CHEMICAL COMPOUNDS

• US 20200131141A1
• Filed: 03/12/2018
• Published: 04/30/2020
• Est. Priority Date: 03/13/2017
• Status: Active Grant

• Current Assignee: NodThera Limited
• Original Assignee: NodThera Limited
• Inventors: HARRISON, David, WATT, Alan Paul, BOUTARD, Nicolas, FABRITIUS, Charles-Henry, GALEZOWSKI, Michal, KOWALCZYK, Piotr, LEVENETS, Oleksandr, WOYCIECHOWSKI, Jakub
• Granted Patent: US 11,345,669 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07C 2603/10 containing five-membered rings
• CPC Class Codes: C07C 275/28 having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 213/06 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/14 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/38 Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 233/10 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring nitrogen atoms
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 233/96 having three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 237/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 237/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 239/26 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 241/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 271/06 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 271/10 : 1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
• CPC Class Codes: C07D 333/24 : Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The present disclosure relates to compounds of Formula (I): and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein inhibit the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as inter alia autoinflammatory and autoimmune diseases and cancers.

Claims

1. A compound of Formula (I) or pharmaceutically acceptable salt thereof:

2. The compound of claim 1, wherein R₃ is Methyl-R₇ or Ethyl-R₇.

3. The compound of claim 1 or claim 2, wherein R₇ is a monocyclic aryl, optionally substituted with at least one hydroxyl group.

4. The compound of claim 1 or claim 2, wherein R₇ is a monocyclic aryl with a cyano substitution.

5. The compound of claim 1 or claim 2, wherein R₇ is a 5 or 6 membered monocyclic aryl ring comprising 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur.

6. The compound of any preceding claim, wherein R₄ is alkyl (C1-C4) or cyclo alkyl (C3-C6).

7. The compound of any preceding claim, wherein R₁ is:

a 12, 13, 14, 15 or 16 membered tricyclic partially unsaturated carbocyclic ring system selected from the group consisting of

8. A compound of any of the preceding claims wherein the compound is selected from the group consisting of:

11. A pharmaceutical composition comprising a compound as defined in any of the preceding claims or a pharmaceutically acceptable salt thereof, in a mixture with a pharmaceutically acceptable diluent or carrier.

12. A method of inhibiting the NLRP3 inflammasome activity in vitro or in vivo, said method comprising contacting a cell with an effective amount of a compound according to any preceding claim or a pharmaceutically acceptable salt thereof.

13. A method of treating a disease or disorder in which inflammasome activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to any preceding claim or a pharmaceutically acceptable salt or composition thereof.

14. A method of treating an auto-inflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to any preceding claim.

15. A compound according to any preceding claim numbered 1-11 comprising a prodrug, or a pharmaceutically acceptable salt or composition thereof, or a pharmaceutical composition, for use in therapy.

16. A compound according to any preceding claim numbered 1-11, for use in the treatment of a disorder in which inflammasome activity is implicated.

17. The compound according to any of claims 1-11 for use in the treatment of a disorder, wherein the disorder is a cancer is selected from gastrointestinal cancer, skin cancer, non-small-cell lung carcinoma and colorectal adenocarcinoma.

18. The compound according to claim 17 for use in treatment of a disorder, wherein the disorder is selected from the treatment of an auto-inflammatory disorder, an autoimmune disorder, a neurodegenerative disease or cancer.

19. The compound according to any of claim 18, wherein the disorder is selected from cryopyrin-associated auto-inflammatory syndrome (CAPS) including familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever, nonalcoholic fatty liver disease (NAFLD), gout, rheumatoid arthritis, Crohn'"'"'s disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, neuro-inflammation occurring in protein misfolding diseases, Parkinson'"'"'s disease, osteoarthritis, Non-alcoholic steatohepatitis (NASH) and Alzheimer'"'"'s disease.

9. A compound of Formula (I), or a prodrug, or pharmaceutically acceptable salt thereof:

10. A compound of Formula (I), or a prodrug, or pharmaceutically acceptable salt thereof: