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-9926281-B2
Application number	US-201515538393-A
Country	US
Kind code	B2
Filing date	Dec 18, 2015
Priority date	Dec 22, 2014
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

Abstract

The present invention discloses compounds according to Formula I:

Wherein R 1 , R 2 , R 3a , R 3b , 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 according to Formula I:

wherein
R 1 is:
H,
C 1-4 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, or 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 optionally substituted with one or more independently selected R 5 groups,
phenyl fused to a 5-6 membered monocyclic heterocycloalkyl comprising 1, 2 or 3 heteroatoms independently selected from N, O, or S, which heterocycloalkyl is optionally substituted with one or more ═O,
5-6 membered monocyclic heteroaryl comprising 1 or 2 heteroatoms independently selected from N, O, or S, optionally substituted with one or more independently selected R 5 groups;

R 2 is independently selected from:
H,
OH,
C 1-4 alkoxy, or
C 1-4 alkyl optionally substituted with one
OH,
—CN,
C 1-4 alkoxy optionally substituted with one phenyl, or
5-6 membered monocyclic heteroaryl comprising 1 or 2 heteroatoms independently selected from N, O, or S, optionally substituted with one or more independently selected C 1-4 alkyl;

each R 3a , and R 3b is independently selected from:
H, or
C 1-4 alkyl;

Cy is
6-10 membered monocyclic or fused bicyclic aryl optionally substituted with one or more independently selected R 6 groups,
5-10 membered monocyclic or fused bicyclic heteroaryl comprising 1, 2 or 3 heteroatoms independently selected from N, O, or S, optionally substituted with one or more independently selected R 6 groups;

R 4 is
halo,
OH,
—CN,
C 1-4 alkyl,
C 1-4 alkoxy optionally substituted with 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, or O, optionally substituted with one or more halo, or
—C(═O)OC 1-4 alkyl,

phenyl,
—S(═O)C 1-4 alkyl
—C(═O)OR 7a
—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 —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, or 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 OH, or C 1-4 alkoxy;

each R 8a , or R 8b is independently selected from
H, or
C 1-4 alkyl optionally substituted with 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, or C 1-4 alkyl;
or a pharmaceutically acceptable salt, or a solvate, or a pharmaceutically acceptable salt of a solvate thereof; or a biologically active metabolite thereof;
provided that:
R 1 and R 2 are not simultaneously H, and
when R 1 is Me, and R 2 is H, then Cy is not

or a pharmaceutically acceptable salt, or a solvate, or the salt of the solvate thereof.

2. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is Formula II:

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

4. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 1 is C 1-4 alkyl.

5. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 1 is C 3-7 monocyclic cycloalkyl.

6. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is Formula IIIa or IIIb:

7. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein R 2 is C 1-4 alkyl.

8. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein the compound is Formula IVa or IVb:

9. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein each R 3a , and R 3b is independently selected from H or CH 3 .

10. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein Cy is 6-10 membered aryl, substituted with one or more independently selected R 6 groups.

11. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein Cy is phenyl substituted with one or more independently selected R 6 groups.

12. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , wherein each R 6 is F, Cl, CN, CH 3 , or NO 2 .

13. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is
5-[3-[(3S)-4-(3-chloro-4-fluoro-phenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-cyclopropyl-imidazolidine-2,4-dione,
5-[3-[(3S)-4-(3-chloro-5-fluoro-phenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-cyclopropyl-imidazolidine-2,4-dione,
(5S)-5-cyclopropyl-5-[3-[(3S)-4-(3,4-dichlorophenyl)-3-methyl-piperazin-1-yl]-3-oxo-propyl]imidazolidine-2,4-dione,
(5S)-5-cyclopropyl-5-[(2S)-3-[(3S)-4-(3,4-difluorophenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]imidazolidine-2,4-dione,
5-[3-[(3S)-4-(4-chlorophenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-cyclopropyl-imidazolidine-2,4-dione,
5-[3-[4-(3,4-difluorophenyl) piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl) imidazolidine-2,4-dione,
5-[2-[4-(3,5-dichlorophenyl) piperazine-1-carbonyl]butyl]-5-methyl-imidazolidine-2,4-dione,
(S)-5-((S)-3-((S)-4-(3-chloro-4-fluorophenyl)-3-methylpiperazin-1-yl)-2-methyl-3-oxopropyl)-5-(methoxymethyl) imidazolidine-2,4-dione,
5-[3-[4-(3-chlorophenyl) piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-cyclopropyl-imidazolidine-2,4-dione,
5-[3-[4-(3-chloro-2-methyl-phenyl)piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-cyclopropyl-imidazolidine-2,4-dione,
tert-butyl N-[2-[4-[3-[4-(3,4-difluorophenyl)piperazin-1-yl]-2-methyl-3-oxo-propyl]-2,5-dioxo-imidazolidin-4-yl]ethyl]carbamate,
(5S)-5-cyclopropyl-5-[3-[(3S)-4-(3,5-dichlorophenyl)-3-methyl-piperazin-1-yl]-3-oxo-propyl]imidazolidine-2,4-dione,
5-[3-[(3S)-4-(3-chloro-4-fluoro-phenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-(2-pyridyl) imidazolidine-2,4-dione,
5-cyclopropyl-5-[3-[4-(3,5-dichlorophenyl) piperazin-1-yl]-2-methyl-3-oxo-propyl]imidazolidine-2,4-dione,
(5R)-5-[(2S)-3-[(3S)-4-(3-chloro-4-fluoro-phenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,
5-cyclopropyl-5-[3-[(3S)-4-[3-fluoro-5-(1H-pyrazol-4-yl)phenyl]-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]imidazolidine-2,4-dione,
5-cyclopropyl-5-[3-[(3S)-4-(3,4-

Assignees

• Galapagos Nv
• Les Laboratories Servier
• Servier Lab

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

• C07D403/06 Primary

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

• A61P19/04

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

• A61P19/02

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

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title