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

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.