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US-RE50878-E1 - Pyrazolo pyridine derivatives as NADPH oxidase inhibitors

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).

Inventors

  • Patrick Page
  • Mike Orchard
  • Benoit Laleu
  • Francesca Gaggini

Assignees

  • CALLIDITAS THERAPEUTICS SUISSE SA

Dates

Publication Date
20260505
Application Date
20230406
Priority Date
20080923

Claims (20)

  1. 1 . A pyrazolo pyridine derivative according to Formula (I): wherein G 1 is selected from H; 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 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; and 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 optionally substituted C 1 -C 6 alkyl and optionally substituted aryl; G 4 is: a) —(CHR 3 ) m —(CH 2 ) n —R 4 , wherein R 3 and R 4 are H, m=0 and n=0-3; and 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 b) —(CHR 3 ) m —(CH 2 ) n —R 4 , wherein R 3 is selected from 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; 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 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 , wherein 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; optionally substituted aryl; optionally substituted C 1 -C 6 alkyl aryl; optionally substituted aryl C 1 -C 6 alkyl; optionally substituted heteroaryl; 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; 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 ; 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; 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 ; R 14 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; m is an integer selected from 1 to 5; n is an integer selected from 1 to 5; p and q are integers selected from 0 to 5; and 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 7 -C 6 alkenyl heteroaryl; optionally substituted heteroaryl C 1 -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 c) —(CHR 3 ) m —(CH 2 ) n —R 4 , wherein 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; heteroaryl; optionally substituted C 1 -C 6 alkyl heteroaryl; optionally substituted heteroaryl C 1 -C 6 alkyl; optionally substituted C 1 -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 —C(O)R 7 ; -A-B; —CHR 8 R 9 and —(CH 2 )q-E; 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 7 -C 6 alkenyl; optionally substituted C 7 -C 6 alkynyl; —NR 5 R 6 , wherein 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; 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; 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 ; 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; 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 ; 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; m is an integer selected from 1 to 5; n is an integer selected from 1 to 5; p and q are integers selected from 0 to 5; and 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; and pharmaceutically acceptable salts thereof, with the proviso that pyrazolo pyridine derivative according to Formula (I) is not 1H-Pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, 5-(3,3-diphenylpropyl)-4-methyl-2-phenyl-(RN 1010935-27-9) or 1H-Pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione, 5-cyclopropyl-4-methyl-2-(4-nitrophenyl)-(RN 1010882-92-4).
  2. 2 . The derivative according to claim 1 wherein G 1 is H.
  3. 3 . The derivative according to claim 1 wherein G 3 is C 1 -C 6 alkyl.
  4. 4 . The derivative according to claim 1 wherein G 3 is a substituted C 1 -C 6 alkyl.
  5. 5 . The derivative according to claim 1 wherein G 4 is —(CHR 3 ) m —(CH 2 ) n —R 4 ; R 3 , R 4 , m and n are as defined in claim 1 .
  6. 6 . The derivative according to claim 1 wherein R 4 is —C(O)R 7 ; R 7 is as defined in claim 1 .
  7. 7 . The derivative according to claim 1 wherein R 4 is -A-B; A and B are as defined in claim 1 .
  8. 8 . The derivative according to claim 1 wherein R 4 is —CHR 8 R 9 ; R 8 and R 9 are as defined in claim 1 .
  9. 9 . The derivative according to claim 1 wherein R 4 is —(CH 2 )q-E; E and q are as defined in claim 1 .
  10. 10 . The derivative according to claim 1 wherein G 5 is H.
  11. 11 . A pyrazolo pyridine derivative 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(2H,5H)-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-pyrazolo[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-(3-chlorophenyl)-4-methyl-3,6-dioxo-1,2,3,6-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-N-(pyridin-2-ylmethyl)acetamide; 2,4-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,5 H)-dione; 2,4-dimethyl-5-(3-morpholin-4-yl-3-phenylpropyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H, 5 H)-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.
  12. 12 . A pharmaceutical composition containing at least one derivative according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
  13. 13 . The derivative according to claim 1 wherein G 3 is a substituted aryl.
  14. 14 . The derivative according to claim 1 wherein R 4 is —(CH 2 )q-E; E is NR 14 R 15 ; R 14 , R 15 and q are as defined in claim 1 .
  15. 15 . The derivative according to claim 1 wherein R 4 is —(CH 2 )q-E; E is NR 16 C(O)—R 17 ; R 16 , R 17 and q are as defined in claim 1 .
  16. 16 . The derivative according to claim 1 wherein R 4 is H.
  17. 17 . The derivative according to claim 1 wherein G 4 is —(CHR 3 ) m —(CH 2 ) n —R 4 ; R 4 is —(CH 2 )q-E; E is optionally substituted C 3 -C 8 -cycloalkyl; m is an integer selected from 1 to 5; n is an integer selected from 1 to 5; and p and q are integers selected from 0 to 5.
  18. 18 . The derivative according to claim 1 wherein G 4 is —(CHR 3 ) m —(CH 2 ) n —R 4 ; R 4 is —(CH 2 )q-E; E is optionally substituted C 2 -C 6 alkynyl; n is an integer selected from 1 to 5; and p and q are integers selected from 0 to 5.
  19. 19 . The derivative according to claim 1 , wherein R 4 is selected from —C(O)R 7 ; -A-B; —CHR 8 R 9 or —(CH 2 )q-E, and q is an integer selected from 1 to 5.
  20. 20 . The derivative according to claim 1 , wherein E is selected from —NR 14 R 15 ; and —NR 16 C(O)—R 17 .

Description

CROSS-REFERENCE TO RELATED APPLICATION This application is the U.S. national stage application of International Patent Application No. PCT/IB2009/054156, filed Sep. 22, 2009. FIELD OF THE INVENTION The present invention relates to pyrazolo pyridine derivatives of Formula (I), pharmaceutical composition thereof and to their use for the preparation of a medicament for the treatment and/or prophylaxis of cardiovascular diseases, respiratory disorders, disorders affecting the metabolism, skin and/or bone diseases, neurodegenerative diseases, kidney diseases, reproduction disorders, inflammatory disorders and cancers. Specifically, the present invention is related to pyrazolo pyridine derivatives useful for the preparation of a pharmaceutical formulation for the modulation, notably the inhibition of the activity or function of the Nicotinamide adenine dinucleotide phosphate oxidase (NADPH Oxidase). BACKGROUND OF THE INVENTION NADPH oxidases (NOX) are proteins that transfer electrons across biological membranes. In general, the electron acceptor is oxygen and the product of the electron transfer reaction is superoxide. The biological function of NOX enzymes is therefore the generation of reactive oxygen species (ROS) from oxygen. Reactive oxygen species (ROS) are oxygen-derived small molecules, including oxygen radicals (super-oxide anion [.O2−] [⋅O−], hydroxyl [HO.] [HO⋅], peroxyl [ROO.] [ROO⋅], alkoxyl [RO.] [RO⋅] and hydroperoxyl [HOO.] [HOO⋅]) and certain non-radicals that are either oxidizing agents and/or are easily converted into radicals. Nitrogen-containing oxidizing agents, such as nitric oxide are also called reactive nitrogen species (RNS). ROS generation is generally a cascade of reactions that starts with the production of superoxide. Superoxide rapidly dismutates to hydrogen peroxide either spontaneously, particularly at low pH or catalyzed by superoxide dismutase. Other elements in the cascade of ROS generation include the reaction of superoxide with nitric oxide to form peroxynitrite, the peroxidase-catalyzed formation of hypochlorous acid from hydrogen peroxide, and the iron-catalyzed Fenton reaction leading to the generation of hydroxyl radical. ROS avidly interact with a large number of molecules including other small inorganic molecules as well as DNA, proteins, lipids, carbohydrates and nucleic acids. This initial reaction may generate a second radical, thus multiplying the potential damage. ROS are involved not only in cellular damage and killing of pathogens, but also in a large number of reversible regulatory processes in virtually all cells and tissues. However, despite the importance of ROS in the regulation of fundamental physiological processes, ROS production can also irreversibly destroy or alter the function of the target molecule. Consequently, ROS have been increasingly identified as major contributors to damage in biological organisms, so-called “oxidative stress”. During inflammation, NADPH oxidase is one of the most important sources of ROS production in vascular cells under inflammatory conditions (Thabut et al., 2002, J. Biol. Chem., 277:22814-22821). In the lung, tissues are constantly exposed to oxidants that are generated either endogenously by metabolic reactions (e.g. by mitochondrial respiration or activation of recruited inflammatory cells) or exogenously in the air (e.g. cigarette smoke or air pollutants). Further, the lungs, constantly exposed to high oxygen tensions as compared to other tissues, have a considerable surface area and blood supply and are particularly susceptible to injury mediated by ROS (Brigham, 1986, Chest, 89(6): 859-863). NADPH oxidase-dependent ROS generation has been described in pulmonary endothelial cells and smooth muscle cells. NADPH oxidase activation in response to stimuli has been thought to be involved in the development of respiratory disorders such as pulmonary hypertension and enhancement of pulmonary vasoconstriction (Djordjevic et al., 2005, Arterioscler. Thromb. Vasc. Biol., 25, 519-525; Liua et al., 2004, Am. J. Physiol. Lung, Cell. Mol. Physiol., 287: L111-118). Further, pulmonary fibrosis has been characterized by lung inflammation and excessive generation of ROS. Osteoclasts, which are macrophage-like cells that play a crucial role in bone turn-over (e.g. bone resorption), generate ROS through NADPH oxidase-dependent mechanisms (Yang et al., 2002, J. Cell. Chem. 84, 645-654). Diabetes is known to increase oxidative stress (e.g. increased generation of ROS by auto-oxidation of glucose) both in humans and animals and increased oxidative stress has been said to play an important role in the development of diabetic complications. It has been shown that increased peroxide localization and endothelial cell dysfunction in the central retina of diabetic rats coincides with the areas of NADPH oxidase activity in the retinal endothelial cells (Ellis et al., 2000, Free Rad. Biol. Med., 28:91-101). Further, it has been suggested that con