IP Library Granted Patent US 10,813,930
Granted Patent B2
US 10,813,930 · App. 16/238,277 · Granted Oct 27, 2020

Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3

Inventors: Wenqing Yao (Chadds Ford, PA); Colin Zhang (Berwyn, PA); Meizhong Xu (Hockessin, DE); Jincong Zhuo (Garnet Valley, PA); Chunhong He (Boothwyn, PA)
Assignees: Incyte Corporation; Incyte Holdings Corporation
A61K31/5025A61K31/5377C07D235/06C07D401/12C07D401/14C07D403/04C07D403/12C07D405/12C07D405/14C07D407/12C07D487/04
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Quick Facts
Patent No.
US 10,813,930
App. No.
16/238,277
Granted
Oct 27, 2020
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 (124)

1. A method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of 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;

wherein said cancer is associated with elevated expression or activity of FGFR3; and

wherein said cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, head and neck cancer, liver cancer, lung cancer, ovarian cancer, esophageal cancer, gall bladder cancer, multiple myeloma, acute myelogenous leukemia, glioblastoma, and kidney cancer.

2. The method of claim 1 , wherein Ar 1 is phenyl optionally substituted by 1, 2, 3, or 4 independently selected R A1 groups.

3. The method of claim 1 , wherein Ar 1 is phenyl.

4. The method of claim 1 , 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 method of claim 1 , wherein Ar 2 is aryl or heteroaryl, each optionally substituted by 1, 2, 3, or 4 independently selected R A2 groups.

6. The method of claim 1 , wherein Ar 2 is phenyl optionally substituted by 1, 2, 3, or 4 independently selected R A2 groups.

7. The method of claim 1 , wherein Ar 2 is pyrazolyl optionally substituted by 1, 2, or 3 independently selected R A2 groups.

8. The method of claim 1 , wherein Ar 2 is heterocycloalkyl optionally substituted by 1, 2, or 3 independently selected R A2 groups.

9. The method of claim 1 , wherein Ar 2 is 1,2,3,4-tetrahydroisoquinolinyl optionally substituted by 1, 2, 3, or 4 independently selected R A2 groups.

10. The method of claim 1 , wherein B is —(CR 3 R 4 ) m1 —(CR 1 R 2 )—(CR 3 R 4 ) m2 —X.

11. The method of claim 10 , wherein X is Cy 5 , CN, or C(O)NR 5 R 6 .

12. The method of claim 1 , wherein B is -L 1 -(CR 3 R 4 ) n -Cy 1 .

13. The method of claim 12 , wherein L 1 is C(O)NR.

14. The method of claim 12 , wherein n is 1 or 2.

15. The method of claim 1 , wherein B is -Cy 2 -(L 2 ) a -(CR 3 R 4 ) p -Cy 3 .

16. The method of claim 15 , wherein a is 1.

17. The method of claim 15 , wherein a is 0.

18. The method of claim 15 , wherein p is 1 or 2.

19. The method of claim 1 , wherein B is -Cy 4 -L 3 -Y.

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

21. The method of claim 19 , wherein Y is C 3-7 cycloalkyl substituted by 1, 2, 3, 4, or 5 independently selected R B2 groups.

22. The method of claim 19 , 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 method of claim 1 , wherein the compound has Formula IIa:

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

24. The method of claim 1 , wherein the compound has Formula IIb:

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

25. The method of claim 1 , wherein the compound 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-Methyl-1H-pyrazol-4-yl)carbonyl]piperidin-4-yl}-1H-pyrazol-4-yl)-1H-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)-1H-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. The method of claim 1 , wherein said cancer is bladder cancer.

27. The method of claim 1 , wherein said cancer is breast cancer.

28. The method of claim 1 , wherein said cancer is cervical cancer.

29. The method of claim 1 , wherein said cancer is colorectal cancer.

30. The method of claim 1 , wherein said cancer is endometrial cancer.

31. The method of claim 1 , wherein said cancer is head and neck cancer.

32. The method of claim 1 , wherein said cancer is liver cancer.

33. The method of claim 1 , wherein said cancer is lung cancer.

34. The method of claim 33 , wherein said lung cancer is non-small cell lung carcinoma.

35. The method of claim 33 , wherein said lung cancer is adenocarcinoma or small cell lung cancer.

36. The method of claim 1 , wherein said cancer is ovarian cancer.

37. The method of claim 1 , wherein said cancer is esophageal cancer.

38. The method of claim 1 , wherein said cancer is gall bladder cancer.

39. The method of claim 1 , wherein said cancer is multiple myeloma.

40. The method of claim 1 , wherein said cancer is acute myelogenous leukemia.

41. The method of claim 1 , wherein said cancer is glioblastoma.

42. The method of claim 1 , wherein said cancer is kidney cancer.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 2, 2019
From: YAO, WENQING; ZHANG, COLIN; XU, MEIZHONG; ZHUO, JINCONG; HE, CHUNHONG
To: INCYTE CORPORATION
Reel/Frame 049060/0880 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 2, 2019
From: INCYTE CORPORATION
To: INCYTE HOLDINGS CORPORATION; INCYTE CORPORATION
Reel/Frame 049060/0940 →
Continuity (5)
Continuation 15359012 · Nov 22, 2016
Division 14267139 · May 1, 2014
Continuation 13333021 · Dec 21, 2011
Provisional Application 61426273 · Dec 22, 2010
Related Publication 20190240220A1 · Aug 8, 2019
Cited By (5)
US 12,428,420 US 12,473,286 US 12,534,463 US 12,552,792 US 12,552,804