Bicyclic heterocycles as FGFR inhibitors
The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of the FGFR enzyme and are useful in the treatment of FGFR-associated diseases such as cancer.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl; wherein the 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of the 5-10 membered heteroaryl is optionally substituted by oxo to form a carbonyl group; and wherein the C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;
R 1 is OR 3 or NR 4 R 5 ;
R 2 is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , 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 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 ;
A 1 is selected from N and CR 6 ;
A 2 is selected from N and CR 7 ;
A 3 is selected from N and CR 8 ;
A 4 is selected from N and CR 9 ;
R 3 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-14 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, and 5-10 membered heteroaryl-C 1-3 alkylene; wherein said C 1-6 alkyl is substituted with 1, 2, 3, or 4 substituents independently selected from R 30A ; and wherein said C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-14 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5-10 membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 30 ;
R 4 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-14 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, and 5-10 membered heteroaryl-C 1-3 alkylene; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-14 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5-10 membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 ;
R 5 is selected from H and C 1-6 alkyl; wherein said C 1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from R g ;
R 6 , R 7 , R 8 , and R 9 are each independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , 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 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 ;
each R 10 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5-10 membered heteroaryl-C 1-3 alkylene, halo, D, 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(=NOR a1 )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 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5-10 membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ;
each R 11 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5-10 membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 NR c3 C(O)R b3 , NR c3 C(O)OR a3 , 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 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5-10 membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ;
each R 12 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , NR c5 R d5 ,NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 S(O)R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R 20 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a4 , SR a4 , C(O)R b4 , C(O)OR a4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 S(O)R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R 30A is independently selected from C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, CN, OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , NR c6 R d6 NR c6 C(O)R b6 , NR c6 C(O)OR a6 , NR c6 S(O)R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , and S(O) 2 NR c6 R d6 ; wherein said C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 31 ;
each R 30 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, OR a6 , SR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , NR c6 R d6 , NR c6 C(O)R b6 , NR c6 C(O)OR a6 , NR c6 S(O)R b6 , NR c6 S(O) 2 R b6 , NR c6 S(O) 2 NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O) 2 R b6 , and S(O) 2 NR c6 R d6 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 31 ;
each R 31 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a8 , SR a8 , C(O)R b8 , C(O)NR c8 R d8 , C(O)OR a8 , NR c8 R d8 , NR c8 C(O)R b8 , NR c8 C(O)OR a8 , NR c8 S(O)R b8 , NR c8 S(O) 2 R b8 , NR c8 S(O) 2 NR c8 R d8 , S(O)R b8 , S(O)NR c8 R d8 , S(O) 2 R b8 , and S(O) 2 NR c8 R d8 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R 40 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, OR a7 , SR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , NR c7 R d7 NR c7 C(O)R b7 , NR c7 C(O)OR a7 , NR c7 S(O)R b7 , NR c7 S(O) 2 R b7 , NR c7 S(O) 2 NR c7 R d7 , S(O)R b7 , S(O)NR c7 R d7 , S(O) 2 R b7 , and S(O) 2 NR c7 R d7 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 41 ;
each R 41 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a9 , SR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , NR c9 R d9 , NR c9 C(O)R b9 , NR c9 C(O)OR a9 ,NR c9 S(O)R b9 , NR c9 S(O) 2 R b9 , NR c9 S(O) 2 NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O) 2 R b9 , and S(O) 2 NR c9 R d9 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R a1 , R c1 and R d1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ;
or any R c1 and R d1 attached to the same N atom, together with the N atom to which they are attached, form a 4−, 5−, 6− or 7− membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ;
each R b1 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ;
each R e1 is independently selected from H, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkylaminosulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, amino sulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl;
each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 ;
or any R c2 and R d2 attached to the same N atom, together with the N atom to which they are attached, form a 4−, 5−, 6− or 7− membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R 20 ;
each R b2 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 ;
each R a3 , R c3 and R d3 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ;
or any R c3 and R d3 attached to the same N atom, together with the N atom to which they are attached, form a 4−, 5−, 6− or 7− membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R 12 ;
each R b3 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ;
each R a4 , R c4 and R d4 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
or any R c4 and R d4 attached to the same N atom, together with the N atom to which they are attached, form a 4−, 5−, 6− or 7− membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R g ;
each R b4 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R a5 , R c5 and R d5 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
or any R c5 and R d5 attached to the same N atom, together with the N atom to which they are attached, form a 4−, 5−, 6− or 7− membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R b5 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; wherein said C 1-6 alkyl C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R a6 , R c6 and R d6 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 31 ;
or any R c6 and R d6 attached to the same N atom, together with the N atom to which they are attached, form a 4−, 5−, 6− or 7− membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R 31 ;
each R b6 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 31 ;
each R a7 , R c7 and R d7 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 41 ;
or any R c7 and R d7 attached to the same N atom, together with the N atom to which they are attached, form a 4−, 5−, 6− or 7− membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R 41 ;
each R b7 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C 1-6 alkyl C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 41 ;
each R a8 , R c8 and R d8 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R b8 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R a9 , R c9 and R d9 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;
each R b9 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ; and
each R g is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-2 alkylene, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-3 alkoxy-C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkoxy, HO-C 1-3 alkoxy, HO-C 1-3 alkyl, cyano-C 1-3 alkyl, H 2 N-C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carbamyl, C 1-6 alkylcarbamyl, di(C 1-6 alkyl)carbamyl, carboxy, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, and di(C 1-6 alkyl)aminocarbonylamino.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is CR 6 .
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 2 is CR 7 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 3 is CR 8 .
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 3 is N.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 4 is CR 9 .
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is CR 6 ; A 2 is CR 7 ; A 3 is CR 8 ; and A 4 is CR 9 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is CR 6 ; A 2 is CR 7 ; A 3 is N; and A 4 is CR 9 .
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is CR 6 ; A 2 is CR 7 ; and A 4 is CR 9 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , R 8 , and R 9 are each independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2, S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 .
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , R 8 , and R 9 are each independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 5-10 membered heteroaryl, halo, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 .
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , R 8 , and R 9 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a2 , C(O)NR c2 R d2 , and S(O) 2 R b2 .
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 , R 7 , R 8 , and R 9 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 5-10 membered heteroaryl, halo, CN, OR a2 , C(O)NR c2 R d2 , and S(O) 2 R b2 .
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H or C(O)NR c2 R d2 .
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H or C(O)NHCH 3 .
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H or 5-10 membered heteroaryl.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H, C 1-6 alkyl, C 1-6 haloalkyl, halo, CN, OR a2 , or S(O) 2 R b2 .
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H, methyl, CHF 2 , F, CN, OH, or S(O) 2 (CH 3 ) 2 .
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is H or halo.
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is H or F.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is OR 3 .
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is NR 4 R 5 .
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; wherein said C 1-6 alkyl is substituted with 1, 2, 3, or 4 substituents independently selected from R 30A and wherein said 4-6 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 30 .
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is 4-6 membered heterocycloalkyl optionally substituted with 1 or 2 substituents independently selected from R 30 .
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is tetrahydrofuran-3-yl optionally substituted with 1 or 2 substituents independently selected from R 30 .
27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is tetrahydrofuran-3-yl.
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 .
29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is 4-6 membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 .
30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is tetrahydrofuran-3-yl.
31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
32. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.
33. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is 5-6 membered heteroaryl optionally substituted with 1 or 2 substituents independently selected from R 10 .
34. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is phenyl optionally substituted with 1 or 2 substituents independently selected from R 10 .
35. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is selected from phenyl and 5-6 membered heteroaryl; wherein the phenyl and 5-6 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R 10 .
36. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is phenyl, pyrazolyl or pyridinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R 10 .
37. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is phenyl, pyrazolyl, triazolyl, oxazolyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, or pyridinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R 10 .
38. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy 1 is pyrazolyl optionally substituted with 1 or 2 substituents independently selected from R 10 .
39. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a1 , and NR c1 R d1 ; wherein said C 1-6 alkyl and 4-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R 11 .
40. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently selected from methyl, ethyl, propyl, isopropyl, piperidinyl, piperazinyl, azetidinyl, morpholino, cyclopropyl, and cyclobutyl; each of which is optionally substituted with 1 or 2 substituents independently selected from R 11 .
41. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently selected from methyl, ethyl, propyl, isopropyl, piperidinyl, piperazinyl, azetidinyl, morpholino, cyclopropyl, ethylamino, and cyclobutyl; each of which is optionally substituted with 1 or 2 substituents independently selected from R 11 .
42. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently selected from methyl, isopropyl, 2-hydroxypropan-2-yl, NH(CH 3 ), methylpiperidin-4-yl, methylpiperazin-1-yl, morpholinoethyl, 1-methylazetidin-3-yl, morpholino, cyclopropyl, and cyclobutyl.
43. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently selected from methyl, ethyl, isopropyl, 2-hydroxypropan-2-yl, NH(CH 3 ), methylpiperidin-4-yl, methylpiperazin-1-yl, morpholinoethyl, 1-methylazetidin-3-yl, morpholino, cyclopropyl, ethylamino, hydroxyethyl-2-yl, cyanoethyl-2-yl, dimethylamino-2-oxoethyl, 2-hydroxy-2-methylpropyl, 2-methoxyethyl, pyridin-3-ylmethyl, (tetrahydro-2H-pyran-4-yl)methyl, 2-morpholinoethyl, 3-fluoro-1-methylpiperidin-4-yl, ((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl, 1-isopropylpiperidin-4-yl, 4-fluoro-1-methylpiperidin-4-yl, 4-methylpiperazin-1-yl, tetrahydrofuran-3-yl, 1,1-dioxidotetrahydrothiophen-3-yl, and cyclobutyl.
44. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is methyl.
45. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from C 1-6 alkyl, 4-6 membered heterocycloalkyl, and OR a3 ; wherein said C 1-6 alkyl and 4-6 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R 12 .
46. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from C 1-6 alkyl, CN, 4-7 membered heterocycloalkyl, C(O)NR c3 R d3 , halo, 5-10 membered heteroaryl, and OR a3 ; wherein said C 1-6 alkyl and 4-7 membered heterocycloalkyl are each optionally substituted with 1 or 2 substituents independently selected from R 12 .
47. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from C 1-6 alkyl, 4-6 membered heterocycloalkyl, and OR a3 .
48. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from C 1-6 alkyl, CN, 4-7 membered heterocycloalkyl, C(O)NR c3 R d3 , halo, and OR a3 .
49. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from methyl, OH, and morpholino.
50. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 11 is independently selected from methyl, OH, methoxy, CN, C(O)N(CH 3 ) 2 , isopropyl, pyridinyl, tetrahydropyranyl, fluoro, 2-oxa-5-azabicyclo[2.2.1]heptanyl, and morpholino.
51. The compound of claim 1 , each R 20 is independently selected from D.
52. The compound of claim 1 , having Formula IIa:
or a pharmaceutically acceptable salt thereof.
53. The compound of claim 1 , having Formula IIb:
or a pharmaceutically acceptable salt thereof.
54. The compound of claim 1 , having Formula IIIa:
or a pharmaceutically acceptable salt thereof, wherein X is O or NH.
55. The compound of claim 1 , having Formula IIIb:
or a pharmaceutically acceptable salt thereof, wherein X is O or NH.
56. The compound of claim 1 , having Formula IVc:
or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
57. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl; wherein each 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of 5-10 membered heteroaryl is optionally substituted by oxo to form a carbonyl group; and wherein the C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;
R 1 is OR 3 or NR 4 R 5 ;
R 2 is selected from H, D, and halo;
A 1 is selected from N and CR 6 ;
A 2 is selected from N and CR 7 ;
A 3 is selected from N and CR 8 ;
A 4 is selected from N and CR 9 ;
R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-14 membered heterocycloalkyl, wherein said C 3-10 cycloalkyl, and 4-14 membered heterocycloalkyl, are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 30 ;
R 4 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 4-14 membered heterocycloalkyl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, and 4-14 membered heterocycloalkyl, are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 ;
R 5 is H;
R 6 , R 7 , R 8 , and R 9 is each independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 5-10 membered heteroaryl, halo, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2, C(O)OR a2 , NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ; wherein said C 1-6 alkyl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 ;
each R 10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)R a1 , NR c1 R d1 , NR c1 C(O)R b1 , and S(O) 2 R b1 ; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ;
each R 11 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halo, D, CN, OR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , and S(O) 2 R b3 ; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ;
each R 12 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a5 , and NR c5 R d5 ;
each R 20 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a4 , and NR c4 R d4 ;
each R 30 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl halo, D, CN, OR a6 , and NR c6 R d6 ;
each R 40 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a7 , and NR c7 R d7 ;
each R a1 , R c1 and R d1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl;
or any R c1 and R d1 attached to the same N atom, together with the N atom to which they are attached, form a 4−, 5−, or 6− membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ;
each R b1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl;
each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; wherein said C 1-6 alkyl, is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 ;
each R b2 is independently selected from C 1-6 alkyl, and C 1-6 haloalkyl;
each R a3 , R c3 and R d3 , is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R b3 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;
each R a4 , R c4 and R d4 , is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R a5 , R c5 and R d5 , is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R a6 , R c6 and R d6 , is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; and
each R a7 , R c7 and R d7 , is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.
58. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is selected from C 6-10 aryl and 5-10 membered heteroaryl; wherein each 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; wherein the N and S are optionally oxidized; wherein a ring-forming carbon atom of 5-10 membered heteroaryl is optionally substituted by oxo to form a carbonyl group; and wherein the C 6-10 aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ,
R 1 is OR 3 or NR 4 R 5 ;
R 2 is H;
A 1 is selected from N and CR 6 ;
A 2 is selected from N and CR 7 ;
A 3 is selected from N and CR 8 ;
A 4 is selected from N and CR 9 ;
R 3 is 4-14 membered heterocycloalkyl;
R 4 is 4-14 membered heterocycloalkyl;
R 5 is H;
R 6 , R 7 , R 8 , and R 9 is each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 5-10 membered heteroaryl, halo, CN, OR a2 , C(O)NR c2 R d2 , and S(O) 2 R b2 ; wherein said C 1-6 alkyl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 ;
each R 10 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, and NR c1 R d1 ; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ;
each R 11 is independently selected from C 1-6 alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halo, CN, OR a3 , and C(O)NR c3 R d3 ;
R 20 is D;
each R c1 and R d1 is independently selected from H and C 1-6 alkyl;
each R a2 , R c2 ,and R d2 is independently selected from H and C 1-6 alkyl; wherein said C 1-6 alkyl, is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 20 ;
R b2 is C 1-6 alkyl; and
each R a3 , R c3 and R d3 , is independently selected from H and C 1-6 alkyl.
59. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Cy 1 is selected from phenyl and 5-10 membered heteroaryl; wherein each 5-10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; and wherein the phenyl and 5-10 membered heteroaryl are each optionally substituted with 1, 2 or 3 substituents independently selected from R 10 ;
R 1 is OR 3 or NR 4 R 5 ;
R 2 is H;
A 1 is selected from N and CR 6 ;
A 2 is selected from N and CR 7 ;
A 3 is selected from N and CR 8 ;
A 4 is selected from N and CR 9 ;
R 3 is 4-6 membered heterocycloalkyl;
R 4 is 4-6 membered heterocycloalkyl;
R 5 is H;
R 6 , R 7 , R 8 , and R 9 is each independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, 5-6 membered heteroaryl, halo, CN, OR a2 , C(O)NR c2 R d2 , NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
each R 10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, halo, D, CN, OR a1 , and NR c1 R d1 , ; wherein said C 1-6 alkyl and C 3-10 cycloalkyl, and 4-10 membered heterocycloalkyl, are each optionally substituted with 1 or 2 substituents independently selected from R 11 ;
each R 11 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, halo, D, CN, OR a3 , C(O)NR c3 R d3 , and NR c3 R d3 ;
each R 20 is independently selected from D;
each R a1 , R c1 and R d1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;
each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; wherein said C 1-6 alkyl, is optionally substituted with 1, 2, or 3 substituents independently selected from R 20 ;
each R b2 is independently selected from C 1-6 alkyl, and C 1-6 haloalkyl; and
each R a3 , R c3 and R d3 , is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.
60. The compound of claim 1 , wherein the compound is selected from:
N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
4-fluoro-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
4-fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-4-fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3-cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
(S)-3-cyano-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-5-(6-(1-isopropyl-1H-pyrazol-4-yl-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;
(S)-5-(6-(1-isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;
(S)-3,4-difluoro-N-methyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3,4-difluoro-N-methyl-5-(6-(4-(4-methylpiperazin-1-yl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3,4-difluoro-N-methyl-5-(6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3,4-difluoro-N-methyl-5-(6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3,4-difluoro-N-methyl-5-(6-(6-methylpyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-4-fluoro-N,3-dimethyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3,4-difluoro-N-methyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-N-methyl-5-(6-(4-(4-methylpiperazin-1-yl)phenyl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
(S)-N-methyl-5-(6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
(S)-N-methyl-5-(6-(6-morpholinopyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
(S)-5-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;
(S)-5-(6-(1-cyclobutyl-1H-pyrazol-4-yl)- 5 -((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylnicotinamide;
(S)-3-(difluoromethyl)-4-fluoro-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3-(difluoromethyl)-4-fluoro-N-methyl-5-(6-(5-methyl-6-(methylamino)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3-(difluoromethyl)-4-fluoro-5-(6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;
(S)-3-(difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3-cyano-N-methyl-5-(6-(pyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3-cyano-N-methyl-5-(6-(6-methylpyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3-cyano-N-methyl-5-(6-(5-methylpyridin-3-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3-cyano-N-methyl-5-(6-(pyridin-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-4-fluoro-3-hydroxy-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide; and
(S)-3-(6-(1-cyclobutyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methyl-5-(methylsulfonyl)benzamide;
or a pharmaceutically acceptable salt of any of the aforementioned.
61. The compound of claim 1 , wherein the compound is selected from:
(S)-3-(1H-Indazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidine;
(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-4-Fluoro-N,3-dimethyl-5-(6-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-4-Fluoro-3-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-y1)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;
(S)-3-(6-(1-(2-Cyanoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-y1)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4-fluoro-N,5-dimethylbenzamide;
3-(6-(1-(1, 1-Dioxidotetrahydrothiophen-3-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)-4-fluoro-N, 5-dimethylbenzamide;
(S)-3-(6-(1-(2-(Dimethylamino)-2-oxoethyl)- 1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)-4-fluoro-N, 5-dimethylbenzamide;
(S)-4-Fluoro-3-(6-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;
4-Fluoro-N,3-dimethyl-5-(6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5 4((S)-tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)benzamide;
(S)-4-Fluoro-N,3-dimethyl-5-(6-(2-methyloxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)benzamide;
(S)-3-(6-(1-Ethyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)-4-fluoro-N, 5-dimethylbenzamide;
(S)-4-Fluoro-N,3-dimethyl-5-(6-(pyridazin-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)benzamide;
(S)-3-(5-(Ethylsulfonyl)-2, 3-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-N-(tetrahydrofuran-3-yl)pyrazolo [1, 5-a] pyrimidin-5-amine;
(S)-3-(5-(Ethylsulfonyl)-2, 3-difluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo [1, 5-a]pyrimidine;
(S)-3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)benzamide;
(S)-3-(Difluoromethyl)-5-(6-(1-ethyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)-4-fluoro-N-methylbenzamide;
3-(Difluoromethyl)-4-fluoro-N-methyl-5-(6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-5-(((S)-tetrahydrofuran-3-yl)amino)pyrazolo[1, 5-a]pyrimidin-3-yl)benzamide;
(S)-3-(Difluoromethyl)-4-fluoro-5-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)-N-methylbenzamide;
(S)-3-(3-(1H-Pyrazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo [1, 5-a]pyrimidine;
(S)-3,4-Difluoro-N-methyl-5-(6-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo [1, 5-a]pyrimidin-3-yl)benzamide;
(S)-3-(6-(1-Ethyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-4,5-difluoro-N-methylbenzamide;
(S)-3,4-Difluoro-N-methyl-5-(6-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3,4-Difluoro-N-methyl-5-(6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-3,4-Difluoro-5-(6-(1-isopropyl-2-oxo-1,2-dihydropyridin-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;
(S)-3,4-Difluoro-5-(6-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide;
(S)-3,4-Difluoro-N-methyl-5-(6-(2-methyloxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
(S)-N-Methyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
(S)-N-Methyl-5-(6-(2-methyl-2H-1,2,3-triazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
(S)-N-Ethyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
(S)-N-Isopropyl-5-(6-(1-methyl-1H-pyrazol-3-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)nicotinamide;
(S)-5-(6-(1-Isopropyl-1H-pyrazol-4-yl)-5-((tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(methyl-d 3 )nicotinamide;
4-Fluoro-3-(6-(1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(((5)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a] pyrimidin-3-yl)-5-methyl-N-(methyl-d 3 )benzamide;
4-Fluoro-3-(6-(1-((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-5-(((5)-tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide;
3-(6-(6-(((1R,4R)-2-Oxa-5-azabicyclo[2,2,1]heptan-5-yl)methyl)pyridin-3-yl)-5-(((5)-tetrahydrofuran-3-yl)oxy)pyrazolo[1,5-a] pyrimidin-3-yl)-5-(difluoromethyl)-4-fluoro-N-(methyl-d3)benzamide;
(S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)-2H-1,2,3-triazol-4-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d 3 )benzamide;
(S)-4-Fluoro-3-(6-(2-(1-isopropylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-5-methyl-N-(methyl-d 3 )benzamide;
(S)-4-Fluoro-3-(6-(2-(4-fluoro-1-methylpiperidin-4-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,5-dimethylbenzamide; and
(S)-4-Fluoro-N,3-dimethyl-5-(6-(2-(4-methylpiperazin-1-yl)oxazol-5-yl)-5-((tetrahydrofuran-3-yl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide;
or a pharmaceutically acceptable salt of any of the aforementioned.
62. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
63. A method of inhibiting an FGFR3 enzyme comprising contacting said enzyme with a compound of claim 1 or a pharmaceutically acceptable salt thereof.
64. A method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the cancer is associated with abnormal activity or expression of an FGFR enzyme.
65. A method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof in combination with another therapy or therapeutic agent, wherein the cancer is associated with abnormal activity or expression of an FGFR enzyme.
66. The method of claim 64 , wherein said cancer is selected from hepatocellular cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, cholangiocarcinoma, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T cell leukemia, B-cell lymphoma, acute myelogenous leukemia, Hodgkin's or non-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, hairy cell lymphoma, Burkett's lymphoma, glioblastoma, melanoma, and rhabdosarcoma.
67. The method of claim 64 , wherein said cancer is selected from bladder cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, cholangiocarcinoma, lung cancer, ovarian cancer, pancreatic cancer, glioblastoma, melanoma, and rhabdosarcoma.
68. A method for treating a skeletal or chondrocyte disorder in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the skeletal or chondrocyte disorder is associated with abnormal activity or expression of an FGFR enzyme.
69. The method of claim 68 wherein said skeletal or chondrocyte disorder is selected from achrondroplasia, hypochondroplasia, dwarfism, thanatophoric dysplasia (TD), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosis syndrome.