9-(piperazinylalkyl) carbazoles as bax-modulators

1. A compound according to formula I

as well as a pharmaceutically acceptable salt thereof, in racemic form or in an enantiomeric excess, wherein

R 0 and R 1 are selected independently from each other and are cyano, sulfonyl of the formula —SO 2 —R where R is H, aryl, heteraryl, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with a halogen, sulfoxy, substituted or unsubstituted C 1 -C 6 -thioalkoxy, nitro, primary, secondary or tertiary amine or sulfonamide, aminocarbonyl, amino-thiocarbonyl, hydroxy, substituted or unsubstituted C 1 -C 6 -alkoxy, aryloxy, heteroaryloxy, carboxylic amide, alkoxycarbonyl, carboxylic ester, carboxylic acid, substituted or unsubstituted C 1 -C 6 -alkyl carbonyl, substituted or unsubstituted arylcarbonyl or heteroarylcarbonyl, substituted or unsubstituted saturated or unsaturated C 3 -C 8 -cycloalkylcarbonyl, substituted or unsubstituted C 1 -C 6 -alkyl, substituted or unsubstituted C 2 -C 6 -alkenyl, substituted or unsubstituted C 2 -C 6 -alkynyl, substituted or unsubstituted aryl or heteroaryl, substituted or unsubstituted 3-8 membered saturated or unsaturated cyclic alkyl, a lipophilic substituent selected from the group consisting of bromine, aryl, and C 1 -C 6 -alkyl, or a fluorescent moiety selected from the group consisting of (4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-2-yl)acetamide, [(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-yl)methyl]acetamide, (4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)methyl, 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-4-(aminoacetyl)benzoic acid, (6,7-dimethoxy-2H-chromen-2-one)-4-methyl, 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-8-propionyl, and 4-nitro-(2,1,3-benzoxadiazol)-7-yl;

R 2 is C 1 -C 6 -alkylaryl, C 1 -C 6 -alkylheteroaryl, an aryl, or a 5-6-membered heterocyclic group containing at least one of oxygen, nitrogen and sulfur, wherein the aryl and heterocyclic group are substituted by at least one C(═O)ORa, trifluoromethyl, trifluoromethoxy, ORa, OC(═O)Ra, OC(═O)Rc, NRaRb, CH 2 —NRaRb, NO 2 , cyano, halogen, SO 2 NRaRb, SO 2 NRaRc, NRaSO 2 Ra, NRaSO 2 Rc, C 1 -C 6 -alkyleneC(═O)ORa, and OSO 2 -trifluoromethyl, or

R 2 is C 1 -C 6 -alkylaryl or C 1 -C 6 -alkylheteroaryl containing at least one heteroatom selected from oxygen, nitrogen and sulfur, wherein said C 1 -C 6 -alkylaryl or C 1 -C 6 -alkylheteroaryl is substituted by at least one C(═O)ORa, trifluoromethyl, trifluoromethoxy, ORa, ORc, SRa, SRc, OC(═O) Ra, OC(═O) Rc, NRaRb, CH 2 —NRaRb, NO 2 , cyano, halogen, SO 2 NRaRb, SO 2 NRaRc, NRaSO 2 Ra, NRaSO 2 Rc, C 1 -C 6 -alkyleneC(═O)ORa or OSO 2 -trifluoromethyl;

Ra and Rb, in R 2 , are independently hydrogen or C 1 -C 6 -alkyl, optionally substituted by at least one halogen, a C 1 -C 6 -alkoxy or an amino group and Rc, in R 2 , is an unsubstituted or substituted phenyl, an unsubstituted or substituted benzyl or a 3-8-membered unsubstituted or substituted saturated 3-8-membered cyclic alkyl;

R 3 is hydrogen, halogen, substituted or unsubstituted C 1 -C 6 -alkyl, substituted or unsubstituted C 2 -C 6 -alkenyl, substituted or unsubstituted C 2 -C 6 -alkynyl, substituted or unsubstituted aryl or hetero-aryl, substituted or unsubstituted 3-8 membered saturated and unsaturated cyclic alkyl, alkoxycarbonyl, carboxylic amide, C 1 -C 6 -alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted hetero-aryloxy, hydroxy, substituted or unsubstituted C 1 -C 6 -alkyl carbonyl, substituted or unsubstituted arylcarbonyl or heteroarylcarbonyl, substituted or unsubstituted saturated or unsaturated C 4 -C 8 -cycloalkylcarbonyl, or an oxo (═O) group;

k and l are 1;

X is a group of the formula —(CR′R″)—, wherein R′ and R″ are hydrogen, hydroxyl or a substituted or unsubstituted C 1 -C 6 alkoxy, whereby at least one of R′ and/or R″ is not hydrogen but hydroxyl or a substituted or unsubstituted C 1 -C 6 -alkoxy;

m and n are independently from each other an integer from 1 to 3 and o is an integer from 0 to 8.

2. The compound according to claim 1 , wherein R 0 and R 1 of formula I are selected independently from each other and are cyano, substituted or unsubstituted and C 1 -C 6 -alkyl, substituted or unsubstituted 3-8 membered saturated or unsaturated cyclic alkyl, C(═O)ORa, C(═O)NRaRb, C(═O)NRaRc, C(═O)Ra, C(═O)Rc, CRa(═N—N-Rb), CRa(═N—N-Rc), CRa(═N—O-Rb), trifluoromethyl, trifluoromethoxy, ORa, ORc, NRaRb, NRaRc, NRaC(═O)NRaRb, NRaC(═O)NRaRc, NRaC(═O)Rb, NRaC(═O)Rc, OC(═O)Ra, OC(═O)Rc, NRa(SO 2 Rb), NRa(SO 2 Rc), SO 2 NRaRb, SO 2 NRaRc, NO 2 , CH 2 NRaRb, CH 2 NRaRc, CH 2 NRaC(═O)NRaRb, SRa, SRc, CH 2 NRaC(═O)NRaRc, CH 2 NRaC(═O)Rb, CH 2 NRaC(═O)Rc, CH 2 NRa(SO 2 Rb), CH 2 NRa(SO 2 Rc), OSO 2 -trifluoromethyl; or

aryl or a 5-6-membered heteroaryl or heterocyclic group wherein at least one heteroatom in the 5-6 membered heteroaryl or heterocyclic group is oxygen, nitrogen or sulfur, said aryl or heteroaryl or heterocyclic group being optionally substituted by at least one C 1 -C 6 -alkyl, C(═O)ORa, trifluoromethyl, trifluoromethoxy, ORa, ORc, SRa, SRc, OC(═O)Ra, OC(═O)Rc, NRaRb, CH 2 —NRaRb, NO 2 , cyano, halogen, SO 2 NRaRb, SO 2 NRaRc, NRaSO 2 Ra, NRaSO 2 Rc, C 1 -C 6 -alkyleneC(═O)ORa, OSO 2 -trifluoromethyl;

with Ra and Rb, in R 1 , R 0 or both, being the same or different, independently selected from hydrogen and C 1 -C 6 -alkyl, being optionally substituted by at least one halogen, C 1 -C 6 -alkoxy or amino group; and

Rc, in R 1 , R 0 or both, is an unsubstituted or substituted phenyl, an unsubstituted or substituted benzyl, a 3-8-membered unsubstituted or substituted saturated 3-8-membered cyclic alkyl, a lipophilic substituents selected from the group consisting of bromine, aryl, and C 1 -C 6 -alkyl, or a fluorescent moiety selected from the group consisting of (4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-2-yl)acetamide, [(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-yl)methyl]acetamide, (4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)methyl, 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-4-(aminoacetyl)benzoic acid, (6,7-dimethoxy-2H-chromen-2-one)-4-methyl, 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-8-propionyl, and 4-nitro-(2,1,3-benzoxadiazol)-7-yl.

3. The compound according to claim 1 , wherein R 2 of formula I is C 1 -C 6 -alkylaryl, C 1 -C 6 -alkylheteroaryl, or an aryl, wherein the aryl group is substituted by at least one of C(═O)ORa, trifluoromethyl, trifluoromethoxy, ORa, OC(═O)Ra, OC(═O)Rc, NRaRb, CH 2 —NRaRb, NO 2 , cyano, halogen, SO 2 NRaRb, SO 2 NRaRc, NRaSO 2 Ra, NRaSO 2 Rc, C 1 -C 6 -alkyleneC(═O)ORa, and OSO 2 trifluoromethyl;

Ra and Rb, in R 2 , are independently hydrogen or C 1 -C 6 -alkyl, optionally substituted by at least one halogen, a C 1 -C 6 -alkoxy or an amino group and Rc, in R 2 , is an unsubstituted or substituted phenyl, an unsubstituted or substituted benzyl or a 3-8-membered unsubstituted or substituted saturated 3-8-membered cyclic alkyl.

4. The compound according to claim 1 , wherein R 3 of formula I is hydrogen, C 1 -C 6 -alkyl, ORa, ORc, C(═O)ORa, C(═O)ORc C(═O)NRaRb, C(═O)NRaRc, C(═O)Ra, C(═O)Rc, RaC(═O)NRaRc, RaC(═O)Rb, RaC(═O)Rc, Ra(SO 2 Rb), Ra(SO 2 Rc), (═O); or

R 3 of formula I is an aryl or a 5-6-membered heterocyclic group wherein at least one heteroatom in the 5-6 membered heterocyclic group is selected from the group consisting of oxygen, nitrogen and sulfur, both the aryl, heterocyclic group being optionally substituted by at least one C 1 -C 6 -alkyl, C(═O)ORa, C(═O)ORc, trifluoromethyl, trifluoromethoxy, ORa, OC(═O)Ra, OC(═O)Rc, NRaRb, CH 2 —NRaRb, NO 2 , cyano, halogen, SO 2 NRaRb, SO 2 NRaRc, NRaSO 2 Ra, NRaSO 2 Rc, C 1 -C 6 -alkyleneC(═O)ORa, OSO 2 trifluoromethyl;

whereby Ra and Rb are the same or different and they are independently selected from hydrogen and C 1 -C 6 -alkyl, being optionally substituted by at least one halogen, a C 1 -C 6 -alkoxy or an amino group; and

whereby, Rc does represent therein an unsubstituted or substituted phenyl, an unsubstituted or substituted benzyl or a 3-8-membered unsubstituted or substituted saturated 3-8-membered cyclic alkyl.

5. The compound according to claim 1 , wherein R 0 and R 1 represent a lipophilic substitutent selected from the group consisting of bromine, aryl, and C 1 -C 6 -alkyl.

6. The compound according to claim 1 , wherein R 3 is hydrogen or C 1 -C 6 -alkyl.

7. The compound according to claim 1 , wherein R 2 is (4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-2-yl)acetamide, [(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-yl)methyl]acetamide, (4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacen-8-yl)methyl, 2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-4-(aminoacetyl)benzoic acid, (6,7-dimethoxy-2H-chromen-2-one)-4-methyl, 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-8-propionyl, or 4-nitro-(2,1,3-benzoxadiazol)-7-yl.

8. The compound according to claim 1 , which is in an enantiomeric excess of at least 52% ee.

9. The compound according to claim 1 selected from the following group:

(±)-1-[(4-Fluorophenyl)-piperazin-1-yl]-3-(3,6-dibromocarbazol-9-yl)-propan-2-ol;

(±)-1-(3,6-Dibromocarbazol-9-yl)-3-[4-(thien-3-ylmethyl)piperazin-1-yl]propan-2-ol;

(±)-1-(3,6-Dibromo carbazol-9-yl)-3-[4-(4-methoxybenzyl)piperazin-1-yl]propan-2-ol;

(±)-1-(3,6-Dibromocarbazol-9-yl)-3-[4-(4-tert-butylbenzyl)piperazin-1-yl]propan-2-ol;

(±)-4-[3-(3,6-Dibromocarbazol-9-yl)-2-hydroxypropyl]-N-(4-fluorophenyl)piperazine-1-carboxamide;

(±)-1-(3,6-Dibromo-carbazol-9-yl)-3-[4-(3,4-dichlorobenzyl)piperazin-1-yl]propan-2-ol;

(±)-1-(3,6-Dibromo-carbazol-9-yl)-3-[4-(2-morpholin-4-ethyl)piperazin-1-yl]propan-2-ol;

(±)-1-(3,6-Dibromocarbazol-9-yl)-3-[4-(3-piperidin-1-yl-propyl)piperazin-1-yl]propan-2-ol;

(±)-1-(3,6-dibromo-carbazol-9-yl)-3-[4-(4-fluoro-benzyl)-piperazin-1yl]-propan-2-ol;

(±)-1-(3,6-dibromo-carbazol-9-yl)-3-[4-(3-phenyl-propyl)-piperazin-1-yl]-propan-2-ol;

(±)-1-(3,6-dibromo-carbazol-9-yl)-3-[4-(thien-2-ylmethyl)piperazin-1-yl]propan-2-ol;

(±)-1-(3,6-dibromocarbozyl-9-yl)-3-[4-(pyridine-3-ylmethyl)piperazin-1-yl]propan-2-ol;

(±)-1-(3,6-dibromocarbazol-9-yl)-3-[4-trifluoromethylbenzyl]piperazin-1-yl]propan-2-ol; and

(±)-1-(3,6-Dibromocarbazol-9-yl)-3-{[4-(4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene-8-yl)methyl]piperazin-1-yl}propan-2-ol.

10. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

11. The compound according to claim 1 , which is in an enantiomeric excess of at least 92-98% ee.

12. A pharmaceutical composition comprising at least one compound according to claim 2 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

13. A pharmaceutical composition comprising at least one compound according to claim 3 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

14. A pharmaceutical composition comprising at least one compound according to claim 4 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

15. A pharmaceutical composition comprising at least one compound according to claim 5 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

16. A pharmaceutical composition comprising at least one compound according to claim 6 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

17. A pharmaceutical composition comprising at least one compound according to claim 7 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

18. A pharmaceutical composition comprising at least one compound according to claim 8 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

19. A pharmaceutical composition comprising at least one compound according to claim 9 and a pharmaceutically acceptable carrier, diluent or excipient thereof.

20. A pharmaceutical composition comprising at least one compound according to claim 11 and a pharmaceutically acceptable carrier, diluent or excipient thereof.