IP Library › Granted Patent US 10,399,973

Granted Patent B2

US 10,399,973 · App. 15/858,407 · Granted Sep 3, 2019

Compounds I

Inventors: Edward Savory (Cambourne, GB); Michael Higginbottom (Caldecote, GB); Kathryn Oliver (Cambridge, GB); Viet-Anh Anne Horgan (Redhill, GB)

Assignee: BENEVOLENTAI CAMBRIDGE LIMITED

C07D471/04 A61K31/437

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Quick Facts

Patent No.: US 10,399,973
App. No.: 15/858,407
Granted: Sep 3, 2019
Kind: B2

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Abstract

The present invention relates to compounds of formula (I), and their pharmaceutically acceptable salts, solvates, hydrates, geometrical isomers, tautomers, optical isomers or N-oxides, which are inhibitors of SSAO activity. The invention further relates to pharmaceutical compositions comprising these compounds and to the use of these compounds for the treatment of medical conditions wherein inhibition of SSAO activity is beneficial, such as inflammatory diseases and immune disorders.

Claims (153)

1. A method of synthesizing a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, or N-oxide thereof, wherein:

R 1 is selected from:

(a) hydrogen,

(b) C 1-6 -alkyl, and

R 2 is selected from:

(a) hydrogen,

(b) C 1-6 -alkyl,

(d) hydroxy-C 1-6 -alkyl,

(e) C 1-6 -alkoxy-C 1-6 -alkyl,

(f) halo-C 1-6 -alkoxy-C 1-6 -alkyl,

(g) N(R 4A R 4B )—C 1-6 -alkyl,

(h) —C(O)NR 4A R 4B , and

(i) —C(O)O—C 1-6 -alkyl;

R 3 is selected from:

(a) C 1-6 -alkyl,

(b) halo-C 1-6 -alkyl,

(d) C 1-6 -alkoxy-C 1-6 -alkyl,

(e) halo-C 1-6 -alkoxy-C 1-6 -alkyl,

(f) N(R 4A R 4B )—C 1-6 -alkyl,

(g) C 6-10 -aryl-C 1-4 -alkyl,

(h) heteroaryl-C 1-6 -alkyl,

(i) C 6-10 -aryloxy-C 1-4 -alkyl,

(j) heteroaryloxy-C 1-4 -alkyl,

(k) C 3-8 -cycloalkyl,

(l) C 3-8 -cycloalkyl-C 1-4 -alkyl,

(m) heterocyclyl, and

(n) heterocyclyl-C 1-4 -alkyl,

wherein any aryl or heteroaryl residue is optionally substituted with one more substituents independently selected from halogen, hydroxy, cyano, nitro, CF 3 , C 1-4 -alkyl, C 1-4 -alkoxy and —NR 4A R 4B , and wherein any cycloalkyl or heterocyclyl residue is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-4 -alkyl, C 1-4 -alkoxy and —NR 4A R 4B ; and

R 4A and R 4B are each independently selected from:

(a) hydrogen,

(b) C 1-6 -alkyl, and

the method comprising:

reacting together a compound of formula (III) with a compound of formula (IV):

where R 1 , R 2 , and R 3 are as defined in formula (I), in the presence of a base to obtain the compound of formula (I); or

reacting a compound of formula (III) with 4-nitrophenyl chloroformate to form a compound of formula (V):

where R 1 and R 2 are as defined in formula (I), and

reacting the compound of formula (V) with R 3 OH, where R 3 is as defined in formula (I), to obtain the compound of formula (I).

2. The method according to claim 1 , wherein R 1 is H.

3. The method according to claim 1 , wherein:

R 2 is selected from hydrogen,—C(O)O—C 1-3 -alkyl, and —C(O)NR 4A′ R 4B′ , and

R 4A′ and R 4B′ are independently selected from hydrogen and C 1-2 -alkyl.

4. The method according to claim 1 , wherein:

R 3 is selected from halo-C 1-2 -alkyl, halo-C 1-2 -alkoxy-C 1-2 -alkyl, di(C 1-2 -alkyl)amino-C 1-2 -alkyl, phenyl-C 1-2 -alkyl, phenoxy-C 1-2 -alkyl, C 5-6 -heteroaryl-C 1-2 -alkyl, C 5-6 -heteroaryloxy-C 1-2 -alkyl, heterocyclyl and heterocyclyl-C 1-2 -alkyl, and

any phenyl, heteroaryl or heterocyclyl residue is optionally substituted with one or two substituents independently selected from halogen and C 1-2 -alkyl.

5. The method according to claim 1 , wherein the compound of formula (I) is selected from:

2,2,2-Trichloroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

2-Chloro-2,2-difluoroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate;

Benzyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

3-Chlorobenzyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

4-Chlorobenzyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

Pyridin-2-ylmethyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

Pyridin-3-ylmethyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

Pyridin-4-ylmethyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

(5-Chloropyridin-2-yl)methyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo [4,5-c]-pyridine-5-carboxylate;

Pyrazin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

Benzyl (4S,6S)-6-(aminocarbonyl)-4-isopropyl-1,4,6,7-tetrahydro-5H -imidazo[4,5-c]pyridine-5-carboxylate;

Benzyl (4S,6S)-4-isopropyl-6-[(methylamino)carbonyl]-1,4,6,7-tetrahydro-5H -imidazo[4,5-c]pyridine-5-carboxylate;

5-Benzyl 6-methyl (4S,6S)-4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5,6-dicarboxylate;

2-Phenoxyethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

2-(4-Chlorophenoxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

(3S)-Tetrahydrofuran-3-yl (4S)-4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

Tetrahydrofuran-3-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate;

(3-Methyloxetan-3-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate;

2-(Dimethylamino)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate;

(2R)-Tetrahydrofuran-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo [4,5-c]pyridine-5-carboxylate;

1,3-Thiazol-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate;

(5-Methylisoxazol-3-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate;

[(2S)-1-Methylpyrrolidin-2-yl]methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo-[4,5-c]pyridine-5-carboxylate;

(3R)-1-methylpyrrolidin-3-yl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate;

Oxetan-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

2-(Pyridin-3 -yloxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate; and

2-(2,2,2-Trifluoroethoxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate.

6. A method for inhibiting semicarbazide-sensitive amine oxidase activity in a subject, comprising:

administering to the subject in need of such treatment an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, geometrical isomer, tautomer, optical isomer, or N-oxide thereof, wherein:

R 1 is selected from:

(a) hydrogen,

(b) C 1-6 -alkyl, and

R 2 is selected from:

(a) hydrogen,

(b) C 1-6 -alkyl,

(d) hydroxy-C 1-6 -alkyl,

(e) C 1-6 -alkoxy-C 1-6 -alkyl,

(f) halo-C 1-6 -alkoxy-C 1-6 -alkyl,

(g) N(R 4A R 4B )—C 1-6 -alkyl,

(h) —C(O)NR 4A R 4B , and

(i) —C(O)O—C 1-6 -alkyl;

R 3 is selected from:

(a) C 1-6 -alkyl,

(b) halo-C 1-6 -alkyl,

(d) C 1-6 -alkoxy-C 1-6 -alkyl,

(e) halo-C 1-6 -alkoxy-C 1-6 -alkyl,

(f) N(R 4A R 4B )—C 1-6 -alkyl,

(g) C 6-10 -aryl-C 1-4 -alkyl,

(h) heteroaryl-C 1-4 -alkyl,

(i) C 6-10 -aryloxy-C 1-4 -alkyl,

(j) heteroaryloxy-C 1-4 -alkyl,

(k) C 3-8 -cycloalkyl,

(l) C 3-8 -cycloalkyl-C 1-4 -alkyl,

(m) heterocyclyl, and

(n) heterocyclyl-C 1-4 -alkyl,

R 4A and R 4B are each independently selected from:

(a) hydrogen,

(b) C 1-6 -alkyl, and

7. The method according to claim 6 , wherein R 1 is H.

8. The method according to claim 6 , wherein:

R 2 is selected from hydrogen, —C(O)O—C 1-3 -alkyl, and —C(O)NR 4A′ R 4B′ , and

R 4A′ and R 4B′ are independently selected from hydrogen and C 1-2 -alkyl.

9. The method according to claim 6 , wherein:

any phenyl, heteroaryl or heterocyclyl residue is optionally substituted with one or two substituents independently selected from halogen and C 1-2 -alkyl.

10. The method according to claim 6 , wherein the compound of formula (I) is selected from:

2,2,2-Trichloroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

2-Chloro-2,2-difluoroethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]-pyridine-5-carboxylate;

Benzyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

3-Chlorobenzyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

4-Chlorobenzyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c] pyridine-5-carboxylate;

Pyridin-2-ylmethyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

Pyridin-3-ylmethyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

Pyridin-4-ylmethyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

(5-Chloropyridin-2-yl)methyl 4-isopropyl- 1,4,6,7-tetrahydro-5H-imidazo [4,5-c]-pyridine-5-carboxylate;

Pyrazin-2-ylmethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;

Benzyl (4S,6S)-6-(aminocarbonyl)-4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo-[4,5-c]pyridine-5-carboxylate;

Benzyl (4S,6S)-4-isopropyl-6-[(methylamino)carbonyl]-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate;