	US 12,012,409 B2
	Bicyclic heterocycles as FGFR inhibitors
Jeremy Roach, Philadelphia, PA (US); Artem Shvartsbart, Kennett Square, PA (US); Michael Witten, Philadelphia, PA (US); and Wenqing Yao, Chadds Ford, PA (US)
Assigned to Incyte Corporation, Wilmington, DE (US)
Filed by Incyte Corporation, Wilmington, DE (US)
Filed on Jan. 14, 2021, as Appl. No. 17/149,244.
Claims priority of provisional application 62/961,538, filed on Jan. 15, 2020.
Prior Publication US 2021/0214366 A1, Jul. 15, 2021
Int. Cl. C07D 487/04 (2006.01); A61K 45/06 (2006.01); C07D 471/04 (2006.01); C07D 519/00 (2006.01)

CPC C07D 487/04 (2013.01) [A61K 45/06 (2013.01); C07D 471/04 (2013.01); C07D 519/00 (2013.01)]

48 Claims

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹is selected from OR^a1, SR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

R²is selected from C_6-10aryl 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_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R²⁰;

R³and R⁴are each independently selected from H, D, halo, CN, C_1-6alkyl, OR^a8and NR^c8R^d8; wherein the Ci-s alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R^g;

R⁵is selected from C_6-10aryl 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_6-10aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R⁵⁰;

A is N or CR^A;

R^Ais selected from H, D, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)OR^a, NR^cC(O)NR^cR^d, NR^cS(O)R^b, NR^cS(O)₂R^b, NR^cS(O)₂NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^band S(O)₂NR^cR^d; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁶;

R⁶is selected from H, D, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, halo, CN, NO₂, OR^a12, SR^a12, C(O)R^b12, C(O)NR^c12R^d12, C(O)OR^a12, OC(O)R^b12, OC(O)NR^c12R^d12, NR^c12R^d12, NR^c12C(O)R^b12, NR^c12C(O)OR^a12, NR^c12C(O)NR^c12R^d12, NR^c12S(O)R^b12, NR^c12S(O)₂R^b12, NR^c12S(O)₂NR^c12R^d12, S(O)R^b12, S(O)NR^c12R^d12, S(O)₂R^b12and S(O)₂NR^c12R^d12; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R¹⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, halo, D, CN, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D, CN, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)OR^a5, NR^c5S(O)R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, 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 R²⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, D, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, C(═NR^e2)R^b2, C(═NOR^a2)R^b2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2; wherein the 4-10 membered heterocycloalkyl 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 to form N-oxide or sulfonyl; wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²¹;

or two adjacent R²⁰substituents on the R²ring, taken together with the atoms to which they are attached, form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused C_3-6cycloalkyl ring; wherein each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring 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 a ring-forming carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group; and wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused C_3-6cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R²¹;

each R²¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, halo, D, CN, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4; wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, and 5-10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R²²;

each R²²is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, 5-6 membered heteroaryl-C_1-3alkylene, halo, D, CN, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)OR^a6, NR^c6S(O)R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, and S(O)₂NR^c6R^d6; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R⁵⁰is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, D, CN, NO₂, OR^a9, SR^a9, C(O)R^b9, C(O)NR^c9R^d9, C(O)OR^a9, OC(O)R^b9, OC(O)NR^c9R^d9, NR^c9R^d9, NR^c9C(O)R^b9, NR^c9C(O)OR^a9, NR^c9C(O)NR^c9R^d9, C(═NR^e9)R^b9, C(═NOR^a9)R^b9, C(═NR^e9)NR^c9R^d9, NR^c9C(═NR^e9)NR^c9R^d9, NR^c9S(O)R^b9, NR^c9S(O)₂R^b9, NR^c9S(O)₂NR^c9R^d9, S(O)R^b9, S(O)NR^c9R^d9, S(O)₂R^b9, and S(O)₂NR^c9R^d9; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵¹;

or two adjacent R⁵⁰substituents on the R⁵ring, taken together with the atoms to which they are attached, form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused C_3-6cycloalkyl ring; wherein each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring 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 a ring-forming carbon atom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring is optionally substituted by oxo to form a carbonyl group; and wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused C_3-6cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R⁵¹;

each R⁵¹is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, 5-10 membered heteroaryl-C_1-3alkylene, halo, D, CN, OR^a10, SR^a10, C(O)R^b10, C(O)NR^c10R^d10, C(O)OR^a10, NR^c10R^d10, NR^c10R^c10C(O)R^b10, NR^c10C(O)OR^a10, NR^c10S(O)R^b10, NR^c10S(O)₂R^b10, NR^c10S(O)₂NR^c10R^d10, S(O)R^b10, S(O)NR^c10R^d10, S(O)₂R^b10, and S(O)₂NR^c10R^d10; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵²;

each R⁵²is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, 5-6 membered heteroaryl-C_1-3alkylene, halo, D, CN, OR^a11, SR^a11, C(O)R^b11, C(O)NR^c11R^d11, C(O)OR^a11, NR^c11R^d11, NR^c11C(O)R^b11, NR^c11C(O)OR^a11, NR^c11S(O)R^b11, NR^c11S(O)₂R^b11, NR^c11S(O)₂NR^c11R^d11, S(O)R^b11, S(O)NR^c11R^d11, S(O)₂R^b11, and S(O)₂NR^c11R^d11; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C₃-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^a, R^c, and R^dis independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁶;

each R^bis independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl, are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁶;

each R^a1is selected from methyl, ethyl, 2,2-difluoroethyl, isopropyl, 3-cyanocyclobutyl, benzyl, phenyl, methoxyethyl, dimethylaminoethyl, tetrahydrofuran-3-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, oxetan-3-yl, 2-oxopyrrolidin-3-yl, 1-methyl-2-oxopyrrolidin-3-yl, 1-acetylazetidin-3-yl, and tetrahydo-2H-pyran-4-yl;

each R^c1and R^d1is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene; wherein a ring-forming carbon atom of the 4-10 membered heterocycloalkyl or 4-10 membered heterocycloalkyl-C_1-3alkylene is optionally substituted by oxo to form a carbonyl group; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

or any R^c1and R^d1attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R¹⁰;

each R^b1is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹⁰;

each R^a2, R^c2and R^d2is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²1;

or any R^c2and R^d2attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R²¹;

each R^b2is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²¹;

each R^e2is independently selected from H, CN, C_1-6alkyl, C_1-6haloalkyl, Ci-s alkylthio, C_1-6alkylsulfonyl, C_1-6alkylcarbonyl, C_1-6alkylaminosulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, aminosulfonyl, C_1-6alkylaminosulfonyl and di(C_1-6alkyl)aminosulfonyl;

each R^a3, R^c3and R^d3is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C_1-6alkyl C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹;

or any R^c3and R^d3attached 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 R¹¹;

each R^b3is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl; wherein said C_1-6alkyl C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R¹¹;

each R^a4, R^c4and R^d4is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene; wherein said C_1-6alkyl C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²²;

or any R^c4and R^d4attached 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 R²²;

each R^b4is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene; wherein said C_1-6alkyl C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R²²;

each R^a5, R^c5and R^d5is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^b5is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^a6, R^c6and R^d6is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

or any R^c6and R^d6attached 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^b6is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^a8, R^c8and R^d8is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^a9, R^c9and R^d9is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵¹;

or any R^c9and R^d9attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R⁵¹;

each R^b9is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene; wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, 4-10 membered heterocycloalkyl, C_6-10aryl, 5-10 membered heteroaryl, C_3-10cycloalkyl-C_1-3alkylene, 4-10 membered heterocycloalkyl-C_1-3alkylene, C_6-10aryl-C_1-3alkylene, and 5-10 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵¹;

each R^e9is independently selected from H, CN, C_1-6alkyl, C_1-6haloalkyl, Ci-s alkylthio, C_1-6alkylsulfonyl, C_1-6alkylcarbonyl, C_1-6alkylaminosulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, aminosulfonyl, C_1-6alkylaminosulfonyl and di(C_1-6alkyl)aminosulfonyl;

each R^a10, R^c10and R^d10is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene; wherein said C_1-6alkyl C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵²;

or any R^c10and R^d10attached 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 R⁵²;

each R^b10is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene; wherein said C_1-6alkyl C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C_3-6cycloalkyl-C_1-3alkylene, 4-7 membered heterocycloalkyl-C_1-3alkylene, phenyl-C_1-3alkylene, and 5-6 membered heteroaryl-C_1-3alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R⁵²;

each R^a11, R^c11and R^d11is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

or any R^c11and R^d11attached 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^b11is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^a12, R^c12, and R^d12is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g;

each R^b12is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and C_1-6haloalkyl; wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl, are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^g; and

each R^gis independently selected from D, OH, NO₂, CN, halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, C_3-6cycloalkyl, C_3-6cycloalkyl-C_1-2alkylene, C_1-6alkoxy, C_1-6haloalkoxy, C_1-3alkoxy-C_1-3alkyl, C_1-3alkoxy-C_1-3alkoxy, HO—C_1-3alkoxy, HO—C_1-3alkyl, cyano-C_1-3alkyl, H₂N—C_1-3alkyl, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thio, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carbamyl, C_1-6alkylcarbamyl, di(C_1-6alkyl)carbamyl, carboxy, C_1-6alkylcarbonyl, C_1-6alkoxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkoxycarbonylamino, C_1-6alkylcarbonyloxy, aminocarbonyloxy, C_1-6alkylaminocarbonyloxy, di(C_1-6alkyl)aminocarbonyloxy, C_1-6alkylsulfonylamino, aminosulfonyl, C_1-6alkylaminosulfonyl, di(C_1-6alkyl)aminosulfonyl, aminosulfonylamino, C_1-6alkylaminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, aminocarbonylamino, C_1-6alkylaminocarbonylamino, and di(C_1-6alkyl)aminocarbonylamino;

provided that a compound of Formula I is other than

N-cyclopropyl-2-(difluoromethoxy)-6-methoxy-4-[7-(1-methyl-1H-pyrazol-4-yl)-6-(phenylmethoxy)imidazo[1,2-a]pyridin-3-yl]-benzamide.