5-[(piperazin-1-yl)-3-oxo-propyl]-imidazolidine-2,4-dione derivatives as ADAMTS inhibitors for the treatment of osteoarthritis

Patent metadata

Field	Value
Publication number	US-11718588-B2
Application number	US-202117141902-A
Country	US
Kind code	B2
Filing date	Jan 5, 2021
Priority date	Dec 22, 2014
Publication date	Aug 8, 2023
Grant date	Aug 8, 2023

Abstract

The present invention discloses compounds according to Formula I:Wherein R1, R2, R3a, R3b, and Cy are as defined herein.The present invention relates to compounds inhibiting ADAMTS, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of inflammatory conditions, and/or diseases involving degradation of cartilage and/or disruption of cartilage homeostasis by administering a compound of the invention.

First claim

The invention claimed is:

1. A compound of formula (II):

wherein:
R 1 is:
C 2-4 alkyl optionally substituted with one or more independently selected R 4 groups,
C 3-7 monocyclic cycloalkyl optionally substituted with one or more independently selected R 4 groups,
4-7 membered monocyclic heterocycloalkyl comprising 1 to 2 heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected C 1-4 alkyl, —C(═O)C 1-4 alkyl, or —C(═O)OC 1-4 alkyl,
phenyl fused to a 5-6 membered monocyclic heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more ═O, or
imidazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted with one or more independently selected R 5 groups;

R 4 is:
halo,
OH,
CN,
C 1-4 alkyl,
C 1-4 alkoxy optionally substituted with one C 1-4 alkoxy, or phenyl,
C 1-4 thioalkoxy,
4-7-membered monocyclic heterocycloalkyl comprising one or more heteroatoms independently selected from N, S, and O, optionally substituted with one or more independently selected halo, or —C(═O)OC 1-4 alkyl,
phenyl,
—S(═O) 2 C 1-4 alkyl,
—C(═O)NR 7b R 7c ,
—NHC(═O)OR 7d ,
—NHC(═O)R 7e , or
NR 8a R 8b ;

each R 5 is
halo,
OH,
CN,
C 1-4 alkyl optionally substituted with one or more independently selected halo, —NR 9a R 9b , or —C(═O)NR 9c R 9d ,
C 1-4 alkoxy optionally substituted with one —NR 9e R 9f , or
—S(═O) 2 C 1-4 alkyl;

each R 6 is
halo,
—CN,
—NO 2 ,
—CH 3 ,
5-10 membered monocyclic or fused bicyclic heteroaryl comprising 1, 2 or 3 heteroatoms independently selected from N, O, and S, optionally substituted with one or more independently selected halo, C 1-4 alkyl, or C 1-4 alkoxy, or
—NR 9g R 9h ;

each R 7a , R 7b , R 7c , R 7d , or R 7e is
H, or
C 1-4 alkyl optionally substituted with one OH, C 1-4 alkoxy;

each R 8a , or R 8b is independently selected from
H, and
C 1-4 alkyl optionally substituted with one or more independently selected OH, C 1-4 alkoxy, or phenyl;

each R 9a , R 9b , R 9c , R 9d , R 9e , R 9f , R 9g , and R 9h is independently selected from H, and C 1-4 alkyl; or
a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof.

2. The compound of claim 1 , wherein R 1 is:
imidazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, each of which is, optionally substituted with a C 1 alkyl
C 2-4 alkyl, or
C 3 monocyclic cycloalkyl.

3. The compound of claim 1 , selected from the group consisting of:

4. A compound of claim 1 , wherein the compound is:

5. A method of making the compound of formula (II) of claim 1 , comprising reacting a compound of formula (I)

and producing a compound of formula (II).

6. A method of making a compound of formula (III),

comprising reacting compound (163),

with (2S)-1-(3,5-difluorophenyl)-2-methyl-piperazine.

7. A method of making compound (173),

comprising reacting a compound of claim 4 with 1-(3,5-dichlorophenyl) piperazine.

8. A method of making compound (203),

comprising reacting a compound of claim 4 with (2S)-1-(3-fluorophenyl)-2-methyl-piperazine.

9. A method of making compound (204)

comprising reacting a compound of claim 4 with (2S)-1-(3,5-dichlorophenyl)-2-methyl-piperazine.

10. A method of making compound (205)

comprising reacting a compound of claim 4 with (2S)-1-(3,4-difluorophenyl)-2-methyl-piperazine.

11. A method of making compound (207)

comprising reacting a compound of claim 4 with (S)-1-(3,4-Dichloro-phenyl)-2-methyl-piperazine.

12. A method of making compound (357)

comprising reacting a compound of claim 4 with (2S)-1-[3-fluoro-5-(1H-pyrazol-4-l)phenyl]-2-methyl-piperazine.

13. A method of making compound (403)

comprising reacting a compound of claim 4 with (2R)-1-(3,5-difluorophenyl)-2-methyl-piperazine.

14. A method of making compound (416)

comprising reacting a compound of claim 4 with (2S)-1-(3,4-dichlorophenyl)-2-methyl-piperazine.

15. The compound of claim 1 , wherein R 1 is ethyl, propyl, isopropyl, and or tertbutyl.

16. The compound of claim 1 , wherein R 1 is ethyl.

Assignees

• Galapagos Nv

Inventors

• Brebion Franck Laurent
• Alvey Luke Jonathan
• Amantini David
• De Ceuninck Frédéric André
• Deprez Pierre Marc Marie Joseph
• Gosmini Romain Luc Marie
• Jary Hélène Marie
• Peixoto Christophe
• Pop-Botez Iuliana Ecaterina
• Varin Marie Laurence Claire

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P19/02

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

• A61P19/04

  for non-specific disorders of the connective tissue · CPC title

• C07D233/78 Primary

  Radicals substituted by oxygen atoms · CPC title