PCSK9 antagonist compounds

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:

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

11. A compound of claim 2 wherein R 1 and R 2 are joined together with a moiety of the formula:

such that together with the cyclopeptide to which R 1 and R 2 are attached they form a cyclic structure,

or a pharmaceutically acceptable salt thereof.

12. A compound of claim 2 having the structure of Formula IIB, or a pharmaceutically acceptable salt thereof:

B 1 is —((CH 2 ) 0-2 )—; and

D 1 is:

(a) a moiety of the formula:

(b) a moiety of the formula:

 or

(c) a moiety of the formula:

13. A compound of claim 2 having the structure of Formula IIC, or a pharmaceutically acceptable salt thereof:

wherein

D 2 is:

(a) a moiety of the formula:

(b) a moiety of the formula:

14. A Compound of claim 2 having the structure of Formula IID, or a pharmaceutically acceptable salt thereof:

wherein

D 2 is:

(a) a moiety of the formula:

(b) a moiety of the formula:

15. A compound of claim 2 having the structure of Formula IIE, or a pharmaceutically acceptable salt thereof:

16. A compound of claim 2 having the structure of Formula IIF, or a pharmaceutically acceptable salt thereof:

17. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein A is:

(a) —(CH 2 ) 6 ;

(b) a moiety of the formula:

wherein x is 1 to 3; or

(c) a moiety of the formula:

18. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is:

—(CH 2 ) z —R 14A , wherein: z is 1-6, and R 14A is:

(a) —H;

(b) —NH 2 ;

(c) —N + H 3 ;

(d) —N + (H 3 C) 3 ;

(e) —NH—C(O)—[(CH 2 ) 2-4 —O—] 2 —(CH 2 ) 2-4 R 14B wherein R 14B is: —NH 2 ; —N + H 3 ; —N(CH 3 ) 2 ; or —N + (CH 3 ) 3 ; or

(f) —NH—C(O)—[(CH 2 ) y R 14C , wherein, y=1 to 6 and R 14C is:

(ai) —O—(CH 2 ) 2-4 —N + (CH 3 ) 3 ;

(aii) —N + (CH 3 ) 3 ; or

(aiii) a moiety of the formula:

19. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:

(a) —H;

(b) —(CH 2 ) z —R 14A , wherein: z is 1-6, and R 14A is:

(i) —H;

(ii) —N + H 3 ; or

(iii) —NH—C(O)—[(CH 2 ) 2 —O—] 2 —(CH 2 ) 2 —N + (CH 3 ) 3 .

20. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 8 is a moiety of the formula:

wherein R 8b is —H, —CH 3 , or —C(CH 3 ) 3 .

21. A compound of claim 1 , which is selected from the group consisting of:

or any other pharmaceutically acceptable salt form thereof.

22. A composition comprising at least one compound of claim 2 , or a pharmaceutically acceptable salt thereof or freebase form thereof, and at least one pharmaceutically acceptable excipient.

23. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 22 .

24. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 2 .

25. A compound of claim 15 , having the structure of Formula IIE, or a pharmaceutically acceptable salt thereof,

wherein

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

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 ;

A is selected from:

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

(b) 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; and

(c) 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.

26. A compound of claim 25 , or a pharmaceutically acceptable salt thereof,

wherein

R 1 is —(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

R 2 is —(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 ;

A is —CH 2 —(CH 2 ) y —CH 2 —, wherein y is 1 to 6.

27. A compound of claim 26 , or a pharmaceutically acceptable salt thereof,

wherein

R 1 is —(CH 2 ) z —R 14A , wherein: z is 1-6, and R 14A is:

(i) —H;

R 2 is —(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 ;

A is —CH 2 —(CH 2 ) y —CH 2 —, wherein y is 1 to 6.

28. A compound of claim 1 , which is selected from the group consisting of:

wherein A − is a pharmaceutically acceptable anion.

29. The compound having the structure:

wherein A − is a pharmaceutically acceptable anion.

30. A composition comprising the compound of claim 29 , and at least one pharmaceutically acceptable excipient.

31. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 30 .

32. A compound of claim 29 , wherein the compound is:

33. A composition comprising the compound of claim 32 , and at least one pharmaceutically acceptable excipient.

34. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 33 .

35. The compound having the structure:

wherein A − is a pharmaceutically acceptable anion.

36. A composition comprising the compound of claim 35 , and at least one pharmaceutically acceptable excipient.

37. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 36 .

38. A compound of claim 35 , wherein the compound is:

39. A composition comprising the compound of claim 38 , and at least one pharmaceutically acceptable excipient.

40. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 39 .

41. The compound having the structure:

wherein A − is a pharmaceutically acceptable anion.

42. A composition comprising the compound of claim 41 , and at least one pharmaceutically acceptable excipient.

43. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 42 .

44. A compound of claim 41 , wherein the compound is:

45. A composition comprising the compound of claim 44 , and at least one pharmaceutically acceptable excipient.

46. A method of treating hypercholesterolemia, comprising administering to a patient in need thereof a therapeutically effective amount of a composition of claim 45 .

47. A compound of claim 13 wherein D 2 is:

(a) a moiety of the formula:

or

(b) a moiety of the formula:

48. A compound of claim 14 wherein D 2 is:

(a) a moiety of the formula:

or

(b) a moiety of the formula: