IP Library › Granted Patent US 9,676,769

Granted Patent B2

US 9,676,769 · App. 14/775,046 · Granted Jun 13, 2017

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

Inventors: Max Espensen (Cambridge, GB); Lee Patient (Linton, GB); David Evans (Royston, GB); Iain Simpson (Cambridge, GB); Edward Savory (Cambourne, GB)

Assignee: Proximagen Limited

C07D471/04 C07C53/18

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Quick Facts

Patent No.: US 9,676,769
App. No.: 14/775,046
Granted: Jun 13, 2017
Kind: B2

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Abstract

The compounds of formula (I) are inhibitors of semicarbazide-sensitive amine oxidase (SSAO) activity useful in the treatment of inflammation, an inflammatory disease, an immune or an autoimmune disorder, or inhibition of tumor growth.

Claims (145)

1. A compound of formula (Xa)

wherein E is —C═ or —N═,

R 9 and R 10 are each independently one or more substituents selected from hydrogen, halogen, cyano, oxo, C 1-4 -alkyl, —OC 1-4 -alkyl, and halo-C 1-4 -alkyl;

R 11 is one or more substituents selected from hydrogen, halogen, cyano, cyclopropyl, C 1-4 -alkyl, and halo-C 1-4 -alkyl.

2. A pharmaceutical composition comprising a compound of formula (Xa)

wherein E is —C═ or —N═,

R 9 and R 10 are each independently one or more substituents selected from hydrogen, halogen, cyano, oxo, C 1-4 -alkyl, —OC 1-4 -alkyl, and halo-C 1-4 -alkyl;

R 11 is one or more substituents selected from hydrogen, halogen, cyano, cyclopropyl, C 1-4 -alkyl, and halo-C 1-4 -alkyl;

or a pharmaceutically acceptable salt thereof, and one or more suitable excipients.

3. A method for the treatment of a disease wherein inhibition of SSAO activity is beneficial, which comprises administering to a subject suffering such disease an effective amount of a compound of formula (Xa)

wherein E is —C═ or —N═,

R 9 and R 10 are each independently one or more substituents selected from hydrogen, halogen, cyano, oxo, C 1-4 -alkyl, —OC 1-4 -alkyl, and halo-C 1-4 -alkyl;

R 11 is one or more substituents selected from hydrogen, halogen, cyano, cyclopropyl, C 1-4 -alkyl, and halo-C 1-4 -alkyl;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , selected from the group consisting of:

4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine (Example 21);

4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine (Example 22);

(2R,6S)-4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-2,6-dimethylmorpholine (Example 23);

4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-2,2-dimethylmorpholine (Example 24);

4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyrimidin-2-yl}morpholine (Example 26);

4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyrimidin-2-yl}morpholine (Example 27);

4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methoxypyridin-2-yl}morpholine (Example 28);

4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4,6-dimethylpyridin-2-yl}morpholine (Example 29);

4-{5-[3-(2,4-Difluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 41);

4-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 47);

4-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 51);

4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 52);

4-{5-[3-(2-Fluoro-4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 53);

4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 54);

4-{5-[3-(4-Fluoro-2-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 55);

4-{5-[3-(2-Chloro-4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 56);

4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 57);

4-{5-[3-(4-Bromophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 59);

4-{5-[3-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 60);

4-{5-[3-(2-Chloro-4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 61);

4-{5-[3-(4-Fluoro-2-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 62);

4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 63);

4-(5-{3-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-c]pyridin-2-yl}pyridin-2-yl)morpholine (Example 66);

4-{5-[3-(2-Fluoro-4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 67);

4-{5-[3-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 68);

4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-2-methylmorpholine (Example 70);

4-{5-[3-(4-Chloro-3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 74);

4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 77);

4-{5-[3-(2,4-Difluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 78);

4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 80);

4-(5-{3-Phenyl-3H-imidazo[4,5-c]pyridin-2-yl}pyrimidin-2-yl)morpholine (Example 95);

4-{5-[3-(4-Cyclopropylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 96);

4-{4-Methyl-5-[3-(4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 97);

4-{3-Fluoro-5-[3-(4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine (Example 98);

5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-2-(morpholin-4-yl)-1,4-dihydropyridin-4-one (Example 99);

4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methylpyridin-2-yl}morpholine (Example 108);

4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 127);

4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine (Example 129);

4-{5-[1-(4-Methylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 130);

4-(5-{1-Phenyl-1H-pyrrolo[2,3-c]pyridin-2-yl}pyrimidin-2-yl)morpholine (Example 131);

4-{5-[1-(4-Bromophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 133).

5. The compound of claim 1 , wherein the compound is 4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine (Example 57).

6. The pharmaceutical composition of claim 2 , wherein the compound is selected from the group consisting of: