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

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-difluorophenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]imidazolidine-2,4-dione,

5-[3-[4-(3,5-dichlorophenyl) piperazin-1-yl]-2-(hydroxymethyl)-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,

5-[3-[(3S)-4-(3,4-difluorophenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-(2-pyridyl) imidazolidine-2,4-dione,

5-[3-[(3S)-4-(3-chlorophenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-(2-pyridyl) imidazolidine-2,4-dione,

5-[3-[(3S)-4-(4-chloro-3,5-difluoro-phenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-methyl-imidazolidine-2,4-dione,

5-cyclopropyl-5-[3-[(3S)-4-(3,4-dichlorophenyl)-3-methyl-piperazin-1-yl]-3-oxo-propyl]imidazolidine-2,4-dione,

5-[3-[4-(3,5-dichlorophenyl) piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-(2-methylsulfonylethyl)imidazolidine-2,4-dione,

5-[3-[4-(3,5-dichlorophenyl)piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-(2-pyridyl)imidazolidine-2,4-dione,

(5S)-cyclopropyl-5-[3-[(3S)-4-(3,5-difluorophenyl)-3-methyl-piperazin-1-yl]-3-oxo-propyl]imidazolidine-2,4-dione,

5-[3-[(3S)-4-(3-fluorophenyl)-3-methyl-piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-(2-pyridyl) imidazolidine-2,4-dione,

5-[3-[4-(4-chloro-3,5-di fluoro-phenyl) piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl) imidazolidine-2,4-dione,

5-cyclopropyl-5-[3-[4-(5-fluoro-2-methyl-phenyl) piperazin-1-yl]-2-methyl-3-oxo-propyl]imidazolidine-2,4-dione,

5-[3-[4-(3,5-dichlorophenyl)piperazin-1-yl]-2-methyl-3-oxo-propyl]-5-(methoxymethyl)imidazolidine-2,4-dione, or

5-[3-[(3S)-4-(3,4-dichlorophenyl)-3-methyl-piperazin-1-yl]-3-oxo-propyl]-5-(2-pyridyl)imidazolidine-2,4-dione.

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound according to claim 1 .

15. The pharmaceutical composition according to claim 14 , further comprising a second therapeutic agent.

16. The compound or pharmaceutically acceptable salt thereof, according to claim 1 , formulated as a medicament.

17. A method of treating and/or preventing an inflammatory condition, and/or disease involving degradation of cartilage and/or disruption of cartilage homeostasis comprising administering to a subject in need thereof, the compound or pharmaceutically acceptable salt thereof according to claim 1 .

18. The method according to claim 17 , further comprising administering to the subject in need thereof, a therapeutic agent effective in preventing and/or treating an inflammatory condition, and/or disease involving degradation of cartilage and/or disruption of cartilage homeostasis.