Substituted cyclopenta[2,1-b:5,1-b’]dipyrroles as Janus kinase (JAK) inhibitors

Patent metadata

Field	Value
Publication number	US-12528811-B2
Application number	US-202017640357-A
Country	US
Kind code	B2
Filing date	Sep 2, 2020
Priority date	Sep 5, 2019
Publication date	Jan 20, 2026
Grant date	Jan 20, 2026

Abstract

The present invention relates to compounds of formula 1 or 2,

wherein R 1 and R 3 are purine or a purine analog and R 2 and R 4 are a small functional group. The invention also relates to intermediates of the synthesis of compounds of formula 1 or 2. Compounds of formula 1 or 2 are Janus kinase inhibitors and thus useful in the treatment of a disease, particularly an autoimmune disease, cancer, Alzheimer's disease or useful in preventing the rejection of an allograft or xenograft.

First claim

The invention claimed is:

1 . A compound of formula (1):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is

R 2 is C(O)CH 3 , C(O)CH 2 CN, C(O)CH 2 Cl, C(O)CF 3 , C(O)CH 2 CH 3 , C(O)CH 2 CF 3 , or C(O)CH═CH 2 ;
x is 1;
y is 1; and
z is 1.

2 . The compound according to claim 1 , or a stereoisomer thereof, wherein the stereoisomer of the compound is of the following formula:

3 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is:

4 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is:

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

6 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is C(O)CH 3 , C(O)CH 2 CN, C(O)CH 2 Cl, C(O)CH 2 CH 3 , or C(O)CH═CH 2 .

7 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is C(O)CH 2 CN or C(O)CH═CH 2 .

8 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is C(O)CH 2 CN.

9 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2 is C(O)CH═CH 2 .

10 . A method for inhibiting Janus kinase (JAK) activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

11 . The method according to claim 10 , wherein the subject has a disease selected from the group consisting of Alzheimer's disease, ankylosing spondylitis, asthma, atopic dermatitis, an autoimmune disease, axial spondyloarthritis, cancer, Crohn's disease (CD), non-segmental vitiligo, psoriatic arthritis, psoriasis, ulcerative colitis, and uveitis.

12 . The method according to claim 11 , wherein the atopic dermatitis is chronic hand eczema.

13 . The method according to claim 11 , wherein the autoimmune disease is selected from the group consisting of cutaneous lupus, lupus nephropathy, rheumatoid arthritis, and Sjögren syndrome.

14 . The method according to claim 11 , wherein the cancer is myelofibrosis.

15 . The method according to claim 11 , wherein the Crohn's disease (CD) is fistulizing Crohn's disease (CD) or small bowel Crohn's disease (CD).

Assignees

• Univ Bern

Inventors

• Meier Kris
• Reymond Jean-Louis

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title