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

Patent metadata

Field	Value
Publication number	US-9815831-B2
Application number	US-201314389336-A
Country	US
Kind code	B2
Filing date	Feb 27, 2013
Priority date	Mar 30, 2012
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

The present invention provides compounds useful as c-Met protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of c-Met kinase mediated disease or disorders with them.

First claim

We claim:

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-

Assignees

• Rhizen Pharmaceuticals Sa

Inventors

• Vakkalanka Swaroop K V S
• Nagarathnam Dhanapalan
• Viswanadha Srikant
• Muthuppalaniappan Meyyappan
• Babu Govindarajulu
• Bhavar Prashant K

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title