Substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors

1. A compound of formula (I),

wherein n is 0,

X is —S(═O);

A is N;

R a is —O—C(═O)R a3 or —O—C(═O)—T—OR a4 ; wherein

R a3 is a linear or branched C 1-15 alkyl, linear or branched C 2-15 alkenyl, —T—C 3-10 cycloalkyl, —T—NHR a3p , —T—C 3-10 cycloalkenyl, —T—C 6-10 aryl, —T—C 5-10 heteroaryl, —T—NH—C(═O)—O—C 1-10 alkyl, —T—adamantyl or —C 1-3 alkylene—C 6-10 aryl where the alkylene is substituted with —T—NHR a3p ;

R a4 is a linear or branched C 1-15 alkyl, linear or branched C 2-15 alkenyl, —T—C 3-10 cycloalkyl, —T—NHR a3p , —T—C 3-10 cycloalkenyl, —T—C 6-10 aryl, —T—C 5-10 heteroaryl, —T—NH—C(═O)—O-C 1-10 alkyl, —T—adamantyl or —C 1-3 alkylene—C 6-10 aryl where the alkylene is substituted with —T—NHR a3p ;

R a3p is H or an N-protecting group selected from Fmoc or Boc;

R b is H, linear or branched C 1-15 alkyl, linear or branched C 2-15 alkenyl, C 1-3 alkoxy—C 1-15 alkyl—, —T′-C 3-10 cycloalkyl, —T′—C 3-10 cycloalkenyl, —T′—C 6-10 aryl or —T′—C 5-10 heteroaryl;

R c each is independently halogen, linear or branched C 1-15 alkyl, linear or branched C 1-15 alkoxyl, hydroxyl group, or —C 1-10 alkylene—Y—C 6-10 heteroaryl wherein —Y— is —CH 2 —, —NH—, —O— or —S—;

m is an integer from 0 to 4;

-T- is absent, C 1-3 alkylene or C 2-3 alkenylene;

-T′- is C 1-3 alkylene or C 2-3 alkenylene; and

wherein the heteroaryl contains at least one heteroatom, each heteroatom being independently S, N or O;

wherein the alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, alkylene and alkenylene are each independently unsubstituted or substituted with at least one substituent;

wherein the substituent is each independently a halogen, nitro, nitroso, linear or branched C 1-15 alkyl, or linear or branched C 1-15 alkoxy or C 3-10 cycloalkyl;

wherein the alkoxy is unsubstituted; and

when R b is H, the tautomers are included,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein

A is N;

R b is H;

m is 3; and

R c each is independently linear or branched C 1-15 alkyl, linear or branched C 1-15 alkoxyl;

or a pharmaceutically acceptable salt.

3. The compound of claim 1 , wherein m is an integer from 0 to 3.

4. The compound of claim 1 , wherein R a is —O—C(═O)R a3 wherein R a3 is adamantyl; linear or branched C 1-10 alkyl unsubstituted or substituted by halogen; C 1-4 alkoxy; —C 6-10 aryl unsubstituted or substituted by C 1-10 alkyl, nitro, C 1-15 alkoxy or halogen; C 3-10 cycloalkyl; —C 3-10 cycloalkenyl; linear or branched C 2-10 alkenyl; —C 5-10 heteroaryl; —C 1-3 alkylene—C 3-10 cycloalkyl; C 2-3 alkenylene—C 6-10 aryl wherein C 6-10 aryl is unsubstituted or substituted by halogen; —O—C(═O)—O—C 1-10 alkyl.

5. The compound of claim 1 , wherein R a is —O—C(═O)R a3 wherein R a3 is adamantly adamantyl; linear or branched C 1-8 alkyl unsubstituted or substituted by halogen; C 1-4 alkoxy; -phenyl unsubstituted or substituted by C 1-6 alkyl, nitro, C 1-4 alkoxy or halogen; C 3-6 cycloalkyl; —C 3-6 cycloalkenyl; linear or branched C 2-6 alkenyl; —C 5-6 heteroaryl; —C 1-3 alkylene—C 3-6 cycloalkyl; C 2-3 alkenylene-phenyl wherein phenyl is unsubstituted or substituted by halogen; —O—C(═O)—O—C 1-4 alkyl.

6. The compound of claim 1 , wherein R a is —O—C(═O)—C 1-6 alkyl, —O—C(═O)—C 1-3 alkylene-NHFmoc, —O—C(═O)—C 1-3 alkylene-NHBoc or —O—C(═O)—NH—C(═O)—O—C 1-10 alkyl.

7. The compound of claim 1 , wherein R c each is independently halogen, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxyl, or —C 1-10 alkenylene—Y—C 6-10 heteroaryl; wherein Y is S and C 6-10 heteroaryl is unsubstituted or substituted by C 1-15 alkyl, C 1-15 alkoxy, —OH, —NH 2 , —NO 2 or halogen.

8. A compound of selected from the group consisting of:

21122: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl acetate),

21124: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl benzoate),

26096: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl butyrate),

26097: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl cyclohexanecarboxylate),

26098: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-butylbenzoate),

21127: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-methylbenzoate),

27076: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl hexanoate,

27077: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl isobutyrate,

27078: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl cyclohex-3-ene-1-carboxylate),

27079: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl cyclohex-3-enecarboxylate

28087: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-methylbenzoate),

28091: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-nitrobenzoate),

28092: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl cyclopropanecarboxylate),

28093: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-ethylbutanoate),

28094: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-phenylacetate),

28095: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3,5,5-trimethylhexanoate

28096: (2-(((5-methoxy-4,6-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-ethoxybenzoate),

21123: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl propionate),

21125: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-chlorobenzoate),

21126: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-nitrobenzoate),

21128: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl heptanoate

21129: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-fluorobenzoate),

21130: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl (Z)-2-methylbut-2-enoate),

21131: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-chloropropanoate),

21132: tert-butyl (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl) carbonate

12124: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl (Z)-but-2-enoate),

12125: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-methylbut-2-enoate),

12122: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl furan-2-carboxylate),

12123: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl acrylate),

12127: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-methylbutanoate),

12128: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-cyclopentylpropanoate),

12129: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl (E)-3-(2-chlorophenyl)acrylate),

12130: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 6-bromohexanoate),

11021: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-fluorobenzoate),

11020: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-methoxybenzoate),

11022: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl (3r,5r,7r)-adamantane-1-carboxylate)

11023: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl isoxazole-5-carboxylate),

11030: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-(tert-butyl)benzoate),

11031: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3-chloro-4-fluorobenzoate),

25015: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl pivalate),

25016: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl pentanoate),

25017: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 4-nitrobenzoate),

25027: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl cyclobutanecarboxylate),

25028: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl thiophene-2-carboxylate),

25029: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-methylbutanoate),

25030: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 3,3-dimethylbutanoate)

25031: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl 2-methoxyacetate), and

25032: (ethyl (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl) carbonate),

or a pharmaceutically acceptable salt thereof.

9. The compound

13001: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-6-yl 2-((tert-butoxycarbonyl)amino)acetate

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition, comprising a compound of claim 1 .