IP Library Granted Patent US 8,754,114
Granted Patent B2
US 8,754,114 · App. 13/333,021 · Granted Jun 17, 2014

Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3

Inventors: Wenqing Yao (Kenneth Square, PA); Colin Zhang (Ambler, PA); Meizhong Xu (Hockessin, DE); Jincong Zhuo (Garnet Valley, PA); Chunhong He (Boothwyn, PA)
Assignee: Incyte Corporation
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Quick Facts
Patent No.
US 8,754,114
App. No.
13/333,021
Granted
Jun 17, 2014
Kind
B2
Abstract

The present invention relates to substituted imidazopyridazines and substituted benzimidazoles, as well as pharmaceutical compositions comprising the same, which are FGFR3 inhibitors useful in the treatment of cancer and other diseases.

Claims (106)

1. A compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R A1 groups;

Ar 2 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R A2 groups;

B is:

(i) —(CR 3 R 4 ) m1 —(CR 1 R 2 )—(CR 3 R 4 ) m2 —X;

(ii) -L 1 -(CR 3 R 4 ) n -Cy 1 ;

(iii) -Cy 2 -(L 2 ) a -(CR 3 R 4 ) p -Cy 3 ; or

(iv) -Cy 4 -L 3 -Y;

L 1 is C(O)NR, C(O)O, S(O) 2 NR, NRC(O)NR, NRC(S)NR, S, or S(O);

L 2 and L 3 are each independently selected from CO, C(O)O, C(O)NR, S(O) 2 NR, NR, NRC(O)NR, NRC(S)NR, O, S, S(O), and S(O) 2 ;

X is Cy 5 , CN, C(O)NR 5 R 6 , NR 5 C(O)R 7 , NR 5 S(O) 2 R 7 , NR 5 S(O) 2 NR 5 R 6 , NR 5 C(O)OR 8 , or S(O) 2 NR 5 R 6 ;

Y is:

(1) aryl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 independently selected R B1 groups;

(2) C 3-7 cycloalkyl substituted by 1, 2, 3, 4, or 5 independently selected R B2 groups; or

(3) C 1-6 alkyl or C 1-6 haloalkyl, each substituted by 1, 2, 3, 4, or 5 independently selected R X groups;

Cy 1 , Cy 2 , Cy 3 , Cy 4 , and Cy 5 are each independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each of which is optionally substituted by 1, 2, 3, 4, or 5 independently selected R Cy groups;

R is independently selected from H and C 1-4 alkyl;

R 1 is halo, cyano, hydroxy, C 1-4 alkyl, C 2-4 cyanoalkyl, C 2-4 alkoxyalkyl, C 1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R D groups;

R 2 and R 4 are each independently selected from H, halo, hydroxy, C 1-4 alkyl, C 2-4 cyanoalkyl, C 2-4 alkoxyalkyl, and C 1-4 haloalkyl;

R 3 is independently selected from H, halo, cyano, hydroxy, C 1-4 alkyl, C 2-4 cyanoalkyl, C 2-4 alkoxyalkyl, C 1-4 haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted by 1, 2, 3, 4, or 5 independently selected R D groups;

R 5 is independently selected from H, C 1-4 alkyl, C 2-4 cyanoalkyl, C 2-4 alkoxyalkyl, and C 1-4 haloalkyl;

R 6 , R 7 , and R 8 are each independently selected from H, C 1-4 alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, wherein said C 1-4 alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R D groups;

or R 5 and R 6 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl ring optionally substituted by 1, 2, 3, 4, or 5 independently selected R D groups;

each R A1 is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, 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)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are each optionally substituted with 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 , 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 , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;

each R A2 is independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, halosulfanyl, CN, NO 2 , 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)OR a1 , NR c1 C(O)NR c1 R d1 , C(═NR e1 )R b1 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ; wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, are each optionally substituted with 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 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 , C(═NR e1 )NR c1 R d1 , NR c1 C(═NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 ;

each R B1 , R B2 , R Cy , and R D is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO 2 , 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)OR a2 , NR c2 C(O)NR c2 R d2 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are each optionally substituted with 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 , 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 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;

each R X is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, 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)OR a3 , NR c3 C(O)NR c3 R d3 , C(═NR e3 )R b3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are each optionally substituted with 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 , 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 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;

each R a , R b , R c , and R d is independently selected from H, C 1-6 alkyl, C 1-4 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 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(═NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;

or any R c and R d together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or a heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 , wherein said C 1-6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(═NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;

each R e and R f is independently selected from H, C 1-4 alkyl, CN, OR a4 , SR b4 , S(O) 2 R b4 , C(O)R b4 , S(O) 2 NR c4 R d4 , and C(O)NR c4 R d4 ;

each R a1 , R b1 , R c1 , and R d1 is independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(═NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;

or any R c1 and R d1 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or a heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(═NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;

each R e1 and R f1 is independently selected from H, C 1-4 alkyl, CN, OR a4 , SR b4 , S(O) 2 R b4 , C(O)R b4 , S(O) 2 NR c4 R d4 , and C(O)NR c4 R d4 ;

each R a2 , R b2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(═NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;

or any R c2 and R d2 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or a heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(═NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 , wherein said C 1-6 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(═NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;

each R e2 and R f2 is independently selected from H, C 1-4 alkyl, CN, OR a4 , SR b4 , S(O) 2 R b4 , C(O)R b4 , S(O) 2 NR c4 R d4 , and C(O)NR c4 R d4 ;

each R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(═NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;

or any R c3 and R d3 together with the N atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl group or a heteroaryl group, each optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, 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 f4 )NR c4 R d4 , NR c4 C(═NR f4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;

each R e3 and R f3 is independently selected from H, C 1-4 alkyl, CN, OR a4 , SR b4 , S(O) 2 R b4 , C(O)R b4 , S(O) 2 NR c4 R d4 , and C(O)NR c4 R d4 ;

each R a4 , R b4 , R c4 , and R d4 is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein said C 1-4 alkyl, C 1-4 haloalkyl, 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, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

or any R c4 and R d4 together with the N atom to which they are attached form a 3-, 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 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

each R e4 and R f4 is independently selected from H, C 1-4 alkyl, and CN;

a is 0 or 1;

m1 is 0, 1, 2, 3, or 4;

m2 is 0, 1, 2, 3, or 4;

n is 1, 2, 3, 4, 5, or 6; and

p is 1, 2, 3, 4, 5, or 6

wherein aryl refers to a C 6-10 aromatic cyclic hydrocarbon group; wherein heteroaryl refers to a 5-6 membered aromatic heterocycle comprising 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen; wherein cycloalkyl refers to a C 3-14 non-aromatic cyclic hydrocarbon group; and wherein heterocycloalkyl refers to a 3-20 membered non-aromatic heterocycle comprising at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 1 is phenyl optionally substituted by 1, 2, 3, or 4 independently selected R A1 groups.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 1 is phenyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A1 is independently selected from NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , and NR c S(O) 2 NR c R d .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is aryl or heteroaryl, each optionally substituted by 1, 2, 3, or 4 independently selected R A2 groups.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is phenyl optionally substituted by 1, 2, 3, or 4 independently selected R A2 groups.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is pyrazolyl optionally substituted by 1, 2, or 3 independently selected R A2 groups.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is heterocycloalkyl optionally substituted by 1, 2, or 3 independently selected R A2 groups.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ar 2 is 1,2,3,4-tetrahydroisoquinolinyl optionally substituted by 1, 2, 3, or 4 independently selected R A2 groups.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is —(CR 3 R 4 ) m1 —(CR 1 R 2 )—(CR 3 R 4 ) m2 —X.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein X is Cy 5 , CN, or C(O)NR 5 R 6 .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is -L 1 -(CR 3 R 4 ) n -Cy 1 .

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein L 1 is C(O)NR.

14. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is -Cy 2 -(L 2 ) a -(CR 3 R 4 ) p -Cy 3 .

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein a is 1.

17. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein a is 0.

18. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein B is -Cy 4 -L 3 -Y .

20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein Y is aryl, heteroaryl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 independently selected R B1 groups.

21. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein Y is C 3-7 cycloalkyl substituted by 1, 2, 3, 4, or 5 independently selected R B2 groups.

22. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein Y is C 1-6 alkyl or C 1-6 haloalkyl, each substituted by 1, 2, 3, 4, or 5 independently selected R X groups.

23. The compound of claim 1 having Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein R d is C 1-4 alkyl or C 1-4 haloalkyl.

24. The compound of claim 1 having Formula IIb:

or a pharmaceutically acceptable salt thereof, wherein R d is C 1-4 alkyl or C 1-4 haloalkyl.

25. The compound of claim 1 which is selected from:

Cyclopropylmethyl 3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzoate;

N-(Tetrahydrofuran-2-ylmethyl)-3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-[(1-Methylpiperidin-4-yl)methyl]-3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-(2-Morpholin-4-ylethyl)-3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-(Pyridin-3-ylmethyl)-3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-[(1-Methyl-1H-imidazol-2-yl)methyl]-3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-(Cyclopropylmethyl)-4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-(Tetrahydrofuran-2-ylmethyl)-4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-[(2-Hydroxycyclohexyl)methyl]-4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-[(1-Methylpiperidin-4-yl)methyl]-4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-(2-Morpholin-4-ylethyl)-4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-(Pyridin-3-ylmethyl)-4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-[(1-Methyl-1H-imidazol-2-yl)methyl]-4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzamide;

N-Methyl-2-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanamide;

N,N-Dimethyl-2-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanamide;

N-(Cyclopropylmethyl)-2-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanamide;

N-(3-{5-[4-(1-Methyl-2-oxo-2-pyrrolidin-1-ylethyl)phenyl]-1H-benzimidazol-1-yl}phenyl)-N′-(2,2,2-trifluoroethyl)urea;

N-(Tetrahydrofuran-2-ylmethyl)-2-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanamide;

N-[3-(5-{4-[2-(3-Cyanopyrrolidin-1-yl)-1-methyl-2-oxoethyl]phenyl}-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[(1-Methyl-1H-imidazol-2-yl)methyl]-2-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}phenyl)propanamide;

N-[3-(5-{1-[1-(Cyclopropylmethyl)piperidin-4-yl]-1H-pyrazol-4-yl}-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(5-{1-[1-(Cyanomethyl)-2,2,2-trifluoroethyl]-1H-pyrazol-4-yl}-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[5-(1-{1-[(1-Methyl-1H-pyrazol-4-yl)carbonyl]piperidin-4-yl}-1H-pyrazol-4-yl)-1 H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[5-(1-{1-[(1-Methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-4-yl}-1H-pyrazol-4-yl)-1 H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-Pyridin-3-yl-4-(4-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}-1H-pyrazol-1-yl)piperidine-1-carboxamide;

N-[3-(5-{1-[1-(Pyrrolidin-1-ylcarbonyl)piperidin-4-yl]-1H-pyrazol-4-yl}-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(5-{1-[1-(Cyclopropylacetyl)piperidin-4-yl]-1H-pyrazol-4-yl}-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(5-{1-[1-(Cyanoacetyl)piperidin-4-yl]-1H-pyrazol-4-yl}-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea; and

N-[3-(5-{1-[1-(Tetrahydrofuran-2-ylcarbonyl)piperidin-4-yl]-1H-pyrazol-4-yl}-1H-benzimidazol-1-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

or a pharmaceutically acceptable salt of any of the aforementioned.

26. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

Assignments (3)
CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY INFORMATION PREVIOUSLY RECORDED ON REEL 035920 FRAME 0576. ASSIGNOR(S) HEREBY CONFIRMS THE RECEIVING PARTY NAME SHOULD BE RECORDED AS TWO PARTIES. Recorded Jul 2, 2015
From: INCYTE CORPORATION
To: INCYTE HOLDINGS CORPORATION; INCYTE CORPORATION
Reel/Frame 036054/0740 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 16, 2015
From: INCYTE CORPORATION
To: INCYTE HOLDINGS CORPORATION AND INCYTE CORPORATION
Reel/Frame 035920/0576 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 9, 2012
From: YAO, WENQING; ZHANG, COLIN; XU, MEIZHONG; ZHUO, JINCONG; HE, CHUNHONG
To: INCYTE CORPORATION
Reel/Frame 027500/0069 →
Continuity (2)
Provisional Application 61426273 · Dec 22, 2010
Related Publication 20120165305A1 · Jun 28, 2012