Cyanopyrrolidines as dub inhibitors for the treatment of cancer

1. A compound of formula (I):

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

R 1 , R 2 and R 7 each independently represent a hydrogen atom or C 1 -C 6 alkyl;

R 3 , R 4 , R 5 and R 6 each independently represent a hydrogen atom, a halogen atom, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, a 3 to 10 membered cycloalkyl or heterocyclyl, or a 5 to 10 membered heteroaryl or aryl;

R 9 forms a 5 to 10-membered monocyclic or bicyclic heterocyclyl or heteroaryl ring with R 8 ;

wherein the ring formed between R 8 and R 9 is optionally substituted with one or more R 10 substituents;

each R 10 is independently selected from a halogen atom, oxo, cyano, —OR 11a , —SR 11a , —NO 2 , —NR 11a R 12a , —CONR 11a R 12a , —NR 11a COR 12a , —NR 11a CONR 12a R 13a , —COR 11a , —C(O)OR 11a , —SO 2 R 11a , —SO 2 NR 11a R 12a , —NR 11a SO 2 R 12a , —NR 11a SO 2 NR 12a R 13a , —NR 11a C(O)OR 12a , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, and —C 2 -C 6 alkenyl;

R 11a , R 12a and R 13a each independently represent a hydrogen atom or C 1 -C 6 alkyl;

wherein the ring formed between R 8 and R 9 is also optionally substituted with one, two, or more, R 14 substituents, which are each attached to the ring through Q;

Q is selected from a covalent bond, an oxygen atom, a sulphur atom, —NR 11 —, —CONR 11 —, —NR 11 CO—, —NR 11 CONR 12 —, —CO—, —C(O)O—, —SO—, —SO 2 —, —SO 2 NR 11 —, —NR 11 SO 2 —, —NR 11 SO 2 NR 12 —, —NR 11 C(O)O—, —NR 11 C(O)OR 13 —, —C 1 -C 6 alkylene, —C 1 -C 6 alkyleneoxy and —C 2 -C 6 alkenylene;

R 11 and R 12 each independently represent a hydrogen atom or C 1 -C 6 alkyl;

R 13 represents a C 1 -C 6 alkylene group;

R 14 represents a 3 to 10-membered monocyclic or bicyclic cycloalkyl or heterocyclyl or a 5 to 10-membered monocyclic or bicyclic heteroaryl or aryl;

and each occurrence of R 14 and Q is the same or different;

wherein R 14 is optionally substituted with one or more substituents each independently selected from a halogen atom, oxo, cyano, —OR 15 , —SR 15 , —NO 2 , —NR 15 R 16 , —CONR 15 R 16 , —NR 15 COR 16 , —NR 15 CONR 16 R 17 , —COR 15 , —C(O)OR 15 , —SO 2 R 15 , —SO 2 NR 15 R 16 , —NR 15 SO 2 R 16 , —NR 15 SO 2 NR 16 R 17 , —NR 15 C(O)OR 16 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 alkylene, —C 1 -C 6 alkyleneoxy, —C 2 -C 6 alkenyl, —C 2 -C 6 alkenylene, methoxymethyl, methoxyethoxy, 3 to 10-membered cycloalkyl or heterocyclyl, and 5 to 10-membered heteroaryl or aryl, wherein the —C 1 -C 6 alkylene, —C 1 -C 6 alkyleneoxy or —C 2 -C 6 alkenylene group is attached to a 3 to 10-membered cycloalkyl or heterocyclyl or 5 to 10-membered heteroaryl or aryl;

R 15 , R 16 and R 17 each independently represent a hydrogen atom, C 1 -C 6 alkyl, a 3 to 10-membered cycloalkyl or heterocyclyl or 5 to 10-membered heteroaryl or aryl;

each C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 1 -C 6 alkylene, C 1 -C 6 alkyleneoxy and C 2 -C 6 alkenylene, is optionally substituted with one or more substituents, which may be the same or different, selected from halogen, hydroxyl, thiol, cyano, amino, nitro and SF 5 ; and

each cycloalkyl, aryl, heterocyclyl and heteroaryl ring of R 3 , R 4 , R 5 and R 6 is optionally substituted with one or more substituents, which may be the same or different, selected from halogen, hydroxyl, thiol, cyano, amino, nitro, SF 5 , C 1 -C 6 alkyl and C 1 -C 6 alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen.

2. The compound according to claim 1 , wherein R 1 , R 2 , R 5 , R 6 and R 7 are each hydrogen.

3. The compound according to claim 1 , wherein R 3 and R 4 independently represent a hydrogen atom, a halogen atom, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy or an optionally substituted 6-membered aryl.

4. The compound according to claim 1 , wherein R 10 is selected from a halogen atom, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, —NR 11a R 12a , and —CONR 11a R 12a .

5. The compound according to claim 1 , wherein the optionally substituted ring formed by R 8 and R 9 is selected from isoindolinyl, indolinyl, benzomorpholinyl, pyrrolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and tetrahydropyrrolopyrazolyl.

6. The compound according to claim 1 , wherein R 14 represents an optionally substituted 5 or 6-membered heteroaryl, aryl, heterocyclyl or an optionally substituted 3 to 5-membered cycloalkyl.

7. The compound according to claim 1 , wherein the optionally substituted heteroaryl, aryl, heterocyclyl, or cycloalkyl ring of R 14 is selected from phenyl, isoxazolyl, pyridinyl, pyrazolyl, cyclopropyl, tetrahydrofuran, pyrimidinyl, pyrrolopyridinyl, pyrazinyl, imidazopyridinyl, benzodioxolyl, triazolyl, imidazolyl, indazolyl, pyrrolopyrazinyl, pyridazinyl, pyrazolopyridinyl, and quinolinyl.

8. The compound according to claim 1 , wherein Q is selected from a covalent bond, an oxygen atom, optionally substituted C 1 -C 6 alkylene, and optionally substituted C 1 -C 6 alkyleneoxy.

9. The compound according to claim 1 , wherein R 14 is substituted with one or more substituents selected from fluorine, chlorine, cyano, nitro, methyl, ethyl, cyclopropyl, CF 3 , methoxy, ethoxy, methoxymethyl, methoxyethoxy, propoxy, OCF 3 , C(O)NHMe, NHC(O)Me, NMeC(O)Me, NMeS(O) 2 Me, S(O) 2 Me, NH 2 , NHMe and N(Me) 2 .

10. The compound according to claim 1 , having the stereochemistry of formula (II):

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

11. A compound, wherein said compound is:

(S)-2-(4-ethoxyindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-isopropoxyindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-phenoxyindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-phenoxyindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(3,5-dimethylisoxazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(3-methoxyphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(4-methoxyphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(2,6-dimethylphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(2-methoxyphenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

3-(1-(cyano-L-prolyl)indolin-4-yl)-N-methylbenzamide;

(S)-2-(4-cyclopropylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(2S,4S)-4-methoxy-2-(4-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(2S,4R)-4-methoxy-2-(4-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(5-methylisoxazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(5-(trifluoromethyl)-1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(5-methyl-1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(4-cyanophenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(3-cyanophenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(2-cyanophenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(3,5-dimethyl-1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(1H-pyrazol-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(1H-pyrrolo[2,3-b]pyridin-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-4,4-difluoro-2-(4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(2S,4S)-4-fluoro-2-(4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-4,4-difluoro-2-(4-(5-methyl-1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(1H-pyrazol-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-phenylisoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-phenylisoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(pyridin-2-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(pyridazin-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(pyrimidin-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(3-cyclopropyl-1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(2-aminopyrimidin-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(pyridin-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(5-methylisoxazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(3,5-dimethylisoxazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(pyridin-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(6-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

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

(S)-2-(5-phenyl-1,2,3,4-tetrahydroquinoline-1-carbonyl)pyrrolidine-1-carbonitrile;

ethyl 4-(1-(cyano-L-prolyl)indolin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylate;

(S)-2-(4-(3-methylisoxazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(1H-imidazol-1-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

4-(1-(cyano-L-prolyl)indolin-4-yl)-1H-pyrazole-5-carbonitrile;

(S)-2-(5-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(2-aminopyridin-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

1-(cyano-L-prolyl)-4-phenylindoline-6-carboxamide;

1-(cyano-L-prolyl)-N-ethyl-4-phenylindoline-6-carboxamide;

1-(cyano-L-prolyl)-4-(3-ethylphenyl)-N-methylindoline-6-carboxamide;

1-(cyano-L-prolyl)-N-methyl-4-(quinolin-6-yl)indoline-6-carboxamide;

1-(cyano-L-prolyl)-N-methyl-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)indoline-6-carboxamide;

(S)-2-(6-(1H-imidazol-2-yl)-4-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-phenyl-6-(4H-1,2,4-triazol-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(6-(5-methyl-4H-1,2,4-triazol-3-yl)-4-phenylindoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(4-cyanophenyl)-6-(5-methyl-4H-1,2,4-triazol-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(3-cyanophenyl)-6-(5-methyl-4H-1,2,4-triazol-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(2S,4S)-4-fluoro-2-(4-(5-methyl-1H-pyrazol-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

N-(4-(1-(cyano-L-prolyl)indolin-4-yl)pyridin-2-yl)acetamide;

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

1-(cyano-L-prolyl)-N-methyl-4-(4-(trifluoromethyl)phenyl)indoline-6-carboxamide;

1-(cyano-L-prolyl)-4-(3-cyanophenyl)-N-methylindoline-6-carboxamide;

1-(cyano-L-prolyl)-4-(4-cyanophenyl)-N-methylindoline-6-carboxamide;

4-(4-chlorophenyl)-1-(cyano-L-prolyl)-N-methylindoline-6-carboxamide;

1-(cyano-L-prolyl)-N-methyl-4-(m-tolyl)indoline-6-carboxamide;

4-(2-chlorophenyl)-1-(cyano-L-prolyl)-N-methylindoline-6-carboxamide;

1-(cyano-L-prolyl)-4-(3,4-dichlorophenyl)-N-methylindoline-6-carboxamide;

4-(benzo[d][1,3]dioxol-5-yl)-1-(cyano-L-prolyl)-N-methylindoline-6-carboxamide;

(S)-2-(1-phenyl-1,4,5,6-tetrahydropyrrolo[3,2-c]pyrazole-4-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(3-chlorophenyl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(4-cyanophenyl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(3-cyanophenyl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

4-(1-(cyano-L-prolyl)indolin-4-yl)nicotinonitrile;

(S)-2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(6-aminopyridin-2-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(6-aminopyrazin-2-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(2-(methylamino)pyrimidin-4-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(2-aminopyrimidin-5-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(1H-pyrazolo[3,4-b]pyridin-3-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(4-(5H-pyrrolo[2,3-b]pyrazin-7-yl)indoline-1-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(3-(trifluoromethoxy)phenyl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(3-methyl-1H-indazol-6-yl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(1-methyl-1H-indazol-5-yl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(4-(methylsulfonyl)phenyl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(2-cyanophenyl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

(S)-2-(5-(3-nitrophenyl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile; and

(S)-2-(5-(3-cyano-2-fluorophenyl)isoindoline-2-carbonyl)pyrrolidine-1-carbonitrile;

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

12. A pharmaceutical composition, comprising the compound according to claim 1 , a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, and one or more pharmaceutically acceptable excipients.

13. A method of treating a disease selected from breast cancer, colon cancer, lung or kidney tumors, osteosarcoma, multiple myeloma and Parkinson's disease, comprising the step of administering a therapeutically effective amount of the compound according to claim 1 , a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, to a patient in need thereof, wherein the patient is suffering from the disease.

14. A pharmaceutical composition, comprising the compound according to claim 11 , a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, and one or more pharmaceutically acceptable excipients.

15. A method of treating a disease selected from breast cancer, colon cancer, lung or kidney tumors, osteosarcoma, multiple myeloma and Parkinson's disease, comprising the step of administering a therapeutically effective amount of the compound according to claim 11 , a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, to a patient in need thereof, wherein the patient is suffering from the disease.