N-cyanopyrrolidines with activity as USP30 inhibitors

1 . A compound of formula (I), which is selected from formula (I)(i) and formula (I)(ii):

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer,

wherein:

R 1 is selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )fluoroalkyl and CH 2 OCH 3 ;

R 2 is selected from (C 1 -C 4 )alkyl, CF 3 and cyclopropyl; and

R 3 , R 4 and R 5 are each independently selected from hydrogen and halogen.

2 . The compound according to claim 1 , wherein R 1 is selected from methyl, CH 2 F, CHF 2 , CF 3 and CH 2 OCH 3 .

3 . The compound according to claim 2 , wherein R 1 is selected from methyl and CH 2 OCH 3 .

4 . The compound according to claim 1 , wherein R 2 is selected from methyl, CF 3 and cyclopropyl.

5 . The compound according to claim 4 , wherein R 2 is selected from methyl and cyclopropyl.

6 . The compound according to claim 1 , wherein R 3 is selected from hydrogen and fluorine.

7 . The compound according to claim 6 , wherein R 3 is hydrogen.

8 . The compound according to claim 1 , wherein R 4 and R 5 are each hydrogen.

9 . The compound according to claim 1 , having the formula (I)(i):

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

10 . The compound according to claim 9 , having the formula (IA)(i):

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

11 . The compound according to claim 10 , which is selected from:

5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-1-cyano-5-(fluoromethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-methoxyphenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)oxazole-2-carboxamide; and

5-(5-cyano-4-fluoro-2-methoxyphenyl)-N-((3R,5R)-1-cyano-5-methylpyrrolidin-3-yl)oxazole-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

12 . The compound according to claim 9 , having the formula (IB)(i):

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

13 . The compound according to claim 12 , which is selected from:

4-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide and

4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

14 . The compound according to claim 1 , having the formula (I)(ii):

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

15 . The compound according to claim 14 , having the formula (IA)(ii):

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

16 . The compound according to claim 15 , which is selected from:

5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5S)-1-cyano-5-methylpyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-methoxyphenyl)-N-((3R,5S)-1-cyano-5-methylpyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-methoxyphenyl)-N-((3R,5R)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5R)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-2-(trifluoromethoxy)phenyl)-N-((3R,5S)-1-cyano-5-methylpyrrolidin-3-yl)oxazole-2-carboxamide;

5-(5-cyano-4-fluoro-2-methoxyphenyl)-N-((3R,5S)-1-cyano-5-methylpyrrolidin-3-yl)oxazole-2-carboxamide; and

5-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-1-cyano-5-(fluoromethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

17 . The compound according to claim 14 , having the formula (IB)(ii):

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

18 . The compound according to claim 17 , which is selected from:

4-(5-cyano-2-cyclopropoxyphenyl)-N-((3R,5R)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide; and

4-(5-cyano-2-methoxyphenyl)-N-((3R,5R)-1-cyano-5-(methoxymethyl)pyrrolidin-3-yl)oxazole-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

19 . A pharmaceutical composition, comprising a compound of formula (I) according to claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, together with one or more pharmaceutically acceptable excipients.

20 . A compound, which is selected from formulae (II)(i), (III)(i), (II)(ii) and (III)(ii):

or a tautomer thereof, or a salt of said compound or tautomer;

wherein R 1 is selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )fluoroalkyl and CH 2 OCH 3 ; R 2 is selected from (C 1 -C 4 )alkyl, CF 3 and cyclopropyl; and R 3 , R 4 and R 5 are each independently selected from hydrogen and halogen; and PG is a protecting group, which is selected from the group consisting of tert-butyloxycarbonyl, benzyloxycarbonyl, p-methoxybenzyl carbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl, 3,4-dimethoxybenzyl, p-methoxyphenyl, tosyl, trichloroethoxycarbonyl, 4-nitrobenzenesulfonyl and 2-nitrophenylsulfenyl.