Spiro-condensed pyrrolidine derivatives as deubiquitylating enzymes (dub) inhibitors

Abstract

The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of Cezanne 1. The invention further relates to the use of DUB inhibitors in the treatment of cancer.

1 - 15 . (canceled) 
     
     
         16 . A method for treating a neurodegenerative disease, comprising the step of administering an effective amount of a compound of formula I, a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer, to a patient in need thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1a , R 1b , R 1c  and R 1d  each independently represent hydrogen or C 1 -C 6  alkyl; 
         R 1e  and R 1f  each independently represent hydrogen or C 1 -C 6  alkyl; 
         ring A is a 9, 10 or 11-membered fused bicyclic heterocyclyl ring, which in addition to the amide nitrogen optionally comprises 1, 2 or 3 heteroatoms each independently selected from N, O and S; wherein the ring fused to the amide-containing ring is aromatic; and which may be optionally substituted with one -Q 1 -(R 2 ) n , wherein n is 1; and optionally one, two or three -Q 1 -(R 2 ) n , wherein n is 0; wherein each -Q 1 -(R 2 ) n  is the same or different; 
         when n is 0, Q 1  represents halogen, cyano, oxo, hydroxyl, —NR 3 R 4 , —CONR 3 R 4 , —NR 3 COR 4 , —NR 3 CONR 4 R 4a , —COR 3 , —C(O)OR 3 , —C 1 -C 6  alkyl, or —C 1 -C 6  alkoxy; wherein the alkyl and alkoxy groups are optionally substituted with one to four halogen substituents; 
         when n is 1, Q 1  represents a covalent bond, an oxygen atom, a sulphur atom, —SO—, —SO 2 —, —CO—, —C(O)O—, —CONR 3 —, —NR 3 —, —NR 3 CO—, —NR 3 CONR 4 —, SO 2 NR 3 —, —NR 3 SO 2 —, —NR 3 SO 2 NR 4 —, —NR 3 C(O)O—, —NR 3 C(O)OR 5 —, C 1 -C 6  alkylene, or —C 2 -C 6  alkenylene; 
         R 2  represents a phenyl ring or a 5 to 10-membered heterocyclyl or heteroaryl ring, wherein said heterocyclyl and heteroaryl rings comprise 1, 2 or 3 heteroatoms, each independently selected from N, O and S; 
         wherein said R 2  ring is optionally substituted with one to two substituents independently selected from halogen, cyano, oxo, hydroxyl, —NR 6 R 7 , —CONR 6 R 7 , —NR 6 COR 7 , —NR 6 CONR 7 R 7a , —COR 6 , —C(O)OR 6 , —C 1 -C 6  alkyl, —C 1 -C 6  alkoxy, -Q 2a -R 8 , -Q 2b -CONR 6 -Q 2c -R 8 , and -Q 2 -NR 6 SO 2 -Q 2c -R 8 ; wherein the alkyl and alkoxy groups are optionally substituted with one to four substituents selected from halogen and hydroxyl; 
         Q 2a  represents a covalent bond, an oxygen atom, a sulphur atom, —SO—, —SO 2 —, —CO—, or C 1 -C 6  alkylene; 
         Q 2b  and Q 2c  each represent a covalent bond; 
         R 3 , R 4  and R 4a  each independently represent hydrogen or C 1 -C 6  alkyl; 
         R 6 , R 7  and R 7a  each independently represent hydrogen or C 1 -C 6  alkyl; and 
         R 8  is selected from phenyl, piperazinyl, cyclopropyl, morpholinyl and piperidinyl; wherein R 8  is optionally substituted by fluorine, chlorine, oxo, cyano, C 1 -C 3  alkyl, or C 1 -C 3  alkoxy. 
       
     
     
         17 . The method according to  claim 16 , wherein ring A is selected from indoline-2-one,
 3,4-dihydroquinolin-2(1H)-one, 1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one,   3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-one, 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one,   3,4-dihydro-1,5-naphthyridin-2(1H)-one, 3,4-dihydro-1,6-naphthyridin-2(1H)-one,   3,4-dihydro-1,7-naphthyridin-2(1H)-one, 3,4-dihydro-1,8-naphthyridin-2(1H)-one,   3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-one and   1,2,3,5-tetrahydro-4H-pyrido[2,3-b][1,4]diazepin-4-one.   
     
     
         18 . The method according to  claim 16 , wherein n is 1, and Q 1  is selected from a covalent bond and C 1 -C 3  alkylene. 
     
     
         19 . The method according to  claim 16 , wherein R 2  is phenyl or a 5 or 6-membered monocyclic, or a 9 or 10-membered bicyclic, optionally substituted, heterocyclyl or heteroaryl ring. 
     
     
         20 . The method according to  claim 19 , wherein R 2  is selected from optionally substituted, piperidinyl, pyrrolyl, phenyl, pyrazolyl, isoxazolyl, indazolyl, pyridinyl, dihydropyridinyl, benzothiazolyl and pyrimidinyl. 
     
     
         21 . The method according to  claim 16 , wherein R 2  is unsubstituted, or substituted with one or two substituents selected from halogen, cyano, oxo, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, —CONR 6 R 7 , —NR 6 COR 7 , -Q 2a -R 8 , and -Q 2b -NR 6 SO 2 -Q 2c -R 8 ; wherein
 alkyl and alkoxy are optionally substituted with fluorine; 
 Q 2a  is a covalent bond, an oxygen atom, —CO—, —SO 2 — or —C 1 -C 3  alkylene; 
 R 6  and R 7  are each independently selected from hydrogen and C 1 -C 3  alkyl. 
 
     
     
         22 . The method according to  claim 16 , wherein n is 0; Q 1  is selected from oxo, methyl, ethyl, CF 3 , methoxy, halogen and —C(O)NR 3 R 4 ; and R 3  and R 4  are each independently selected from hydrogen and methyl. 
     
     
         23 . The method according to  claim 16 , wherein R 1a , R 1b , R 1c , R 1d , R 1f  and R 1e  are each hydrogen. 
     
     
         24 . The method according to  claim 16 , wherein the compound of formula I is selected from:
 2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-chloro-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-methoxy-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(5-isopropyl-2-methoxyphenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-([1,1′-biphenyl]-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(4-(benzyloxy)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(2-fluoro-5-methylphenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(3-cyanophenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(1-methyl-1H-pyrazol-5-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   2′-oxo-7′-(4-phenoxyphenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(4-cyanophenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(2-chloro-5-(trifluoromethoxy)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   5-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-7′-yl)-N-methylpicolinamide;   7′-(2-(benzyloxy)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   4-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-7′-yl)-N-methylbenzamide;   7′-(3-((2-chlorobenzyl)oxy)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(4-(4-methylpiperazin-1-yl)phenyl)-2′-oxo -1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(6-methoxypyridin-3-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(5-fluoro-2-isopropoxyphenyl)-2′-oxo-1′,4′-dihydro -2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(3-methyl-1H-indazol-6-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(4-(4-methylpiperazine-1-carbonyl)phenyl)-2′-oxo -1′,4′-dihydro -2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(1-methyl-1H-indazol-5-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(5-methyl-1H-indazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   N-(3-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-7′-yl)phenyl)cyclopropane sulfonamide;   7′-(3-methyl-1H-pyrazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   2′-oxo-7′-(pyrimidin-5-yl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   N-(3-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-7′-yl)phenyl)acetamide;   3-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-7′-yl)-N,N-dimethylbenzamide;   N-(4-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-7′-yl)phenyl)acetamide;   7′-(4-(morpholino sulfonyl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(3,5-dimethyl-1H-pyrazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(2-methylpyridin-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   2′-oxo-7′-(3-(piperidin-1-yl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   N-(2-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-7′-yl)phenyl)acetamide;   7′-(4-(morpholine-4-carbonyl)phenyl)-2′-oxo -1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(3-(morpholino sulfonyl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(2-methylbenzo[d]thiazol-5-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   2′-oxo-6′-phenyl -1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(4-cyanophenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(3-cyanophenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(4-fluorophenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(3-fluorophenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   1-cyano-N,N-dimethyl-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-7′-carboxamide;   1-cyano-N-methyl-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-7′-carboxamide;   2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   2-oxo-7-phenyl-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(4-cyanophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(3-cyanophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(4-fluorophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(3-fluorophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   2-oxo-6-phenyl-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   2-oxo-6-(trifluoromethyl)-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   2-oxo-7-phenyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(4-cyanophenyl)-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(4-fluorophenyl)-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(3-fluorophenyl)-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   3-oxo-3,4-dihydro-1H-spiro[pyrido[2,3-b]pyrazine-2,3′-pyrrolidine]-1′-carbonitrile;   (S)-2-oxo-7-phenyl-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   (S)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   (S)-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   (R)-2′-oxo-6′-phenyl-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   (S)-2-oxo-7-phenyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   (S)-7-(3-fluorophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   (S)-7-(4-cyanophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   (S)-7-(3-cyanophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   (S)-7-(4-fluorophenyl)-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   (S)-7-(3-fluorophenyl)-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   (S)-7-(4-fluorophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   (S)-7-(3-cyanophenyl)-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   2-oxo-1,5-dihydro-2H-spiro[benzo[e][1,4]oxazepine-3,3′-pyrrolidine]-1′-carbonitrile;   2-oxo-1,2,4,5-tetrahydrospiro[pyrido[2,3-b][1,4]diazepine-3,3′-pyrrolidine]-1′-carbonitrile;   2-oxo-6-phenyl-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(5-methyl-1H-indazol-4-yl)-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(1,4-dimethyl-1H-pyrazol-5-yl)-2-oxo-1,4-dihydro-2H-spiro[pyrido[2,3-b]pyrazine-3,3′-pyrrolidine]-1′-carbonitrile;   (R)-7′-(5-methyl-1H-indazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(1H-indazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(1H-indazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   1′-cyano-N-(4-fluorophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-6-carboxamide;   2-oxo-6-(piperidine-1-carbonyl)-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(1H-indazol-4-yl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   6-(1H-indazol-4-yl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   1′-cyano-2-oxo-N-phenyl-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-6-carboxamide;   1′-cyano-N-(2-fluorophenyl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-6-carboxamide;   7-(1-methyl-1H-indazol-4-yl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(1-(2-hydroxyethyl)-1H-indazol-4-yl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(1-(2-methoxyethyl)-1H-indazol-4-yl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   7-(6-methoxy-2-methylpyridin-3-yl)-2-oxo-1,2-dihydrospiro[pyrido[2,3-b][1,4]oxazine-3,3′-pyrrolidine]-1′-carbonitrile;   2′-oxo-7′-(3-(trifluoromethoxy)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   4-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-7′-yl)-N,N-dimethylbenzamide;   7′-(3-(4-methylpiperazine-1-carbonyl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   7′-(1-methyl-1H-pyrrol-2-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-([1,1′-biphenyl]-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(4-(benzyloxy)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(1-methyl-1H-pyrazol-5-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   2′-oxo-6′-(3-(trifluoromethoxy)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   2′-oxo-6′-(4-phenoxyphenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(1-methyl-1H-pyrazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   5-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-6′-yl)-N-methylpicolinamide;   6′-(2-(benzyloxy)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   4-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-6′-yl)-N-methylbenzamide;   6′-(5-isopropyl-2-methoxyphenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(3-((2-chlorobenzyl)oxy)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(6-methoxypyridin-3-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(5-fluoro-2-isopropoxyphenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(3-methyl-1H-indazol-6-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(4-(4-methylpiperazine-1-carbonyl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(1-methyl-1H-indazol-5-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(5-methyl-1H-indazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   N-(3-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-6′-yl)phenyl)cyclopropanesulfonamide;   4-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-6′-yl)-N,N-dimethylbenzamide;   2′-oxo-6′-(pyrimidin-5-yl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   N-(3-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-6′-yl)phenyl)acetamide;   N-(4-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-6′-yl)phenyl)acetamide;   6′-(3-(4-methylpiperazine-1-carbonyl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(1-methyl-1H-pyrrol-2-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(4-(morpholinosulfonyl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(3,5-dimethyl-1H-pyrazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   2′-oxo-6′-(3-(piperidin-1-yl)phenyl)-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   N-(2-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-6′-yl)phenyl)acetamide;   6′-(4-(morpholine-4-carbonyl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(3-(morpholinosulfonyl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(2-methylbenzo[d]thiazol-5-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(3,5-dimethylisoxazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(2-chloro-5-(trifluoromethoxy)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(4-(4-methylpiperazin-1-yl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   N-benzyl-4-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-6′-yl)benzamide;   6′-(3-methyl-1H-pyrazol-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   6′-(4-(morpholinomethyl)phenyl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   3-(1-cyano-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinolin]-6′-yl)-N,N-dimethylbenzamide; and   6′-(2-methylpyridin-4-yl)-2′-oxo-1′,4′-dihydro-2′H-spiro[pyrrolidine-3,3′-quinoline]-1-carbonitrile;   a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.   
     
     
         25 . The method according to  claim 16 , wherein the neurodegenerative disease is Parkinson's disease. 
     
     
         26 . The method according to  claim 16 , wherein the neurodegenerative disease is Alzheimer's disease. 
     
     
         27 . The method according to  claim 16 , wherein the neurodegenerative disease is selected from amyotrophic lateral sclerosis, Huntington's disease, ischemia, stroke, dementia with Lewy bodies, and frontotemporal dementia.