Substituted pyrrolo[2,3-b]pyridines as inhibitors of cellular necroptosis

• US 10,457,678 B2
• Filed: 10/13/2016
• Issued: 10/29/2019
• Est. Priority Date: 10/13/2015
• Status: Active Grant

• Current Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH), Centre National De La Recherche Scientifique, Sorbonne Universite, Université Claude Bernard Lyon 1
• Original Assignee: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH)
• Inventors: Dimanche-Boitrel, Marie-Therese, Bach, Stephane, Delehouze, Claire, Goekjian, Peter, Comte, Arnaud
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US15/768,395
• Publication Number:
  US 20180312502A1
• Time in Patent Office: 1,111 Days
• Field of Search: 514300, 546113
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to new N1- and N7-substituted sibiriline derivatives of the following general formula (I): (I) or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as drug, in particular for use as inhibitor of cellular necroptosis. The present invention also relates to a pharmaceutical composition comprising such a compound and processes to prepare such a compound. The present invention also encompasses the use of a compound of the general formula (I) for organs preservation.

Claims

1. A compound of formula (I):

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃ and R₄ are independently —

H, -halo, —

(C₁-C₆)alkyl or —

OR₅₁.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R₁, R₂, R₃ and R₄ are independently —

H, -halo, —

CH₃ or —

OCH₃.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R₅ is —

H.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R₆, R₇ and R₈ are independently —

H, -halo, —

OR₅₆ or —

NR₅₇R₅₈;

or

R₆, R₇ and R₈ are independently —

(C₁-C₆)alkyl, —

(C₁-C₆)alkyl-aryl, —

(C₁-C₆)alkyl-heterocycloalkyl, -heterocycloalkyl, -aryl or -heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of -oxo, -halo, —

NO₂, —

CN, —

OR₇₉, —

NR₈₀R₈₁, —

SR₈₂, —

S(O)R₈₃, —

S(O)₂R₈₄, —

S(O)₂NR₈₅R₈₆, —

OC(O)R₈₇, —

NR₈₈C(O)R₈₉, —

NR₉₀C(O)OR₉₁, —

C(O)OR₉₂, —

C(O)NR₉₃R₉₄, —

C(O)OR₉₅, —

OC(O)NR₉₆R₉₇ and —

C(O)R₉₈.

6. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein:

R₆, R₇ and R₈ are independently —

H, -halo, —

OR₅₆ or —

NR₅₇R₅₈;

or

R₆, R₇ and R₈ are independently —

(C₁-C₆)alkyl, -heterocycloalkyl, -aryl or -heteroaryl.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R₁₀, R₁₁, R₁₂, R₂₅, R₂₉, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₇, R₅₈, R₅₉, R₆₀, R₆₁, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀, R₇₄, R₇₅, R₇₆, R₇₇, R₇₈, R₇₉, R₈₀, R₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, R₈₇, R₈₈, R₈₉, R₉₀, R₉₁, R₉₂, R₉₃, R₉₄, R₉₅, R₉₆, R₉₇ and R₉₈ are independently —

H or -halo;

or

R₁₀, R₁₁, R₁₂, R₂₅, R₂₉, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₇, R₅₈, R₅₉, R₆₀, R₆₁, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀, R₇₄, R₇₅, R₇₆, R₇₇, R₇₈, R₇₉, R₈₀, R₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, R₈₇, R₈₈, R₈₉, R₉₀, R₉₁, R₉₂, R₉₃, R₉₄, R₉₅, R₉₆, R₉₇ and R₉₈ are independently —

(C₁-C₆)alkyl, benzyl, -heterocycloalkyl or phenyl, each optionally substituted with one or more substituents selected from the group consisting of -oxo, -halo, —

(C₁-C₆)alkyl, —

OR_alk, —

S(O)₂R_alk, —

C(O)OR_alk and —

C(O)R_alk.

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein:

R₁₀, R₁₁, R₁₂, R₂₅, R₂₉, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₇, R₅₈, R₅₉, R₆₀, R₆₁, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀, R₇₄, R₇₅, R₇₆, R₇₇, R₇₈, R₇₉, R₈₀, R₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, R₈₇, R₈₈, R₈₉, R₉₀, R₉₁, R₉₂, R₉₃, R₉₄, R₉₅, R₉₆, R₉₇ and R₉₈ are independently —

H or -halo;

or

R₁₀, R₁₁, R₁₂, R₂₅, R₂₉, R₅₁, R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₇, R₅₈, R₅₉, R₆₀, R₆₁, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇, R₆₈, R₆₉, R₇₀, R₇₄, R₇₅, R₇₆, R₇₇, R₇₈, R₇₉, R₈₀, R₈₁, R₈₂, R₈₃, R₈₄, R₈₅, R₈₆, R₈₇, R₈₈, R₈₉, R₉₀, R₉₁, R₉₂, R₉₃, R₉₄, R₉₅, R₉₆, R₉₇ and R₉₈ are independently —

(C₁-C₆)alkyl, benzyl, -heterocycloalkyl or phenyl, each optionally substituted with one or more substituents selected from the group consisting of -oxo, -halo, —

CH₃ and —

S(O)₂CH₃.

9. The compound according to claim 1, wherein the compound is selected from the group consisting of:

10. A pharmaceutical composition comprising at least one compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

11. A method for inhibiting cellular necroptosis in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. The method according to claim 11, wherein the cellular necroptosis is tumor-cell-induced endothelial cell necroptosis.

13. The method according to claim 12, wherein the tumor-cell-induced endothelial cell necroptosis is selected from the group consisting of tumor cell extravasation and tumor cell metastasis.

14. The method according to claim 11, wherein the patient has a disorder associated with cellular necroptosis selected from the group consisting of a trauma in the brain, a viral infection, acute pancreatitis, acute tubular necrosis, alcoholic steatohepatitis, atherosclerosis, bone marrow failure, chronic obstructive pulmonary disease, Crohn'"'"'s colitis, heart transplantation, hepatitis, ischemia reperfusion injury, kidney transplantation, non-alcoholic steatohepatitis, terminal ileitis and ulcerative colitis.

15. The method according to claim 14, wherein the ischemia reperfusion injury is selected from the group consisting of a myocardial infarction and a stroke.

16. A method for preserving and/or protecting a biological material, comprising placing the biological material in a medium comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. The method according to claim 16, wherein the biological material is a cell, a tissue, a body fluid, an organ or a microorganism.

18. A process for preparing a compound of formula (I) according to claim 1:

19. A process for preparing a compound of formula (I) according to claim 1: