Somatostatin receptor antagonist compounds and methods of using the same

1. A compound having the structure of Formula I:

or a salt thereof, wherein:

R C is OH or NHR 16 , wherein R 16 is H or C 1-6 alkyl optionally substituted with one or more substituents;

R N is selected from the group consisting of:

(i) H;

(ii) C 1-6 alkyl;

(iii) —C(O)R 17 , wherein R 17 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

(iv) —C(O)C 1-6 alkylene-C(O)OR 18 , wherein R 18 is H or C 1-6 alkyl optionally substituted with one or more substituents;

(v) —C(O)C 1-6 alkylene-N(R 20 )C(O)R 19 , wherein R 19 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents, and wherein R 20 is H or C 1-6 alkyl;

(vi) —C(O)C 1-6 alkylene-NR 21 R 22 , wherein each of R 21 and R 22 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

(vii) —C(O)C 1-6 alkylene-C(O)NR 23 R 24 , wherein each of R 23 and R 24 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

(viii) —C(O)C 1-6 alkylene-S(O) 2 R 25 , wherein R 25 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and

(ix) —S(O) 2 R 26 , wherein R 26 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

R 1 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, —C 1-6 alkylene(C 6-10 aryl) and —C 1-6 alkylene(5- to 10-membered heteroaryl), wherein the C 1-6 alkyl, the C 6-10 aryl, the C 6-10 aryl of —C 1-6 alkylene(C 6-10 aryl), the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of —C 1-6 alkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C 1-6 alkylene of —C 1-6 alkylene(C 6-10 aryl) and —C 1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents;

R 3 is selected from the group consisting of:

(i) C 6-10 aryl which is optionally substituted with one or more substituents;

(ii) 5- to 10-membered heteroaryl which is optionally substituted with one or more substituents;

(iii) —C 1-6 alkylene(C 6-10 aryl), wherein the C 6-10 aryl is optionally substituted with one or more substituents, and wherein the C 1-6 alkylene is optionally substituted with one or more substituents;

(iv) —C 1-6 alkylene(5- to 10-membered heteroaryl), wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents, and wherein the C 1-6 alkylene is optionally substituted with one or more substituents;

(v) —C 1-6 alkylene-NR 27 C(O)R 28 , wherein:

R 27 is H or C 1-6 alkyl;

R 28 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and —NR 29 R 30 , wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and

wherein each of R 29 and R 30 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

(vi) —(C 6-10 arylene)-C(O)NR 31 R 32 or —C 1-6 alkylene-(C 6-10 arylene)-C(O)NR 31 R 32 , wherein each of R 31 and R 32 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

(vii) —(C 6-10 arylene)-NR 33 R 34 or —C 1-6 alkylene-(C 6-10 arylene)-NR 33 R 34 , wherein:

each of R 33 and R 34 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, —C(O)R 35 , —C(O)NR 36 R 37 , and —SO 2 R 38 , wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

R 35 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents;

each of R 36 and R 37 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and

R 38 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

(viii) —(C 6-10 arylene)-SO 2 NR 39 R 40 or —C 1-6 alkylene-(C 6-10 arylene)-SO 2 NR 39 R 40 , wherein each of R 39 and R 40 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

(ix) —(C 6-10 arylene)-(C 1-6 alkylene)-NR 41 R 42 or —C 1-6 alkylene-(C 6-10 arylene)-(C 1-6 alkylene)-NR 41 R 42 , wherein:

each of R 41 and R 42 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, —C(O)R 43 , and —C(O)NR 44 R 45 , wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

R 43 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and

each of R 44 and R 45 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents;

(x) —(C 6-10 arylene)-OR 46 or —C 1-6 alkylene-(C 6-10 arylene)-OR 46 , wherein R 46 is selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents; and

(xi) —C 1-6 alkylene-(C 6-10 arylene)-N(R 47 )—C(O)—CHR 48 —NR 49 R 50 , wherein R 47 is H or CH 3 , R 48 is H or C 1-6 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, —COOH, —NH 2 , —C(O)NH 2 , and —N(H)C(O)NH 2 , and each of R 49 and R 50 is independently H, CH 3 or acetyl;

R 4 is

wherein each of R 101 and R 102 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl and R 118 is selected from the group consisting of H, halogen, hydroxy, —NO 2 , and C 1-6 alkoxy;

R 5 is selected from the group consisting of:

(i) —NR 79 R 80 , wherein each of R 79 and R 80 is independently selected from the group consisting of H, C 1-6 alkyl, —C(O)R 81 , and —C(═NR 82 )NR 83 R 84 , or R 79 and R 80 , together with the N atom to which they are attached, form 5- to 10-membered heteroaryl or 5- to 10-membered heterocycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents, and wherein the 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents,

R 81 is selected from the group consisting of H, —NH 2 , C 1-16 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

each of R 82 , R 83 , and R 84 is independently selected from the group consisting of H, C 1-16 alkyl, C 1-6 haloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

(ii) —N + R 85 R 86 R 87 , wherein each of R 85 , R 86 , and R 87 is independently C 1-6 alkyl;

n 1 is 1, 2, 3, 4, 5, or 6;

R 6 is C 1-6 alkyl optionally substituted with one or more substituents;

R 8 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, —C 1-6 alkylene(C 6-11 ) aryl) and —C 1-6 alkylene(5- to 10-membered heteroaryl), wherein the C 1-6 alkyl, the C 6-10 aryl, the C 6-10 aryl of —C 1-6 alkylene(C 6-10 aryl), the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of —C 1-6 alkylene(5- to 10-membered heteroaryl) are optionally substituted with one or more substituents, and wherein the C 1-6 alkylene of —C 1-6 alkylene(C 6-10 aryl) and —C 1-6 alkylene(5- to 10-membered heteroaryl) is optionally substituted with one or more substituents;

R 9 is H or C 1-6 alkyl;

R 10 is H or C 1-6 alkyl;

R 11 is H or C 1-6 alkyl;

R 12 is H or C 1-6 alkyl;

R 13 is H or C 1-6 alkyl;

R 14 is H or C 1-6 alkyl;

R 15 is H or C 1-6 alkyl; and

L is selected from the group consisting of:

 wherein X is S or O; and

chiral centre *1 is in the S configuration or the R configuration;

chiral centre *2 is in the S configuration or the R configuration;

chiral centre *3 is in the S configuration or the R configuration;

chiral centre *4 is in the S configuration or the R configuration;

chiral centre *5 is in the S configuration or the R configuration;

chiral centre *6 is in the S configuration or the R configuration;

chiral centre *7 is in the S configuration or the R configuration; and

chiral centre *8 is in the S configuration or the R configuration, provided that:

i) when R C is NH 2 , R N is H or —C(O)CH 2 N 3 , R 1 is

 R 3 is

 R 5 is NH 2 , n 1 is 4, R 6 is —CH(OH)(CH 3 ), R 8 is

 each of R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is H, an L is

 then R 4 is not

 and

ii) when R C is NH 2 , R N is H, R 1 is

 R 3 is

 R 5 is NH 2 , n 1 is 4, R 6 is —CH(CH 3 ) 2 , R 8 is —CH(OH)(CH 3 ), each of R 9 , R 10 , R 11 , R 12 , R 13 , R 14 and R 15 is H, and L is

 then R 4 is not

2. The compound or salt of claim 1 , wherein R 4 is

3. The compound or salt of claim 2 , wherein R 4 is

4. The compound or salt of claim 1 , wherein R 5 is —NR 79 R 80 and each of R 79 and R 80 is independently selected from the group consisting of H, C 1-6 alkyl, —C(O)R 81 , and —C(═NR 82 )NR 83 R 84 , wherein R 81 is C 1-6 alkyl and each of R 82 , R 83 , and R 84 is H.

5. The compound or salt of claim 4 , wherein R 5 is —NR 79 R 80 and each of R 79 and R 80 is independently selected from the group consisting of H and C 1-6 alkyl.

6. The compound or salt of claim 5 , wherein R 5 is —NH 2 , —NHCH 3 or —N(CH 3 ) 2 .

7. The compound or salt of claim 6 , wherein R 5 is —NH 2 .

8. The compound or salt of claim 6 , wherein R 5 is —NHCH 3 .

9. The compound or salt of claim 6 , wherein R 5 is —N(CH 3 ) 2 .

10. The compound or salt of claim 1 , wherein n 1 is 3 or 4.

11. The compound or salt of claim 10 , wherein n 1 is 4.

12. The compound or salt of claim 1 , wherein R C is OH or NH 2 .

13. The compound or salt of claim 12 , wherein R C is NH 2 .

14. The compound or salt of claim 1 , wherein R N is selected from the group consisting of:

(i) H;

(ii) C 1-6 alkyl;

(iii) —C(O)R 17 , wherein R 17 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

(iv) —C(O)C 1-6 alkylene-C(O)OR 18 , wherein R 18 is H or C 1-6 alkyl;

(v) —C(O)C 1-6 alkylene-N(R 20 )C(O)R 19 , wherein R 19 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R 20 is H or C 1-6 alkyl;

(vi) —C(O)C 1-6 alkylene-NR 21 R 22 , wherein each of R 21 and R 22 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

(vii) —C(O)C 1-6 alkylene-C(O)NR 23 R 24 , wherein each of R 23 and R 24 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

(viii) —C(O)C 1-6 alkylene-S(O) 2 R 25 , wherein R 25 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

(ix) —S(O) 2 R 26 , wherein R 26 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.

15. The compound or salt of claim 14 , wherein R N is selected from the group consisting of:

(i) H;

(ii) C 1-6 alkyl;

(iii) —C(O)R 17 , wherein R′ 7 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

(iv) —C(O)C 1-3 alkylene-C(O)OR 18 , wherein R 18 is H or C 1-6 alkyl;

(v) —C(O)C 1-3 alkylene-N(R 20 )C(O)R 19 , wherein R 19 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, and wherein R 20 is H or C 1-6 alkyl;

(vi) —C(O)C 1-3 alkylene-NR 21 R 22 , wherein each of R 21 and R 22 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl;

(vii) —C(O)C 1-3 alkylene-C(O)NR 23 R 24 , wherein each of R 23 and R 24 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; and

(viii) —C(O)C 1-3 alkylene-S(O) 2 R 25 , wherein R 25 is selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl.

16. The compound or salt of claim 14 , wherein R N is selected from the group consisting of H, C 1-6 alkyl, —C(O)R 17 , —C(O)C 1-6 alkylene-C(O)OR 18 , —C(O)C 1-6 alkylene-N(R 20 )C(O)R 19 , C(O)C 1-6 alkylene-NR 21 R 22 , C(O)C 1-6 alkylene-C(O)NR 23 R 24 , and —C(O)C 1-6 alkylene-S(O) 2 R 25 , wherein R 17 is C 1-6 alkyl or 5- to 6-membered heteroaryl, R 18 is C 1-6 alkyl, R 19 is C 1-6 alkyl or C 6 aryl, each of R 20 , R 21 , R 22 , R 23 and R 24 is H, and R 25 is C 6 aryl.

17. The compound or salt of claim 16 , wherein R N is selected from the group consisting of H, C 1-3 alkyl, —C(O)R 17 , —C(O)C 1-3 alkylene-C(O)OR 18 , —C(O)C 1-3 alkylene-N(R 20 )C(O)R 19 , —C(O)C 1-3 alkylene-NR 21 R 22 , —C(O)C 1-3 alkylene-C(O)NR 23 R 24 , and —C(O)C 1-3 alkylene-S(O) 2 R 25 , wherein R 17 is C 1-6 alkyl or 5- to 6-membered heteroaryl, R 18 is C 1-3 alkyl, R 19 is C 1-3 alkyl or C 6 aryl, each of R 20 , R 21 , R 22 , R 23 and R 24 is H, and R 25 is C 6 aryl.

18. The compound or salt of claim 17 , wherein R N is H.

19. The compound or salt of claim 1 , wherein R 1 is —C 1-3 alkylene(C 6-10 aryl), wherein the C 6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, —NO 2 , and C 1-6 alkoxy.

20. The compound or salt of claim 19 , wherein R 1 is —C 1-2 alkylene(C 6 aryl), wherein the C 6 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, —NO 2 , and C 1-6 alkoxy.

21. The compound or salt of claim 20 , wherein R 1 is

wherein R 88 is H, halogen, hydroxyl or C 1-3 alkoxy.

22. The compound or salt of claim 21 , wherein R 88 is Cl.

23. The compound or salt of claim 1 , wherein R 3 is —C 1-3 alkylene(C 6-10 aryl), wherein the C 6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, —NO 2 , and C 1-6 alkoxy.

24. The compound or salt of claim 23 , wherein R 3 is —C 1-2 alkylene(C 6 aryl), wherein the C 6 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, —NO 2 , and C 1-6 alkoxy.

25. The compound or salt of claim 24 , wherein R 3 is

wherein R 89 is H, halogen, hydroxyl or C 1-3 alkoxy.

26. The compound or salt of claim 25 , wherein R 89 is Cl or hydroxyl.

27. The compound or salt of claim 26 , wherein R 89 is hydroxyl.

28. The compound or salt of claim 1 , wherein R 6 is C 1-6 alkyl optionally substituted with hydroxyl.

29. The compound or salt of claim 28 , wherein R 6 is selected from the group consisting of —CH(CH 3 )OH, —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OH and —CH 2 CH 3 .

30. The compound or salt of claim 29 , wherein R 6 is —CH(CH 3 )OH.

31. The compound or salt of claim 1 , wherein R 8 is —C 1-3 alkylene(C 6-10 aryl), wherein the C 6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxy, —NO 2 , and C 1-6 alkoxy.

32. The compound or salt of claim 31 , wherein R 8 is —C 1-2 alkylene(C 6 aryl), wherein the C 6 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, —NO 2 , and C 1-6 alkoxy.

33. The compound or salt of claim 32 , wherein R 8 is

wherein R 151 is H, halogen, hydroxyl or C 1-3 alkoxy.

34. The compound or salt of claim 33 , wherein R 151 is Cl or hydroxyl.

35. The compound or salt of claim 34 , wherein R 151 is hydroxyl.

36. The compound or salt of claim 1 , wherein each of R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 is independently H or C 1-3 alkyl.

37. The compound or salt of claim 36 , wherein each of R 9 , R 10 , R 11 , R 13 , R 14 , and R 15 is H.

38. The compound or salt of claim 36 , wherein R 12 is H or CH 3 .

39. The compound or salt of claim 38 , wherein R 12 is H.

40. The compound or salt of claim 1 , wherein L is

41. The compound or salt of claim 1 , wherein chiral centre *1 is in the S configuration, chiral centre *2 is in the S configuration, chiral centre *3 is in the S configuration, chiral centre *4 is in the R configuration, chiral centre *5 is in the S configuration, chiral centre *6 is in the S configuration, chiral centre *7 is in the R configuration, and chiral centre *8 is in the R configuration.

42. A compound selected from:

Compound

No.

Structure

 1

H-Cpa-cyclo[D-Cys-Tyr-D-Cit-Lys-Thr-Cys]-D-Tyr-NH 2

 2

H-Cpa-cyclo[D-Cys-Tyr-D-HoCit-Lys-Thr-Cys]-D-Tyr-NH 2

 3

H-Cpa-cyclo[D-Cys-Tyr-D-Lys(N ε -nicotinoyl)-Lys-Thr-Cys]-D-Tyr-NH 2

 4

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH 2

 5

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-aminomethyl)-Lys-Thr-Cys]-D-Tyr-NH 2

 6

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-ureidomethyl)-Lys-Thr-Cys]-D-Tyr-NH 2

 7

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-acetamidomethyl)-Lys-Thr-Cys]-D-Tyr-NH 2

 8

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Gly)-Lys-Thr-Cys]-D-Tyr-NH 2

 9

H-Cpa-cyclo[D-Cys-Tyr-D-4-(Gly-Ac)Aph-Lys-Thr-Cys]-D-Tyr-NH 2

10

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Pro)-Lys-Thr-Cys]-D-Tyr-NH 2

11

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(2-(4-morpholinyl)ethyl)-Lys-Thr-Cys]-D-Tyr-NH 2

12

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-n-pentylamino)-Lys-Thr-Cys]-D-Tyr-NH 2

13

H-Cpa-cyclo[D-Cys-Tyr-D-Tyr(2-(4-morpholinyl)ethyl)-Lys-Thr-Cys]-D-Tyr-NH 2

14

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(benzenesulfonyl)-Lys-Thr-Cys]-D-Tyr-NH 2

15

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-phenylureido)-Lys-Thr-Cys]-D-Tyr-NH 2

16

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Ser)-Lys-Thr-Cys]-D-Tyr-NH 2

17

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Lys)-Lys-Thr-Cys]-D-Tyr-NH 2

18

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Asp)-Lys-Thr-Cys]-D-Tyr-NH 2

19

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Asn)-Lys-Thr-Cys]-D-Tyr-NH 2

20

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Glu)-Lys-Thr-Cys]-D-Tyr-NH 2

21

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Gln)-Lys-Thr-Cys]-D-Tyr-NH 2

22

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Cit-Lys-Thr-Cys]-D-Tyr-NH 2

23

H-Cpa-cyclo[D-Cys-Tyr-D-Aph(Val)-Lys-Thr-Cys]-D-Tyr-NH 2

24

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

25

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-phenylureido)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

26

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Ac)-Thr-Cys]-D-Tyr-NH 2

27

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-benzamidophenyl)-Lys-Thr-Cys]-D-Tyr-NH 2

28

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-(4-methoxyphenyl)ureido)-Lys-Thr-Cys]-D-Tyr-NH 2

29

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Arg-Thr-Cys]-D-Tyr-NH 2

30

H-Cpa-cyclo[D-Cys-Tyr-D-Lys(N ε -nicotinoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

31

H-Cpa-cyclo[D-Cys-Tyr-D-Cit-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

32

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -diMe)-Thr-Cys]-D-Tyr-NH 2

33

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Val-Cys]-P-Tyr-NH 2

34

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Tle-Cys]-D-Tyr-NH 2

35

H-Cpa-cyclo[D-Cys-Phe-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH 2

36

H-Cpa-cyclo[D-Cys-Cpa-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH 2

37

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Ser-Cys]-D-Tyr-NH 2

38

H-Cpa-cyclo[D-Cys-Tyr(Me)-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH 2

39

H-Cpa-cyclo[Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH 2

40

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Phe-NH 2

41

H-Cpa-cyclo[D-Cys-Phe-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Phe-NH 2

42

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Cpa-NH 2

43

H-Cpa-cyclo[D-Cys-Cpa-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Cpa-NH 2

44

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr(Me)-NH 2

45

H-Cpa-cyclo[D-Cys-Tyr(Me)-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr(Me)-NH 2

46

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Cpa-NH 2

47

H-Cpa-cyclo[D-Cys-Cpa-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Cpa-NH 2

48

H-Cpa-cyclo[D-Cys-Cpa-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

49

H-β-Ala-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

50

Ph(CO)NHCH 2 (CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

51

PhSO 2 CH 2 (CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

52

t-BuCH 2 (CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

53

2-Pyridyl(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

54

H 2 N(CO)(CH 2 ) 2 (CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

55

Ac-Gly-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]D-Tyr-NH 2

56

CH 3 (CH 2 ) 4 (CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

57

(Furan-2-carboxy)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

58

CH 3 O 2 C(CH 2 ) 2 (CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

59

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-CN)-Lys-Thr-Cys]-D-Tyr-NH 2

60

61

62

63

64

65

66

67

68

69

70

71

72

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-(N α -Me)Lys-Thr-Cys]-D-Tyr-NH 2

73

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-(N-Me)Thr-Cys]-D-Tyr-NH 2

74

H-Cpa-cyclo[D-Cys-(N-Me)Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH 2

75

H-Cpa-cyclo[D-Cys-(N-Me)Tyr-D-Phe(4-carbamoyl)-Lys-(N-Me)Thr-Cys]D-Tyr-NH 2

76

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-(N-Me)Cys]-D-Tyr-NH 2

77

H-(N-Me)Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH 2

78

H-Cpa-cyclo[D-(N-Me)Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH 2

79

H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-(N-Me)Tyr-NH 2

80

H-(N-Me)Cpa-cyclo[D-Cys-(N-Me)Tyr-D-Phe(4-carbamoyl)-Lys-(N-Me)Thr-Cys]-D-(N-Me)Tyr-NH 2

81

CH 3 SO 2 -Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

82

PhSO 2 -Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N ε -Me)-Thr-Cys]-D-Tyr-NH 2

43. A pharmaceutical composition comprising a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

44. A method of inhibiting an activity of an SSTR2 receptor in a subject, the method comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

45. A method of preventing or treating hypoglycemia in a subject, the method comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

46. The method of 45 , wherein the hypoglycemia is insulin-induced hypoglycemia.

47. A method of treating diabetes in a subject, the method comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

48. A compound having the structure:

or a salt thereof.