Anti-proprotein convertase subtilisin kexin type 9 (anti-PCSK9) compounds and methods of using the same in the treatment and/or prevention of cardiovascular diseases
Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), as well as therapeutic methods for use of such compounds to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia.
1. A compound of the formula:
including pharmaceutically acceptable salts and stereoisomers of said compound, wherein:
X a and X b are independently selected from the group consisting of H and CH 3 ;
Y a , Y b and Y c may be the same or different and are selected from the group consisting of H, halogen and (C 1 -C 3 )-alkoxy;
Z a , Z b and Z c are the same or different and are selected from the group of H, (C 1 -C 3 )-alkoxy, (C 1 -C 4 )-alkyl, COOH, CONR 10 R 11 , 2-oxazole, 2-oxazoline and 2-benzoxazole; wherein R 10 and R 11 are independently selected from the group of H, optionally substituted (C 1 -C 3 )-alkyl and optionally substituted aryl; and
n=2;
wherein either:
(i) X a is methyl; one of Y a , Y b and Y c is substituted at the 5-position or the 7-position of the benzofuran ring and is methoxy and the others are H; one of Z a , Z b and Z c is substituted at the 4-position of the benzene ring and is selected from the group of CONR 10 R 11 , methylaminocarbonyl, branched (C 3 -C 4 )-alkyl, methoxy, 2-oxazolyl, 4,5-dihydro-oxazol-2-yl, and 2-benzoxazole substituents, and the others are H, wherein R 10 and R 11 are independently selected from the group of H, optionally substituted (C 1 -C 3 )-alkyl and optionally substituted aryl; or
(ii) X a is methyl; one of Y a , Y b and Y c is substituted at the 5-position or the 7-position of the benzofuran ring and is methoxy and the others are H; one of Z a , Z b and Z c is substituted at the 3-position of the benzene ring and is selected from the group of CONR 10 R 11 , methylaminocarbonyl, branched (C 3 -C 4 )-alkyl, methoxy, 2-oxazolyl, 4,5-dihydro-oxazol-2-yl, and 2-benzoxazole substituents, and the others are H, wherein R 10 and R 11 are independently selected from the group of H, optionally substituted (C 1 -C 3 )-alkyl and optionally substituted aryl.
2. The compound of claim 1 , wherein X a is methyl, one of Y a , Y b and Y c is substituted at the 5-position or the 7-position of the benzofuran ring and is methoxy and the others are H, one of Z a , Z b and Z c is substituted at the 4-position of the benzene ring and is selected from the group of CONR 10 R 11 , methylaminocarbonyl, branched (C 3 -C 4 )-alkyl, methoxy, 2-oxazolyl, 4,5-dihydro-oxazol-2-yl, and 2-benzoxazole substituents, and the others are H, wherein R 10 and R 11 are independently selected from the group of H, optionally substituted (C 1 -C 3 )-alkyl and optionally substituted aryl.
3. The compound of claim 1 , wherein X a is methyl, one of Y a , Y b and Y c is substituted at the 5-position or the 7-position of the benzofuran ring and is methoxy and the others are H, one of Z a , Z b and Z c is substituted at the 3-position of the benzene ring and is selected from the group of CONR 10 R 11 , methylaminocarbonyl, branched (C 3 -C 4 )-alkyl, methoxy, 2-oxazolyl, 4,5-dihydro-oxazol-2-yl, and 2-benzoxazole substituents, and the others are H, wherein R 10 and R 11 are independently selected from the group of H, optionally substituted (C 1 -C 3 )-alkyl and optionally substituted aryl.
4. A compound of the formula:
wherein: R 1 is selected from the group consisting of H and CH 3 ; R 3 is independently selected from the group consisting of H and (C 1 -C 3 )-alkoxy; one of R 6 and R 7 is H and the other is
wherein R 8 is selected from the group consisting of CO 2 H, CONHR 9 , 2-oxazole, 2-oxazoline, 2-benzoxazole; R 9 is H or optionally substituted (C 1 -C 3 )-alkyl; or a pharmaceutically acceptable salt or stereoisomer of the compound.
5. A compound selected from the group consisting of N—(4-{[4-(1,3-benzoxazol-2-yl)phenyl](methyl)carbamoyl}phenyl)-1-benzofuran-2-carboxamide (SBC-115,423); N—(4-{[4-(1,3-benzoxazol-2-yl)phenyl]carbamoyl}phenyl)-5-methoxy-3-methyl-1-benzofuran-2-carboxamide (SBC-115,418); N—{4-[(4-carbamoylphenyl)carbamoyl]phenyl}-1-benzofuran-2-carboxamide (SBC-115,424); N—(4-{[4-(4,5-dihydro-1,3-oxazol-2-yl)phenyl]carbamoyl} phenyl)-1-benzofuran-2-carboxamide (SBC-115,432); N—(4-{[4-(1,3-oxazol-2-yl)phenyl]carbamoyl}phenyl)-1-benzofuran-2-carboxamide (SBC-115,433); 7-methoxy-3-methyl-N—(4-{[4-(1,3-oxazol-2-yl) phenyl]carbamoy}phenyl)-1-benzofuran-2-carboxamide (SBC-115,445); and pharmaceutically acceptable salts or stereoisomers thereof.
6. The compound of claim 5 , which is N—(4-{[4-(1,3-benzoxazol-2-yl)phenyl]carbamoyl}phenyl)-5-methoxy-3-methyl-1-benzofuran-2-carboxamide (SBC-115,418) or a pharmaceutically acceptable salt or stereoisomer thereof.
7. The compound of claim 5 , which is N—(4-{[4-(1,3-benzoxazol-2-yl)phenyl](methyl)carbamoyl}phenyl)-1-benzofuran-2-carboxamide (SBC-115,423) or a pharmaceutically acceptable salt or stereoisomer thereof.