IP Library › Granted Patent US 8,987,269
Granted Patent B2
US 8,987,269 · App. 13/501,222 · Granted Mar 24, 2015

Certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor

Inventors: Wei-Guo Su (Shanghai, CN); Hong Jia (Shanghai, CN); Guangxiu Dai (Shanghai, CN)
Assignee: Hutchison Medipharma Limited
C07D471/04A61K31/437A61K31/4985C07D487/04C07D519/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 8,987,269
App. No.
13/501,222
Granted
Mar 24, 2015
Kind
B2
Abstract

Provided are certain triazolopyridines and triazolopyrazines, compositions thereof and methods of use therefor.

Claims (134)

1. A compound of formula 1:

or a pharmaceutically acceptable salt thereof wherein

X is N, Y is absent and R 1 is a fused bicyclic heteroaryl selected from:

optionally substituted with one or more groups selected from halo, —CF 3 , —CF 2 H, cycloalkyl, —C(O)R 11 , —C(O)OR 11 , —CN, —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —NO 2 , —S(O) n R 12 , —S(O) n NR 13 R 14 , heterocycle, heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NR 13 R 14 , and lower alkyl substituted with heterocycle;

R 2 and R 3 are independently selected from hydrogen, and alkyl, or R 2 and R 3 , together with the carbon to which they are attached, form a ring chosen from 3- to 7-membered cycloalkyl and 3- to 7-membered heterocycle;

R 4 is selected from halo, alkyl, cycloalkyl, heterocycle, aryl and heteroaryl, each of which, except for halo, is optionally substituted with one or more groups selected from:

(i) lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 14 ;

(ii) lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;

(iii) cycloalkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;

(iv) heterocycloalkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;

(v) heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(vi) heteroaryloxy optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(viii) aryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(ix) heteroaryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(x) halo;

(xi) cyano;

(xii) —C(O)R 11 ;

(xiii) —C(O)OR 11 ;

(xiv) —NR 13 R 14 ;

(xv) —NR 13 C(O)R 11 ;

(xvi) —NR 13 S(O) n R 12 ;

(xvii) —NR 13 S(O) n NR 13 R 14 ;

(xviii) —NR 13 C(O)OR 12 ;

(xix) —NR 13 C(O)NR 13 R 14 ;

(xx) —C(O)NR 13 R 14 ,

(xxi) —S(O) n R 12 ; and

(xxii) —S(O) n NR 13 R 14 ;

R 5 is selected from hydrogen, halo, OH, NH 2 , CF 3 , —CF 2 H, alkyl, alkenyl, and alkynyl;

each n is independently 0, 1, or 2;

R 11 , R 12 , R 13 , and R 14 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocycle, each of which except for hydrogen, is optionally substituted with one or more groups selected from halo, lower alkyl, hydroxy, and lower alkoxy, or R 13 and R 14 , with the nitrogen to which they are attached, combine to form a heterocycle ring, which is optionally substituted with one or more groups selected from halo, lower alkyl, hydroxy, and lower alkoxy and further optionally includes one or two additional heteroatoms in the heterocycle ring wherein the one or two additional heteroatoms are selected from —O—, —S—, and —N(R 15 )—; and

R 15 is selected from hydrogen, lower alkyl, —C(O)R 11 , —C(O)OR 11 , —C(O)NR 13 R 14 , —S(O) n R 12 , and —S(O) n NR 13 R 14 ;

provided that:

when R 2 is hydrogen or methyl and R 3 and R 5 are hydrogen, then R 1 is not 3-quinazolin-6-yl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a ring system selected from:

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are independently selected from hydrogen and C 1 -C 6 alkyl or R 2 and R 3 , together with the carbon to which they are attached, form a 3-membered cycloalkyl.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is aryl optionally substituted with one or more groups selected from:

(i) lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 1 ;

(ii) lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;

(iii) heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(iv) heteroaryloxy optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(v) aryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(vi) heteroaryl optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(vii) halo;

(viii) cyano;

(ix) —C(O)R 11 ;

(x) —C(O)OR 11 ;

(xi) —NR 13 R 14 ;

(xii) —NR 13 C(O)R 11 ;

(xiii) —NR 13 S(O) n R 12 ;

(xiv) —NR 13 S(O) n NR 13 R 14 ;

(xv) —NR 13 C(O)OR 12 ;

(xvi) —NR 13 C(O)NR 13 R 14 ;

(xvii) —C(O)NR 13 R 14 ;

(xviii) —S(O) n R 12 ; and

(xix) —S(O) n NR 13 R 14 .

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is heterocycle optionally substituted with one or more groups selected from:

(i) lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 14 ;

(ii) lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;

(iii) heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(iv) halo;

(v) cyano;

(vi) C(O)R 11 ;

(vii) —C(O)OR 11 ;

(viii) —NR 13 R 14 ;

(ix) —NR 13 C(O)R 11 ;

(x) —NR 13 S(O) n R 12 ;

(xi) —NR 13 S(O) n NR 13 R 14 ;

(xii) —NR 13 C(O)OR 12 ;

(xiii) —NR 13 C(O)NR 13 R 14 ;

(xi) —C(O)NR 13 R 14 ;

(xii) —S(O) n R 12 ; and

(xiii) —S(O) n NR 13 R 14 .

7. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from pyrrolidin-1-yl, piperidin-1-yl, tetrahydro-2H-pyran-4-yl, morpholin-4-yl, and 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl, each of which is optionally substituted with one or more groups selected from:

(i) lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 14 ;

(ii) lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;

(iii) heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(iv) halo;

(v) cyano;

(vi) C(O)R 11 ;

(vii) —C(O)OR 11 ;

(viii) —NR 13 R 14 ;

(ix) —NR 13 C(O)R 11 ;

(x) —NR 13 S(O) n R 12 ;

(xi) —NR 13 S(O) n NR 13 R 14 ;

(xii) —NR 13 C(O)OR 12 ;

(xiii) —NR 13 C(O)NR 13 R 14 ;

(xiv) —C(O)NR 13 R 14 ;

(xv) —S(O) n R 12 ; and

(xvi) —S(O) n NR 13 R 14 .

8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is heteroaryl optionally substituted with one or more groups selected from:

(i) lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 14 ;

(ii) lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;

(iii) heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(iv) halo;

(v) cyano;

(vi) —C(O)R 11 ;

(vii) —C(O)OR 11 ;

(viii) —NR 13 R 14 ;

(ix) —NR 13 C(O)R 11 ;

(x) —NR 13 S(O) n R 12 ;

(xi) —NR 13 S(O) n NR 13 R 14 ;

(xii) —NR 13 C(O)OR 12 ;

(xiii) —NR 13 C(O)NR 13 R 14 ;

(xiv) —C(O)NR 13 R 14 ;

(xv) —S(O) n R 12 ; and

(xvi) —S(O) n NR 13 R 14 .

9. The compound according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, oxazol-2-yl, thiazol-2-yl, isoxazol-3-yl, isoxazol-5-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl, thiophen-2-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl, each of which is optionally substituted with one or more groups selected from:

(i) lower alkyl optionally substituted with one or more groups selected from hydroxy, lower alkoxy, cyano, halo, —C(O)OR 11 , —C(O)NR 13 R 14 , —NR 13 R 14 , —OC(O)R 11 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , and —NR 13 C(O)NR 13 R 14 ;

(ii) lower alkoxy optionally substituted with one or more groups selected from halo, hydroxy, and lower alkoxy;

(iii) heterocycle optionally substituted with one or more groups selected from lower alkyl, halo, hydroxy, and lower alkoxy;

(iv) halo;

(v) cyano;

(vi) C(O)R 11 ;

(vii) —C(O)OR 11 ;

(vii) —NR 13 R 14 ;

(viii) —NR 13 C(O)R 11 ;

(ix) —NR 13 S(O) n R 12 ;

(x) —NR 13 S(O) n NR 13 R 14 ;

(xi) —NR 13 C(O)OR 12 ;

(xii) —NR 13 C(O)NR 13 R 14 ;

(xiii) —C(O)NR 13 R 14 ;

(xiv) —S(O) n R 12 ; and

(xv) —S(O) n NR 13 R 14 .

10. The compound according to claim 1 of Formula:

enantiomers thereof, or a pharmaceutically acceptable salt thereof.

11. The compound of formula 1 as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a ring system selected from:

wherein each of said ring systems is optionally substituted with one or more groups selected from halo, CF 3 , —CF 2 H, cycloalkyl, —C(O)R 11 , C(O)OR 11 , —CN, —C(O)NR 13 R 14 , —NR 13 R 14 , —NR 13 C(O)R 11 , —NR 13 S(O) n R 12 , —NR 13 S(O) n NR 13 R 14 , —NR 13 C(O)OR 12 , —NR 13 C(O)NR 13 R 14 , —NO 2 , —S(O) n R 12 , —S(O) n NR 13 R 14 , heterocycle, heteroaryl, aryl, alkenyl, alkynyl, lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NR 13 R 14 , and lower alkyl substituted with heterocycle.

12. The compound of formula 1 as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a ring system selected from

13. The compound of formula 1 as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

14. The compound of formula 1 as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen and R 3 is selected from hydrogen and methyl.

15. The compound of formula 1 as claimed in claim 1 , or a pharmaceutically acceptable salt there which is selected from:

16. The compound of formula 1 as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, which is selected from:

17. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 13, 2012
From: SU, WEI-GUO; JIA, HONG; DAI, GUANGXIU
To: HUTCHISON MEDIPHARMA LIMITED
Reel/Frame 028950/0952 →
Priority Claims (1)
CN PCT/CN2009/076321 · Dec 31, 2009 · national
Continuity (1)
Related Publication 20120264739A1 · Oct 18, 2012