IP Library Granted Patent US 9,644,000
Granted Patent B2
US 9,644,000 · App. 14/400,282 · Granted May 9, 2017

V1a receptor agonists

Inventors: Kazimierz Wisniewski (San Diego, CA); Geoffrey S. Harris (Cardiff, CA); Robert Felix Galyean (Cottonwood, CA)
Assignee: Ferring B.V.
C07K7/06C07K7/16A61K38/00
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Quick Facts
Patent No.
US 9,644,000
App. No.
14/400,282
Granted
May 9, 2017
Kind
B2
Abstract

Compounds of formula (I), salts thereof, and compositions and uses thereof are described. The compounds are useful as V1a vasopressin agonists, for the treatment of, e.g., complications of cirrhosis, including bacterial peritonitis, HRS2 and refractory ascites.

Claims (165)

1. A compound according to formula (I):

or a salt thereof, wherein:

R 1 is selected from (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylNH, Ar 1 -L 1 - and unsubstituted or substituted cycloalkyl;

Ar 1 -L 1 - is selected from Ar 1 —, Ar 1 —CH 2 —, Ar 1 —CH 2 CH 2 —, Ar 1 —O—, Ar 1 —CH 2 O—, Ar 1 —NH— and Ar 1 —CH 2 NH—;

Ar 1 is unsubstituted aryl or substituted aryl;

R 2 is selected from hydrogen, (C 1 -C 6 )alkyl, hydroxy, (C 1 -C 6 )alkoxy and halogen;

R 3 is selected from (C 1 -C 6 )alkyl, unsubstituted or substituted cycloalkyl and Cy 3 -CH 2 —;

Cy 3 - is unsubstituted or substituted aryl or unsubstituted or substituted cycloalkyl;

R 4 is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, —((C 1 -C 6 )alkylene)-OR 4a , —((C 1 -C 6 )alkylene)-NR 4a 2 , —((C 1 -C 6 )alkylene)-S(C 1 -C 6 )alkyl, —((C 1 -C 6 )alkylene)-C(═O)OR 4a 2 , —((C 1 -C 6 )alkylene)-C(═O)NR 4a 2 , —((C 1 -C 6 )alkylene)-C(═NR 4a )NR 4a 2 , —((C 1 -C 6 )alkylene)-OC(═O)R 4a , —((C 1 -C 6 )alkylene)-OC(═O)OR 4a , —((C 1 -C 6 )alkylene)-OC(═O)NR 4a 2 , —((C 1 -C 6 )alkylene)-NR 4a C(═O)R 4a , —((C 1 -C 6 )alkylene)-NR 4a C(═O)OR 4a , —((C 1 -C 6 )alkylene)-NR 4a C(═O)NR 4a 2 , —((C 1 -C 6 )alkylene)-NR 4a C(═NR 4a )NR 4a 2 , Ar 4 and —((C 1 -C 6 )alkylene)-Ar 4 ;

each R 4a is independently selected from hydrogen and (C 1 -C 6 )alkyl;

Ar 4 is selected from unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl;

R 5 is selected from —((C 1 -C 6 )alkylene)-NR 5a 2 and —((C 1 -C 6 )alkylene)-NR 5a C(═NR 5a )NR 5a 2 ;

each R 5a is independently selected from hydrogen and (C 1 -C 6 )alkyl;

Q is selected from the groups Q 1 , Q 2 , Q 3 and Q 4 :

a and b denote the bonds attaching Q to the remainder of the molecule;

R 6 is selected from hydrogen, (C 1 -C 6 )alkyl and —C(═NR 6a )NR 6a 2 ;

each R 6a is hydrogen or (C 1 -C 6 )alkyl;

R 7 is selected from (C 1 -C 6 )alkyl, unsubstituted aryl, substituted aryl, unsubstituted cycloalkyl and substituted cycloalkyl;

R 8 is selected from NH 2 and hydroxyl;

R 9 is selected from hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )haloalkyl, —((C 1 -C 6 )alkylene)-OR 9a , —((C 1 -C 6 )alkylene)-NR 9a 2 , —((C 1 -C 6 )alkylene)-SR 9a , —((C 1 -C 6 )alkylene)-C(═O)OR 9a 2 , —((C 1 -C 6 )alkylene)-C(═O)NR 9a 2 , —((C 1 -C 6 )alkylene)-C(═NR 9a )NR 9a 2 , —((C 1 -C 6 )alkylene)-OC(═O)R 9a , —((C 1 -C 6 )alkylene)-OC(═O)OR 9a , —((C 1 -C 6 )alkylene)-OC(═O)NR 9a 2 , —((C 1 -C 6 )alkylene)-NR 9a C(═O)R 9b , —((C 1 -C 6 )alkylene)-NR 9a C(═O)OR 9a , —((C 1 -C 6 )alkylene)-NR 9a C(═O)NR 9a 2 , —((C 1 -C 6 )alkylene)-NR 9a C(═NR 9a )NR 9a 2 , Ar 9 and —((C 1 -C 6 )alkylene)-Ar 9 ;

each R 9a is independently selected from hydrogen and (C 1 -C 6 )alkyl;

each R 9b is independently selected from hydrogen and (C 1 -C 10 )alkyl;

Ar 9 is selected from unsubstituted aryl, substituted aryl, unsubstituted heteroaryl, and substituted heteroaryl;

R 10 is selected from —((C 1 -C 6 )alkylene)-OR 10a , —((C 1 -C 6 )alkylene)-C(═O)NR 10a 2 and Ar 10 —CH 2 —;

Ar 10 is unsubstituted heteroaryl or substituted heteroaryl;

each R 10a is selected from hydrogen and (C 1 -C 6 )alkyl;

Ar is selected from aryl and substituted aryl;

each X is NH and each Y is C═O; or

each X is C═O and each Y is NH;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1, 2, 3 or 4;

o is 1 or 2;

p is 1, 2 or 3; and

r is 0, 1, 2, 3, 4, 5 or 6; provided that R 9 is hydrogen if r is greater than one.

2. The compound or salt thereof according to claim 1 , wherein:

R 1 is selected from (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylNH, Ar 1 -L 1 - and Cy 1 ;

Cy 1 is unsubstituted cycloalkyl or cycloalkyl substituted by 1, 2 or 3 substituents independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —OR 1a and oxo;

Ar 1 is unsubstituted aryl or aryl substituted by 1, 2 or 3 substituents independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —CN, —NO 2 , —OR 1a , —NR 1a 2 and —NR 1a C(═O)R 1a ;

each R 1a is independently selected from hydrogen and (C 1 -C 6 )alkyl;

Cy 3 is Ar 3 or unsubstituted cycloalkyl or cycloalkyl substituted by 1, 2 or 3 substituents independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —OR 3a and oxo;

Ar 3 — is unsubstituted aryl or aryl substituted by 1, 2 or 3 substituents independently selected from C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —CN, —NO 2 , —OR 3a , —NR 3a 2 and —NR 3a C(═O)R 3a ;

each R 3a is independently selected from hydrogen and (C 1 -C 6 )alkyl;

Ar 4 is selected from unsubstituted aryl, unsubstituted heteroaryl and aryl and heteroaryl substituted by 1, 2 or 3 substituents independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —CN, —NO 2 , —OR 4b , —NR 4b 2 and —NR 4b C(═O)R 4b ;

each R 4b is selected from hydrogen and (C 1 -C 6 )alkyl;

R 7 is selected from (C 1 -C 6 )alkyl, Ar 7 and Cy 7 ;

Cy 7 is unsubstituted cycloalkyl or cycloalkyl substituted by 1, 2 or 3 substituents independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —OR 7a and oxo;

Ar 7 is unsubstituted aryl or aryl substituted by 1, 2 or 3 substituents independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —CN, —NO 2 , —OR 7a , —NR 7a 2 and —NR 7a C(═O)R 7a ;

each R 7a is independently selected from hydrogen and (C 1 -C 6 )alkyl;

Ar 9 is selected from unsubstituted aryl, unsubstituted heteroaryl and aryl and heteroaryl substituted by 1, 2 or 3 substituents selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —CN, —NO 2 , —OR 9c , —NR 9c 2 and —NR 9c C(═O)R 9c ;

each R 9c is selected from hydrogen and (C 1 -C 6 )alkyl;

Ar 10 is selected from unsubstituted heteroaryl and heteroaryl substituted by 1, 2 or 3 substituents selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —CN, —NO 2 , —OR 10b , —NR 10b 2 and —NR 10b C(═O)R 10b ;

each R 10b is independently selected from hydrogen and (C 1 -C 6 )alkyl;

Ar is selected from unsubstituted aryl and aryl substituted by 1, 2 or 3 substituents selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, halogen, (C 1 -C 6 )haloalkyl, —CN, —NO 2 , —OR Ar , —NR Ar 2 and —NR Ar C(═O)R Ar ; and

each R Ar is independently selected from hydrogen and (C 1 -C 6 )alkyl.

3. The compound or salt thereof according to claim 1 , wherein R 1 is (C 1 -C 10 )alkyl, (C 5 -C 7 )cycloalkyl or Ar 1 —CH 2 —.

4. The compound or salt thereof according to claim 3 , wherein R 1 is isobutyl, n-hexyl, cyclohexyl or benzyl.

5. The compound or salt thereof according to claim 1 , wherein R 2 is selected from hydroxy, (C 1 -C 6 )alkoxy and halogen.

6. The compound or salt thereof according to claim 5 , wherein R 2 is (C 1 -C 6 )alkoxy.

7. The compound or salt thereof according to claim 5 , wherein R 2 is methoxy.

8. The compound or salt thereof according to claim 1 , wherein R 3 is selected from (C 1 -C 6 )alkyl and Ar 3 —CH 2 —, wherein Ar 3 — is unsubstituted or halo-substituted aryl.

9. The compound or salt thereof according to claim 1 , wherein R 3 is selected from (C 1 -C 6 )alkyl and Ar 3 —CH 2 —, wherein Ar 3 is phenyl or halo-substituted phenyl.

10. The compound or salt thereof according to claim 9 , wherein R 3 is selected from s-butyl, neopentyl, benzyl and 4-chlorobenzyl.

11. The compound or salt thereof according to claim 1 , wherein R 4 is selected from (C 1 -C 6 )alkyl, —((C 1 -C 6 )alkylene)-OR 4a , —((C 1 -C 6 )alkylene)-NR 4a 2 , —((C 1 -C 6 )alkylene)-C(═O)NR 4a 2 , —((C 1 -C 6 )alkylene)-NR 4a C(═O)NR 4a 2 , —((C 1 -C 6 )alkylene)-NR 4a C(═NR 4a )NR 4a 2 and —((C 1 -C 6 )alkylene)-Ar 4 .

12. The compound or salt thereof according to claim 11 , wherein R 4 is selected from (C 1 -C 6 )alkyl, —(CH 2 ) 1-6 —OR 4a , —(CH 2 ) 1-6 —NR 4a 2 , —(CH 2 ) 1-6 —C(═O)NR 4a 2 , —(CH 2 ) 1-6 —NR 4a C(═O)NR 4a 2 , —(CH 2 ) 1-6 —NR 4a C(═NR 4a )NR 4a 2 and —(CH 2 ) 1-6 —Ar 4 .

13. The compound or salt thereof according to claim 12 , wherein each R 4a is hydrogen or methyl and Ar 4 is imidazolyl or indolyl.

14. The compound or salt thereof according to claim 11 , wherein R 4 is selected from Me, isobutyl, —CH 2 OH, —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 , —(CH 2 ) 4 —NH 2 , —(CH 2 ) 2 —C(═O)NH 2 , —(CH 2 ) 3 —NHC(═NH)NH 2 , —(CH 2 ) 3 —NHC(═O)NH 2 and —CH 2 (1H-imidazol-4-yl).

15. The compound or salt thereof according to claim 1 , wherein R 5 is selected from —(CH 2 ) 1-6 —NR 5a 2 and —(CH 2 ) 1-6 —NR 5a C(═NR 5a )NR 5a 2 .

16. The compound or salt thereof according to claim 15 , wherein each R 5a is independently selected from hydrogen and methyl.

17. The compound or salt thereof according to claim 15 , wherein R 5 is —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 , —(CH 2 ) 4 —NH 2 or —(CH 2 ) 3 —NHC(═NH)NH 2 .

18. The compound or salt thereof according to claim 1 , wherein R 7 is (C 1 -C 6 )alkyl or (C 4 -C 7 )cycloalkyl.

19. The compound or salt thereof according to claim 18 , wherein R 7 is s-butyl.

20. The compound or salt thereof according to claim 1 , wherein R 8 is —NH 2 .

21. The compound or salt thereof according to claim 1 , wherein R 8 is —OH.

22. The compound or salt thereof according to claim 1 , wherein R 10 is selected from —(CH 2 ) 1-6 —C(═O)NR 10a 2 and Ar 10 —CH 2 —.

23. The compound or salt thereof according to claim 1 , wherein each R 10a is hydrogen or methyl and Ar 10 is pyridyl.

24. The compound or salt thereof according to claim 1 , wherein R 10 is selected from 1-hydroxyethyl, —(CH 2 ) 2 —C(═O)NH 2 and 3-pyridyl-CH 2 —.

25. The compound or salt thereof according to claim 1 , wherein Ar is phenyl or substituted phenyl.

26. The compound or salt thereof according to claim 25 , wherein Ar is phenyl.

27. The compound or salt thereof according to claim 1 , wherein each X is NH and each Y is C═O.

28. The compound or salt thereof according to claim 1 , wherein each X is C═O and each Y is NH.

29. The compound or salt thereof according to claim 1 , wherein m is 0, 1, 2, 3 or 4.

30. The compound or salt thereof according to claim 1 , wherein o is 1 or 2.

31. The compound or salt thereof according to claim 1 , wherein p is 1, 2 or 3.

32. The compound or salt thereof according to claim 1 , wherein Q is Q 1 .

33. The compound or salt thereof according to claim 32 , wherein n is 1, 2 or 3.

34. The compound or salt thereof according to claim 32 , wherein Q 1 is a —NH(CH 2 ) 4 CH(NH 2 )—C(═O)— b , a —NH(CH 2 ) 4 CH(NHC(═NH)NH 2 )—C(═O)— b or a —C(═O)(CH 2 ) 2 CH(NH 2 )—C(═O)— b .

35. The compound or salt thereof according to claim 32 , wherein Q 1 is a —NH(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b , a —NH(CH 2 ) 4 C (S) H(NHC(═NH)NH 2 )—C(═O)— b or a —C(═O)(CH 2 ) 2 C (S) H(NH 2 )—C(═O)— b or a —C(═O)(CH 2 ) 2 C (R) H(NH 2 )—C(═O)— b .

36. The compound or salt thereof according to claim 1 , wherein Q is Q 3 .

37. The compound or salt thereof according to claim 36 , wherein n is 3.

38. The compound or salt thereof according to claim 36 , wherein r is 0 or 3.

39. The compound or salt thereof according to claim 36 , wherein R 9 is selected from —(CH 2 ) 1-6 —NR 9a 2 and —(CH 2 ) 1-6 —NR 9a C(═O)R 9b , each R 9a is hydrogen and each R 9b is hydrogen or (C 1 -C 6 )alkyl.

40. The compound or salt thereof according to claim 1 , wherein Q is Q 1 or Q 3 and R 6 is hydrogen or —C(═NH)NH 2 .

41. The compound or salt thereof according to claim 36 , wherein Q 3 is a —NH(CH 2 ) 4 —C(═O)—NH—(CH 2 ) 4 CH(NH 2 )—C(═O)— b , a —NHCH((CH 2 ) 4 NH 2 )—C(═O)—NH—(CH 2 ) 4 CH(NH 2 )—C(═O)— b , a —NHCH((CH 2 ) 4 NHAc)—C(═O)—NH—(CH 2 ) 4 CH(NH 2 )—C(═O)— b or a —NHCH((CH 2 ) 4 NHHeptanoyl)-C(═)—NH—(CH 2 ) 4 CH(NH 2 )—C(═O)— b .

42. The compound or salt thereof according to claim 36 , wherein Q 3 is a —NH(CH 2 ) 4 —C(═O)—NH—(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b , a —NHC (S) H((CH 2 ) 4 NH 2 )—C(═O)—NH—(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b , a —NHC (S) H((CH 2 ) 4 NHAc)—C(═O)—NH—(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b , a —NHC (S) H((CH 2 ) 4 NHAc)—C(═O)—NH—(CH 2 ) 4 C (R) H(NH 2 )—C(═O)— b or a —NHC (S) H((CH 2 ) 4 NHHeptanoyl)-C(═O)—NH—(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b .

43. The compound or salt thereof according to claim 1 , wherein Q is Q 2 .

44. The compound or salt thereof according to claim 43 , wherein n is 0, 1, 2 or 3.

45. The compound or salt thereof according to claim 44 , wherein Q 2 is a —NH(CH 2 ) 4 — b , a —NH(CH 2 ) 5 — b , a —NH(CH 2 ) 6 — b , a —C(═O)—(CH 2 ) 3 — b or a —C(═O)—(CH 2 ) 5 — b .

46. The compound or salt thereof according to claim 1 , wherein Q is Q 4 .

47. The compound or salt thereof according to claim 46 , wherein n is 1, 2 or 3.

48. The compound or salt thereof according to claim 46 , wherein r is 1, 2 or 3.

49. The compound or salt thereof according to claim 46 , wherein Q 4 is a —NH—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 5 — b , a —NH—(CH 2 ) 4 —C(═O)—NH—(CH 2 ) 6 — b , a —C(═O)—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 6 — b or a —C(═O)—(CH 2 ) 3 —C(═O)—NH—(CH 2 ) 4 — b .

50. The compound or salt thereof according to claim 1 , wherein:

R 1 is (C 1 -C 10 )alkyl, (C 5 -C 7 )cycloalkyl or Ar 1 —CH 2 —;

R 2 is (C 1 -C 6 )alkoxy;

R 3 is selected from (C 1 -C 6 )alkyl and Ar 3 —CH 2 —, wherein Ar 3 is phenyl or halo-substituted phenyl;

R 4 is selected from (C 1 -C 6 )alkyl, —(CH 2 )—OR 4a , —(CH 2 ) 2-4 —NR 4a 2 , —(CH 2 ) 1-3 —C(═O)NR 4a 2 , —(CH 2 ) 2-4 —NR 4a C(═O)NR 4a 2 , —(CH 2 ) 2-4 —NR 4a C(═NR 4a )NR 4a 2 and —(CH 2 )—Ar 4

each R 4a is hydrogen or methyl;

Ar 4 is imidazolyl or indolyl;

R 5 is selected from —(CH 2 ) 1-6 —NR 5a 2 and —(CH 2 ) 1-6 —NR 5a C(═NR 5a )NR 5a 2 ;

each R 5a is independently selected from hydrogen and methyl;

R 6 is hydrogen or —C(═NH)NH 2 ;

R 7 is (C 1 -C 6 )alkyl or (C 4 -C 7 )cycloalkyl;

R 9 is selected from —(CH 2 ) 1-6 —NR 9a 2 and —(CH 2 ) 1-6 —NR 9a C(═O)R 9b ;

each R 9a is hydrogen;

each R 9b is hydrogen or (C 1 -C 6 )alkyl;

R 10 is selected from —(CH 2 ) 1-6 —C(═O)NR 10a 2 and Ar 10 —CH 2 —;

each R 10a is hydrogen or methyl;

Ar 10 is pyridyl;

Ar is phenyl;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2 or 3

o is 1 or 2

p is 1, 2 or 3; and

r is 0, 1, 2 or 3.

51. The compound or salt thereof according to claim 1 , wherein:

R 1 is isobutyl, n-hexyl, cyclohexyl or benzyl;

R 2 is methoxy;

R 3 is selected from s-butyl, neopentyl, benzyl and 4-chlorobenzyl;

R 4 is selected from Me, sobutyl, —CH 2 OH, —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 , —(CH 2 ) 4 —NH 2 , —(CH 2 ) 2 —C(═O)NH 2 , —(CH 2 ) 3 —NHC(═NH)NH 2 , —(CH 2 ) 3 —NHC(═O)NH 2 and —CH 2 (1H-imidazol-4-yl);

R 5 is —(CH 2 ) 2 —NH 2 , —(CH 2 ) 3 —NH 2 , —(CH 2 ) 4 —NH 2 or —(CH 2 ) 3 —NHC(═NH)NH 2 ;

R 7 is s-butyl;

R 10 is selected from 1-hydroxyethyl, —(CH 2 ) 2 —C(═O)NH 2 and 3-pyridyl-CH 2 —;

Ar is phenyl;

Q 1 is a —NH(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b , a —NH(CH 2 ) 4 C (S) H(NHC(═NH)NH 2 )—C(═O)— b or a —C(═O)(CH 2 ) 2 C (S) H(NH 2 )—C(═O)— b or a —C(═O)(CH 2 ) 2 C (R) H(NH 2 )—C(═O)— b ;

Q 2 is a —NH(CH 2 ) 4 — b , a —NH(CH 2 ) 5 — b , a —NH(CH 2 ) 6 — b , a —C(═O)—(CH 2 ) 3 — b or a —C(═O)—(CH 2 ) 5 — b ;

Q 3 is a —NH(CH 2 ) 4 —C(═O)—NH—(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b , a —NHC (S) H((CH 2 ) 4 NH 2 )—C(═O)—NH—(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b , a —NHC (S) H((CH 2 ) 4 NHAc)—C(═O)—NH—(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b , a —NHC (S) H((CH 2 ) 4 NHAc)—C(═O)—NH—(CH 2 ) 4 C (R) H(NH 2 )—C(═O)— b or a —NHC (S) H((CH 2 ) 4 NHHeptanoyl)-C(═O)—NH—(CH 2 ) 4 C (S) H(NH 2 )—C(═O)— b ; and

Q 4 is a —NH—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 5 — b , a —NH—(CH 2 ) 4 —C(═O)—NH—(CH 2 ) 6 — b , a —C(═O)—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 6 — b or a —C(═O)—(CH 2 ) 3 —C(═O)—NH—(CH 2 ) 4 — b .

52. A compound selected from compounds of the following formulae, and salts thereof:

53. The compound or salt thereof according to claim 52 , wherein the compound is a compound of the following formula:

54. The compound or salt thereof according to claim 52 , wherein the compound is a compound of the following formula:

55. The compound or salt thereof according to claim 52 , wherein the compound is a compound of the following formula:

56. A compound or a salt thereof, wherein the compound is selected from compounds of the following structures:

57. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

58. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

59. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

60. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

61. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

62. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

63. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

64. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

65. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

66. The compound or salt thereof according to claim 56 , wherein the compound is of the following structure:

67. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

68. A method of treating a complication arising from cirrhosis, wherein the complication is spontaneous bacterial peritonitis, type II hepatorenal syndrome (HRS2) or ascites, the method comprising administering to an individual in need of such treatment an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

69. The method according to claim 68 , wherein the complication is spontaneous bacterial peritonitis.

70. The method according to claim 68 , wherein the complication is type II hepatorenal syndrome (HRS2).

71. The method according to claim 68 , wherein the complication is refractory ascites.

72. A method of treatment of bleeding esophageal varices comprising administering to an individual in need of such treatment an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

73. A method of treatment of type II hepatorenal syndrome comprising administering to an individual in need of such treatment an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

74. A method of treatment of ascites comprising administering to an individual in need of such treatment an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

75. The method according to claim 68 , wherein the compound is a compound of one of the following structures:

76. The method according to claim 68 , wherein the compound is a compound of one of the following structures:

77. The method according to claim 68 , wherein the compound is a compound of the following formula:

78. The method according to claim 68 , wherein the compound is a compound of the following formula:

79. The method according to claim 68 , wherein the compound is a compound of the following formula:

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 22, 2022
From: FERRING BV
To: OCELOT BIO, INC.
Reel/Frame 059061/0704 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 28, 2015
From: WISNIEWSKI, KAZIMIERZ; HARRIS, GEOFFREY S.; GALYEAN, ROBERT
To: FERRING B.V.
Reel/Frame 035280/0409 →
Continuity (2)
Provisional Application 61645558 · May 10, 2012
Related Publication 20150126432A1 · May 7, 2015