IP Library Granted Patent US 9,944,645
Granted Patent B2
US 9,944,645 · App. 15/016,841 · Granted Apr 17, 2018

Imidazotriazines and imidazopyrimidines as kinase inhibitors

Inventors: Jincong Zhuo (Boothwyn, PA); Meizhong Xu (Hockessin, DE); Chunhong He (Boothwyn, PA); Colin Zhang (Ambler, PA); Ding-Quan Qian (Newark, DE); David M. Burns (Philadelphia, PA); Yun-Long Li (Chadds Ford, PA); Brian Metcalf (Moraga, CA); Wenqing Yao (Kennett Square, PA)
Assignees: Incyte Corporation; Incyte Holdings Corporation
C07D487/04A61K31/4709A61K31/53C07D403/06
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 9,944,645
App. No.
15/016,841
Granted
Apr 17, 2018
Kind
B2
Abstract

The present invention is directed to imidazo[1,2-b][1,2,4]triazines and imidazo[1,2-a]pyrimidines, and pharmaceutical compositions thereof, which are inhibitors of kinases such as c-Met and are useful in the treatment of cancer and other diseases related to the dysregulation of kinase pathways.

Claims (67)

1. A compound of Formula I:

or pharmaceutically acceptable salt thereof or prodrug thereof, wherein:

A is CR 3 ;

Cy 1 is heteroaryl, optionally substituted by 1, 2, 3, 4, or 5 —W—X—Y—Z groups;

Cy 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 —W′—X′—Y′—Z′ groups;

L 1 is (CR 4 R 5 ) m , (CR 4 R 5 ) p -(cycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(arylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(heterocycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(heteroarylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p O(CR 4 R 5 ) q , (CR 4 R 5 ) p S(CR 4 R 5 ) q , (CR 4 R 5 ) p C(O)(CR 4 R 5 ) q , (CR 4 R 5 ) p C(O)NR 6 (CR 4 R 5 ) q , (CR 4 R 5 ) p C(O)O(CR 4 R 5 ) q , (CR 4 R 5 ) p OC(O)(CR 4 R 5 ) q , (CR 4 R 5 ) p OC(O)NR 6 (CR 4 R 5 ) q , (CR 4 R 5 ) p NR 6 (CR 4 R 5 ) q , (CR 4 R 5 ) p NR 6 C(O)NR 6 (CR 4 R 5 ) q , (CR 4 R 5 ) p S(O)(CR 4 R 5 ) q , (CR 4 R 5 ) p S(O)NR 6 (CR 4 R 5 ) q , (CR 4 R 5 ) p S(O) 2 (CR 4 R 5 ) q , or (CR 4 R 5 ) p S(O) 2 NR 6 (CR 4 R 5 ) q , wherein said cycloalkylene, arylene, heterocycloalkylene, or heteroarylene is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 3 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d ;

L 2 is (CR 7 R 8 ) r , (CR 7 R 8 ) s -(cycloalkylene)-(CR 7 R 8 ) t , (CR 7 R 8 ) s -(arylene)-(CR 7 R 8 ) t , (CR 7 R 8 ) s -(heterocycloalkylene)-(CR 7 R 8 ) t , (CR 7 R 8 ) s (heteroarylene)-(CR 7 R 8 ) t , (CR 7 R 8 s O(CR 7 R 8 ) t , (CR 7 R 8 ) s S(CR 7 R 8 ) t , (CR 7 R 8 ) s C(O)(CR 7 R 8 ) t , (CR 7 R 8 ) s C(O)NR 9 (CR 7 R 8 ) t , (CR 7 R 8 ) s C(O)O(CR 7 R 8 ) t , (CR 7 R 8 ) s OC(O)(CR 7 R 8 ) t , (CR 7 R 8 ) s OC(O)NR 9 (CR 7 R 8 ) t , (CR 7 R 8 ) s NR 9 (CR 7 R 8 ) t , (CR 7 R 8 ) s NR 9 C(O)NR 9 (CR 7 R 8 ) t , (CR 7 R 8 ) s S(O)(CR 7 R 8 ) t , (CR 7 R 8 ) s S(O)NR 7 (CR 8 R 9 ) t , (CR 7 R 8 ) s S(O) 2 (CR 7 R 8 ) t , or (CR 7 R 8 ) s S(O) 2 NR 9 (CR 7 R 8 ) t , wherein said cycloalkylene, arylene, heterocycloalkylene, or heteroarylene is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 4 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR g )NR c1 R d1 , NR c1 C(═NR g )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;

R 1 is H or —W″—X″—Y″—Z″;

R 2 is H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR A , SR A , C(O)R B , C(O)NR c R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A , S(O)R B , S(O)NR C R D , S(O) 2 R B , NR C S(O) 2 R B , or S(O) 2 NR C R D ;

R 3 is H, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO 2 , OR A , SR A , C(O)R B , C(O)NR C R D , C(O)OR A , OC(O)R B , OC(O)NR C R D , NR C R D , NR C C(O)R B , NR C C(O)NR C R D , NR C C(O)OR A , S(O)R B , S(O)NR C R D , S(O) 2 R B , NR C S(O) 2 R B , and S(O) 2 NR C R D ; wherein said cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 5 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)NR c1 R d1 , NR c1 C(O)OR a1 , C(═NR g )NR c1 R d1 , NR c1 C(═NR g )NR c1 R d1 , P(R f1 ) 2 , P(OR e1 ) 2 , P(O)R e1 R f1 , P(O)OR e1 OR f1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , NR c1 S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;

or R 2 and -L 2 -Cy 2 are linked together to form a group of formula:

wherein ring B is a fused aryl or fused heteroaryl ring, each optionally substituted with 1, 2, or 3 —W′—X′—Y′—Z′ groups;

R 4 and R 5 are independently selected from H, halo, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C 1-6 haloalkyl, CN, and NO 2 ;

or R 4 and R 5 together with the C atom to which they are attached form a 3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl, C 1-6 haloalkyl, CN, and NO 2 ;

R 6 is H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

R 7 and R 8 are independently selected from H, halo, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, CN, and NO 2 ;

or R 7 and R 8 together with the C atom to which they are attached form a 3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituent independently selected from halo, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, CN, and NO 2 ;

R 9 is H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;

W, W′, and W″ are independently absent or independently selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, O, S, NR h , CO, COO, CONR h , SO, SO 2 , SONR h and NR h CONR i , wherein each of the C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and C 2-8 dialkylamino;

X, X′, and X″ are independently absent or independently selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO 2 , OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkoxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-8 alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O)OR j , C(O)NR h R i , amino, C 1-6 alkylamino, and C 2-8 dialkylamino;

Y, Y′, and Y″ are independently absent or independently selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, O, S, NR h , CO, COO, CONR h , SO, SO 2 , SONR h , and NR h CONR i , wherein each of the C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and C 2-8 dialkylamino;

Z, Z′, and Z″ are independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR g )NR c2 R d2 , NR c2 C(═NR g )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 OR f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , S(O) 2 NR c2 R d2 , aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)NR c2 R d2 , NR c2 C(O)OR a2 , C(═NR g )NR c2 R d2 , NR c2 C(═NR g )NR c2 R d2 , P(R f2 ) 2 , P(OR e2 ) 2 , P(O)R e2 R f2 , P(O)OR e2 R f2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , NR c2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

wherein two adjacent —W—X—Y—Z, together with the atoms to which they are attached, optionally form a fused 4-20 membered cycloalkyl ring or a fused 4-20 membered heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR g )NR c3 R d3 , NR c3 C(═NR g )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , S(O) 2 NR c3 R d3 , aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;

wherein two adjacent —W′—X′—Y′—Z′, together with the atoms to which they are attached, optionally form a fused 4-20 membered cycloalkyl ring or a fused 4-20 membered heterocycloalkyl ring, each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(═NR g )NR c3 R d3 , NR c3 C(═NR g )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , NR c3 S(O) 2 R b3 , S(O) 2 NR c3 R d3 , aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;

Cy 3 , Cy 4 , and Cy 5 are independently selected from aryl, cycloalkyl, heteroaryl, and heteorcycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR g )NR c4 R d4 , NR c4 C(═NR g )NR c4 R d4 , P(R f4 ) 2 , P(OR 4 ) 2 , P(O)R f3 R f4 , P(O)OR e4 OR f4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , and S(O) 2 NR c4 R d4 ;

R A is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1-4 alkyl;

R B is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein said C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1-4 alkyl;

R C and R D are independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1-4 alkyl;

or R C and R D together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, and C 1-4 alkyl;

R a , R a1 , R a2 , R a3 , and Ra 4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R b , R b1 , R b2 , R b3 , and R b4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R c and R d are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

or R c and R d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R c1 and R d1 are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

or R c1 and R d1 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R c2 and R d2 are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C(O)OR a4 , C(O)R b4 , S(O) 2 R b3 , alkoxyalkyl, and alkoxyalkoxy;

or R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C(O)OR a4 , C(O)R b4 , S(O) 2 R b3 , alkoxyalkyl, and alkoxyalkoxy;

R c3 and R d3 are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

or R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R c4 and R d4 are independently selected from H, C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein said C 1-10 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

or R c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

R e , R e1 , R e2 , and R e4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, (C 1-6 alkoxy)-C 1-6 alkyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl;

R f , R f1 , R f2 , and R f4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;

R g is H, CN, and NO 2 ;

R h and R i are independently selected from H and C 1-6 alkyl;

R j is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl;

m is 0, 1, 2, 3, 4, 5, or 6;

p is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, or 4;

r is 0, 1, 2, 3, 4, 5, or 6;

s is 0, 1, 2, 3, or 4; and

t is 0, 1, 2, 3, or 4,

with the proviso that when A is CH, then L 1 is other than CO or (CR 4 R 5 ) u wherein u is 1.

2. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein A is CH.

3. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy 1 is quinonlinyl optionally substituted by 1, 2, 3, 4, or 5 —W—X—Y—Z groups.

4. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy 1 is quinolinyl.

5. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy 2 is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 —W′—X′—Y′—Z′ groups.

6. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy 2 is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 —W′—X′—Y′—Z′ groups wherein at least one of said —W′—X′—Y′—Z′ group is C(O)NR c2 R d2 .

7. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy 2 is aryl optionally substituted by 1, 2, 3, 4, or 5 —W′—X′—Y′—Z′ groups.

8. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy 2 is heteroaryl optionally substituted by 1, 2, 3, 4, or 5 —W′—X′—Y′—Z′ groups.

9. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L 1 is (CR 4 R 5 ) m , (CR 4 R 5 ) p -(cycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(arylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(heterocycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(heteroarylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p O(CR 4 R 5 ) q , or (CR 4 R 5 ) p S(CR 4 R 5 ) q , wherein said cycloalkylene, arylene, heterocycloalkylene, or heteroarylene is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 3 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .

10. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L 1 is (CR 4 R 5 ) m , (CR 4 R 5 ) p -(cyclo alkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(arylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(heterocycloalkylene)-(CR 4 R 5 ) q , or (CR 4 R 5 ) p -(heteroarylene)-(CR 4 R 5 ) q , wherein said cycloalkylene, arylene, heterocycloalkylene, or heteroarylene is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 3 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .

11. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L 1 is (CR 4 R 5 ) m or (CR 4 R 5 ) p -(cycloalkylene)-(CR 4 R 5 ) q wherein said cycloalkylene is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 3 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .

12. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L 1 is CH 2 or CH 2 CH 2 or cycloalkylene.

13. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L 1 is CH 2 or cyclopropylene.

14. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L 1 is (CR 4 R 5 ) p -(Cycloalkylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(arylene)-(CR 4 R 5 ) q , (CR 4 R 5 ) p -(heterocycloalkylene)-(CR 4 R 5 ) q , or (CR 4 R 5 ) p -(heteroarylene)-(CR 4 R 5 ) q , wherein said cycloalkylene, arylene, heterocycloalkylene, or heteroarylene is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 3 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .

15. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein L 1 is (CR 4 R 5 ) p -(cycloalkylene)-(CR 4 R 5 ) q wherein said cycloalkylene is optionally substituted with 1, 2, or 3 substituents independently selected from Cy 3 , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, CN, NO 2 , N 3 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)NR c R d , NR c C(O)OR a , C(═NR g )NR c R d , NR c C(═NR g )NR c R d , P(R f ) 2 , P(OR e ) 2 , P(O)R e R f , P(O)OR e OR f , S(O)R b , S(O)NR c R d , S(O) 2 R b , NR c S(O) 2 R b , and S(O) 2 NR c R d .

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 5, 2017
From: INCYTE CORPORATION
To: INCYTE CORPORATION; INCYTE HOLDINGS CORPORATION
Reel/Frame 041865/0393 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 12, 2017
From: ZHUO, JINCONG; XU, MEIZHONG; HE, CHUNHONG; ZHANG, COLIN; QIAN, DING-QUAN; BURNS, DAVID M.; LI, YUN-LONG; METCALF, BRIAN; YAO, WENQING
To: INCYTE CORPORATION
Reel/Frame 040955/0527 →
Continuity (7)
Continuation 13895799 · May 16, 2013
Continuation 12813148 · Jun 10, 2010
Continuation 11942130 · Nov 19, 2007
Provisional Application 60860840 · Nov 22, 2006
Provisional Application 60861459 · Nov 29, 2006
Provisional Application 60957236 · Aug 22, 2007
Related Publication 20160326178A1 · Nov 10, 2016