IP Library Granted Patent US 9,974,791
Granted Patent B2
US 9,974,791 · App. 14/750,019 · Granted May 22, 2018

Pyrazolo pyridine derivatives as NADPH oxidase inhibitors

Inventors: Patrick Page (Saint-Julien-en-Genevois, FR); Mike Orchard (Oxfordshire, GB); Benoit Laleu (Collonges-sous-Saleve, FR); Francesca Gaggini (Geneva, CH)
Assignee: GENKYOTEX SUISSE SA
A61K31/5377A61K31/437A61K31/496A61K31/5025C07D401/04C07D471/04
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Quick Facts
Patent No.
US 9,974,791
App. No.
14/750,019
Granted
May 22, 2018
Kind
B2
Abstract

The present invention is related to pyrazolo pyridine derivatives of Formula (I), pharmaceutical composition thereof and to their use for the treatment and/or prophylaxis of disorders or conditions related to Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase).

Claims (135)

1. A method for treating a patient suffering from a liver disease selected from the group consisting of liver fibrosis, alcohol induced fibrosis, steatosis and non-alcoholic steatohepatitis comprising administering a pyrazolo pyridine derivative according to Formula (I):

wherein G 1 is selected from H; optionally substituted acyl; optionally substituted acyl C 1 -C 6 alkyl; optionally substituted alkyl C 3 -C 8 -cycloalkyl alkyl; optionally substituted heterocycloalkyl alkyl; optionally substituted aryl alkyl; and optionally substituted heteroaryl alkyl; G 2 is selected from H; optionally substituted C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkynyl; optionally substituted aryl; optionally substituted optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; optionally substituted alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl aryl; optionally substituted aryl C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkenyl heteroaryl; optionally substituted heteroaryl C 2 -C 6 alkenyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl and optionally substituted heterocycloalkyl C 1 -C 6 alkyl; G 3 is selected from H; optionally substituted amino; optionally substituted aminoalkyl; optionally substituted aminocarbonyl; optionally substituted alkoxy; optionally substituted alkoxy C 1 -C 6 alkyl; optionally substituted carbonyl; optionally substituted C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkynyl; optionally substituted aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl aryl; optionally substituted aryl C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkenyl heteroaryl; optionally substituted heteroaryl C 2 -C 6 alkenyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl and optionally substituted heterocycloalkyl C 1 -C 6 alkyl; G 4 is selected from —NR 2 —C(O)—R 1 and —(CHR 3 ) m —(CH 2 ) n —R 4 , wherein R 1 is selected from H; amino; —NR 5 R 6 ; optionally substituted alkoxy; optionally substituted alkoxy C 1 -C 6 alkyl; optionally substituted aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C 1 -C 6 alkyl; R 2 is selected from H; optionally substituted alkoxy C 1 -C 6 alkyl; optionally substituted aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; optionally substituted heterocycloalkyl C 1 -C 6 alkyl; R 3 is selected from H; halogen; optionally substituted alkoxy; optionally substituted alkoxy C 1 -C 6 alkyl aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C 1 -C 6 alkyl; R 4 is selected from H; —C(O)R 7 ; -A-B; —CHR 8 R 9 and —(CH 2 )q-E; R 5 and R 6 are independently selected from H; optionally substituted alkoxy C 1 -C 6 alkyl; optionally substituted aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C 1 -C 6 alkyl or —NR 5 R 6 form together a ring selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; R 7 is selected from optionally substituted amino; optionally substituted alkoxy; optionally substituted aminoalkyl; optionally substituted alkoxy C 1 -C 6 alkyl; optionally substituted C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkynyl; —NR 5 R 6 ; optionally substituted aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C 1 -C 6 alkyl; R 8 and R 9 are independently selected from optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C 3 -C 8 -cycloalkyl and optionally substituted heterocycloalkyl; R 10 is selected from optionally substituted aryl and optionally substituted heteroaryl; R 11 and R 12 are independently selected from H; optionally substituted acyl; optionally substituted C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkynyl; optionally substituted aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C 1 -C 6 alkyl or —NR 11 R 12 form together a ring selected from optionally substituted heteroaryl and optionally substituted optionally substituted heterocycloalkyl; R 13 is selected from optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C 3 -C 8 -cycloalkyl and optionally substituted heterocycloalkyl; R 14 , R 15 and R 16 are independently selected from H and optionally substituted C 1 -C 6 alkyl; R 17 is selected from optionally substituted C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkynyl; optionally substituted aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C 1 -C 6 alkyl; A is selected from optionally substituted aryl, and optionally substituted heteroaryl; B is selected from —OR 10 , —NR 11 R 12 and —(CH2)p-R 13 ; E is selected from optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 2 -C 6 alkynyl; —NR 14 R 15 ; and —NR 16 C(O)—R 17 ; m, n, p and q are integers selected from 0 to 5; wherein when m is 0 and R 4 is H, then n is 1; G 5 is selected from H; optionally substituted C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkynyl; optionally substituted aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl aryl; optionally substituted aryl C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkenyl heteroaryl; optionally substituted heteroaryl C 2 -C 6 alkenyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl and optionally substituted heterocycloalkyl C 1 -C 6 alkyl; or a tautomer, geometrical isomer, enantiomer, diastereomer, racemate or pharmaceutically acceptable salts thereof, to a patient suffering from a liver disease selected from the group consisting of liver disease is liver fibrosis, alcohol induced fibrosis, steatosis or non-alcoholic steatohepatitis.

2. The method according to claim 1 , wherein said liver disease is liver fibrosis.

3. The method according to claim 1 , wherein G 1 is H.

4. The method according to claim 1 , wherein G 2 is optionally substituted aryl.

5. The method according to claim 1 , wherein G 3 is optionally substituted aryl.

6. The method according to claim 1 , wherein G 4 is —NR 2 —C(O)—R 1 ; wherein R1 is selected from H; amino; —NR5R6; optionally substituted alkoxy; optionally substituted alkoxy C1-C6 alkyl; optionally substituted aryl; optionally substituted C1-C6 alkyl aryl; optionally substituted aryl C1-C6 alkyl; optionally substituted heteroaryl; optionally substituted C1-C6 alkyl heteroaryl; optionally substituted heteroaryl C1-C6 alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6 alkyl C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl C1-C6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C1-C6 alkyl; R2 is selected from H; optionally substituted alkoxy C1-C6 alkyl; optionally substituted aryl; optionally substituted C1-C6 alkyl aryl; optionally substituted aryl C1-C6 alkyl; optionally substituted heteroaryl; optionally substituted C1-C6 alkyl heteroaryl; optionally substituted heteroaryl C 1-C6 alkyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C1-C6 alkyl C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl C1-C6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C1-C6 alkyl heterocycloalkyl; optionally substituted heterocycloalkyl C1-C6 alkyl.

7. The method according to claim 1 , wherein G 4 is —(CHR 3 ) m —(CH 2 ) n —R 4 ; R 3 is selected from H; halogen; optionally substituted alkoxy; optionally substituted alkoxy C 1 -C 6 alkyl aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C 1 -C 6 alkyl; R 4 is selected from H; —C(O)R 7 ; -A-B; —CHR 8 R 9 and —(CH 2 )q-E; m, n and q are integers selected from 0 to 5; wherein when m is 0 and R 4 is H, then n is 1.

8. The method according to claim 7 , wherein G 4 is —(CHR 3 ) m —(CH 2 ) n —R 4 ; R 4 is H, R 3 is selected from H; halogen; optionally substituted alkoxy; optionally substituted alkoxy C 1 -C 6 alkyl aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C 1 -C 6 alkyl; m and n are integers selected from 0 to 5; wherein when m is 0 and R 4 is H, then n is 1.

9. The method according to claim 1 , wherein R 4 is —C(O)R 7 ; R 7 is selected from optionally substituted amino; optionally substituted alkoxy; optionally substituted aminoalkyl; optionally substituted alkoxy C 1 -C 6 alkyl; optionally substituted C 1 -C 6 alkyl; optionally substituted C 2 -C 6 alkenyl; optionally substituted C 2 -C 6 alkynyl; —NR 5 R 6 ; optionally substituted aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 3 -C 8 -cycloalkyl; optionally substituted C 1 -C 6 alkyl C 3 -C 8 -cycloalkyl; optionally substituted C 3 -C 8 -cycloalkyl C 1 -C 6 alkyl; optionally substituted heterocycloalkyl; optionally substituted C 1 -C 6 alkyl heterocycloalkyl; and optionally substituted heterocycloalkyl C 1 -C 6 alkyl.

10. The method according to claim 1 , wherein R 4 is -A-B.

11. The method according to claim 1 , wherein R 4 is —CHR 8 R 9 ; R 8 and R 9 are independently selected from optionally substituted aryl; optionally substituted heteroaryl; optionally substituted C 3 -C 8 -cycloalkyl and optionally substituted heterocycloalkyl.

12. The method according to claim 1 , wherein R 4 is —(CH 2 )q-E.

13. The method according to claim 1 , wherein G 5 is H.

14. The method according to claim 1 selected from the following compounds:

2-(2-chlorophenyl)-4-methyl-5-(2-morpholin-4-ylbenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-{4-[(4-methylpiperazin-1-yl)methyl]benzyl}-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-(2-morpholin-4-yl-2-phenylethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-fluorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-methyl-5-(3-phenoxybenzyl)-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4,5-dimethyl-2-(4-phenyl-1,3-thiazol-2-yl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H5H)-dione;

N-2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-2-(4-fluorophenoxy)acetamide;

2-(2-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-fluorophenyl)-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-fluorophenyl)-4-methyl-5-[(6-morpholin-4-ylpyridin-2-yl)methyl]-1H-pyrazol[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-fluorophenyl)-4-methyl-5-[4-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[(6-morpholin-4-ylpyridin-2-yl)methyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

3-(4,5-dimethyl-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)benzonitrile;

2-(2-fluorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-[(6-morpholin-4-ylpyridin-2-yl)methyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[4-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-[2-(2-fluorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

2-(2-chlorophenyl)-4-methyl-5-[4-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-methyl-5-(3-phenoxybenzyl)-2-[1,2,4]triazolo[4,3-b]pyridazin-6-yl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-[4-(benzyloxy)phenyl]-4,5-dimethyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-[4-(benzyloxy)phenyl]-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

3-{4-methyl-5-[4-(morpholin-4-ylmethyl)benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl}benzonitrile;

2-[2-(2-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

2-[2-(3-cyanophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

2-[2-(3chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

2,4-dimethyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-[3-(diethylamino)propyl]-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-(cyclohexylmethyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-(3-morpholin-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-(3-phenylprop-2-yn-1-yl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-fluorophenyl)-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4,5-dimethyl-2-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-fluorophenyl)-4-methyl-5-(3-morpholin-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2,5-dichlorophenyl)-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2,5-dichlorophenyl)-4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

N-{2-[2-(2,5-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]ethyl}acetamide;

2-(2-chloro-4-fluorophenyl)-4-(methoxymethyl)-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-[2-(dimethylamino)ethyl]-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-[4-(benzyloxy)phenyl]-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chlorophenyl)-4-methyl-5-[2-(4-methylpiperazin-1-yl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H-5H)-dione;

2-(3,4-dichlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-2-(2,5-dichlorophenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-(3-phenylprop-2-yn-1-yl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-benzyl-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3,4-dichlorophenyl)-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-fluorophenyl)-4,5-dimethyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-[4-(benzyloxy)phenyl]-4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3,4-dichlorophenyl)-4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

methyl[2-(2,5-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]acetate;

N-{3-[2-(2,3-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]phenyl}acetamide;

2-(2,3-dichlorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

N-{3-[2-(3-chloro-4-fluorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]phenyl}acetamide;

5-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-2-(3,4-dichlorophenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2,4-dimethyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2,4-dimethyl-5-(3-morpholin-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

N-{3-[2-(2-chloro-4-fluorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]phenyl}acetamide;

2-(2,4-dimethyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-N-(pyridin-2-ylmethyl)acetamide;

2-(3-chloro-4-fluorophenyl)-4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(3-chloro-4-fluorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-fluorophenyl)-4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

5-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-2-(2-chloro-4-fluorophenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-[4-(benzyloxy)phenyl]-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2,3-dichlorophenyl)-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chloro-4-fluorophenyl)-4-methyl-5-[2-(4-methylpiperazin-1-yl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

N-(3-{[2-(3-chloro-4-fluorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]methyl}phenyl)acetamide;

5-[2-(4-benzylpiperazin-1-yl)-2-oxoethyl]-2-(3-chloro-4-fluorophenyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

N-(3-{[2-(2-chloro-4-fluorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]methyl}phenyl)acetamide;

2-(2-chloro-4-fluorophenyl)-4-methyl-5-[4-(4-methylpiperazin-1-yl)-4-oxobutyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

3-{4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl}benzonitrile;

N-{2-[2-(3-chloro-4-fluorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]ethyl}-4-fluorobenzamide;

N-{2-[2-(2-chloro-4-fluorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro -5H-pyrazolo[4,3-c]pyridin-5-yl]ethyl}-4-fluorobenzamide;

2-[2-(2-chloro-4-fluorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

N-(2-{2-[4-(benzyloxy)phenyl]-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl}ethyl)-4-fluorobenzamide;

2-(3-chloro-4-fluorophenyl)-4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

N-(3-{4-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-3,6-dioxo-1,3,5,6-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl}phenyl)acetamide;

2-(4-chlorophenyl)-4-methyl-5-(3-phenoxybenzyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-[2-(3-chloro-4-fluorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

2-[4-butyl-2-(3-chloro -4-fluorophenyl)-3,6-dioxo-1,2,3,6-tetrahydro -5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

2-[2-(2,3-dichlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

2-[2,4-bis(3-chlorophenyl)-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

2-[4-(3-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

N-(3-{[4-(3-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]methyl}phenyl)acetamide;

2-(2-chlorophenyl)-4-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-2-methyl-5-(2-morpholin-4-yl-2-oxoethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-methyl-5-[4-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-2-methyl-5-[3-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide;

4-(3-chlorophenyl)-2-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-2-methyl-5-[4-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-(3-chlorophenyl)-2-methyl-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-methyl-5-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-methyl-5-[2-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

N-(3-{[4-(4-chlorophenyl)-2-methyl -3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]methyl}phenyl)acetamide;

4-(4-chlorophenyl)-2-methyl-5-[3-(morpholin-4-ylmethyl)benzyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-methyl-5-[(6-morpholin-4-ylpyridin-2-yl)methyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

N-{2-[4-(4-chlorophenyl)-2-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]ethyl}acetamide;

4-(4-chlorophenyl)-5-[3-(dimethylamino)benzyl]-2-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-(4-chlorophenyl)-2-methyl-5-[(6-pyrrolidin-1-ylpyridin-2-yl)methyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-(4-chlorophenyl)-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-(2-fluorophenyl)-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-(4-chlorophenyl)-5-[3-(dimethylamino)propyl]-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-5-methyl-4-(3-morpholin-4-ylphenyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

2-(2-chlorophenyl)-4-[1-(3,4-difluorophenoxy)ethyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

4-[1-(benzyloxy)ethyl]-2-(2-chlorophenyl)-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione; or

4-[3-(dimethylamino)phenyl]-2-(2-methoxyphenyl)-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione.

15. The method of claim 1 , wherein the compound of Formula (I) is 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione.

16. The method of claim 2 , wherein the compound of Formula (I) is 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione.

17. The method according to claim 1 , wherein said liver disease is alcohol induced fibrosis.

18. The method according to claim 1 , wherein said liver disease is steatosis.

19. The method according to claim 1 , wherein said liver disease is non-alcoholic steatohepatitis.

20. A method for treating a patient suffering from a liver disease selected from the group consisting of liver fibrosis, alcohol induced fibrosis, steatosis and non-alcoholic steatohepatitis comprising administering a pyrazolo pyridine derivative selected from 2-(2-chlorophenyl)-5-[2(4hydroxyphenyl)ethyl]-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione and 2-(3-chlorophenyl)-5-(3-hydroxypropyl)-4-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione to a patient suffering from a liver disease selected from the group consisting of liver fibrosis, alcohol induced fibrosis, steatosis or non-alcoholic steatohepatitis.

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CHANGE OF NAME Recorded Mar 16, 2023
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To: CALLIDITAS THERAPEUTICS SUISSE SA
Reel/Frame 063112/0430 →
CHANGE OF NAME Recorded Aug 14, 2017
From: GENKYOTEX SA
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ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 26, 2015
From: PAGE, PATRICK; ORCHARD, MIKE; LALEU, BENOIT; GAGGINI, FRANCESCA
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Priority Claims (1)
EP 08164857 · Sep 23, 2008 · regional
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Division 13120440
Related Publication 20150290208A1 · Oct 15, 2015