3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of c-Met protein kinases

1. A compound of formula (IA-I)

or a tautomer, stereoisomer, enantiomer, diastereomer, a pharmaceutically acceptable salt, or N-oxide thereof, wherein

X is CR 1 or N;

D is monocyclic aryl or monocyclic heteroaryl; wherein D is substituted with a group E is —C(O)—NH—O—CH 2 —CH 2 —OH, and further D can optionally be substituted with one or more of R z;

L 2 is —(CR a R b ) n —;

Cy 2 is substituted or unsubstituted heteroaryl;

each occurrence of R 1 and R 2 is hydrogen;

each occurrence of R a and R b may be same or different and are independently selected from hydrogen, hydroxy, halogen, and substituted or unsubstituted C 1-6 alkyl;

each occurrence of R z is independently hydrogen, halogen, or substituted or unsubstituted alkyl; and

each occurrence of n independently represents 0, 1, 2, 3 or 4.

2. A compound of claim 1 , wherein

D is

E is —C(O)—NH—O—CH 2 —CH 2 —OH, and

X 1 , X 2 and X 3 are independently selected from —CR z , —CR z ═CR z , —CR z ═N, —N═CR z , —N═N—, O—, —S— or —N—; wherein each occurrence of R z is independently hydrogen, halogen, or substituted or unsubstituted alkyl.

3. A compound of claim 1 , wherein Cy 2 is unsubstituted heteroaryl.

4. A compound of claim 1 , wherein Cy 2 is selected from

5. A compound of claim 1 , wherein Cy 2 is selected from

6. A compound of claim 1 , wherein L 2 is —CR a R b —.

7. A compound of claim 6 , wherein L 2 is —CH 2 —, —CH(OH)—, —CHF—, —CF 2 —, —CH(CH 3 )— or —C(CH 3 ) 2 —.

8. A compound of claim 1 , wherein L 2 is —CH 2 —.

9. A compound of claim 1 , having the formula (IA-I):

or a tautomer, stereoisomer, enantiomer, diastereomer, a pharmaceutically acceptable salt, or N-oxide thereof, wherein

-L 2 -Cy 2 is

 (where the squiggly line represents the bond to the bicyclic core in formula (IA-I);

each occurrence of R a and R b are independently selected from hydrogen, halogen, and substituted or unsubstituted (C 1-6 ) alkyl;

Z is selected from CR c , S, O, NR c , R c C═CR c , —N═CR c , and —R c C═N—;

Z 1 is selected from N, NR c and CR c ;

Z 2 and Z 3 are independently selected from C or N;

each occurrence of R c is independently absent or selected from hydrogen, hydroxy and halogen;

X is CR 1 or N;

D is monocyclic aryl or monocyclic heteroaryl; wherein D is substituted with a group E which is —C(O)—NH—O—CH 2 —CH 2 —OH, and further D can optionally be substituted with one or more of R z ;

each occurrence of R 2 and R 2 is hydrogen; and

each occurrence of R z is independently hydrogen, halogen, or substituted or unsubstituted alkyl.

10. A compound of claim 1 , having the formula (IA-I):

or a tautomer, stereoisomer, enantiomer, diastereomer, a pharmaceutically acceptable salt, or N-oxide thereof, wherein

D is

L 2 -Cy 2 is

 (where the squiggly line represents the bond to the bicyclic core in formula (IA-I);

X is CR 1 or N;

X 1 , X 2 and X 3 are independently selected from —CR z , —CR z ═CR z , —CR z ═N, —N═CR z , —N═N—, O—, —S— or —N—;

Z is selected from CR c , S, O, NR c , R c C═CR c , —N═CR c —, and —R c C═N—;

Z 1 is selected from N, NR c and CR c ;

Z 2 and Z 3 are independently selected from C or N;

each occurrence of R c is independently absent or selected from hydrogen, hydroxy and halogen;

E is —C(O)—NH—O—CH 2 —CH 2 —OH, and further D can optionally be substituted with one or more of R z ;

each occurrence of R 1 and R 2 is hydrogen;

each occurrence of R a and R b may be same or different and are independently selected from hydrogen, halogen, and substituted or unsubstituted C 1-6 alkyl; and

each occurrence of R z is independently hydrogen, halogen, or substituted or unsubstituted alkyl.

11. A compound of claim 2 , wherein X 1 and X 2 are CR z and X 3 is independently selected from —CR z ═CR z and —S—.

12. A compound of claim 11 , wherein X 1 is CH, X 2 is CR z and X 3 is —CR z ═CR z , wherein R z is hydrogen, halogen or substituted or unsubstituted C 1-3 alkyl.

13. A compound of claim 1 , wherein D is selected from

14. A compound of claim 13 , wherein D is selected from

15. A compound of claim 1 , wherein D is selected from

wherein E and R z are as defined in claim 1 .

16. A compound of claim 15 , wherein each occurrence of R z is selected from hydrogen, halogen and substituted or unsubstituted alkyl.

17. A compound of claim 9 , wherein each occurrence of R z is selected from hydrogen, fluoro, chloro, methyl and CF 3 and each occurrence of R c is selected from hydrogen and fluoro.

18. A compound of claim 1 , wherein each of R a and R b is hydrogen, alkyl or halogen, X is N or CR 1 and R 1 is H, substituted or unsubstituted C 1-6 alkyl, NH 2 , OH, CN or CONH 2 .

19. A compound of claim 9 , wherein

(a) X is N;

(b) R 2 is H;

(c) (i) both R a and R b are hydrogen,

(ii) R a is methyl and R b is hydrogen,

(iii) R a is fluoro and R b is hydrogen,

(iv) R a and R b both are fluoro, or

(v) R a and R b both are methyl; and

(d) Z is CR c , N, S, O, HC═CH— or —N═CH—;

(e) Z 1 is CH or N;

(f) Z 2 is C; and

(g) Z 3 is C or N.

20. A compound of claim 9 , wherein

a) Z is —HC═CH—, —S— or —O—; Z 1 is CH; Z 2 is C and Z 3 is C or N;

b) Z is —HC═CH—, Z 1 is CH; Z 2 is C; and Z 3 is C;

c) Z is CH, Z 1 is CH, Z 2 is C and Z 3 is N;

d) Z is —S—, Z 1 is CH, Z 2 is C and Z 3 is C;

e) Z is —O—, Z 1 is CH, Z 2 is C and Z 3 is C; or

f) Z is —CH—, Z 1 is NH, Z 2 is C and Z 3 is C.

21. A compound selected from:

2-chloro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;

2-chloro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide hydrochloride;

2-chloro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide 4-methylbenzenesulfonate;

2-chloro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide hydrobromide;

sodium (2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoyl)(2-hydroxyethoxy)amide;

2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)benzamide;

2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)benzamide hydrochloride;

sodium(2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-y1)benzoyl)(2-hydroxyethoxy)amide;

2-chloro-4-(3-((7-fluoro-2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)benzamide;

2,6-difluoro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;

2,6-difluoro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide hydrochloride;

sodium (2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoyl)(2-hydroxyethoxy)amide;

2,6-difluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)benzamide;

2,6-difluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)benzamide hydrochloride;

sodium (2,6-difluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoyl)(2-hydroxyethoxy)amide;

2-fluoro-N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;

2-chloro-N-(2-hydroxyethoxy)-4-(3-((2-methylquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;

4-(3-(benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-chloro-N-(2-hydroxyethoxy)benzamide;

4-(3-(benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2,6-difluoro-N-(2-hydroxyethoxy)benzamide;

sodium (4-(3-(benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2,6-difluorobenzoyl)(2-hydroxyethoxy)amide;

4-(3-(benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluoro-N-(2-hydroxyethoxy)benzamide;

2,6-difluoro-N-(2-hydroxyethoxy)-4-(3-((2-methylquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;

2,6-difluoro-N-(2-hydroxyethoxy)-4-(3-((2-methylquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide hydrochloride;

N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;

N-(2-hydroxyethoxy)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(trifluoromethyl)benzamide;

4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)-2-(trifluoromethyl)benzamide;

4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)-2-(trifluoromethyl)benzamide hydrochloride;

N-(2-hydroxyethoxy)-2-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;

N-(2-hydroxyethoxy)-2-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide hydrochloride;

N-(2-hydroxyethoxy)-2-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide hydrobromide;

N-(2-hydroxyethoxy)-2-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide 4-methylbenzenesulfonate;

N-(2-hydroxyethoxy)-2-methyl-4-(3-((2-oxo-1,2-dihydroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;

6((5-(4-(2-hydroxyethoxycarbamoyl)-3-methylphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline 1-oxide;

4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)-2-methylbenzamide;

4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)-2-methylbenzamide hydrochloride;

2-fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)benzamide;

2-fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2-hydroxyethoxy)benzamide hydrochloride;

and pharmaceutically acceptable salts thereof.

22. A compound selected from:

N-(2-Hydroxy-ethoxy)-2-methyl-4-(3-quinolin-6-ylmethyl-3H-imidazo[4,5-b]pyridin-5-yl)-benzamide;

2-Chloro-N-(2-hydroxy-ethoxy)-4-(3-quinolin-6-ylmethyl-3H-imidazo[4,5-b]pyridin-5-yl)-benzamide;

and pharmaceutically acceptable salts thereof.

23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

24. The pharmaceutical composition of claim 23 , further comprising one or more additional therapeutic agents and mixtures thereof.

25. The pharmaceutical composition of claim 24 , wherein the one or more additional therapeutic agent is an anti-cancer agent, anti-inflammatory agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, or a mixture thereof.

26. A method of inhibiting the HGF/c-Met kinase signaling pathway in a cell comprising contacting said cell with a compound of claim 1 .

27. A method of inhibiting the proliferative activity of a cell comprising contacting said cell with a compound of claim 1 .

28. A method of treating a cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , wherein the cancer is carcinoma of the gastric, hepatocellular cancer, carcinoma of the breast, carcinoma of the lung, and prostate cancer.

29. A compound selected from N-(2-hydroxyethoxy)-2-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide and pharmaceutically acceptable salts thereof.

30. A method of treating carcinoma of the breast in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 29 .

31. A method of treating carcinoma of the lung in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 29 .

32. A method of treating prostate cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 29 .