Azaspiro derivatives

1. A compound of the general formula (I)

wherein

U is O, and V is CH 2 ,

U is O, and V is C═O,

U is CH 2 , and V is O, or

U is C═O and V is O;

one of the variables W, X, Y and Z are nitrogen, the remaining variables being CR 8 ;

R 1 is H,

C 1-12 -alkyl, optionally substituted with CN or OH,

C 1-6 -haloalkyl,

C 2-12 -alkenyl,

—(CR i R ii ) m —R a ,

wherein R i and R ii are independently from each other H, methyl, or ethyl;

wherein m is from 0 to 4;

wherein R a is

phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which are optionally substituted with one or more A, or

—NR b R c , wherein R b and R c are each independently

 hydrogen,

 hydroxy,

 C 1-6 -alkyl,

 —S(O) 2 —C 1-6 -alkyl, or

 —C(O)—C 1-6 -alkyl,

—(CR iii R iv ) n —C(O)R d ,

wherein R iii and R iv are independently from each other H, methyl, or ethyl;

wherein n is from 0 to 4;

wherein R d is

C 1-6 -alkoxy,

—NR e R f , wherein R e and R f are each independently

 hydrogen,

 C 1-6 -alkyl, or

—(C 2-6 -alkylene)-NR g R h ; wherein R g and R h are each independently hydrogen, C 1-6 -alkyl, or —C(O)O—C 1-6 -alkyl, or

phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which are optionally substituted with one or more A,

—S(O) 2 -phenyl, wherein phenyl is optionally substituted with one or more halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, nitro, hydroxy or cyano;

—S(O) 2 —C 1-6 -alkyl,

—S(O) 2 N(C 1-6 -alkyl) 2 , or

—S(O) 2 NH(C 1-6 -alkyl);

A is halo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -cyanoalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, —S(O) 0-2 C 1-6 -alkyl, nitro, hydroxy, cyano, —(C 1-6 -alkylene)-O—C 1-6 -alkyl, —(C 1-6 -alkylene)-O—C 1-6 -haloalkyl, —(C 1-6 -alkylene)-OR′″, —C(O)OC 1-6 -alkyl, —C(O)C 1-6 -alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″, —S(O) 2 NR′R″, —(CH 2 ) x —NR′R″, —(CH 2 ) x —NR′C(O)—C 1-6 -alkyl, —(CH 2 ) x —NR′S(O) 2 —C 1-6 -alkyl, —(CH 2 ) x —C 3-6 -cycloalkyl, or —(CH 2 ) x —R′″,

wherein x is from 0 to 4,

R′ and R″ are each independently H or C 1-6 -alkyl, or

R′ and R″ together with the nitrogen to which they are bound form a 5 or 6-membered heterocycle comprising one or two heteroatoms selected from N, O and S, and

R′″ is phenyl or 5- to 6-membered heteroaryl, optionally substituted with one, two, or three halo, C 1-6 -haloalkyl, C 1-6 -alkyl, or C 1-6 -alkoxy,

R 2 is hydrogen,

C 1-6 -alkyl, or

—C(O)R n , wherein R n is

C 1-6 -alkyl,

3 to 7-membered heterocycloalkyl, optionally substituted with one, two or three C 1-6 -alkyl, —C(O)O—C 1-6 -alkyl, or —S(O) 2 —C 1-6 -alkyl, or

NR j R k , wherein R j and R k are each independently

hydrogen,

C 1-6 -alkyl, or

—(C 2-6 -alkylene)-NR l R m ; wherein R l and R m are each independently hydrogen, C 1-6 -alkyl, or —C(O)O—C 1-6 -alkyl;

R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halo, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy or halo-C 1-6 -alkoxy;

or R 1 and R 6 together with the indole ring to which they are attached form a 6 membered heterocycle which is optionally substituted with residues selected from ═O, C(O)O—C 1-6 -alkyl and C 1-6 -alkyl;

R 7 is hydrogen or C 1-6 -alkyl;

R 8 is hydrogen, halo, methyl, methoxy, CF 3 , or OCF 3 ;

wherein 5- to 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; and

3- to 7-membered heterocycloalkyl is selected from the group consisting of oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydro-furanyl, tetrahydro-thiophenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, and tetrahydropyranyl;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein

R 1 is H,

C 2-6 -alkyl, optionally substituted with CN or OH,

C 1-6 -haloalkyl,

—(CR i R ii ) m —R a ,

wherein R i and R ii are independently from each other H, methyl, or ethyl;

wherein m is from 0 to 4;

wherein R a is

phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl,

which are optionally substituted with one or more A, or

—NR b R c , wherein R b and R c are each independently hydrogen, C 1-6 -alkyl, —S(O) 2 —C 1-6 -alkyl, or —C(O)—C 1-6 -alkyl,

—(CR iii R iv ) n —C(O)R d ,

wherein R iii and R iv are independently from each other H, methyl, or ethyl;

wherein n is from 0 to 4;

wherein R d is

C 1-6 -alkoxy,

—NR e R f , wherein R e and R f are each independently

 hydrogen,

 C 1-6 -alkyl, or

—(C 2-6 -alkylene)-NR g R h ; wherein R g and R h are each independently hydrogen, C 1-6 -alkyl, or —C(O)O—C 1-6 -alkyl, or

phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which are optionally substituted with one or more A,

—S(O) 2 —C 1-6 -alkyl,

—S(O) 2 N(C 1-6 -alkyl) 2 , or

—S(O) 2 NH(C 1-6 -alkyl);

A is halo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -cyanoalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, —S(O) 0-2 C 1-6 -alkyl, nitro, hydroxy, cyano, —(C 1-6 -alkylene)-O—C 1-6 -alkyl, —(C 1-6 -alkylene)-O—C 1-6 -haloalkyl, —(C 1-6 -alkylene)-OR′″, —C(O)OC 1-6 -alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″, —S(O) 2 NR′R″, —(CH 2 ) x —NR′R″, —(CH 2 ) x —NR′C(O)—C 1-6 -alkyl, —(CH 2 ) x —NR′S(O) 2 —C 1-6 -alkyl, —(CH 2 ) x —C 3-6 -cycloalkyl, or —(CH 2 ) x —R′″,

wherein x is from 0 to 4,

R′ and R″ are each independently H or C 1-6 -alkyl, or

R′ and R″ together with the nitrogen to which they are bound form a 5 or 6-membered heterocycle comprising one or two heteroatoms selected from N, O and S, and

R′″ is phenyl or 5- to 6-membered heteroaryl, optionally substituted with one, two, or three halo, C 1-6 -haloalkyl, C 1-6 -alkyl, or C 1-6 -alkoxy

wherein 5- to 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; and

3- to 7-membered heterocycloalkyl is selected from the group consisting of oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydro-furanyl, tetrahydro-thiophenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, and tetrahydropyranyl.

3. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are not simultaneously hydrogen.

4. The compound of claim 1 , wherein R 1 is hydrogen.

5. The compound of claim 1 , wherein R 1 is C 1-12 -alkyl, optionally substituted with CN or OH.

6. The compound of claim 1 , wherein R 1 is C 1-6 -haloalkyl or C 2-12 Alkenyl.

7. The compound of claim 1 , wherein R 1 is S(O) 2 -phenyl, wherein phenyl is optionally substituted with one or more halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, nitro, hydroxyl or cyano.

8. The compound of claim 1 , wherein R 1 is —S(O) 2 —C 1-6 -alkyl, —S(O) 2 N(C 1-6 -alkyl) 2 , or —S(O) 2 NH(C 1-6 -alkyl).

9. The compound of claim 1 , wherein

A is halo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -cyanoalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, C 1-6 -thioalkyl, —S(O) 2 —C 1-6 -alkyl, cyano, —CH 2 OCH 3 , —C(O)O—C 1-6 -alkyl, —C(O)NR′R″, —S(O) 2 NR′R″, —NR′C(O)—C 1-6 -alkyl, —NR′S(O) 2 —C 1-6 -alkyl, benzyl, or phenyl wherein R′ and R″ are each independently H or C 1-6 -alkyl.

10. The compound of claim 1 , wherein R 2 is hydrogen or C 1-6 -alkyl.

11. The compound of claim 1 , wherein R 3 , R 4 , R 5 , and R 6 are hydrogen.

12. The compound of claim 1 , wherein R 3 , R 4 , R 5 , and R 6 are each independently hydrogen, halo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, or C 1-6 -haloalkoxy.

13. The compound of claim 1 , wherein R 4 is hydrogen, Cl, F, or methyl.

14. The compound of claim 1 , wherein R 5 is hydrogen, halo, CF 3 , methoxy, or —OCF 3 .

15. The compound of claim 1 , wherein R 3 and R 6 is hydrogen, R 4 is hydrogen, F, Cl, or methyl, and R 5 is halo, CF 3 , methoxy, or OCF 3 .

16. The compound of claim 1 , wherein R 7 is hydrogen or C 1-6 -alkyl.

17. The compound of claim 1 , wherein R 8 is hydrogen, halo, methyl, methoxy, CF 3 , or OCF 3 .

18. The compound of claim 1 , wherein

W is N, X is CH, Y is CH, and Z is CH,

W is CH, X is N, Y is CH, and Z is CH,

W is CH, X is CH, Y is N, and Z is CH, or

W is CH, X is CH, Y is CH, and Z is N.

19. The compound of formula (I) according to claim 1 , wherein the compound is selected from the group consisting of

1′-[(6-chloro-1H-indol-3-yl)carbonyl]-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine],

tert-butyl (2S)-2-{[6-chloro-3-(1′H,7H-spiro[furo[3,4-b]pyridine-5,4′-piperidin]-1′-ylcarbonyl)-1H-indol-1-yl]methyl}pyrrolidine-1-carboxylate,

1′-({6-chloro-1-[(2S)-pyrrolidin-2-ylmethyl]-1H-indol-3-yl}carbonyl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]dihydrochloride,

1′-[(6-chloro-1-{[(2S)-1-methylpyrrolidin-2-yl]methyl]-1H-indol-3-yl)carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine],

1′-{[6-chloro-1-(3,5-difluorobenzyl)-1H-indol-3-yl]carbonyl}-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine],

1′-[(6-chloro-1H-indol-3-yl)carbonyl]-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidine],

tert-butyl (2S)-2-{[6-chloro-3-(1H,1′H-spiro[furo[3,4-c]pyridine-3,4′-piperidin]-1′-ylcarbonyl)-1H-indol-1-yl]methyl}pyrrolidine-1-carboxylate,

1′-({6-chloro-1-[(2S)-pyrrolidin-2-ylmethyl]-1H-indol-3-yl}carbonyl)-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidine]dihydrochloride,

1′-[(6-chloro-1-{[(2S)-1-methylpyrrolidin-2-yl]methyl]-1H-indol-3-yl)carbonyl}-1H-spiro[furo[3,4-c]pyridine-3,4′-piperidine],

1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine],

tert-butyl (2S)-2-{[6-chloro-3-(1H,1′H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-1′-ylcarbonyl)-1H-indol-1-yl]methyl}pyrrolidine-1-carboxylate,

1′-({6-chloro-1-[(2S)-pyrrolidin-2-ylmethyl]-1H-indol-3-yl}carbonyl)-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine]dihydrochloride,

1′-[(6-chloro-1-{[(2S)-1-methylpyrrolidin-2-yl]methyl]-1H-indol-3-yl)carbonyl}-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine], and

1′-{[6-chloro-1-(3,5-difluorobenzyl)-1H-indol-3-yl]carbonyl}-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine].

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I

wherein

U is O, and V is CH 2 ,

U is O, and V is C═O,

U is CH 2 , and V is O, or

U is C═O and V is O;

one of the variables W, X, Y and Z are nitrogen, the remaining variables being CR 8 ;

R 1 is H,

C 1-12 -alkyl, optionally substituted with CN or OH,

C 1-6 -haloalkyl,

C 2-12 -alkenyl,

—(CR i R ii ) m —R a ,

wherein R i and R ii are independently from each other H, methyl, or ethyl;

wherein m is from 0 to 4;

wherein R a is

phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which are optionally substituted with one or more A, or

—NR b R c , wherein R b and R c are each independently

hydrogen,

hydroxy,

C 1-6 -alkyl,

—S(O) 2 —C 1-6 -alkyl, or

—C(O)—C 1-6 -alkyl,

—(CR iii R iv ) n —C(O)R d ,

wherein R iii and R iv are independently from each other H, methyl, or ethyl;

wherein n is from 0 to 4;

wherein R d is

C 1-6 -alkoxy,

—NR e R f , wherein R e and R f are each independently

hydrogen,

C 1-6 -alkyl, or

—(C 2-6 -alkylene)-NR g R h ; wherein R g and R h are each independently hydrogen, C 1-6 -alkyl, or —C(O)O—C 1-6 -alkyl, or

phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered heterocycloalkyl or 3 to 7-membered cyloalkyl, which are optionally substituted with one or more A,

—S(O) 2 -phenyl, wherein phenyl is optionally substituted with one or more halo, C 1-6 -haloalkyl, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, nitro, hydroxy or cyano;

—S(O) 2 —C 1-6 -alkyl,

—S(O) 2 N(C 1-6 -alkyl) 2 , or

—S(O) 2 NH(C 1-6 -alkyl);

A is halo, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -hydroxyalkyl, C 1-6 -cyanoalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, —S(O) 0-2 C 1-6 -alkyl, nitro, hydroxy, cyano, —(C 1-6 -alkylene)-O—C 1-6 -alkyl, —(C 1-6 -alkylene)-O—C 1-6 -haloalkyl, —(C 1-6 -alkylene)-OR′″, —C(O)OC 1-6 -alkyl, —C(O)C 1-6 -alkyl, —C(O)OR′″, —C(O)R′″, —C(O)NR′R″, —S(O) 2 NR′R″, —(CH 2 ) x —NR′R″, —(CH 2 ) x —NR′C(O)—C 1-6 -alkyl, —(CH 2 ) x —NR′S(O) 2 —C 1-6 -alkyl, —(CH 2 ) x —C 3-6 -cycloalkyl, or —(CH 2 ) x —R′″,

wherein x is from 0 to 4,

R′ and R″ are each independently H or C 1-6 -alkyl, or

R′ and R″ together with the nitrogen to which they are bound form a 5 or 6-membered heterocycle comprising one or two heteroatoms selected from N, O and S, and

R′″ is phenyl or 5- to 6-membered heteroaryl, optionally substituted with one, two, or three halo, C 1-6 -haloalkyl, C 1-6 -alkyl, or C 1-6 -alkoxy,

R 2 is hydrogen,

C 1-6 -alkyl, or

—C(O)R n , wherein R n is

C 1-6 -alkyl,

3 to 7-membered heterocycloalkyl, optionally substituted with one, two or three C 1-6 -alkyl, —C(O)O—C 1-6 -alkyl, or —S(O) 2 —C 1-6 -alkyl, or

NR j R k , wherein R j and R k are each independently

hydrogen,

C 1-6 -alkyl, or

—(C 2-6 -alkylene)-NR l R m ; wherein R l and R m are each independently hydrogen, C 1-6 -alkyl, or —C(O)O—C 1-6 -alkyl;

R 3 , R 4 , R 5 , R 6 are each independently hydrogen, halo, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy or halo-C 1-6 -alkoxy;

or R 1 and R 6 together with the indole ring to which they are attached form a 6 membered heterocycle which is optionally substituted with residues selected from ═O, C(O)O—C 1-6 -alkyl and C 1-6 -alkyl;

R 7 is hydrogen or C 1-6 -alkyl;

R 8 is hydrogen, halo, methyl, methoxy, CF 3 , or OCF 3 ;

wherein 5- to 6-membered heteroaryl is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; and

3- to 7-membered heterocycloalkyl is selected from the group consisting of oxiranyl, thiiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydro-furanyl, tetrahydro-thiophenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazidinyl, isoxazidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazidinyl, morpholinyl, and tetrahydropyranyl;

or a pharmaceutically acceptable salt thereof.