Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3

1. A method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 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 e1 R d1 ; wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl 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 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, and glioblastoma.

2. The method of claim 1 wherein said cancer is bladder cancer.

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

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

5. 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 .

6. 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.

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

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

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

10. 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.

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

12. The method of claim 1 , wherein X is Cy 5 , CN, or C(O)NR 5 R 6 .

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

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

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

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

17. The method of claim 1 , wherein a is 1.

18. The method of claim 1 , wherein a is 0.

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

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

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

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

23. The method of claim 1 , 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.

24. The method of claim 1 , wherein R d is C 1-4 alkyl or C 1-4 haloalkyl.

25. The method of claim 1 , wherein the compound is a compound of Formula Ib:

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

26. The method of claim 1 , wherein the compound is selected from:

N-[3-(7-{1-[1-(Methoxyacetyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-4-yl}-1H-pyrazol-4-yl)imidazo[1, 2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{1-[(1-Methyl-1H-pyrazol-4-yl)carbonyl]piperidin-4-yl}-1H-pyrazol-4-yl)imidazo[1, 2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{1-[(Dimethylamino)acetyl]piperidin-4-yl}-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-(Benzylsulfonyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-(cyclopentylacetyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-(Pyrrolidin-1-ylcarbonyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-(morpholin-4-ylcarbonyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-Pyridin-3-yl-4-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]-carbonyl})amino)-phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)piperidine-1-carboxamide;

N-Benzyl-4-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl})-amino)phenyl]imidazo[1,2-b]pyridazin-7-yl)}-1H-pyrazol-1-yl)piperidine-1-carboxamide;

N-(tetrahydrofuran-2-ylmethyl)-4-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl})-amino)phenyl]imidazo[1,2-b]pyridazin-7-yl)}-1H-pyrazol-1-yl)piperidine-1-carboxamide;

N-[3-(7-{1-[1-(Cyclopropylacetyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{1-[(1-Methylcyclopropyl)carbonyl]piperidin-4-yl}-1H-pyrazol-4-yl)imidazo[1, 2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{1-[(1-hydroxycyclopropyl)carbonyl]piperidin-4-yl}-1H-pyrazol-4-yl)imidazo[1, 2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-(Cyanoacetyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{1-[(1-Cyanocyclopropyl)carbonyl]piperidin-4-yl}-1H-pyrazol-4-yl)imidazo[1, 2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-(3-Cyclopropylpropanoyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{1-[(3-hydroxycyclobutyl)carbonyl]piperidin-4-yl}-1H-pyrazol-4-yl)imidazo[1, 2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-(2, 2,2-trifluoroethyl)-N′-[3-(7-{1-[1-(3,3,3-trifluoro-2-hydroxypropanoyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]urea;

N-[3-(7-{1-[1-(tetrahydrofuran-2-ylacetyl)piperidin-4-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{6-[4-(methoxyacetyl)piperazin-1-yl]pyridin-3-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{6-[4-(Cyclopentylacetyl)piperazin-1-yl]pyridin-3-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{6-[4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl]pyridin-3-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-Cyclopropyl-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}-amino)phenyl]imidazo[1, 2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N-Methyl-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]-carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N,N-Dimethyl-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}-amino)phenyl]imidazo[1, 2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N-(Tetrahydro-2H-pyran-4-yl)-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl})amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N-(3-{7-[1-(1-Methyl-2-morpholin-4-yl-2-oxoethyl)-1H-pyrazol-4-yl]imidazo[1,2-b]pyridazin-3-yl}phenyl)-N′-(2,2,2-trifluoroethyl)urea;

N-Methyl-N-(tetrahydro-2H-pyran-4-yl)-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)-amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N-[3-(7-{1-[1-Methyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-(Pyridin-2-ylmethyl)-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}-amino)phenyl]imidazo[1, 2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N-[2-(2-Oxopyrrolidin-1-yl)ethyl]-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)-amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N-(2-Hydroxypropyl)-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}-amino)phenyl]imidazo[1, 2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N-[3-(7-{1-[2-(3-Hydroxyazetidin-1-yl)-1-methyl-2-oxoethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[2-(3,3-Difluoropyrrolidin-1-yl)-1-methyl-2-oxoethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-(Cyanomethyl)-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}-amino)phenyl]imidazo[1, 2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N-[3-(7-{1-[2-(3-Cyanopyrrolidin-1-yl)-1-methyl-2-oxoethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[2-(3-Methoxypyrrolidin-1-yl)-1-methyl-2-oxoethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[2-(4-Methoxypiperidin-1-yl)-1-methyl-2-oxoethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[2-(4-Cyanopiperidin-1-yl)-1-methyl-2-oxoethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-(1-Methylpiperidin-4-yl)-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl})amino)-phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanamide;

N-[3-(7-{1-[2-(3-Cyanoazetidin-1-yl)-1-methyl-2-oxoethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{3-(Cyanomethyl)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]azetidin-3-yl}-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{3-(Cyanomethyl)-1-[(5-methylisoxazol-4-yl)sulfonyl]azetidin-3-yl}-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[3-(Cyanomethyl)-1-(methoxyacetyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{3-(Cyanomethyl)-1-[(dimethylamino)acetyl]azetidin-3-yl)}-1H-pyrazol-4-yl)imidazo[1, 2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-(Cyanoacetyl)-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[3-(Cyanomethyl)-1-(cyclopropylacetyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(1-{3-(Cyanomethyl)-1-[(1-methylcyclopropyl)carbonyl]azetidin-3-yl}-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-[(1-Cyanocyclopropyl)carbonyl]-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl)}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[3-(Cyanomethyl)-1-(tetrahydrofuran-2-ylacetyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[3-(Cyanomethyl)-1-(tetrahydrofuran-3-ylcarbonyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[3-(Cyanomethyl)-1-(cyclopropylmethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

3-(Cyanomethyl)-N-phenyl-3-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl})-amino)phenyl]imidazo[1, 2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)azetidine-1-carboxamide;

N-[3-(7-{1-[3-(Cyanomethyl)-1-(morpholin-4-ylcarbonyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[3-(Cyanomethyl)-1-(pyrrolidin-1-ylcarbonyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

3-(Cyanomethyl)-N-(cyclopropylmethyl)-3-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino-]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)azetidine-1-carboxamide;

Cyclopropylmethyl 3-(cyanomethyl)-3-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]-carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)azetidine-1-carboxylate;

N-(3-{7-[1-(2-Cyano-1-methylethyl)-1H-pyrazol-4-yl]imidazo[1,2-b]pyridazin-3-yl}phenyl)-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[1-(Cyanomethyl)-2,2,2-trifluoroethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{1-[2-Cyano-1-(2-furyl)ethyl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-(3-{7-[1-(2-Cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl]imidazo[1,2-b]pyridazin-3-yl}phenyl)-N′-(2,2,2-trifluoroethyl)urea;

N-(3-{7-[1-(2-Cyano-1-phenylethyl)-1H-pyrazol-4-yl]imidazo[1,2-b]pyridazin-3-yl}phenyl)-N′-(2,2,2-trifluoroethyl)urea;

Trans-N-{[(2-hydroxycyclohexyl)]methyl}-3-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl})amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}benzamide;

cis-N-{[(2-Hydroxycyclohexyl)]methyl}-3-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}benzamide;

N-(2-Fluorobenzyl)-3-[3-(3-{[(methylamino)carbonyl]amino}phenyl)imidazo[1,2-b]pyridazin-7-yl]benzamide;

N-[1-(2-Fluorophenyl)ethyl]-3-[3-(3-{[(methylamino)carbonyl]amino}-phenyl)imidazo[1,2-b]pyridazin-7-yl]benzamide;

N-Methyl-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}-amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanamide;

N,N-Dimethyl-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}-amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanamide;

N-[(2S)-Tetrahydrofuran-2-ylmethyl]-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanamide;

N-{3-[7-(4-{2-[(3 S)-3-Hydroxypyrrolidin-1-yl]-1-methyl-2-oxoethyl}phenyl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea;

N-[3-(7-{4-[2-(4-Hydroxypiperidin-1-yl)-1-methyl-2-oxoethyl]phenyl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-[(3R)-Tetrahydrofuran-3-yl]-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]-carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanamide;

N-[3-(7-{4-[2-(3-Hydroxyazetidin-1-yl)-1-methyl-2-oxoethyl]phenyl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea;

N-(3-{7-[4-(1-Methyl-2-morpholin-4-yl-2-oxoethyl)phenyl]imidazo[1,2-b]pyridazin-3-yl}phenyl)-N′-(2,2,2-trifluoroethyl)urea;

N-{3-[7-(4-{2-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]-1-methyl-2-oxoethyl}phenyl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea; and

N-(2-Morpholin-4-ylethyl)-2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanamide,

or a pharmaceutically acceptable salt of any of the aforementioned.

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 1 , wherein said cancer is ovarian cancer.

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

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

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

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

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