IP Library › Granted Patent US 10,144,739

Granted Patent B2

US 10,144,739 · App. 15/287,958 · Granted Dec 4, 2018

Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one compounds and derivatives as MDM2-P53 inhibitors

Inventors: Andreas Gollner (Vienna, AT); Joachim Broeker (Moedling, AT); Nina Kerres (Vienna, AT); Christiane Kofink (Perchtoldsdorf, AT); Juergen Ramharter (Vienna, AT); Harald Weinstabl (Vienna, AT)

Assignee: Boehringer Ingelheim International GmbH

C07D487/22 A61K31/4162 A61K31/437 A61K31/4545 A61K31/5377 A61K45/06 C07D471/22

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Quick Facts

Patent No.: US 10,144,739
App. No.: 15/287,958
Granted: Dec 4, 2018
Kind: B2

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Abstract

The present invention encompasses compounds of formula (I) wherein the groups R 1 to R 4 , R 7 , A, D, E, F, V, W, X, Y, n, r and q are defined in claim 1 , their use as inhibitors of MDM2-p53 interaction, pharmaceutical compositions which contain compounds of this kind, their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases, and synthetic intermediates.

Claims (154)

1. A compound of formula (I)

wherein

R 1 is a group, optionally substituted by one or more, identical or different R b1 and/or R c1 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R b1 is independently selected from among —OR c1 , —NR c1 R c1 , halogen, —CN, —C(O)R c1 , —C(O)OR c1 , —C(O)NR c1 R c1 , —S(O) 2 R c1 , —S(O) 2 NR c1 R c1 , —NHC(O)R c1 , —N(C 1-4 alkyl)C(O)R c1 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;

each R c1 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d1 and/or R e1 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R d1 is independently selected from among —OR e1 , —NR e1 R e1 , halogen, —CN, —C(O)R e1 , —C(O)OR e1 , —C(O)NR e1 R e1 , —S(O) 2 R e1 , —S(O) 2 NR e1 R e1 , —NHC(O)R e1 , —N(C 1-4 alkyl)C(O)R e1 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;

each R e1 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R f1 and/or Rg g1 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R f1 is independently selected from among —OR g1 , —NR g1 R g1 , halogen, —CN, —C(O)R g1 , —C(O)OR g1 , —C(O)NR g1 R g1 , —S(O) 2 R g1 , —S(O) 2 NR g1 R g1 , —NHC(O)R g1 , —N(C 1-4 alkyl)C(O)R g1 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;

each R g1 is independently selected from among hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

R 2 and R 3 , each independently, is selected from among hydrogen, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl, wherein said C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl is optionally substituted by one or more, identical or different R b2 and/or R c2 ;

each R b2 is independently selected from among —OR c2 , —NR c2 R c2 , halogen, —CN, —C(O)R c2 , —C(O)OR c2 , —C(O)NR c2 R c2 , —S(O) 2 R c2 , —S(O) 2 NR c2 R c2 , —NHC(O)R c2 , —N(C 1-4 alkyl)C(O)R c2 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;

each R c2 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d2 and/or R e2 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R d2 is independently selected from among —OR e2 , —NR e2 R e2 , halogen, —CN, —C(O)R e2 , —C(O)OR e2 , —C(O)NR e2 R e2 , —S(O) 2 R e2 , —S(O) 2 NR e2 R e2 , —NHC(O)R e2 , —N(C 1-4 alkyl)C(O)R e2 and the bivalent substituent ═O, while ═O may only be a substituent in non-aromatic ring systems;

each R e2 independently of one another denotes hydrogen or a group selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

A is selected from among phenyl and 5-6 membered heteroaryl if F is carbon or

A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen;

each R 4 is independently selected from among R a4 and R b4 ;

each R a4 independently of one another is a group, optionally substituted by one or more, identical or different R b4 and/or R c4 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R b4 is independently selected from among —OR c4 , —NR c4 R c4 , halogen, —CN, —C(O)R c4 , —C(O)OR c4 , —C(O)NR c4 R c4 , —C(O)NR g4 OR c4 , —S(O) 2 R c4 , —S(O) 2 NR c4 R c4 , —NHSO 2 R c4 , —N(C 1-4 alkyl)SO 2 R c4 , —NHC(O)R c4 and —N(C 1-4 alkyl)C(O) c4 ;

each R c4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d4 and/or R e4 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R d4 is independently selected from among —OR e4 , —NR e4 R e4 , halogen, —CN, —C(O)R e4 , —C(O)OR e4 , —C(O)NR e4 R e4 , —C(O)NR g4 OR e4 , —S(O) 2 R e4 , —S(O) 2 NR e4 R e4 , —NHC(O)R e4 and —N(C 1-4 alkyl)C(O)R e4 ;

each R e4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R f4 and/or Rg g4 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R f4 is independently selected from among —OR g4 , —NR g4 R g4 , halogen, —CN, —C(O)R g4 , —C(O)OR g4 , —C(O)NR g4 R g4 , —C(O)NR g4 OR g4 , —S(O) 2 R g4 , —S(O) 2 NR g4 R g4 , —NHC(O)R g4 and —N(C 1-4 alkyl)C(O)R g4 ;

each R g4 is independently selected from among hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

r denotes the number 0, 1, 2 or 3;

n denotes the number 1, 2 or 3;

each R 7 is independently selected from among halogen, C 1-4 alkyl, —CN, C 1-4 haloalkyl, —OC 1-4 alkyl and —OC 1-4 haloalkyl;

q denotes the number 0, 1, 2 or 3;

W, X and Y is each —CH═, wherein the hydrogen in each —CH═ may be replaced by a substituent R 7 ;

V is oxygen or sulfur;

D is nitrogen, E is carbon and F is carbon; or

D is carbon, E is nitrogen and F is carbon; or

D is carbon, E is carbon and F is nitrogen;

or a salt thereof.

2. The compound according to claim 1 of formula (Ia) or (Ib) or (Ic)

or a salt thereof.

3. The compound according to claim 2 of formula (Ia*) or (Ib*) or (Ic*)

or a salt thereof.

4. The compound according to claim 1 , wherein

each R b1 is independently selected from among —OR c1 , —NR c1 R c1 , halogen, —CN, —C(O)R c1 , —C(O)OR c1 , —C(O)NR c1 R c1 , —S(O) 2 R c1 , —S(O) 2 NR c1 R c1 , —NHC(O)R c1 and —N(C 1-4 alkyl)C(O)R c1 ;

each R d1 is independently selected from among —OR e1 , —NR e1 R e1 , halogen, —CN, —C(O) R e1 , —C(O)OR e1 , —C(O)NR e1 R e1 , —S(O) 2 R e1 , —S(O) 2 NR e1 R e1 , —NHC(O)R e1 and —N(C 1-4 alkyl)C(O)R e1 ;

each R e1 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R f1 and/or R g1 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R f1 is independently selected from among —OR g1 , —NR g1 R g1 , halogen, —CN, —C(O)R g1 , —C(O)OR g1 , —C(O)NR g1 R g1 , —S(O) 2 R g1 , —S(O) 2 NR g1 R g1 , —NHC(O)R g1 and —N(C 1-4 alkyl)C(O)R g1 ;

or a salt thereof.

5. The compound according to claim 1 , wherein

each R b2 is independently selected from among —OR c2 , —NR c2 R c2 , halogen, —CN, —C(O)R c2 , —C(O)OR c2 , —C(O)NR c2 R c2 , —S(O) 2 R c2 , —S(O) 2 NR c2 R c2 , —NHC(O)R c2 and —N(C 1-4 alkyl)C(O)R c2 ;

each R d2 is independently selected from among —OR e2 , —NR e2 R e2 , halogen, —CN, —C(O)R e2 , —C(O)OR e2 , —C(O)NR e2 R e2 , —S(O) 2 R e2 , —S(O) 2 NR e2 R e2 , —NHC(O)R e2 and —N(C 1-4 alkyl)C(O)R e2 ;

or a salt thereof.

6. The compound according to claim 5 , wherein

one of R 2 and R 3 is hydrogen and the other is selected from among phenyl and 5-6 membered heteroaryl, wherein said phenyl and 5-6 membered heteroaryl is optionally substituted by one or more, identical or different R b2 and/or R c2 ;

each R c2 independently of one another denotes hydrogen or a group selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 4-6 cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocyclyl;

or a salt thereof.

7. The compound according to claim 6 , wherein

or a salt thereof.

8. The compound according to claim 1 , wherein

R 3 is hydrogen;

or a salt thereof.

9. The compound according to claim 1 , wherein

A is phenyl and F is carbon;

each R 4 is independently selected from among R a4 and R b4 ;

each R a4 independently of one another is a group, optionally substituted by one or more, identical or different R b4 and/or R c4 , selected from among C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-10 membered heterocyclyl;

each R b4 is independently selected from among —OR c4 , —NR c4 R c4 , halogen, —C(O)R c4 , —C(O)NR c4 OR c4 , —C(O)NR c4 R c4 , —C(O)NR g4 OR c4 , —S(O) 2 R c4 and —NHC(O)R c4 ;

each R c4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R d4 and/or R e4 , selected from among C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl and 3-10 membered heterocyclyl;

each R d4 is independently selected from among —OR e4 , —NR e4 R e4 and —S(O) 2 R e4 ;

each R e4 independently of one another denotes hydrogen or a group, optionally substituted by one or more, identical or different R f4 and/or R g4 , selected from among C 1-6 alkyl and 3-10 membered heterocyclyl;

each R f4 is —OR g4 ;

each R g4 is independently selected from among hydrogen and C 1-6 alkyl;

r denotes the number 0, 1, 2 or 3;

or a salt thereof.

10. The compound according to claim 1 , wherein

A is selected from among phenyl and 5-6 membered heteroaryl if F is carbon or

A is 5-6 membered, nitrogen-containing heteroaryl if F is nitrogen;

each R 4 is independently selected from among R a4 and R b4 ;

each R a4 independently of one another is a group, optionally substituted by one or more identical or different R b4 and/or R c4 , selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

each R b4 is independently selected from among —OR c4 , —NR c4 R c4 , halogen, —CN, —C(O)R c4 , —C(O)OR c4 , —C(O)NR c4 R c4 , —C(O)NHOR c4 , —S(O) 2 R c4 , —S(O) 2 NR c4 R c4 , —NHSO 2 R c4 , —N(C 1-4 alkyl)SO 2 R c4 , —NHC(O)R c4 and —N(C 1-4 alkyl)C(O)R c4 ;

each R c4 independently of one another is selected from among hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-10 membered heterocyclyl;

r denotes the number 0, 1, 2 or 3;

or a salt thereof.

11. The compound according to claim 1 , wherein

A together with the r substituents R 4 is

R 8 is selected from among hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CN, —C(O)OH, —C(O)OC 1-6 alkyl, —C(O)NH 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 and —S(O) 2 C 1-6 alkyl;

R 9 is selected from among hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CN, —C(O)OH, —C(O)OC 1-6 alkyl, —C(O)NH 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 and —S(O) 2 C 1-6 alkyl;

R 10 is selected from among hydrogen, C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CN, —C(O)OH, —C(O)OC 1-6 alkyl, —C(O)NH 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 and —S(O) 2 C 1-6 alkyl;

with the proviso that at least one of R 8 to R 10 but not all of R 8 to R 10 is/are hydrogen;

or a salt thereof.

12. The compound according to claim 1 , wherein

n denotes the number 1 or 2;

or a salt thereof.

13. The compound according to claim 1 , wherein

each R 7 independently is halogen or —CN and q is 1 or 2;

or a salt thereof.

14. The compound according to claim 1 , wherein

W, X and Y are —CH═ wherein the hydrogen in each —CH═ may be replaced by a substituent R 7 ;

or a salt thereof.

15. A compound selected from a group consisting of:

or a salt thereof.

16. A method of treating cancer comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt according to claim 1 to a patient in need thereof.

17. A pharmaceutical composition comprising at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof—and a pharmaceutically acceptable carrier.

18. A pharmaceutical preparation comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof—and at least one other cytostatic and/or cytotoxic active substance.

19. A compound of formula Ia-25 or a pharmaceutically acceptable salt thereof

20. A compound of formula Ia-27 or a pharmaceutically acceptable salt thereof

21. A compound of formula Ia-28 or a pharmaceutically acceptable salt thereof

22. A compound of formula Ia-29 or a pharmaceutically acceptable salt thereof

23. A compound of formula Ia-30 or a pharmaceutically acceptable salt thereof

24. A compound of formula Ia-32 or a pharmaceutically acceptable salt thereof

25. A compound of formula Ia-33 or a pharmaceutically acceptable salt thereof

26. A compound of formula Ia-34 or a pharmaceutically acceptable salt thereof

27. A compound of formula Ia-35 or a pharmaceutically acceptable salt thereof

28. A compound of formula Ia-36 or a pharmaceutically acceptable salt thereof

29. A compound of formula Ia-38 or a pharmaceutically acceptable salt thereof

30. A compound of formula Ia-40 or a pharmaceutically acceptable salt thereof

31. A compound of formula Ia-50 or a pharmaceutically acceptable salt thereof

32. A compound of formula Ia-55 or a pharmaceutically acceptable salt thereof

33. A compound of formula Ia-56 or a pharmaceutically acceptable salt thereof

34. A pharmaceutical composition comprising at least one compound according to claim 15 or a pharmaceutically acceptable salt thereof—and a pharmaceutically acceptable carrier.

35. A pharmaceutical preparation comprising a compound according to claim 15 or a pharmaceutically acceptable salt thereof—and at least one other cytostatic and/or cytotoxic active substance.

36. A compound of formula

37. A pharmaceutical composition comprising the compound according to claim 36 and a pharmaceutically acceptable carrier.

38. A compound of formula

39. A pharmaceutical composition comprising the compound according to claim 38 and a pharmaceutically acceptable carrier.

40. A compound of formula

41. A pharmaceutical composition comprising the compound according to claim 40 and a pharmaceutically acceptable carrier.

42. A compound of formula

43. A pharmaceutical composition comprising the compound according to claim 42 and a pharmaceutically acceptable carrier.

44. A compound of formula

45. A pharmaceutical composition comprising the compound according to claim 44 and a pharmaceutically acceptable carrier.

46. A compound of formula

47. A pharmaceutical composition comprising the compound according to claim 46 and a pharmaceutically acceptable carrier.

48. A compound of formula

49. A pharmaceutical composition comprising the compound according to claim 48 and a pharmaceutically acceptable carrier.

50. A compound of formula

51. A pharmaceutical composition comprising the compound according to claim 50 and a pharmaceutically acceptable carrier.

52. A compound of formula

53. A pharmaceutical composition comprising the compound according to claim 52 and a pharmaceutically acceptable carrier.

54. A compound of formula

55. A pharmaceutical composition comprising the compound according to claim 54 and a pharmaceutically acceptable carrier.

56. A compound of formula

57. A pharmaceutical composition comprising the compound according to claim 56 and a pharmaceutically acceptable carrier.

58. A compound of formula

59. A pharmaceutical composition comprising the compound according to claim 58 and a pharmaceutically acceptable carrier.

60. A compound of formula

61. A pharmaceutical composition comprising the compound according to claim 60 and a pharmaceutically acceptable carrier.

62. A compound of formula

63. A pharmaceutical composition comprising the compound according to claim 62 and a pharmaceutically acceptable carrier.

64. A compound of formula

65. A pharmaceutical composition comprising the compound according to claim 64 and a pharmaceutically acceptable carrier.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 26, 2017

From: GOLLNER, ANDREAS; BROEKER, JOACHIM; GILLE, ANNIKA; GOEPPER, STEFAN; HENRY, MANUEL; HUCHLER, GUENTHER; KOFINK, CHRISTIANE; RAMHARTER, JUERGEN; WEINSTABL, HARALD; KERRES, NINA

To: BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Reel/Frame 042146/0094 →

Priority Claims (1)

EP 15189210 · Oct 9, 2015 · regional

Continuity (1)

Related Publication 20170174695A1 · Jun 22, 2017

Cited By (2)

US 50,594 US 12,312,363