Imidazo[4,5-c]pyridine and pyrrolo[2,3-c]pyridine derivatives as SSAO inhibitors

1. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, or N-oxide thereof

comprising reacting a compound of formula (IIIb) with a compound of formula (IX) to form the compound of formula (I)

wherein:

Y is selected from hydrogen, hydroxyl, —NH 2 , —NH—C 1-4 -alkyl, —NH-halo-C 1-4 -alkyl, and —C 1-4 -alkoxy;

Z is selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, C 1-4 -alkoxy, halo-C 1-4 -alkoxy, —CONH 2 , —SO 2 NH 2 , —NH 2 , —NHC 1-4 -alkyl, and —NHhalo-C 1-4 -alkyl;

R 1 is a phenyl ring, or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more substituents selected from halogen, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, cyano-C 1-4 -alkyl, a 3-7 membered cycloalkyl ring, —OR 5 , —NR 6 C(O)OR 5 , —NR 6 C(O)R 5 , —NR 6 C(O)NR 4A R 4B , —C(O)NR 4A R 4B , —C(O)R 5 , —C(O)OR 5 , and —NR 6 S(O) 2 R 5 ;

R 4A , R 4B , R 5 , and R 6 are each independently selected from hydrogen, C 1-4 -alkyl, and halo-C 1-4 -alkyl, or

R 4A and R 4B together with the nitrogen to which they are attached form a 3-7 membered cyclic amino group, optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, C 1-4 -alkoxy, halo-C 1-4 -alkoxy, —CONH 2 , —SO 2 NH 2 , —NH 2 , —NHC 1-4 -alkyl, and —NHhalo-C 1-4 -alkyl;

X is —C(R 2 )═;

R 2 is selected from hydrogen, halogen, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, cyano-C 1-4 -alkyl, —OR 5 , —NR 4A R 4B , —NR 6 C(O)OR 5 , —NR 6 C(O)R 5 , —NR 6 C(O)NR 4A R 4B , —SO 2 R 5 , —SO 2 NR 4A R 4B and —NR 6 S(O) 2 R 5 ;

W is a phenyl ring or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more substituents selected from halogen, cyano, oxo C 1-4 -alkyl, halo-C 1-4 -alkyl, cyano-C 1-4 -alkyl, —OR 5 , —NR 7A R 7B , —NR 6 C(O)OR 5 , —NR 6 C(O)R 5 , —NR 6 C(O)NR 7A R 7B , —C(O)NR 7A R 7B , —C(O)R 5 , —C(O)OR 5 , —SO 2 R 5 , —SO 2 NR 7A R 7B , and —NR 6 S(O) 2 R 5 ;

R 7A and R 7B are independently hydrogen, C 1-4 -alkyl, or halo-C 1-4 -alkyl;

V is selected from a bond, —O—, —N(R 6 )—, —(C═O)—, —CONR 6 —, —NR 6 C(O)—, and —C 1-4 -alkylene-, wherein the C 1-4 -alkylene group is optionally substituted by halogen, and wherein any one of the carbon atoms of the C 1-4 -alkylene group may be replaced by —O— or —N(R 6 )—;

R 3 is selected from hydrogen, —C 1-4 -alkyl, —C 1-4 -alkyl-C 1-4 -alkoxy, a 3-7 membered heterocyclic ring, a 3-7 membered cycloalkyl ring, and a 5 or 6-membered heteroaryl ring, any one of the rings being optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, cyano-C 1-4 -alkyl, —OR 5 , —NR 4A R 4B , —NR 6 C(O)OR 5 , —NR 6 C(O)R 5 , —NR 6 C(O)NR 4A R 4B , —C(O)NR 4A R 4B , —C(O)R 5 , —C(O)OR 5 , —SO 2 R 5 , —SO 2 NR 4A R 4B , and —NR 6 S(O) 2 R 5 ;

provided that groups —WVR 3 and/or R 1 are not:

wherein:

n is 0, 1, or 2;

R′ and R″ are independently selected from the group consisting of H, —C 1 -C 6 alkyl, —(C═O)—C 1 -C 6 alkyl, and —(C═O)OC(CH 3 ) 3 ; and

R′″ is H, OH, or C 1 -C 6 alkyl; and

further provided that when —R 3 is H, R 1 is not a phenyl ring substituted with one —OCH 3 .

2. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, or N-oxide thereof

comprising reacting a compound of formula (IIIb) with a compound of formula (IX) to form the compound of formula (I)

wherein:

Y is selected from hydrogen, hydroxyl, —NH 2 , —NH—C 1-4 -alkyl, —NH-halo-C 1-4 -alkyl, and —C 1-4 -alkoxy;

Z is selected from hydrogen, halogen, hydroxyl, cyano, C 1-4 -alkyl, halo-C 14 -alkyl, C 1-4 -alkoxy, halo-C 1-4 -alkoxy, —CONH 2 , —SO 2 NH 2 , —NH 2 , —NHC 1-4 -alkyl, and —NHhalo-C 1-4 -alkyl;

R 1 is a phenyl ring, or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more substituents selected from halogen, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, cyano-C 14 -alkyl, —OR 5 , —NR 6 C(O)OR 5 , —NR 6 C(O)R 5 , —NR 6 C(O)NR 4A R 4B , —C(O)NR 4A R 4B , —C(O)R 5 , —C(O)OR 5 , and —NR 6 S(O) 2 R 5 ;

R 4A , R 4B , R 5 , and R 6 are each independently selected from hydrogen, C 1-4 -alkyl, and halo-C 1-4 -alkyl, or

R 4A and R 4B together with the nitrogen to which they are attached form a 3-7 membered cyclic amino group, optionally substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, C 1-4 -alkoxy, halo-C 1-4 -alkoxy, —CONH 2 , —SO 2 NH 2 , —NH 2 , —NHC 1-4 -alkyl, and —NHhalo-C 1-4 -alkyl;

X is —C(R 2 )═;

R 2 is selected from hydrogen, halogen, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, cyano-C 1-4 -alkyl, —OR 5 , —NR 4A R 4B , —NR 6 C(O)OR 5 , —NR 6 C(O)R 5 , —NR 6 C(O)NR 4A R 4B , —C(O)NR 4A R 4B , —C(O)R 5 , —C(O)OR 5 , —SO 2 R 5 , —SO 2 NR 4A R 4B , and —NR 6 S(O) 2 R 5 ,

W is a phenyl ring or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more substituents selected from halogen, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, cyano-C 1-4 -alkyl, —OR 5 , —NR 7A R 7B , —NR 6 C(O)OR 5 , —NR 6 C(O)R 5 , —NR 6 C(O)NR 7A R 7B , —SO 2 R 5 , —SO 2 NR 7A R 7B , and —NR 6 S(O) 2 R 5 ;

R 7A and R 7B are independently hydrogen, C 1-4 -alkyl, and halo-C 1-4 -alkyl;

V is selected from a bond, —O—, —N(R 6 )—, —(C═O)—, —CONR 6 —, —NR 6 C(O)—, and —C 1-4 -alkylene-, wherein the C 1-4 -alkylene group is optionally substituted by halogen, and wherein any one of the carbon atoms of the C 1-4 -alkylene group may be replaced by —O— or —N(R 6 )—;

R 3 is hydrogen, or a 3-7 membered heterocyclic ring, or 3-7 membered cycloalkyl ring selected from cyclopropyl, cyclopentyl or cyclohexyl, or a 5 or 6-membered heteroaryl ring, any one of the rings being optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, cyano, C 1-4 -alkyl, halo-C 1-4 -alkyl, cyano-C 1-4 -alkyl, —OR 5 , —NR 4A R 4B , —NR 6 C(O)OR 5 , —NR 6 C(O)R 5 , —NR 6 C(O)NR 4A R 4B , —C(O)NR 4A R 4B , —C(O)R 5 , —C(O)OR 5 , —SO 2 R 5 , —SO 2 NR 4A R 4B ; and —NR 6 S(O) 2 R 5 ;

provided that when —R 3 is H, R 1 is not a phenyl ring substituted with one —OCH 3 .

3. The process as claimed in claim 1 , wherein the compound of formula (IIIb) is formed by reacting a compound of formula (IIb) with a compound of formula R 1 —I

wherein Z, Y, and R 1 are as defined in claim 1 .

4. The process as claimed in claim 1 , wherein the compound of formula (IIIb) is converted into a boronate ester prior to its reaction with the compound of formula (IX).

5. The process as claimed in claim 4 , wherein the boronate ester is formed in a reaction that comprises lithium diisopropylamide and (iPrO) 3 B.

6. The process as claimed in claim 4 , wherein the compound of formula (I) is formed by reacting the boronate ester of the compound of formula (IIIb) with the compound of formula (IX) under Suzuki coupling conditions.

7. The process as claimed in claim 6 , wherein the Suzuki coupling conditions comprise Pd(PPh 3 ) 4 and Na 2 CO 3 .

8. The process as claimed in claim 1 , wherein the compound of formula (IIIb) is reacted with the compound of formula (IX) in a reaction that comprises lithium diisopropylamide, (iPrO) 3 B, Pd(PPh 3 ) 4 , and Na 2 CO 3 .

9. The process as claimed in claim 3 , wherein the compound of formula (IIb) is reacted with the compound R 1 —I in the presence of 1,2-dimethylethylenediamine, K 3 PO 4 , and CuI.

10. The process as claimed in claim 1 , wherein Z is hydrogen.

11. The processes as claimed in claim 1 , wherein R 1 is phenyl or 6-membered heteroaryl, optionally substituted with one or more substituents selected from halogen, C 1-4 -alkyl, and halo-C 14 -alkyl.

12. The process as claimed in claim 1 , wherein R 1 is phenyl or pyridyl, optionally substituted with one or more substituents selected from F, Cl, and CH 3 .

13. The process as claimed in claim 1 , wherein R 2 is hydrogen, halogen, cyano, C 1-4 -alkyl, or halo-C 1-4 -alkyl.

14. The process as claimed in claim 1 , wherein R 2 is hydrogen.

15. The process as claimed in claim 1 , wherein W is a phenyl ring optionally substituted with one or more substituents as defined in claim 1 .

16. The process as claimed in claim 1 , wherein W is a 6-membered heteroaryl ring selected from pyridine, pyridazine, pyrazine, and pyrimidine optionally substituted with one or more substituents as defined in claim 1 .

17. The process as claimed in claim 1 , wherein W is a 5-membered heteroaryl ring selected from oxazole, thiazole, and imidazole optionally substituted with one or more substituents as defined in claim 1 .

18. The process as claimed in claim 1 , wherein W is an imidazolyl ring optionally substituted as in claim 1 , and wherein the imidazolyl ring is connected to the pyrrolopyridine core via an imidazolyl ring carbon atom.

19. The process as claimed in claim 1 , wherein W is optionally substituted with one or more substituents selected from fluoro, chloro, cyano, CH 3 , and CF 3 .

20. The process as claimed in claim 1 , wherein V is —CH 2 —, —(CH 2 ) 2 , —N(R 6 )CH 2 —, or —CH 2 —N(R 6 )—.

21. The process as claimed in claim 1 , wherein R 3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted as defined in claim 1 .

22. The process as claimed in claim 1 , wherein R 3 is formed from NR 4A R 4B , wherein R 4A and R 4B , together with the nitrogen atom to which they are attached, join together to form a 4-7 membered heterocyclic ring optionally substituted as defined in claim 1 .

23. The process as claimed in claim 1 , wherein R 3 is selected from the group consisting of:

wherein R 8 is selected from hydrogen, CH 3 , —CONH 2 , —NHCONH 2 , —S(O) 2 CH 3 , and —COCH 3 .

24. The process as claimed in claim 1 , wherein R 1 is a phenyl ring, or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more 3-7 membered cycloalkyl rings.

25. The process as claimed in claim 1 , wherein W is a phenyl ring or a 5 or 6-membered heteroaryl ring, the ring being optionally substituted with one or more oxo substituents.

26. The process as claimed in claim 1 , wherein R 3 is selected from —C 1-4 -alkyl and —C 1-4 -alkyl-C 1-4 -alkoxy.

27. The process as claimed in claim 1 , wherein the compound of formula (I) is selected from:

4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;

2-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;

3-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;

5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidine;

2-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrazine;

1-({4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]phenyl}carbonyl)-4-methylpiperazine;

4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine;

4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}piperazin-2-one;

4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine;

4-{5-[1-(4-Methylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine;

4-(5-{1-Phenyl-1H-pyrrolo[2,3-c]pyridin-2-yl}pyrimidin-2-yl)morpholine;

4-{5-[1-(4-Bromophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine;

5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1H-pyrazole;

4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1H-pyrazole;

5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1H-imidazole;

5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-N,N-dimethylpyrimidin-2-amine;

4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-cyclopropyl-1,2-dihydropyridin-2-one;

5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-N-(oxan-4-yl)pyrimidin-2-amine;

4-({5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridin-2-yl}methyl)morpholine;

5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-amine;

4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1,2-dihydropyridin-2-one;

4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1,2-dihydropyridin-2-one;

4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-ethyl-1,2-dihydropyridin-2-one;

6-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1,2-dihydropyridin-2-one;

5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-2,3-dihydropyridazin-3-one;

4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridin-2-amine;

3-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-5-fluoropyridine;

5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-N-(cyclopropylmethyl)pyrimidin-2-amine;

3-Chloro-5-[1-(4-chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;

5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-2-(1H-pyrazol-1-yl)pyridine;

4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-3-fluoropyridine;

3-Chloro-4-[1-(4-chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine;

4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-3-methylpyridine;

1-Cyclopropyl-4-{1-phenyl-1H-pyrrolo[2,3-c]pyridin-2-yl}-1,2-dihydropyridin-2-one; and

pharmaceutically acceptable salts thereof.