Morpholine and 1，4-oxazepane compounds and its use in therapy

Abstract

The present invention provides compounds of formula (I), or a salt, solvate or 5 stereoisomer thereof as G9a inhibitors, wherein: R1 is CRxR'xRy; A represents (CH2)m, wherein m is 0 or 1; Z represents (CH2)n, wherein n is 2 or 3; R2 is selected from the group consisting of: (a) an aromatic 5 or 6-membered ring system, wherein the members are selected from the group con sisting of: CRz1, S, N, NH, and O; and (b) an aromatic fused ring system consisting of two rings, wherein one or both rings are aromatic rings, and each one of the aromatic rings have 5 or 6 members selected from the group consisting of CRz2, S, N, NH, and O. The invention also provides uses of the compounds of formula (I) in the treatment of G9a-mediated diseases, as well as pharmaceutical compositions including these compounds. Advantageously, the compounds of the invention are highly potent and selective towards G9a target, among others.

Description

This invention provides compounds of formula (I) or their salts, solvates, or stereoisomers as G9a inhibitors, wherein: R1 is CRxR'xRy; A represents (CH2)m, where m is 0 or 1; Z represents (CH2)n, where n is 2 or 3; R2 is selected from: (a) an aromatic 5- or 6-membered ring system, wherein the ring atoms are selected from: CRz1, S, N, NH, and O; and (b) an aromatic fused ring system consisting of two rings, one or both of which are aromatic rings, and each aromatic ring has 5 or 6 ring atoms selected from CRz2, S, N, NH, and O. This invention also provides the use of compounds of formula (I) in the treatment of G9a-mediated diseases, and pharmaceutical compositions comprising these compounds. Advantageously, the compounds of this invention are particularly potent and selective for targets such as G9a. Abstract

Claims

CLAIMS1. A compound of formula (I), or a salt, solvate or stereoisomer thereof:for use in therapy, wherein:Ri is CRxR’xRy,A represents (CH2)m, wherein m is 0 or 1 ,Z represents (CH2)n, wherein n is 2 or 3,R2 is selected from the group consisting of: a) an aromatic 5 or 6-membered ring system, wherein the members are selected from the group consisting of: CRzi, S, N, NH, and O; and b) an aromatic fused ring system consisting of two rings, wherein one or both rings are aromatic rings, and each one of the aromatic rings have 5 or 6 members selected from the group consisting of CRZ2, S, N, NH, and O;Rxand R’xare the same or different, and are independently selected from -H, (C1- Cs)alkyl, (Ci-Cs)haloalkyl;Ryis selected from -H, (Ci-Cs)alkyl, (Ci-Cs)haloalkyl, or an aromatic known ring system, which is selected from the group consisting of: a) an aromatic 6-membered ring system, wherein the members are selected from the group consisting of: CRZ3, and N; b) an aromatic 5-membered ring system, wherein the members are selected from the group consisting of: CRZ4, S, N, NH, and O; c) an aromatic fused ring system consisting of two rings, wherein one or both rings are aromatic rings, and each one of the aromatic rings having 5 or 6 members selected from the group consisting of: CRzs, N and NH;Rzi to RZ3 and Rzs are independently selected from the group consisting of: H; OH; CN; halogen; (Ci-Cw)alkyl; (C2-C )alkenyl; (C2-C )alkynyl; (Ci-Cw)alkyl substituted with one or more Sui; (C2-C )alkenyl substituted with one or more SU2; (C2-C )alkynyl substituted with one or more SU3; -0-(Ci-Cio)alkyl; -O-(Ci-Cw)haloalkyl; SF5; S(O)2Rs; NR4R5; CONReR?; and COORs;RZ4 is selected from the group consisting of: H; OH; CN; halogen; (Ci-Cw)haloalkyl; -O- (Ci-Cw)alkyl; -O-(Ci-Cw)haloalkyl; SF5; S(O)2R’3; NR^R’s; CONR’eR’?; and COOR’s;R3 and R’3 are independently selected from (Ci-Cw)alkyl; (C3-C8)cycloalkyl; aryl; or heteroaryl;R4, Rs, Re, R7, R’4, R’s, R’e and R’7, are independently selected from the group consisting of: -H, (Ci-Cw)alkyl; (Ci-Cw)haloalkyl; and (C3-C8)cycloalkyl;Rs and R’s are independently selected from the group consisting of: selected from the group consisting of -H, (Ci-Cw)alkyl; (C3-Cs)cycloalkyl; and (Ci-Cw)haloalkyl;“aryl” means an aromatic ring system comprising 6 CRcmembers, being Rc selected from H, halogen, CN, nitro, (Ci-Cs)alkyl, (Ci-Cs)haloalkyl, -O-(Ci-Cs)alkyl, or -O-(Ci- Cs)haloalkyl;“heteroaryl” means an aromatic ring system comprising 5 or 6 members selected from the group consisting of: CRd, O, N, NH, and S; being Rd selected from H, halogen, CN, nitro, (Ci-Cs)alkyl, (Ci-Cs)haloalkyl, -O-(Ci-Cs)alkyl, -O-(Ci-Cs)haloalkyl;Sui to Su3are independently selected from the group consisting of: halogen, CN, nitro, (Ci-Ce)haloalkyl, (Ci-Ce)alkyl, (Ci-Ce)hydroxyalkyl, (Ci-Ce)alkoxy, (Ci-Ce)alkylsulfinyl, (Ci-Ce)alkylsulfonyl, (Ci-Ce)alkylcarbonyl, (Ci-Ce)alkoxycarbonyl, carbamoyl, / \ / -(Ci- C4)alkylcarbamoyl, / V, / V-di-(Ci-C4)alkylcarbamoyl, (Ci-Ce)alkylcarbonyloxy, (C3- C6)cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, / V-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, / V-(Ci-C4)alkylsulfamoyl, and / V, / V-di-(Ci-C4)alkylsulfamoyl.

2. The compound for use of claim 1 , wherein m is 1 and n is 3.

3. The compound for use of any one of the preceding claims, wherein Rxand R’xare the same, particularly Rxand R’xare H.

4. The compound for use of any one of the preceding claims, wherein Ryis an aromatic 6-membered ring system, particularly Ryrepresents phenyl.

5. The compound for use of any one of the preceding claims, wherein R2 is an aromatic5 or 6-membered ring system, particularly R2 is an aromatic 6-membered ring system.

6. The compound for use of any one of the preceding claims, wherein Rziis selected from H; OH; halogen; (Ci-Cio)alkyl; (C2-C )alkenyl; (C2-C )alkynyl; (Ci-Cw)alkyl substituted with one or more Sui; (C2-C )alkenyl substituted with one or more SU2; (C2- Cw)alkynyl substituted with one or more SU3; -0-(Ci-Cio)alkyl; -O-(Ci-Cw)haloalkyl; or NR4R5; particularly Rziis selected from H, OH, halogen, (Ci-Cw)alkyl, -0-(Ci-Cio)alkyl, or NR4R5.

7. The compound for use of any one of the preceding claims, which is selected from the group consisting of:

1. 4-benzyl-2-[(4-phenylpiperidin-1-yl)methyl]-1 ,4-oxazepane,2. 4-benzyl-2-{[4-(4-chlorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,3. 4-benzyl-2-{[4-(4-bromophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,4. 4-benzyl-2-{[4-(4-fluorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,5. 4-benzyl-2-{[4-(3-bromophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,6. 4-benzyl-2-{[4-(3,5-dichlorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,7. 4-benzyl-2-{[4-(2-fluorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,8. 4-benzyl-2-{[4-(p-tolyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,9. 4-benzyl-2-{[4-(m-tolyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,10. 4-benzyl-2-{[4-(o-tolyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,11. 3-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,12. 4-benzyl-2-{[4-(4-methoxyphenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,13. 4-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,14. 3-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline,15. 4-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline;16. 3-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}benzonitrile,17. 2-{[4-(1 / 7-pyrazol-1-yl)piperidin-1-yl]methyl}-4-benzyl-1 ,4-oxazepane,18. 3-{1-[(4-benzylmorpholin-2-yl)methyl]piperidin-4-yl}phenol,19. 3-{ 1 -[(4-benzylmorpholin-2-yl)methyl]piperidin-4-yl}aniline,20. 4-benzyl-2-{[4-(3-methylsulfonylphenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,21 . 4-benzyl-2-{[4-(pyridin-4-yl)piperidin-1 -yl]methyl}- 1 ,4-oxazepane,22. 4-benzyl-2-{[4-(3-trifluoromethylphenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,23. 4-benzyl-2-{[4-(3-chlorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,24. 2-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,25. methyl 3-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}benzoate,26. 4-benzyl-2-{4-(pyrimidin-2-yl)piperidin-1 -yl)methyl}-1 ,4-oxazepane,27. 2-{[4-(1 / 7-benzo[d]imidazol-2-yl)piperidin-1-yl]methyl}-4-benzyl-1,4-oxazepane,28. 4-benzyl-2-{[4-(pyridin-3-yl)piperidin-1-yl]methyl}-1 ,4-oxazepane,29. 2-{[4-(1 / 7-indol-3-yl)piperidin-1-yl]methyl}-4-benzyl-1 ,4-oxazepane,30. 3-{1-[(4-(4-chlorobenzyl)-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,31. 3-{1-[(4-(4-methylbenzyl)-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,32. 4-benzyl-2-{[4-(4-chlorophenyl)piperidin-1-yl]methyl}morpholine,33. 4-{1-[(4-benzylmorpholin-2-yl)methyl]piperidin-4-yl}phenol,34. 4-benzyl-2-{[4-phenylpiperidin-1-yl]methyl}morpholine,35. 4-benzyl-2-{[4-(3-trifluoromethylphenyl)piperidin-1-yl]methyl}morpholine,36. 4-benzyl-2-{[4-(o-tolyl)piperidin-1-yl]methyl}morpholine.

37. 2-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline,38. 5-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}-2-methylphenol,39. 5-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}-2-fluorophenol,40. 3-{1-[(4-(4-methoxybenzyl)-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,41. 3-{1-[(4-(3,4-dichlorobenzyl)-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,42. 3-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,43. 3-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline,44. 4-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,45. 2-{[4-(4-methoxyphenyl)piperidin-1-yl]methyl}-4-methyl-1,4-oxazepane,46. 4-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline,47. 4-methyl-2-{[4-(o-tolyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,48. 2-{[4-(3-methoxyphenyl)piperidin-1-yl]methyl}-4-methyl-1,4-oxazepane,49. 3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]pyrrolidin-3-yl}phenol,50. 4-{1 -[(4-benzylmorpholin-2-yl)methyl]piperidin-4-yl}aniline, and any salt, solvate or stereoisomer thereof.

8. The compound as defined in any one of the preceding claims 1-7 for use in preventing or treating an G9a-mediated disorder in a subject in need thereof, particularly by inhibiting G9a.

9. The compound for use of claim 8 for use in preventing or treating a blood disorder, cancer, an immune-mediated disease, an imprinting disorder, or in reducing substance (alcohol) consumption by a subject.

10. The compound for use of any one of the preceding claims 8-9 for use in the treatment and / or prevention of a disease selected from the group consisting of Alzheimer’s disease, amyotrophic lateral sclerosis, age-related tau astrogliopathy, aortic amyloidosis, argyrophilic grain disease, British familial dementia, cardiac amyloidosis, cerebral amyloid angiopathy, chronic traumatic encephalopathy, corneal dystrophies, corticobasal degeneration, Creutzfeldt-Jakob disease, Danish familial dementia, Down syndrome, familial amyloidosis, familial corneal amyloidosis, fatal insomnia, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, globular glial tauopathy, hereditary cerebral hemorrhage with amyloidosis, Huntington’s disease, inflammation-associated amyloidosis, kuru, Lewy bodies dementia, Mediterranean fever, Niemann-Pick disease type C, Parkinson’s disease, Pick’s disease, primary age-related tauopathy, progressive subcortical gliosis, progressive supranuclear palsy systemic amyloidosis, including transthyretin-associated amyloidosis and light-chain amyloidosis, subacute sclerosing panencephalitis and tuberous sclerosis.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of the claims 1-10, and one or more pharmaceutically acceptable excipients or carriers.

12. A compound of formula (Ibis), a salt, solvate or stereoisomer thereof:wherein Ri, A, and Z are as defined in any one of the preceding claims 1-11 , andR2bis is selected from the group consisting of: a) an aromatic 6-membered ring system, wherein the members are selected from the group consisting of: CRzi, and N; and b) an aromatic fused ring system consisting of two rings, wherein one or both rings are aromatic rings, and each one of the aromatic rings have 5 or 6 members selected from the group consisting of CRZ2, S, N, NH, and 0;CRzi and CRZ2 are as defined in any of the preceding claims; provided that the compound of formula (Ibis) is other than 3-{1-[(4-benzyl-1 ,4-oxazepan- 2-yl)methyl]piperidin-4-yl}phenol.

13. The compound of claim 12, wherein R2bis is an aromatic 6-membered ring system, wherein all the members are the same or different and represent CRzi, wherein Rziis as defined in any of the preceding claims.

14. The compound of any one of the claims 12-13, which is selected from:

1. 4-benzyl-2-[(4-phenylpiperidin-1-yl)methyl]-1 ,4-oxazepane,2. 4-benzyl-2-{[4-(4-chlorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,3. 4-benzyl-2-{[4-(4-bromophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,4. 4-benzyl-2-{[4-(4-fluorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,5. 4-benzyl-2-{[4-(3-bromophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,6. 4-benzyl-2-{[4-(3,5-dichlorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,7. 4-benzyl-2-{[4-(2-fluorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,8. 4-benzyl-2-{[4-(p-tolyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,9. 4-benzyl-2-{[4-(m-tolyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,10. 4-benzyl-2-{[4-(o-tolyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,11 . 4-benzyl-2-{[4-(4-methoxyphenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,12. 4-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,13. 3-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline,14. 4-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline;15. 3-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}benzonitrile,16. 2-{[4-(1 / 7-pyrazol-1-yl)piperidin-1-yl]methyl}-4-benzyl-1 ,4-oxazepane,17. 3-{1-[(4-benzylmorpholin-2-yl)methyl]piperidin-4-yl}phenol,18. 3-{ 1 -[(4-benzylmorpholin-2-yl)methyl]piperidin-4-yl}aniline,19. 4-benzyl-2-{[4-(3-methylsulfonylphenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,20. 4-benzyl-2-{[4-(pyridin-4-yl)piperidin-1-yl]methyl}-1 ,4-oxazepane,21. 4-benzyl-2-{[4-(3-trifluoromethylphenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,22. 4-benzyl-2-{[4-(3-chlorophenyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,23. 2-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,24. methyl 3-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}benzoate,25. 4-benzyl-2-{4-(pyrimidin-2-yl)piperidin-1-yl)methyl}-1 ,4-oxazepane,26. 2-{[4-(1 / 7-benzo[d]imidazol-2-yl)piperidin-1-yl]methyl}-4-benzyl-1 ,4-oxazepane,27. 4-benzyl-2-{[4-(pyridin-3-yl)piperidin-1-yl]methyl}-1 ,4-oxazepane,28. 2-{[4-(1 / 7-indol-3-yl)piperidin-1-yl]methyl}-4-benzyl-1 ,4-oxazepane,29. 3-{1-[(4-(4-chlorobenzyl)-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,30. 3-{1-[(4-(4-methylbenzyl)-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,31. 4-benzyl-2-{[4-(4-chlorophenyl)piperidin-1-yl]methyl}morpholine,32. 4-{1-[(4-benzylmorpholin-2-yl)methyl]piperidin-4-yl}phenol,33. 4-benzyl-2-{[4-phenylpiperidin-1-yl]methyl}morpholine,34. 4-benzyl-2-{[4-(3-trifluoromethylphenyl)piperidin-1-yl]methyl}morpholine,35. 4-benzyl-2-{[4-(o-tolyl)piperidin-1-yl]methyl}morpholine.

36. 2-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline,37. 5-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}-2-methylphenol,38. 5-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}-2-fluorophenol,39. 3-{1-[(4-(4-methoxybenzyl)-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,40. 3-{1-[(4-(3,4-dichlorobenzyl)-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,41. 3-{1-[(4-methyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,42. 3-{1-[(4-methyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline,43. 4-{1-[(4-methyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}phenol,44. 2-{[4-(4-methoxyphenyl)piperidin-1-yl]methyl}-4-methyl-1 ,4-oxazepane,45. 4-{1-[(4-methyl-1 ,4-oxazepan-2-yl)methyl]piperidin-4-yl}aniline,46. 4-methyl-2-{[4-(o-tolyl)piperidin-1-yl]methyl}-1 ,4-oxazepane,47. 2-{[4-(3-methoxyphenyl)piperidin-1-yl]methyl}-4-methyl-1 ,4-oxazepane,48. 3-{1-[(4-benzyl-1 ,4-oxazepan-2-yl)methyl]pyrrolidin-3-yl}phenol,49. 4-{1-[(4-benzylmorpholin-2-yl)methyl]piperidin-4-yl}aniline, or any salt, solvate or stereoisomer thereof.