Pyrazolo pyridine derivatives as NADPH oxidase inhibitors

1. A method for the treatment of a patient suffering from a disease or condition selected from diabetic nephropathy, liver fibrosis, alcohol induced fibrosis, steatosis or non-alcoholic steatohepatitis, cancer, hypertension, atherosclerosis, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary diseases (COPD), Alzheimer's disease, diabetes, asthma, hearing loss and balance problems in response to ototoxic drugs, vascular injuries after balloon surgery, inflammation, cardiovascular complications of type 1 or type II diabetes, intimal hyperplasia, coronary heart disease, cerebral, coronary or arterial vasospasm, endothelial dysfunction, inflammatory bowel disease, Crohn's disease, multiple sclerosis, or pain, the method comprising administering a pyrazolo pyridine derivative according to Formula (I):

wherein G 1 is selected from —C(O)—R 1 and —(CH 2 ) n —C(O)—R 4 ; R 1 is selected from H; optionally substituted amino; optionally substituted alkoxy; optionally substituted alkoxy C 1 -C 6 alkyl;

—NR 2 R 3 ; 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; R 2 and R 3 independently 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; 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 —NR 2 R 3 can form together a ring selected from optionally substituted heteroaryl or optionally substituted heterocycloalkyl; R 4 is selected from H; optionally substituted alkoxy; 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; 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 C 1 -C 6 alkyl; n is an integer selected from 1 to 5; 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; 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 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 H; optionally substituted acyl; optionally substituted acyl amino; optionally substituted acyl 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; 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 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 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 in need of treatment of said disease or condition.

2. The method according to claim 1 , wherein said disease or condition is cancer.

3. The method according to claim 1 , wherein said disease or condition is selected from pulmonary hypertension, chronic obstructive pulmonary diseases (COPD), hypertension, atherosclerosis and pulmonary fibrosis.

4. The method according to claim 1 , wherein said disease or condition is selected from Alzheimer's disease, diabetes, asthma and hearing loss and balance problems in response to ototoxic drugs.

5. The method according to claim 1 , wherein said disease or condition is vascular injuries after balloon surgery, inflammation, cardiovascular complications of type 1 or type II diabetes, intimal hyperplasia, coronary heart disease, or cerebral, coronary or arterial vasospasm.

6. The method according to claim 1 , wherein said disease or condition is, endothelial dysfunction, inflammatory bowel disease, Crohn's disease, multiple sclerosis or pain.

7. The method according to claim 1 , wherein said disease or condition is diabetic nephropathy.

8. The method according to claim 1 , wherein said disease or condition is liver fibrosis, alcohol induced fibrosis, steatosis or non-alcoholic steatohepatitis.

9. The method according to claim 2 , wherein said cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelium sarcoma, lymphangiosarcoma, lymphangioendothelioma, periosteoma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, renal cancer, prostatic carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, orchioncus, lung cancer, small-cell lung cancer, lung adenocarcinoma, bladder cancer or epithelial cancer.

10. The method according to claim 1 , wherein the pyrazolo pyridine derivative is administered in combination with a co-agent useful in the treatment of cancer.

11. A method for inhibiting angiogenesis in a patient suffering from angiogenesis or angiogenesis dependent disorder, wherein the method comprises administering an angiogenesis inhibitory dose of a compound of Formula (I):

wherein G 1 is selected from —C(O)—R 1 and —(CH 2 ) n —C(O)—R 4 ; R 1 is selected from H; optionally substituted amino; optionally substituted alkoxy; optionally substituted alkoxy C 1 -C 6 alkyl; —NR 2 R 3 ; 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; R 2 and R 3 independently 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; 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 —NR 2 R 3 can form together a ring selected from optionally substituted heteroaryl or optionally substituted heterocycloalkyl; R 4 is selected from H; optionally substituted alkoxy; 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; 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 C 1 -C 6 alkyl; n is an integer selected from 1 to 5; 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; 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 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 H; optionally substituted acyl; optionally substituted acyl amino; optionally substituted acyl 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; 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 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 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, in a patient in need thereof.

12. The method according to claim 11 , wherein G 1 is —C(O)—R 1 ; R 1 is as defined in claim 11 .

13. The method according to claim 11 , wherein G 1 is —(CH 2 ) n —C(O)—R 4 ; R 4 and n are as defined in claim 11 .

14. The method according to claim 11 , wherein G 3 is optionally substituted C 1 -C 6 alkyl.

15. The method according to claim 11 , wherein G 5 is H.

16. The method according to claim 11 , wherein the pyrazolo pyridine derivative is selected from the following compounds:

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

tert-butyl 4-{[4-methyl-3,6-dioxo-2-phenyl-5-(pyridin-3-ylmethyl)-2,3,5,6-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl]carbonyl}piperidine-1-carboxylate;

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

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

1-[(3-methoxyphenyl)acetyl]-4-methyl-2-phenyl-5-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione;

1-acetyl-4-methyl-2-(2-methylphenyl)-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione; or

1-acetyl-2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione.

17. The method according to claim 1 , wherein said method comprises administering a pyrazolo pyridine derivative according to Formula (I) for the treatment of said patient suffering from said disease or condition.

18. The method according to claim 2 , wherein said cancer is a cancer selected from acute myeloid leukemia, lung cancer, prostate cancer, breast cancer, pancreatic cancer, renal cancer, lung carcinoma and prostatic carcinoma.

19. The method according to claim 2 , wherein the pyrazolo pyridine derivative is administered in combination with a co-agent useful for the treatment of cancer.

20. The method according to claim 1 , wherein said disease or condition is hypertension.

21. The method according to claim 1 , wherein said disease or condition is atherosclerosis.

22. The method according to claim 1 , wherein said disease or condition is pulmonary fibrosis.

23. The method according to claim 1 , wherein said disease or condition is pulmonary hypertension.

24. The method according to claim 1 , wherein said disease or condition is chronic obstructive pulmonary diseases (COPD).

25. The method according to claim 1 , wherein said disease or condition is diabetes.

26. The method according to claim 1 , wherein said disease or condition is cardiovascular complications of type 1 or type II diabetes.