Morpholine and 1,4-oxazepane compounds and their therapeutic use

Abstract

The present invention provides a compound of formula (I) as a G9a inhibitor, or a salt, solvate, or stereoisomer thereof, wherein R1 is CR x R' x R y And A is (CH2) m This represents a function where m is 0 or 1 and Z is (CH2) n This represents n is 2 or 3, and R2 is (a) an aromatic 5 or 6-membered ring system (where the member is CR). z1 (b) an aromatic condensed ring system consisting of two rings (selected from the group consisting of S, N, NH and O), and (b) an aromatic condensed ring system consisting of two rings, wherein one or both rings are aromatic rings, and each of the aromatic rings is CR z2 The present invention also provides the use of compounds of formula (I) in the treatment of G9a-mediated diseases, as well as pharmaceutical compositions comprising these compounds. Advantageously, the compounds of the present invention are, among other things, very potent and selective against G9a targets.

Claims

1. Compounds of formula (I), or their salts, solvates, or stereoisomers: 【Chemistry 1】 It is for therapeutic purposes, During the ceremony, R １ CR ｘ R' ｘ R ｙ , and A is (CH ２ ) ｍ This represents m being 0 or 1, Z is (CH ２ ) ｎ This represents n being 2 or 3, R ２ is a) Members ｚ１ Aromatic 5- or 6-membered ring system selected from the group consisting of S, N, NH, and O, and b) A two-ring aromatic fused ring system in which one or both rings are aromatic rings, and each aromatic ring is CR ｚ２ Selected from the group consisting of aromatic condensed ring systems having 5 or 6 members selected from the group consisting of S, N, NH, and O, R ｘ and R' ｘ The same or different, -H, (C １ -C ５ ) alkyl, (C １ -C ５ ) independently selected from haloalkyl groups, R ｙ is -H, (C １ -C ５ ) alkyl, (C １ -C ５ ) Haloalkyl, or a known aromatic ring system selected from the group consisting of the following: a) Members ｚ３ and an aromatic six-membered ring system selected from the group consisting of N, b) Members CR ｚ４ A five-membered aromatic ring system selected from the group consisting of S, N, NH, and O, c) A two-ring aromatic fused ring system in which one or both rings are aromatic rings, and each of the aromatic rings is CR ｚ５ Selected from aromatic condensed ring systems having 5 or 6 members selected from the group consisting of N and NH, R ｚ１ ~R ｚ３ and R ｚ５ These are independently H, OH, CN, halogen, (C １ -C １０ ) alkyl, (C ２ -C １０ ) Alkenil, (C ２ -C １０ ) Alkinyl, one or more Su １ Replaced with (C １ -C １０ ) Alkyl, one or more Su ２ Replaced with (C ２ -C １０ ) Alkenil, one or more Su ３ Replaced with (C ２ -C １０ ) Alkinyl, -O-(C １ -C １０ ) alkyl, -O-(C １ -C １０ ) Haloalkyl, SF ５ , S(O) ２ R ３ , NR ４ R ５ CONR ６ R ７ , and COOR ８ Selected from the group consisting of R ｚ４ H, OH, CN, halogen, (C １ -C １０ ) Haloalkyl, -O-(C １ -C １０ ) alkyl, -O-(C １ -C １０ ) Haloalkyl, SF ５ , S(O) ２ R' ３ NR' ４ R' ５ CONR' ６ R' ７ , and COOR' ８ Selected from the group consisting of, R ３ and R' ３ (C １ -C １０ ) alkyl, (C ３ -C ８ ) Selected from cycloalkyl, aryl, or heteroaryl, R ４ 、 R ５ 、 R ６ 、 R ７ 、 R', ４ 、 R', ５ 、 R', ６ and R' ７ are independently selected from the group consisting of -H, (C １ -C １０ ), alkyl, (C １ -C １０ ), haloalkyl, and (C ３ -C ８ ), cycloalkyl, R ８ and R' ８ are each independently selected from the group consisting of -H, (C １ -C １０ -alkyl, (C ３ -C ８ -cycloalkyl, and (C １ -C １０ -haloalkyl), "Aryl" has 6 CR ｃ It means an aromatic ring system containing a member, R ｃ H, halogen, CN, nitro, (C １ -C ５ ) alkyl, (C １ -C ５ ) Haloalkyl, -O-(C １ -C ５ ) alkyl, or -O-(C １ -C ５ ) Selected from haloalkyl, "Heteroaryl" is CR ｄ This means an aromatic ring system containing five or six members selected from the group consisting of O, N, NH, and S, R ｄ H, halogen, CN, nitro, (C １ -C ５ ) alkyl, (C １ -C ５ ) Haloalkyl, -O-(C １ -C ５ ) alkyl, -O-(C １ -C ５ ) Selected from haloalkyl, Su １ ~Su ３ These are, independently, halogen, CN, nitro, (C １ -C ６ ) Haloalkyl, (C １ -C ６ ) alkyl, (C １ -C ６ ) Hydroxyalkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) Alkyl sulfinyl, (C １ -C ６ ) alkylsulfonyl, (C １ -C ６ ) Alkylcarbonyl, (C １ -C ６ ) Alkoxycarbonyl, Carbamoyl, N-(C １ -C ４ ) Alkylcarbamoyl, N,N-G-(C １ -C ４ ) Alkylcarbamoyl, (C １ -C ６ ) Alkylcarbonyloxy, (C ３ -C ６ )Cycloalkyl, phenyl, benzyl, phenoxy, benzyloxy, anilino, N-methylanilino, phenylmercapto, phenylsulfonyl, phenylsulfinyl, sulfamoyl, N-(C １ -C ４ ) alkylsulfamoyl, and N,N-di-(C １ -C ４ ) Selected from the group consisting of alkylsulfamoyl.

2. The compound according to claim 1, wherein m is 1 and n is 3.

3. R ｘ and R' ｘ They are the same, and especially R ｘ and R' ｘ A compound according to any one of the prior claims, wherein is H.

4. R ｙ It is an aromatic six-membered ring system, and especially R ｙ A compound according to any one of the prior claims, wherein represents phenyl.

5. R ２ is an aromatic 5- or 6-membered ring system, and especially R ２ The compound according to any one of the prior claims, wherein the compound is an aromatic six-membered ring system.

6. R ｚ１ However, H, OH, halogen, (C １ -C １０ ) alkyl, (C ２ -C １０ ) Alkenil, (C ２ -C １０ ) Alkinyl, one or more Su １ Replaced with (C １ -C １０ ) Alkyl, one or more Su ２ Replaced with (C ２ -C １０ ) Alkenil, one or more Su ３ Replaced with (C ２ -C １０ ) Alkinyl, -O-(C １ -C １０ ) alkyl, -O-(C １ -C １０ ) Haloalkyl, or NR ４ R ５ , especially, R ｚ１ H, OH, halogen, (C １ -C １０ ) alkyl, -O-(C １ -C １０ ) alkyl, or NR ４ R ５ A compound selected from any one of the prior claims.

7. A compound according to any one of the prior claims, selected from the group consisting of the following: 1,4-benzyl-2-[(4-phenylpiperidine-1-yl)methyl]-1,4-oxazepane, 2.4-benzyl-2-{[4-(4-chlorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 3. 4-benzyl-2-{[4-(4-bromophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 4.4-benzyl-2-{[4-(4-fluorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 5. 4-benzyl-2-{[4-(3-bromophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 6.4-benzyl-2-{[4-(3,5-dichlorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 7. 4-benzyl-2-{[4-(2-fluorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 8.4-benzyl-2-{[4-(p-tolyl)piperidine-1-yl]methyl}-1,4-oxazepane, 9. 4-benzyl-2-{[4-(m-tolyl)piperidine-1-yl]methyl}-1,4-oxazepane, 10.4-benzyl-2-{[4-(o-tolyl)piperidine-1-yl]methyl}-1,4-oxazepane, 11.3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 12.4-benzyl-2-{[4-(4-methoxyphenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 13.4-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 14.3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline, 15.4-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline; 16.3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}benzonitrile, 17.2-{[4-(1H-pyrazole-1-yl)piperidine-1-yl]methyl}-4-benzyl-1,4-oxazepane, 18.3-{1-[(4-benzylmorpholin-2-yl)methyl]piperidine-4-yl}phenol, 19.3-{1-[(4-benzylmorpholin-2-yl)methyl]piperidine-4-yl}aniline, 20.4-benzyl-2-{[4-(3-methylsulfonylphenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 21.4-benzyl-2-{[4-(pyridine-4-yl)piperidine-1-yl]methyl}-1,4-oxazepane, 22.4-benzyl-2-{[4-(3-trifluoromethylphenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 23.4-benzyl-2-{[4-(3-chlorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 24.2-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 25. Methyl 3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}benzoate, 26.4-benzyl-2-{4-(pyrimidine-2-yl)piperidine-1-yl)methyl}-1,4-oxazepane, 27.2-{[4-(1H-benzo[d]imidazole-2-yl)piperidine-1-yl]methyl}-4-benzyl-1,4-oxazepane, 28.4-benzyl-2-{[4-(pyridine-3-yl)piperidine-1-yl]methyl}-1,4-oxazepane, 29.2-{[4-(1H-indole-3-yl)piperidine-1-yl]methyl}-4-benzyl-1,4-oxazepane, 30.3-{1-[(4-(4-chlorobenzyl)-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 31.3-{1-[(4-(4-methylbenzyl)-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 32.4-benzyl-2-{[4-(4-chlorophenyl)piperidine-1-yl]methyl}morpholine, 33.4-{1-[(4-benzylmorpholin-2-yl)methyl]piperidine-4-yl}phenol, 34.4-benzyl-2-{[4-phenylpiperidine-1-yl]methyl}morpholine, 35.4-benzyl-2-{[4-(3-trifluoromethylphenyl)piperidine-1-yl]methyl}morpholine, 36.4-benzyl-2-{[4-(o-tolyl)piperidine-1-yl]methyl}morpholine, 37.2-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline, 38.5-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}-2-methylphenol, 39.5-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}-2-fluorophenol, 40.3-{1-[(4-(4-methoxybenzyl)-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 41.3-{1-[(4-(3,4-dichlorobenzyl)-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 42.3-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 43.3-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline, 44.4-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 45.2-{[4-(4-methoxyphenyl)piperidine-1-yl]methyl}-4-methyl-1,4-oxazepane, 46.4-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline, 47. 4-methyl-2-{[4-(o-tolyl)piperidine-1-yl]methyl}-1,4-oxazepane, 48.2-{[4-(3-methoxyphenyl)piperidine-1-yl]methyl}-4-methyl-1,4-oxazepane, 49.3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]pyrrolidine-3-yl}phenol, 50.4-{1-[(4-benzylmorpholin-2-yl)methyl]piperidine-4-yl}aniline, and Any salt, solvate, or stereoisomer thereof.

8. A compound as defined in any one of the prior claims 1 to 7, for use in preventing or treating G9a-mediated disorders in subjects requiring such inhibition, particularly by inhibiting G9a.

9. The compound according to claim 8, for use in the prevention or treatment of blood disorders, cancer, immune-mediated diseases, imprinting disorders, or in reducing the consumption of a substance (alcohol) by a subject.

10. Alzheimer's disease, amyotrophic lateral sclerosis, age-related tau astrocyte disease, aortic amyloidosis, argyrophilic granulopathy, familial dementia (UK), cardiac amyloidosis, cerebral amyloid angiopathy, chronic traumatic encephalopathy, corneal dystrophy, corticobasal degeneration, Creutzfeldt-Jakob disease, familial dementia (Denmark), Down syndrome, familial amyloidosis, familial corneal amyloidosis, fatal insomnia, frontotemporal dementia, Gerstmann-Straussler-Scheinker disease, glial tauopathy, amyloidosis A compound according to any one of the prior claims 8 to 9 for use in the prevention or treatment of a disease selected from the group consisting of hereditary cerebral hemorrhage, Huntington's disease, inflammation-related amyloidosis, kuru, Lewy body disease, 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-related amyloidosis and light chain amyloidosis, subacute sclerosing panencephalitis, and tuberous sclerosis.

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

12. Compounds of formula (Ibis), their salts, solvates, or stereoisomers: 【Chemistry 2】 In the formula, R １ A and Z are as defined in any one of the prior claims 1 to 11, R ２ｂｉｓ teeth, a) CR ｚ１ A six-membered aromatic ring system selected from the group consisting of and N, and b) A two-ring aromatic fused ring system in which one or both rings are aromatic rings, and each aromatic ring is CR ｚ２ Selected from the group consisting of aromatic condensed ring systems having 5 or 6 members selected from the group consisting of S, N, NH, and O, CR ｚ１ and CR ｚ２ This is as defined in any of the prior claims, However, the compound of formula (Ibis) is not 3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol.

13. R ２ｂｉｓ It is an aromatic six-membered ring system, where all members are either the same or different, CR ｚ１ Represents R ｚ１ The compound according to claim 12, wherein is as defined in any of the prior claims.

14. A compound according to any one of claims 12 to 13, selected from the following: 1,4-benzyl-2-[(4-phenylpiperidine-1-yl)methyl]-1,4-oxazepane, 2.4-benzyl-2-{[4-(4-chlorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 3. 4-benzyl-2-{[4-(4-bromophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 4.4-benzyl-2-{[4-(4-fluorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 5. 4-benzyl-2-{[4-(3-bromophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 6.4-benzyl-2-{[4-(3,5-dichlorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 7. 4-benzyl-2-{[4-(2-fluorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 8.4-benzyl-2-{[4-(p-tolyl)piperidine-1-yl]methyl}-1,4-oxazepane, 9. 4-benzyl-2-{[4-(m-tolyl)piperidine-1-yl]methyl}-1,4-oxazepane, 10.4-benzyl-2-{[4-(o-tolyl)piperidine-1-yl]methyl}-1,4-oxazepane, 11.4-benzyl-2-{[4-(4-methoxyphenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 12.4-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 13.3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline, 14.4-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline; 15.3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}benzonitrile, 16.2-{[4-(1H-pyrazole-1-yl)piperidine-1-yl]methyl}-4-benzyl-1,4-oxazepane, 17.3-{1-[(4-benzylmorpholin-2-yl)methyl]piperidine-4-yl}phenol, 18.3-{1-[(4-benzylmorpholin-2-yl)methyl]piperidine-4-yl}aniline, 19.4-benzyl-2-{[4-(3-methylsulfonylphenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 20.4-benzyl-2-{[4-(pyridine-4-yl)piperidine-1-yl]methyl}-1,4-oxazepane, 21.4-benzyl-2-{[4-(3-trifluoromethylphenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 22.4-benzyl-2-{[4-(3-chlorophenyl)piperidine-1-yl]methyl}-1,4-oxazepane, 23.2-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 24. Methyl 3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}benzoate, 25.4-benzyl-2-{4-(pyrimidine-2-yl)piperidine-1-yl)methyl}-1,4-oxazepane, 26.2-{[4-(1H-benzo[d]imidazole-2-yl)piperidine-1-yl]methyl}-4-benzyl-1,4-oxazepane, 27. 4-benzyl-2-{[4-(pyridine-3-yl)piperidine-1-yl]methyl}-1,4-oxazepane, 28.2-{[4-(1H-indole-3-yl)piperidine-1-yl]methyl}-4-benzyl-1,4-oxazepane, 29.3-{1-[(4-(4-chlorobenzyl)-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 30.3-{1-[(4-(4-methylbenzyl)-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 31.4-benzyl-2-{[4-(4-chlorophenyl)piperidine-1-yl]methyl}morpholine, 32.4-{1-[(4-benzylmorpholin-2-yl)methyl]piperidine-4-yl}phenol, 33.4-benzyl-2-{[4-phenylpiperidine-1-yl]methyl}morpholine, 34.4-benzyl-2-{[4-(3-trifluoromethylphenyl)piperidine-1-yl]methyl}morpholine, 35.4-benzyl-2-{[4-(o-tolyl)piperidine-1-yl]methyl}morpholine, 36.2-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline, 37.5-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}-2-methylphenol, 38.5-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}-2-fluorophenol, 39.3-{1-[(4-(4-methoxybenzyl)-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 40.3-{1-[(4-(3,4-dichlorobenzyl)-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 41.3-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 42.3-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline, 43.4-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}phenol, 44.2-{[4-(4-methoxyphenyl)piperidine-1-yl]methyl}-4-methyl-1,4-oxazepane, 45.4-{1-[(4-methyl-1,4-oxazepan-2-yl)methyl]piperidine-4-yl}aniline, 46. ​​4-methyl-2-{[4-(o-tolyl)piperidine-1-yl]methyl}-1,4-oxazepane, 47.2-{[4-(3-methoxyphenyl)piperidine-1-yl]methyl}-4-methyl-1,4-oxazepane, 48.3-{1-[(4-benzyl-1,4-oxazepan-2-yl)methyl]pyrrolidine-3-yl}phenol, 49.4-{1-[(4-benzylmorpholin-2-yl)methyl]piperidine-4-yl}aniline, or Any salt, solvate, or stereoisomer thereof.

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