NOVEL COMPOUNDS

• US 20190055232A1
• Filed: 02/16/2017
• Published: 02/21/2019
• Est. Priority Date: 02/18/2016
• Status: Active Grant

• Current Assignee: MISSION Therapeutics Ltd.
• Original Assignee: MISSION Therapeutics Ltd.
• Inventors: GIBSON, Karl Richard, JONES, Alison, KEMP, Mark Ian, MADIN, Andrew, STOCKLEY, Martin Lee, WHITLOCK, Gavin Alistair, WOODROW, Michael D.
• Granted Patent: US 10,640,498 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/10 : Spiro-condensed systems

Abstract

The present invention relates to novel compounds of formula (I) and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase 30 or ubiquitin specific peptidase 30 (USP30). The invention further relates to the use of DUB inhibitors in the treatment of conditions involving mitochondrial dysfunction and in the treatment of cancer.

Claims

1. A compound with the formula I:

2. The compound according to claim 1 wherein R³ or the ring formed by R² and R³ is substituted with one or more of -Q¹-(R⁴)_n moieties, wherein each occurrence of -Q¹(R⁴)_n is the same or different, wherein;

n is 0 or 1;

Q¹ represents halogen, cyano, oxo, nitro, —

OR⁵, —

SR⁵, —

NR⁵R⁶, —

CONR⁵R⁶, —

NR⁵COR⁶, —

NR⁵CONR⁶R⁷, —

COR⁵, —

C(O)OR⁵, —

SO₂R⁵, —

SO₂NR⁵R⁶, —

NR⁵SO₂R⁶, —

NR⁵SO₂NR⁶R⁷, —

NR⁵C(O)OR⁶, optionally substituted —

C₁-C₆ alkyl, optionally substituted —

C₁-C₆ alkoxy, optionally substituted —

C₂-C₆ alkenyl, a covalent bond, an oxygen atom, a sulphur atom, —

SO—

, —

SO₂—

, —

CO—

, —

C(O)O—

, —

CONR⁵—

, —

NR⁵—

, —

NR⁵CO—

, NR⁵CONR⁶—

, —

SO₂NR⁵—

, NR⁵SO₂—

, —

NR⁵SO₂NR⁶—

, —

NR⁵C(O)O—

, —

NR⁵C(O)OR⁶—

, optionally substituted C₁-C₆ alkylene, optionally substituted —

C₁-C₆, alkyleneoxy, or optionally substituted —

C₂-C₆ alkenylene, wherein the optional substituents for the alkyl, alkoxy, alkenyl, alkylene, alkyleneoxy and alkenylene are selected from halogen, deutero, hydroxyl, thiol, cyano, amino, nitro and SF₅;

R⁴ is an optionally substituted 3 to 10 membered monocyclic or bicyclic ring, wherein the optional substituents are selected from halogen, cyano, oxo, nitro, —

OR⁸, —

SR⁸, —

NR⁸R⁹, —

CONR⁸R⁹, —

NR⁸COR⁹, —

NR⁸CONR⁹R¹⁰, —

COR⁸, —

C(O)OR⁸, —

SO₂R⁸, —

SO₂NR⁸R⁹, —

NR⁸SO₂R⁹, NR⁸SO₂NR⁹R¹⁰, —

NR⁸C(O)OR⁹, optionally substituted —

C₁-C₆ alkyl, optionally substituted —

C₁-C₆ alkoxy, optionally substituted —

C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substituted heterocyclyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, -Q²-R⁸, -Q²-NR⁸CONR⁹R¹⁰, -Q²-NR⁸R⁹, -Q²-COR⁸, -Q²-NR⁸COR⁹, -Q²-NR⁸C(O)OR⁹, -Q²-SO₂R⁸, Q²-CONR⁸R⁹, -Q²-C₂R⁸, -Q²-SO₂NR⁸R⁹, -Q²-NR⁸SO₂R⁹ and -Q²-NR⁸SO₂NR⁹R¹⁰, wherein the optional substituents for the alkyl, alkoxy, alkenyl and alkynyl are selected from halogen, deutero, hydroxyl, thiol, cyano, amino, nitro and SF₅ and wherein the optional substituents for the heterocyclyl, cycloalkyl, heteroaryl and aryl are selected from halo, deutero, hydroxy, cyano, amino, nitro, aryl, heteroaryl, heterocyclyl, C₃-C₆ cycloalkyl, C_1-3 alkylamino, C_2-6 alkenylamino, di-C_1-3 alkylamino, C_1-3 acylamino, di-C_1-3 acylamino, carboxy, C_1-3 alkoxycarbonyl, carbamoyl, mono-C_1-3 carbamoyl and di-C_1-3 carbamoyl wherein the C₁-C₃ alkyl, C₁-C₃ alkoxy, C_1-3 alkylamino, C_2-6 alkenylamino, C₁-C₃ acylamino, carboxy-, C₁-C₃ alkoxycarbonyl, carboxamidyl, carbaaoyl, mono-C_1-3 carbamoyl or di-C_1-3 carbamoyl is optionally substituted by one or more halogen, deutero, hydroxyl, cyano, amino, nitro or SF₅, wherein Q² represents a covalent bond, an oxygen atom, a sulphur atom, —

SO—

, —

SO₂—

, —

CO—

,—

or a C₁-C₆ alkylene, optionally substituted —

C₁-C₆ alkyleneoxy or optionally substituted C₂-C₆ alkenylene, wherein the optional substituents for the alkylene, alkyleneoxy and alkenylene are selected from halogen, deutero, hydroxyl, thiol, cyano, amino, nitro and SF₅, wherein R⁸, R⁹, R¹⁰ each independently represent hydrogen, optionally substituted C₁-C₆ alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, or an optionally substituted cycloalkyl, wherein the optional substituents are selected from halo, deutero, hydroxy, cyano, amino, nitro, aryl, heteroaryl, heterocyclyl, C₃-C₆ cycloalkyl, C_1-3 alkylamino, C_2-6 alkenylamino, di-C_1-3 alkylamino, C_1-3 acylamino, di-C_1-3 acylamino, carboxy, C_1-3 alkoxycarbonyl, carbamoyl, mono-C_1-3 carbamoyl and di-C_1-3 carbamoyl, wherein the C₁-C₃ alkyl, C₁-C₃ alkoxy, C_1-3 alkylamino, C_2-6 alkenylamino, C₁-C₃ acylamino, carboxy, C₁-C₃ alkoxycarbonyl, carboxamidyl, carbamoyl, mono-C_1-3 carbamoyl or di-C_1-3 carbamoyl is optionally substituted by one or more halogen, deutero, hydroxyl, cyano, amino, nitro or SF₅;

R⁵, R⁶, R⁷ each independently represent hydrogen optionally substituted C₁-C₆ alkyl or optionally substituted C₁-C₆ alkylene.

3. The compound according to claim 2, wherein R³ or the ring formed by R² and R³ is unsubstituted or substituted with one or two -Q¹-(R⁴)_n moieties, which are the same or different, and wherein n is 1 for at least one of the moieties.

4. The compound according to claim 1, wherein R³ is an optionally substituted nitrogen-containing monocyclic or icyclic heteroaryl ring.

5. The compound according to claim 1, wherein R² and R³ together form an optionally substituted 9 or 10 membered bicyclic ring.

6. The compound according to claim 1, wherein R³ is selected from thiazolyl, pyridinyl, pyridazinyl, benzothiazolyl and isoxazolyl, or when R² together with R³ form a ring the ring is selected from indolinyl, dihydropyrrolopyridinyl, tetrahydroquinolinyl and dihydrobenzoxazinyl.

7. The compound according to claim 2, wherein R⁴ is selected from phenyl, pyridinyl, pyrazolyl and indazolyl.

8. The compound according to claim 1, wherein R^1a represents hydrogen, fluorine, cyano, hydroxyl, amino, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy or an optionally substituted 5 or 6 membered heteroaryl or aryl ring, or R^1a is linked to R^1b to form an optionally substituted cycloalkyl ring, or R^1a is linked to R² to form an optionally further substituted ring, wherein the optional substituents for the alkyl or alkoxy are selected from halogen, deutero, hydroxyl, thiol, cyano, amino, nitro and SF₅, and wherein the optional substituents for the rings are selected from halogen, deutero, cyano, oxo, nitro, amino, hydroxy, C₁-C₃ alkyl, C₁-C₃ alkoxy, C_1-3 alkylamino, C_2-6 alkenylamino, C₁-C₃ acylamino, carboxy, C₁-C₃ alkoxycarbonyl, carboxamidyl, carbamoyl, wherein any hydrocarbyl moiety may itself be substituted by one or more halogen.

9. The compound according to claim 8, wherein R² together with R^1a or R^1g forms a 5 or 6 membered heterocyclyl ring.

10. The compound according to claim 8, wherein R^1a is hydrogen or fluorine.

11. The compound according to claim 1, wherein R^1b, R^1c, R^1d and R^1e each independently represent hydrogen or an optionally substituted C₁-C₆ alkyl, or R^1b is linked to R^1c or R^1a to form an optionally substituted cycloalkyl ring, or R^1e is linked to R^1d or R^1f to form an optionally substituted cycloalkyl ring, wherein the optional substituents for the alkyl are selected from halogen, deutero, hydroxyl, thiol, cyano, amino, nitro and SF₅, and wherein the optional substituents for the rings are selected from halogen, deutero, cyano, oxo, nitro, amino, hydroxy, C₁-C₃ alkyl, C₁-C₃ alkoxy, C_1-3 alkylamino, C_2-6 alkenylamino, C₁-C₃ acylamino, carboxy, C₁-C₃ alkoxycarbonyl, carboxamidyl, carbamoyl, wherein C₁-C₃ alkyl, C₁-C₃ alkoxy, C_1-3 alkylamino, C_2-6 alkenylamino, C₁-C₃ acylamino, carboxy, C₃-C₃ alkoxycarbonyl, carboxamidyl, carbamoyl, mono-C_1-3 carbamoyl or di-C_1-3 carbamoyl is optionally substituted by one or more halogen.

12. The compound according claim 1, wherein R^1a, R^1b, R^1c, R^1d, R^1e and R^1g each represent hydrogen.

13. The compound according to claim 1, wherein R² represents an optionally substituted C₁-C₃ alkyl wherein the optional substituents are selected from halogen, deutero, hydroxyl, thiol, cyano, amino, nitro and SF₅.

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

15. The compound of formula I as defined in claim 1, selected from the group consisting of:

1-cyano-N-ethyl-N-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

1-cyano-N-ethyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

(S)-1-cyano-N-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

(S)-1-cyano-N-methyl-N-(4-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;

(S)-1-cyano-N-methyl-N-(6-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;

1-cyano-N-isopropyl-N-(5-(pyridin-4-yl)thiazol-2-yl)pyrrolidine-3-carboxamide;

1-cyano-N-isopropyl-N-(4-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

1-cyano-3-fluoro-N-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

N-(benzo[d]thiazol-2-yl)-1-cyano-3-fluoro-N-methylpyrrolidine-3-carboxamide;

(S)-3-(4-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(6-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-(3-chlorophenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(3S,4S)-3-(5-(2-chlorophenyl)indoline-1-carbonyl)-4-methylpyrrolidine-1-carbonitrile;

3-fluoro-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(6-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(6-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(3S,4S)-3-methyl-4-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(3R,4R)-3-methyl-4-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-phenyl-2,3-dihydro-1 i-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(6-phenyl-1,2,3,4-tetrahydroquinoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(7-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(8-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(4-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(4-(3-chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-1-(1-cyanopyrrolidine-3-carbonyl)-5-(1-methyl-1H-pyrazol-4-yl)indoline-6-carbonitrile;

(R)-3-(7-(1H-pyrazol-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(S)-1-cyano-N-methyl-N-(5-phenylpyridin-2-yl)pyrrolidine-3-carboxamide;

(R)-1-cyano-N-methyl-N-(5-phenylpyridazin-3-yl)pyrrolidine-3-carboxamide;

1-cyano-3-fluoro-N-methyl-N-(5-phenylisoxazol-3-yl)pyrrolidine-3-carboxamide;

(3S,4S)-1-cyano-4-(hydroxymethyl)-N-methyl-N-(5-phenylthiazol-2-yl)pyrrolidine-3-carboxamide;

3-(5-(1-benzyl-1H-pyrazol-5-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-fluoro-3-(5-((1-methyl-1H-pyrazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(4-(4-methylpiperazin-1-yl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(4-(4-methylpiperazine-1-carbonyl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(1-methyl-1H-indazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(2-fluoro-5-methylphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(5-methyl-1H-indazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

N-(3-(1-(1-cyano-3-fluoropyrrolidine-3-carbonyl)indolin-5-yl)phenyl)cyclopropanesulfonamide;

3-fluoro-3-(5-(6-methoxypyridin-3-yl)indoine-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-1-cyano-N-(5-(4-cyanophenyl)pyridin-2-yl)-N-ethylpyrrolidine-3-carboxamide;

N-(benzo[d]thiazol-2-ylmethyl)-1-cyano-N-methylpyrrolidine-3-carboxamide;

I-cyano-N-methyl-N-((3-phenylisoxazol-5-yl)methyl)pyrrolidine-3-carboxamide;

1-cyano-N-methyl-N-((2-phenylthiazol-4-yl)methyl)pyrrolidine-3-carboxamide;

(3aR,6aS)-4-oxo-5-(5-phenylthiazol-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonitrile; and

7-([1,1′

-biphenyl]-3-yl)-6-oxo-2,7-diazaspiro[4.4]nonane-2-carbonitrile, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, selected from the group consisting of:

(S)-3-(4-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(6-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-(3-chlorophenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(3S,4S)-3-(5-(2-chlorophenyl)indoline-1-carbonyl)-4-methylpyrrolidine-1-carbonitrile;

3-fluoro-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(6-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(6-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(3S,4S)-3-methyl-4-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(3R,4R)-3-methyl-4-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(S-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(6-phenyl-1,2,3,4-tetrahydroquinoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(7-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(6-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(8-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(4-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(4-(3-chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-1-(1-cyanopyrrolidine-3-carbonyl)-5-(1-methyl-1H-pyrazol-4-yl)indoline-6-carbonitrile;

(R)-3-(7-(1H-pyrazol-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)pyrrolidine-1-carbonitrile;

3-(5-(1-benzyl-1-H-pyrazol-5-yl)indoline-1-carbonyl-3-fluoropyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(1-methy-1H-pyrazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(4-(4-methylpiperazin-1-yl)phenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(4-(4-methylpiperazine-1-carbonyl)pyrrolidine-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(1-methyl-1H-indazol-5-yl)indoline-1-carbonyl)pyrrolidine-I-carbonitrile;

3-fluoro-3-(5-(2-fluoro-5-methylphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(5-(5-methyl-H-indazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

N-(3-(1-(1-cyano-3-fluoropyrrolidine-3-carbonyl)indolin-5-yl)phenyl)cyclopropanesulfonamide

3-fluoro-3-(5-(6-methoxypyridin-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-(4-(3-ethylphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-1-(1-cyanopyrrolidine-3-carbonyl)-N-methyl-4-phenylindoline-6-carboxamide;

(R)-1-(1-cyanopyrrolidine-3-carbonyl)-4-(3-ethylphenyl)-N-methylindoline-6-carboxamide;

(R)-3-(5-(1H-indazol-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-(1H-indazol-4-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

3-(5-phenyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

(trans)-3-methyl-4-(5-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(1-isobutyl-1H-pyrazol-5-yl)indoline-I-carbonyl)pyrrolidine-1-carbonitrile;

3-(5-(1-benzyl-1H-pyrazol-4-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-fluoro-3-5-(1-(pyridin-2-ylmethyl)-1H-pyrazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

N-benzyl-1-(1-cyano-3-fluoropyrrolidine-3-carbonyl)indoline-5-carboxamide;

3-(5-(1-(2-chlorobenzyl)-1H-pyrazol-5-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-(5-(1-(3-chlorobenzyl)-1-pyrazol-5-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-5-(1-(4-chlorobenzyl)-1H-pyrazol-5-yl)indoline-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile;

3-fluoro-3-3(5-(1-(pyridin-3-ylmethyl)-11-pyrazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-fluoro-3-(5-(pyridin-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(R)-3-fluoro-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-fluoro-3-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-3-(5-(3-chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile; and

(R)-3-(5-(3-chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile,

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16, wherein said compound is 3-fluoro-3-(5-(2-fluoro-5-methylphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile or (R)-3-(5-(3-chlorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carbonyl)-3-fluoropyrrolidine-1-carbonitrile, or a pharmaceutically accept able salt thereof.

18. A process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof as defined according to claim 1, which comprises reacting an amine of formula (IV) with cyanogen bromide:

20. A method for the treatment of a disease or disorder related to USP30 modulation, comprising the step of administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a patent in need thereof.

21. A method for the treatment of a condition involving mitochondrial dysfunction, comprising the step of administering a therapeutical v effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

22. The method according to claim 21, wherein the condition involving mitochondrial dysfunction is selected from a neurodegenerative disease;

multiple Sclerosis (MS), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome;

Leber'"'"'s hereditary optic neuropathy (LHON);

cancer;

neuropathy, ataxia, retinitis pigmentosa-maternally inherited Leigh syndrome (NARP-MILS);

Danon disease;

diabetes;

diabetic nephropathy;

metabolic disorders;

heart failure;

ischemic heart disease leading to myocardial infarction;

psychiatric diseases, for example schizophrenia;

multiple sulfatase deficiency (MSD);

mucolipidosis II (ML II);

mucolipidosis Ill (ML III);

mucolipidosis IV (ML IV);

GM1-gangliosidosis (GM1);

neuronal ceroid-lipofuscinoses (NCL1);

Alpers disease;

Barth syndrome;

Beta-oxidation defects;

carnitine-acyl-carnitine deficiency;

carnitine deficiency;

creatine deficiency syndromes;

co-enzyme Q10 deficiency;

complex 1 deficiency;

complex II deficiency;

complex III deficiency;

complex IV deficiency;

complex V deficiency;

COX deficiency;

chronic progressive external ophthalmnoplegia syndrome (CPEO);

CPT I deficiency;

CPT II deficiency;

glutaric aciduria type II;

Kearns-Sayre syndrome;

lactic acidosis;

long-chain acyl-CoA dehydrogenase deficiency (LCHAD);

Leigh disease or syndrome;

lethal infantile cardiomyopathy (LIC);

Luft disease;

glutaric aciduria type II;

medium-chain acyl-CoA dehydrogenase deficiency (MCAD);

miyoclonic epilepsy and ragged-red fiber (MERRF) syndrome;

mitochondrial cytopathy;

mitochondrial recessive ataxia syndrome;

mitochondrial DNA depletion syndrome;

myoneurogastrointestinal disorder and encephalopathy;

Pearson syndrome;

pyruvate dehydrogenase deficiency;

pyruvate carboxylase deficiency;

POLG mutations;

medium/short-chain 3-hydroxyacyl-CoA de hydrogenase (M/SCHAD) deficiency; and

very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.

23. The method according to claim 21, wherein the condition involving mitochondrial dysfunction is a central nervous system disorder.

24. A method the treatment of cancer, comprising the step of administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

25. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutical acceptable salt thereof, together with one or more pharmaceutically acceptable excipients.

19. (canceled)