PCSK9 antagonist compounds

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 C1-6 alkyl;
• Ra is independently selected from H, —CR2—S(O)2OR9, or —C(O)OR9;
• Rb is independently selected from H, C1-6 alkyl, or C1-6 alkyl-N+(CH3)2;
• Rd is independently selected from H or —C(O)OR9;
• R1 is selected from:
• (a) —H,
• (b) C1-6 alkyl,
• (c) —(CR2)z—NRb—C(O)R10, and
• (d) —(CR2)z—NR—C(O)—(CR2)z[O(CR2)n]—N+(CH3)3;
• R2 is selected from:
• (a) —H
• (b) C1-6 alkyl,
• (c) —(CR2)z—NRb—C(O)R10, and
• (d) —(CR2)z—NR—C(O) —(CR2)z[O(CR2)n]—N+(CH3)3;
• provided that at least one of R1 and R2 is —(CR2)z—NRb—C(O)R10;
• R4 is
• R5 is independently selected from —(CRa2)x, —(CRa2)xO(CRa2)x—, and C1-8 alkyl;
• R6 is independently selected from —(CRa2)xNRC(O)—, —(CR2)xNRS(O)2—, and —(CRa2)nO(CRa2)qNRC(O)—;
• R9 is independently selected from H or C1-6 alkyl;
• R10 is independently selected from:
• a) —(R5—N+(CH3)2—R6)u—(R20)n—(R6)m—R12,
• b) —(R20)n—(R6)m—R5—N+(CH3)2—R6—R12,
• c) —(R20)n—R5—N+(CH3)2—(R20)s—(R6)q—R12,
• d) —R6—R20—N+(CH3)2—(R20)n—(R6)m—R12,
• e) —R20—N+(CH3)2—(R6)m—(R20)n—(R6)q—R12,
• f) —(R20)n—(R6)m—R12,
• g) —R5—N+(CH3)2—(R20)n—(R6)m—R5—[NRC(O)—R5]q,
• h) —R20—N+(CH3)2—(R6)m—R5,
• i) —R5—N+(CH3)2—(R20)n—(R6)m—R5,
• j) —R5—N+(CH3)2—(R20)n—(R6)m—R12,
• k) —(R20)n—N+(CH3)2—(R20)n—(R6)q—R12,
• l) —R6—R5—N+(CH3)2—(R20)n—(R6)q—R12,
• m) —(R20)n—N+(CH3)2—(R6)q—R12,
• n) —(R20)n—(R6)m—R20—N+(CH3)2—(R20)s—(R6)q—R12,
• o) —R20—N+(CH3)2—(R6)m—R4,
• p) —(R20)n—N+(CH3)2—(R6)q—(R20)n—(R6)m—R12,
• q) —R20—N+(CH3)2—(R6)m—(R20)n—N+(CH3)2—(R20)n—(R6)q—R12,
• r) —R5—N+(CH3)2—(R6)m—R5—N+(CH3)2—(R20)n—(R6)q—R12, and
• s) —CRb2—(R20)n—(R6)m—R12;
• R12 is independently selected from —C11-20 alkyl-Rd, —(CR2)x—O—(CR2)x—Rd, —C11-20 alkyl-C(O)NR—(CRd2)2H, and C2-16 alkenyl;
• R20 is independently selected from
• a) —(CRa2)tO(CRa2)qO—(CRa2)t—,
• b) —(CRa2)tO(CRa2)qO—(CRa2)t—NRC(O)—,
• c) —(CRa2)tO(CRa2)q—NRC(O)—(CRa2)nO(CRa2)nO—,
• d) —(CRa2)t—NRC(O)—(CRa2)qO(CRa2)qO—(CRa2)t—,
• e) —(CRa2)tO(CRa2)qO—(CRa2)t—, and
• f) —(CRa2)t—O—(CRa2)qO(CRa2)qO—(CRa2)t—;
• A is selected from C2-6 alkyl or C2-6 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.