 14A is:
(i) —H;
(ii) —NH 2 ;
(iii) —N + H 3 ;
(iv) —N + (H 3 C) 3 ;
(v) —NH—C(O)—[(CH 2 ) 2 —O—] 2 —(CH 2 ) 2 R 14B wherein R 14B is: —NH 2 ; —N + H 3 ; —N(CH 3 ) 2 ; or —N + (CH 3 ) 3 ;
(vi) —NH—C(O)—[(CH 2 ) y12 —O—] 2 —(CH 2 ) y13 R 14B wherein:
y12 and y13 are not both 2 and are independently 2 to 4; and
R 14B is: —NH 2 ; —N + H 3 ; —N(CH 3 ) 2 ; or —N + (CH 3 ) 3 ;

(vii) —NH—C(O)—(CH 2 ) y R 14C , wherein, y=1 to 6 and R 14C is —O—(CH 2 ) 3-4 —N + (CH 3 ) 3 ; and
(viii) —NH—C(O)—(CH 2 ) y R 14C , wherein, y=1 to 6 and R 14C is:
(ai) —O—(CH 2 ) 2 —N + (CH 3 ) 3 ;
(aii) —N + (CH 3 ) 3 ; or
(aiii) a moiety of the formula:

R 2 is selected from:
(a) —H; and
(b) —(CH 2 ) z —R 14A , wherein: z is 1-6, and R 14A is selected from:
(i) —H;
(ii) —NH 2 ;
(iii) —N + H 3 ;
(iv) —N + (H 3 C) 3 ;
(v) —NH—C(O)—[(CH 2 ) 2 —O—] 2 —(CH 2 ) 2 R 14B wherein R 14B is: —NH 2 ; —N + H 3 ; —N(CH 3 ) 2 ; or —N + (CH 3 ) 3 ;
(vi) —NH—C(O)—[(CH 2 ) y12 —O—] 2 —(CH 2 ) y13 R 14B wherein:
y12 and y13 are not both 2 and are independently 2 to 4; and
R 14B is: —NH 2 ; —N + H 3 ; —N(CH 3 ) 2 , or —N + (CH 3 ) 3 ;

(vii) —NH—C(O)—(CH 2 ) y R 14C , wherein, y=1 to 6 and R 14C is —O—(CH 2 ) 3-4 —N + (CH 3 ) 3 ; and
(viii) —NH—C(O)—(CH 2 ) y R 14C , wherein, y=1 to 6 and R 14C is:
(ai) —O—(CH 2 ) 2 —N + (CH 3 ) 3 ;
(aii) —N + (CH 3 ) 2 R 14ca , wherein R 14ca is —CH 3 or —(CH 2 ) 1-4 —OCH 3 ;
(aiii) a moiety of the formula:

 or
(aiv) a moiety of the formula:

where y 14Cb and y 14Cc are 1 to 4; or

R 1 and R 2 may be bonded together to form a moiety of the formula:

wherein:
G 1 , R G1a and R G1b are defined as follows:
(a) G 1 is a linker moiety of the formula:

wherein n q1 is 1 to 6, m q1 is 0, 1 or 2 and together the value of n q1 and m q1 are selected such that the length of the linker moiety they define does not exceed a total of 8 carbon and/or oxygen atoms comprising the chain including the carbon atom in the chain that forms the carbonyl moiety;
R G1a is selected from: (i) —H; and (ii) alkyl of up to 4 carbon atoms; and
R G1b is selected from:
(i) a moiety of the formula:

 and
(ii) a moiety of the formula:

or
(b) G 1 is a linker moiety of the formula:

wherein n q2 is 0, 1 or 2, m q2 is 1 to 6, and together the value of n q2 and m q2 are selected such that the length of the linker moiety they define does not exceed a total of 8 carbon and/or oxygen atoms comprising the chain including the carbon atom in the chain that forms the carbonyl moiety;
R G1a is selected from:
(i) a moiety of the formula:

 and
(ii) a moiety of the formula:

 and

R G1b is selected from: (i) —H; and (ii) alkyl of up to 4 carbon atoms;

R 8 is —CH 3 or a moiety of the formula:

wherein R 8a is —H, or a linear, branched or cyclic alkyl of up to four carbon atoms;

A is selected from:
(a) a moiety of the formula:

(b) —CH 2 —(CH 2 ) y —CH 2 —, wherein y is 1 to 6;

(c) a moiety of the formula:

wherein A b1 is:
(i) a moiety of the formula:

wherein x is 1 to 6; or
(ii) a moiety of the formula:

wherein y is 1 to 5;
(d) a moiety of the formula: —CH 2 —(CH 2 ) m —O—(CH 2 ) n —, wherein m=1 to 5, and n=0 or 1 to 4;

B is:
(a) a bond;
(b) —(CH 2 ) 1-2 —; or
(c) a moiety of the formula:

D is:
(a) a moiety of the Formula:

wherein E is —CH 2 — or —(CH 2 ) 2-4 —O;

(b) a moiety of the formula:

(c) a moiety of the formula:

wherein n a is 1, 2, or 3, m a is 2, 3, or 4, and n a +m a is ≥3;
(d) a moiety of the formula:

wherein, R 34b is —H or a liner, branched or cyclic alkyl of up to four carbon atoms,
or a pharmaceutically acceptable salt of any thereof.

2. A compound of claim 1 , wherein X is F, or a pharmaceutically acceptable salt of any thereof.

3. A compound of claim 2 wherein D is a moiety of the formula:

wherein, E is —CH 2 — or —(CH 2 ) 2 —O—, or a pharmaceutically acceptable salt thereof.

4. A compound of claim 2 wherein D is a moiety of the formula:

wherein, E is —CH 2 — or —(CH 2 ) 2 —O—, or a pharmaceutically acceptable salt thereof.

5. A compound of claim 2 wherein D is a moiety of the formula:

or a pharmaceutically acceptable salt thereof.

6. A compound of claim 2 wherein D is a moiety of the formula:

Assignees

• Merck Sharp & Dohme Llc

Inventors

• Wood Harold B
• Josien Hubert B
• Tucker Thomas Joseph
• Kerekes Angela Dawn
• Tong Ling
• Walji Abbas M
• Nair Anilkumar G
• Ding Fa-Xiang
• Bianchi Elisabetta
• Branca Danila
• Wu Chengwei
• Xiong Yusheng
• Ha Sookhee Nicole
• Liu Jian
• Boga Sobhana Babu

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K38/00

  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) · CPC title

• C12N9/6454

  Dibasic site splicing serine proteases, e.g. kexin (3.4.21.61); furin (3.4.21.75) and other proprotein convertases · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title