Substituted indoles and pyrroles as RIP kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9725452-B2
Application number	US-201414214360-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

The present invention relates to heterocyclic compounds (e.g., compounds described by Formula (I)) and pharmaceutically acceptable salts thereof. The invention also features pharmaceutical compositions that include these compounds and their use in therapy for treating conditions in which necroptosis is likely to play a substantial role. The heterocyclic compounds described herein can also achieve improved activity and selectivity towards RIP1 and/or RIP3.

First claim

The invention claimed is:

1. A compound of formula (I):

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof, wherein
m is 0 or 1;
Het 1 is a bicyclic heteroaryl, wherein the bicyclic heteroaryl is unsubstituted or substituted by 1 or 2 substituents selected from halogen, CN, NO 2 , C1-C6 alkyl, and C1-C6 alkoxy;
L 1 is a covalent bond, a C1-C4 alkylene, a C2-C4 alkenylene, a C2-C4 alkynylene, a C3-C6 cycloalkyl, or a 3-6 membered heterocyclyl;
n is 0, 1, 2, 3, or 4;
o is 0 or 1;
p is 0 or 1;
each R 1 , when present, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C9 cycloalkyl, C5-C9 cycloalkenyl, 3-9 membered heterocyclyl, C6-C10 aryl, 5-11 membered heteroaryl, halogen, —OH, N 3 , NO 2 , —CO 2 H, —NC, or CN; or is a group selected from —OC(═O)R 4A , —C(═O)R 4A , —OR 4A , —NR 4A C(═O)R 4B , —C(═O)NR 4A R 4B , —NR 4A R 4B , —CO 2 R 4A , —OC(═O)NR 4A R 4B , —NR 4A C(═O)OR 4B , —S(═O) 2 OR 4A , —S(═O) 2 NR 4A R 4B , —NR 4A S(═O) 2 R 4B , and —S(═O) 2 R 4A , where each R 4A and R 4B is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C9 cycloalkyl, 3-9 membered heterocyclyl, C6-C10 aryl, or 5-11 membered heteroaryl;
R 2 is H or C1-C6 alkyl, or R 2 combines with R 3 to form a C1-C3 alkylene moiety;
L 2 is a covalent bond or C1-C4 alkylene;
R 3 is H or C1-C6 alkyl, or R 3 combines with R 2 to form a C1-C3 alkylene moiety;
A 1 is

 wherein
each X 1 and X 2 is independently O or S;
X 3 is O or NR H ;
n is 0 or 1;
each of R 5 , R 6 , R 7 and R 8 is independently H, OH, C1-C6 alkyl, C1-C6 alkoxy, halogen, N(R 12 ) 2 , CO 2 R 12 , NO 2 , NHC(O)R 12 , aryl, heteroaryl, or piperazinyl;
R 9 is H or C1-C6 alkyl;
R 10 is H or C1-C6 alkyl;
R 11 is H or C1-C6 alkyl; and
each R 12 is independently H, C1-C6 alkyl, aryl, alkaryl, C2-C6 alkenyl, C2-C6 alkynyl, or heteroaryl;

or

wherein
R 13 is H, halogen, C1-C6 alkyl, C1-C6 cycloalkyl, or aryl;
R 14 is H or C1-C6 alkyl;
each of R 15 and R 16 is independently H, halogen, carboxamido, nitro or cyano;
R 17 is H, aryl or C1-C6 alkyl; and
each of R 18 , R 19 , R 20 , R 21 and R 22 is independently H, C1-C6 alkyl, halogen, amino, carboxamido, C1-C6 alkoxy, nitro or cyano.

2. The compound of claim 1 , wherein said compound has a structure according to formula (II), formula (III), formula (IV) or formula (V):

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

3. The compound of claim 1 , wherein said compound has a structure according to formula (VI) or formula (VII),

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

4. The compound of claim 1 , wherein o is 0,
or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

5. The compound of claim 4 , wherein said compound has a structure according to formula (VIII) or formula (IX),

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

6. The compound of claim 1 , wherein said compound has a structure according to formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII), formula (XIX), formula (XX) or formula (XXI),

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

7. The compound of claim 1 , wherein m is 0 and said compound has a structure according to formula (XXII),

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

8. The compound of claim 7 , wherein
L 1 is C2 alkynylene; and/or
o is 0; and/or
L 2 is C1 alkylene; and/or
R 3 is H,
or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

9. The compound of claim 1 , wherein said compound has a structure according to a structure according to formula (XXIII), formula (XXIV), or formula (XXV), or formula (XXVI),

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

10. The compound of claim 9 , wherein L 2 is C1-C4 alkylene,
or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

11. The compound of claim 1 , wherein A 1 is

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

12. The compound of claim 11 , wherein A 1 is

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

13. The compound of claim 11 , wherein A 1 is

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

14. The compound of claim 1 , wherein A 1 is

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

15. The compound of claim 14 , wherein A 1 is

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

16. The compound of claim 14 , wherein A 1 is

or any pharmaceutically acceptable salt thereof, or stereoisomer thereof.

17. The compound of claim 1 , wherein A 1 is

wherein
X 3 is O or NH;
R 9 is H or C1 alkyl; and
R 5 is H, halogen, OH, C1-C3 alkyl, or C1-C3 alkoxy; or

wherein each of R 18 and R 22 is independently H, F or Cl.

18. The compound of claim 17 , wherein
A 1 has a structure according to (a), and R 5 is H, Cl, OH, CH 3 , or OCH 3 ; or wherein
A 1 has a structure according to (b), and R 18 is F and R 22 is Cl, or R 18 is F and R 22 is H.

19. The compound of claim 1 , wherein Het 1 is indolyl, indazolyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolinyl or isoquinolinyl, each of which is unsubstituted or substituted by 1 or 2 substituents selected from halogen, CN, NO 2 , C1-C6

Assignees

• Harvard College
• Shanghai Inst Organic Chemistry Cas
• Univ Tufts
• Univ Houston
• Presidents And Fellows Of Harvard College

Inventors

• Yuan Junying
• Degterev Alexei
• Cuny Gregory D

Classifications

• A61P7/06

  Antianaemics · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title