Imidazopyridazine and imidazopyridine compounds as activin receptor-like kinase-2 inhibitors

Abstract

Compounds of Formula (I), methods of inhibiting ALK2 activity using the compounds, and pharmaceutical compositions comprising such compounds are disclosed. The compounds are useful for treating, preventing or ameliorating diseases or conditions associated with ALK2 activity, such as cancer. # imgabs0 #

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980092367.1 (filing date: December 19, 2019; invention title: Imidazopyridazine and imidazopyridine compounds as inhibitors of activin receptor-like kinase-2). Technical Field

[0002] The present disclosure provides compounds, their compositions, and methods of use. The compounds modulate activin receptor-like kinase-2 (ALK2) activity and can be used to treat various diseases, including cancer. Background of the Invention

[0004] Bone morphogenetic protein (BMP) signaling belongs to the transforming growth factor-β (TGF-β) superfamily and TGF-β signaling ligands include more than 25 different ligands: TGF-β growth and differentiation factors, BMPs, and activins. Binding of BMP ligands causes assembly of a tetrameric receptor complex consisting of two constitutively active type II receptor serine / threonine kinases (BMPRII, ACTRIIA, or ACTRIIB), and activates two type I receptor serine / threonine kinases (ALK1, ALK2, ALK3, or ALK6). In addition, the activated type I receptor phosphorylates BMP receptor-responsive SMAD proteins 1 / 5 / 8 and the activated SMAD1 / 5 / 8 associated with co-SMAD4 translocates to the nucleus to regulate gene transcription. (Ross, S.L. et al., Cell Metabolism 2012, 15, 905-917; Blobe, G.C. et al., New England Journal of Medicine 2000, 342, 1350-1358).

[0005] Type I BMPR kinase activin A receptor (ACVR1), also known as activin receptor-like kinase-2 (ALK2), consists of a ligand-binding extracellular domain and a cytoplasmic domain and is serine / threonine specific. ALK2 has been reported to mediate a variety of human diseases (Massague, J. et al., Cell 2000, 103, 295-309; Taylor, K.R. et al., Cancer Research 2014, 74, 4565-4570). ALK2 and ALK3 have been shown to play essential roles in regulating hepcidin levels and influencing anemia of chronic disease (Andriopoulos, B. et al., Nature Genetics 2009 41, 482-487; Steinbicker, A.U. et al., Blood 2011, 118, 4224-4230; Steinbicker, A.U. et al., Blood 2011, 117, 4915-4923). Hepcidin is a small peptide hormone mainly synthesized in hepatocytes and reduces duodenal iron absorption and iron export from monocytes / macrophages by binding to the iron exporter ferroportin (FPN1) and inducing its internalization and degradation (Theurl, I. et al., Haematologica 2011, 96, 1761-1769; Zhao, N. et al., Journal of Clinical Investigation 2013, 123, 2337-2343). Elevated serum hepcidin levels enhance iron storage within the reticuloendothelial system and cause reduced iron utilization and iron-restricted erythropoiesis. Aberrant increases in hepcidin expression cause severe functional iron deficiency anemia in humans and are critical to the pathophysiology of anemia of chronic disease (ACD) (Weiss, G. et al., New England Journal of Medicine 2005, 352, 1011-1023). Accordingly, there is a need for novel compounds that modulate ALK2 activity. SUMMARY OF THE INVENTION

[0006] The present disclosure particularly provides a compound of Formula I:

[0007]

[0008] or a pharmaceutically acceptable salt thereof, wherein the component variables are as defined herein.

[0009] The present disclosure further provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0010] The present disclosure further provides a method for inhibiting ALK2 activity, the method comprising administering to a patient a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0011] The present disclosure further provides a method for treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0012] The present disclosure further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use in any of the methods described herein. Detailed Description

[0013] Compound

[0014] The present disclosure provides a compound of formula I:

[0015]

[0016] or a pharmaceutically acceptable salt thereof, wherein:

[0017] R 1 is selected from Cy 1 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halo, CN, NO2, 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(=NOR a )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)2R b , NR c S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)2NR c R d ; 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 10 ;

[0018] Cy 1 is selected from C 3-14 cycloalkyl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said 4- to 14-membered heterocycloalkyl and 5- to 10-membered heteroaryl each have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein said N and S are optionally oxidized; wherein the ring-forming carbon atoms of the 5- to 10-membered heteroaryl and 4- to 14-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; and wherein said C 3-14 cycloalkyl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0019] R 2 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said 5- to 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 said N and S are optionally oxidized; wherein the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 20 ;

[0020] or two adjacent R 2 substituents on R 20 together with the atom to which they are attached form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused C 3-7Cycloalkyl ring; wherein each fused 4-, 5-, 6- or 7-membered heteroalkyl 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 the ring-forming carbon atoms of each fused 4-, 5-, 6- or 7-membered heteroalkyl ring are optionally substituted by oxo groups to form carbonyl groups; and wherein the fused 4-, 5-, 6- or 7-membered heteroalkyl rings and fused C 3-7 cycloalkyl rings are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 21 .

[0021] R 3 is selected from H, D, halo, CN, C 1-6 alkyl, OR a7 and NR c7 R d7 ; wherein the C 1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from R g .

[0022] R 4 is selected from H, D, halo, CN, C 1-6 alkyl, OR a8 and NR c8 R d8 ; wherein the C 1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from R g .

[0023] R 5 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted by oxo groups to form carbonyl groups; and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 50 .

[0024] Or two adjacent R 5 substituents on R 50 together with the atoms to which they are attached form a fused 4-, 5-, 6- or 7-membered heteroalkyl ring, or a fused C 3-7A cycloalkyl ring; wherein each of the fused 4-, 5-, 6- or 7-membered heterocycloalkyl rings 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 ring-forming carbon atoms of each of the fused 4-, 5-, 6- or 7-membered heterocycloalkyl rings are optionally substituted with oxo groups to form carbonyl groups; and wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl rings and the fused C 3-7 cycloalkyl rings are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0025] A is N or CR A ;

[0026] R A is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halo, CN, NO2, OR a12 , SR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)OR a12 , OC(O)R b12 , OC(O)NR c12 R d12 , NR c12 R d12 , NR c12 C(O)R b12 , NR c12 C(O)OR a12 , NR c12 C(O)NR c12 R d12 , NR c12 S(O)R b12 , NR c12 S(O)2R b12 , NR c12 S(O)2NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O)2R b12 and S(O)2NR c12 R d12 ; wherein the 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 ;

[0027] 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 heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5-10 membered heteroaryl-C 1-3 alkylene, halo, D, CN, NO2, 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)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NRc1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-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 ;

[0028] Or two R 10 substituents together with the carbon atom to which they are attached form a spiro 4-7 membered heteroalkyl ring, or a spiro C 3-6 cycloalkyl ring; wherein each spiro 4-7 membered heteroalkyl ring has at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms independently selected from N, O and S; wherein each ring-forming carbon atom of the spiro 4-7 membered heteroalkyl ring is optionally substituted with an oxo group to form a carbonyl group; and wherein said spiro 4-7 membered heteroalkyl ring and spiro C 3-6 cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0029] 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 heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-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 , NRc3 C(O)R b3 、NR c3 C(O)OR a3 、NR c3 S(O)R b3 、NR c3 S(O)2R b3 、NR c3 S(O)2NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 and S(O)2NR c3 R d3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-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 ;

[0030] 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 heteroalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4-7 membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5-10 membered heteroaryl-C 1-3 alkylene, 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)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR 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, 4-7 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4-7 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 g ;

[0031] Each R 20 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 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, NO2, 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(=NOR a2 )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)2R b2 , NR c2 , S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0032] Each R 21 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , 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)2R b4 , NR c4 , S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 and S(O)2NR c4 R d4 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0033] Each R 22 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- or 6-membered heteroaryl-C 1-3 Alkylene, halogen, 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)2R b6 , NR c6 S(O)2NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 and S(O)2NR c6 R d6 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0034] Each R 50 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-10Cycloalkyl, 4-10 membered heteroalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene, 5-10 membered heteroaryl-C 1-3 Alkylene, halo, D, CN, NO2, OR a9 , SR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , OC(O)R b9 , OC(O)NR c9 R d9 , NR c9 R d9 , NR c9 C(O)R b9 , NR c9 C(O)OR a9 , NR c9 C(O)NR c9 R d9 , C(=NR e9 )R b9 , C(=NOR a9 )R b9 , C(=NR e9 )NR c9 R d9 , NR c9 C(=NR e9 )NR c9 R d9 , NR c9 S(O)R b9 , NR c9 S(O)2R b9 , NR c9 S(O)2NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heteroalkyl, C 6-10Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 The alkylene, 4- to 10-membered heterocycloalkyl-C alkylene, aryl-C alkylene and 5- to 10-membered heteroaryl-C alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0035] Each R 51 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a10 , SR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , NR c10 R d10 , NR c10 C(O)R b10 , NR c10 C(O)OR a10 , NR c10 , S(O)R b10 , NR c10 , S(O)2R b10 , NR c10 , S(O)2NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O)2R b10 and S(O)2NR c10 R d10 ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 The alkylene, alkylene, cycloalkyl-C alkylene, 4- to 7-membered heterocycloalkyl-C alkylene, aryl-C alkylene, 5- to 6-membered heteroaryl-C alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ;

[0036] Each R 52 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5- to 6-membered heteroaryl-C 1-3 Alkylene, halogen, D, CN, OR a11 , SR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 S(O)R b11 , NR c11 S(O)2R b11 , NR c11 , NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O)2R b11 And S(O)2NR c11 R d11 ; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6Cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- to 6-membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0037] Each R a , R c and R d 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0038] or any R c and R d attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0039] Each R b is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Each alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0040] Each R e 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl;

[0041] 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- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C1-3 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, 4-10 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 Each alkylene is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0042] Or any R c1 and R d1 together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0043] Each R b1 is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, 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; 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 Each alkylene is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R11 is substituted with a substituent;

[0044] 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl;

[0045] 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- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0046] Or any R c2 and R d2 that are attached to the same N atom together with the N atom to which they are attached form an optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21a 4- to 10-membered heterocycloalkyl group substituted with substituents;

[0047] 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0048] Each R e2 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl;

[0049] 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 1-6Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3 Each alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 12 ;

[0050] Or any R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R 12 ;

[0051] Each R b3 is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3Each alkylene group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 12 ;

[0052] 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0053] 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 optionally substituted with 1, 2 or 3 substituents independently selected from R 22 ;

[0054] 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0055] 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 is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0056] 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 optionally substituted with 1, 2 or 3 substituents independently selected from R g ;

[0057] 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 is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0058] 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 and C 1-6 haloalkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl and C2-6 Each alkynyl group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;

[0059] or any R attached to the same N atom c6 and R d6 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from R g ;

[0060] Each R b6 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; wherein the 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 ;

[0061] Each R a7 , R c7 , and R d7 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; wherein the 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 ;

[0062] Each R a8 , R c8 , and R d8 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; wherein the 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 ;

[0063] Each R a9 , R c9 , and R d9 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4 - 10 membered heteroalkyl, C 6-10 aryl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 membered heteroalkyl - C 1-3 alkylene, C 6-10 aryl - C 1-3 alkylene and 5 - 10 membered heteroaryl - C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4 - 10 membered heteroalkyl, C 6-10 aryl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 membered heteroalkyl - C 1-3 alkylene, C 6-10 aryl - C 1-3 alkylene and 5 - 10 membered heteroaryl - C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0064] or any R c9 and R d9 attached to the same N atom together with the N atom to which they are attached form a 4 - 10 membered heteroalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0065] each R b9 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 heteroalkyl, C 6-10 aryl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 membered heteroalkyl - C 1-3 alkylene, C 6-10 aryl - C 1-3 alkylene and 5 - 10 membered heteroaryl - C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4 - 10 membered heteroalkyl, C6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 The alkylene, 4- to 10-membered heterocycloalkyl-C alkylene, aryl-C alkylene, 5- to 10-membered heteroaryl-C alkylene, and C alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0066] Each R e9 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl;

[0067] Each R a10 , R c10 , and R d10 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, and 5- to 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, and 5- to 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 ;

[0068] or any R attached to the same N atom c10 and R d10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R 52 ;

[0069] Each R b10 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ;

[0070] Each R a11 , R c11 and R d11 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; wherein the 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 ;

[0071] or any R attached to the same N atom c11 and R d11 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R ga 4-, 5-, 6- or 7-membered heterocycloalkyl substituted with substituents;

[0072] Each R b11 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 ;

[0073] Each R a12 , R c12 and R d12 are 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0074] Or any R c12 and R d12 connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0075] Each Rb12 independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ; and

[0076] each R g is independently selected from OH, NO2, CN, halogen, 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, H2N-C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thio, C 1-6 alkylthio, C 1-6Alkylsulfinyl, C 1-6 Alkylsulfonyl, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, carboxyl, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, sulfamoyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, sulfamoylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino and di(C 1-6 alkyl)aminocarbonylamino;

[0077] Provided that:

[0078] 1) When Cy 1 is C 6-10 aryl, then R 10 is not a substituted cyclobutyl; and

[0079] 2) The compound of formula I is not 3-(2-benzofuranyl)-6-chloro-7-phenyl-imidazo[1,2-b]pyridazine and 3-(2-benzofuranyl)-6-[3-(methylsulfonyl)propoxy]-7-phenyl-imidazo[1,2-b]pyridazine.

[0080] In some embodiments, the compound of formula I is a compound wherein:

[0081] R 1 is selected from Cy 1 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, 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 cC(O)OR a NR c C(O)NR c R d 、C(=NR e )R b 、C(=NOR a )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)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d wherein said C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by 1, 2, 3 or 4 independently selected from R 10 Substituents are substituted;

[0082] Cy 1 Selected from C 3-14 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 wherein the 4-14 membered heterocycloalkyl and the 5-10 membered heteroaryl each have 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 the ring-forming carbon atoms of the 5-10 membered heteroaryl and the 4-14 membered heterocycloalkyl are optionally substituted with oxo to form a carbonyl; and wherein the C 3-14 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 10 Substituents are substituted;

[0083] R 2 Selected from C 6-10Aryl and 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the C 6-10 Aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 20 ;

[0084] or two adjacent R 2 substituents on R 20 together with the atom to which they are attached form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring, or a fused C 3-7 cycloalkyl ring; wherein each of the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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 ring-forming carbon atoms of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring are optionally substituted with oxo groups to form carbonyl groups; and wherein each of the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings and the fused C 3-7 cycloalkyl rings are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0085] R 3 is selected from H, D, halo, CN, C 1-6 alkyl, OR a7 and NR c7 R d7 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R g ;

[0086] R 4 is selected from H, D, halo, CN, C 1-6 alkyl, OR a8 and NR c8 R d8 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R g ;

[0087] R 5 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the C6-10 An aryl and a 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 50 ;

[0088] or two adjacent R 5 substituents on R 50 together with the atoms to which they are attached form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring, or a fused C 3-7 cycloalkyl ring; wherein each of the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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 each ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring is optionally substituted with an oxo group to form a carbonyl; and wherein each of the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings and the fused C 3-7 cycloalkyl ring is each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0089] A is N or CR A ;

[0090] R A is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halo, CN, NO2, OR a12 , SR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)OR a12 , OC(O)R b12 , OC(O)NR c12 R d12 , NR c12 R d12 , NR c12 C(O)R b12 , NR c12 C(O)OR a12 , NR c12 C(O)NR c12 R d12 , NR c12 S(O)R b12 , NR c12 S(O)2R b12 , NR c12 S(O)2NR c12 R d12 , S(O)R b12 , S(O)NRc12 R d12 、S(O)2R b12 and S(O)2NR c12 R d12 wherein said C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by 1, 2, 3 or 4 independently selected from R g Substituents are substituted;

[0091] Each R 10 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 5-10 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, halogen, D, CN, NO2, 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)Rb1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4 - 10 - membered heteroalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 - membered heteroalkyl - 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 ;

[0092] or two R 10 substituents together with the carbon atom to which they are attached form a spiro 4 - 7 - membered heteroalkyl ring, or a spiro C 3-6 cycloalkyl ring; wherein each spiro 4 - 7 - membered heteroalkyl ring has at least one ring - forming carbon atom and 1, 2 or 3 ring - forming heteroatoms independently selected from N, O and S; wherein each ring - forming carbon atom of each spiro 4 - 7 - membered heteroalkyl ring is optionally substituted with an oxo group to form a carbonyl group; and wherein said spiro 4 - 7 - membered heteroalkyl ring and spiro C 3-6 cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0093] 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 heteroalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 - membered heteroalkyl - C 1-3 alkylene, C 6-10 aryl - C 1-3 alkylene, 5 - 10 - membered heteroaryl - C1-3 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)2R b3 , NR c3 , S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 12 ;

[0094] 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- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3Alkylene, 5- to 10-membered heteroaryl-C 1-3 Alkylene, 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)2R b5 , NR c5 , S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR 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- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0095] Each R 20 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halo, D, CN, NO2, 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(=NOR a2 )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)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Each alkylene is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0096] Each R 21 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halogen, D, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , 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)2R b4 , NR c4 S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 and S(O)2NR c4 R d4 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C6-10 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 22 ;

[0097] Each R 22 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, C 3-6 cycloalkyl-C 1-3 alkylene, 4-7 membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, 5-6 membered heteroaryl-C 1-3 alkylene, 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)2R b6 , NR c6 S(O)2NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 and S(O)2NR c6 R d6 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4-7 membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5-6 membered heteroaryl-C 1-3Each alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0098] each R 50 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halo, D, CN, NO2, OR a9 , SR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , OC(O)R b9 , OC(O)NR c9 R d9 , NR c9 R d9 , NR c9 C(O)R b9 , NR c9 C(O)OR a9 , NR c9 C(O)NR c9 R d9 , C(=NR e9 )R b9 , C(=NOR a9 )R b9 , C(=NR e9 )NR c9 R d9 , NR c9 C(=NR e9 )NR c9 R d9 , NR c9 S(O)R b9 , NR c9 S(O)2R b9 , NR c9 S(O)2NR c9 R d9 , S(O)R b9 , S(O)NR c9 Rd9 , S(O)2R b9 and S(O)2NR c9 R d9 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4 - 10 - membered heteroalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 - membered heteroalkyl - 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 by 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0099] Each R 51 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 heteroalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 - membered heteroalkyl - C 1-3 alkylene, C 6-10 aryl - C 1-3 alkylene, 5 - 10 - membered heteroaryl - C 1-3 alkylene, halo, D, CN, OR a10 , SR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , NR c10 R d10 , NR c10 C(O)R b10 , NR c10 C(O)OR a10 , NR c10 S(O)R b10 , NR c10 S(O)2R b10 , NR c10 S(O)2NR c10 R d10 , S(O)R b10 , S(O)NRc10 R d10 、S(O)2R b10 and S(O)2NR c10 R d10 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 Each alkylene group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 52 Substituents are substituted;

[0100] Each R 52 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, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4-7 membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, halogen, D, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 S(O)R b11 NR c11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11, S(O)2R b11 and S(O)2NR c11 R d11 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4-7 membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5-6 membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0101] Each R a , R c and R d are 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, 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; 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 10 ;

[0102] or any R c and R d attached to the same N atom together with the N atom to which they are attached form an optionally substituted with 1, 2, 3 or 4 substituents independently selected from R10 a 4- to 10-membered heterocycloalkyl group substituted with substituents;

[0103] Each R b 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0104] Each R e 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl;

[0105] 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, C1-6 haloalkyl, C 3-10 cycloalkyl, 4 - 10 - membered heteroalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 - membered heteroalkyl - 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 - 10 - membered heteroalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 - membered heteroalkyl - C 1-3 alkylene, C 6-10 aryl - C 1-3 alkylene and 5 - 10 - membered heteroaryl - C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0106] 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 - 10 - membered heteroalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0107] 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 heteroalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-3 alkylene, 4 - 10 - membered heteroalkyl - 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 - 10 - membered heteroalkyl, C 6-10Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0108] 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, Carbamoyl, C 1-6 Alkylcarbamoyl, Di(C 1-6 Alkyl)carbamoyl, Aminosulfonyl, C 1-6 Alkylaminosulfonyl and Di(C 1-6 Alkyl)aminosulfonyl;

[0109] 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- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C1-3 Each alkylene is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0110] or any R attached to the same N atom c2 and R d2 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0111] 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0112] Each R e2 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6Alkylaminosulfonyl and bis(C 1-6 alkyl)aminosulfonyl;

[0113] 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 12 ;

[0114] or any R c3 and R d3 connected to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R 12 ;

[0115] 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ;

[0116] 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 22 ;

[0117] 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 optionally substituted with 1, 2, or 3 substituents independently selected from R 22 ;

[0118] Each R b4 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3 Alkylene; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0119] 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 is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0120] Or any R c5 and R d5 connected to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R g ;

[0121] 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 is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0122] Each R a6 、R c6 and R d6 are 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 ;

[0123] 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 optionally substituted with 1, 2 or 3 substituents independently selected from R g ;

[0124] Each R b6 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 ;

[0125] Each R a7 、R c7 and R d7 are 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 ;

[0126] Each R a8 、R c8 and R d8 are 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 2-6An alkenyl and a C 2-6 alkynyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0127] 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, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0128] Or any R c9 and R d9 connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heteroalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0129] Each R b9 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- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3Alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Each alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0130] Each R e9 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl;

[0131] Each R a10 , R c10 and R d10 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- to 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3 The alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ;

[0132] Or any R c10 and R d10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R 52 ;

[0133] Each R b10 is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenoalkyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- or 6-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ;

[0134] Each R a11 , R c11 and R d11 is independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Halogenoalkyl; wherein the C 1-6 Alkyl, C2-6 The alkenyl and C 2-6 alkynyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0135] Or any R c11 and R d11 connected to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R g ;

[0136] Each R b11 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; wherein the 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 ;

[0137] Each R a12 , R c12 and R d12 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from Rg is substituted with a substituent;

[0138] or any R attached to the same N atom c12 and R d12 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;

[0139] Each R b12 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ; and

[0140] Each R g is independently selected from OH, NO2, 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-C1-3 Alkoxy, HO-C 1-3 Alkoxy, HO-C 1-3 Alkyl, cyano-C 1-3 Alkyl, H2N-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, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, sulfamoyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, sulfamoylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino and di(C 1-6 alkyl)aminocarbonylamino.

[0141] In some embodiments, the compound of formula I is a compound wherein:

[0142] R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, C(O)R b , C(O)NR c R d , C(O)OR a , C(=NR e )R b , C(=NOR a )R b and C(=NR e )NR c R d , 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 10 ;

[0143] R 2Selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said 5- to 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 said N and S are optionally oxidized; wherein the ring-forming carbon atoms of said 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 20 ;

[0144] or R 2 two adjacent R 20 substituents on together with the atoms to which they are attached form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused C 3-7 cycloalkyl ring; wherein said fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring each 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 ring-forming carbon atoms of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring are optionally substituted with oxo groups to form carbonyl groups; and wherein said fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused C 3-7 cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0145] R 3 is selected from H, D, halo, CN, C 1-6 alkyl, OR a7 and NR c7 R d7 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from R g ;

[0146] R 4 is selected from H, D, halo, CN, C 1-6 alkyl, OR a8 and NR c8 R d8 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2 or 3 substituents independently selected from R g ;

[0147] R 5 is selected from C 6-10Aryl and 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyls; and wherein the C 6-10 Aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 50 ;

[0148] or R 5 Two adjacent R on 50 substituents together with the atoms to which they are attached form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring, or a fused C 3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring each 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 ring-forming carbon atoms of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring are optionally substituted with oxo groups to form carbonyls; and wherein the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3-7 cycloalkyl ring are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0149] A is N or CR A ;

[0150] R A is selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halo, CN, NO2, OR a12 , SR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)OR a12 , OC(O)R b12 , OC(O)NR c12 R d12 , NR c12 R d12 , NR c12 , C(O)R b12 , NR c12 , C(O)OR a12 , NR c12 , C(O)NR c12 R d12 , NR c12 , S(O)R b12, NR c12 S(O)2R b12 , NR c12 S(O)2NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O)2R b12 and S(O)2NR c12 R d12 ; 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 ;

[0151] Each R 10 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 4-10 membered heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5-10 membered heteroaryl-C 1-3 alkylene, halo, D, CN, NO2, 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 )NRc1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 and S(O)2NR 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 Each alkylene group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 11 Substituents are substituted;

[0152] or two R 10 The substituents together with the carbon atoms to which they are attached form a spiro 4-7 membered heterocycloalkyl ring, or a spiro C 3-6 Cycloalkyl ring; wherein each spiro 4-7 membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of each spiro 4-7 membered heterocycloalkyl ring are optionally substituted with oxo to form a carbonyl group; and wherein the spiro 4-7 membered heterocycloalkyl ring and the spiro C 3-6 Each cycloalkyl ring is optionally substituted by 1, 2, 3 or 4 independently selected R 11 Substituents are substituted;

[0153] Each R 11 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, C3-10 Cycloalkyl-C 1-3 Alkylene, 4-10 membered heteroalkyl-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)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5-10 membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 12 ;

[0154] 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 6-10Aryl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene, 5- to 10-membered heteroaryl-C 1-3 Alkylene, halogen, 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)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR 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- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0155] Each R 20 Is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene, 5- to 10-membered heteroaryl-C 1-3 Alkylene, halo, D, CN, NO2, 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(=NOR a2 )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)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein the ring-forming carbon atoms of the 4- to 10-membered heteroalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Each alkylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0156] Each R 21 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- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene, 5- to 10-membered heteroaryl-C 1-3 Alkylene, halogen, D, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , 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)2R b4 , NR c4 S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 and S(O)2NR c4 R d4 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Each alkylene is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 22 ;

[0157] Each R 22 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- to 6-membered heteroaryl, 4- to 7-membered heteroalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heteroalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, 5- to 6-membered heteroaryl-C 1-3 alkylene, 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)2R b6 , NR c6 S(O)2NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 and S(O)2NR c6 R d6 ; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 The alkylene groups are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R g ;

[0158] Each R 50 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halogen, D, CN, NO2, OR a9 , SR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , OC(O)R b9 , OC(O)NR c9 R d9 , NR c9 R d9 , NR c9 C(O)R b9 , NR c9 C(O)OR a9 , NR c9 C(O)NR c9 R d9 , C(=NR e9 )R b9 , C(=NOR a9 )R b9 , C(=NR e9 )NR c9 R d9 , NR c9 C(=NR e9 )NR c9 R d9 , NR c9 S(O)Rb9 , NR c9 S(O)2R b9 , NR c9 S(O)2NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 ; 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 51 ;

[0159] Each R 51 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, halogen, D, CN, OR a10 , SR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , NR c10 R d10 , NR c10 , C(O)R b10 , NR c10 , C(O)OR a10 , NR c10S(O)R b10 NR c10 S(O)2R b10 NR c10 S(O)2NR c10 R d10 、S(O)R b10 、S(O)NR c10 R d10 、S(O)2R b10 and S(O)2NR c10 R d10 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 Each alkylene group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R 52 Substituents are substituted;

[0160] Each R 52 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, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4-7 membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene, 5-6 membered heteroaryl-C 1-3 Alkylene, halogen, D, CN, OR a11 , SR a11 、C(O)R b11 、C(O)NR c11 R d11 、C(O)OR a11 NR c11 R d11 NR c11 C(O)R b11 NR c11 C(O)OR a11 NR c11 S(O)R b11 NRc11 S(O)2R b11 NR c11 S(O)2NR c11 R d11 、S(O)R b11 、S(O)NR c11 R d11 、S(O)2R b11 and S(O)2NR c11 R d11 wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4-7 membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5-6 membered heteroaryl-C 1-3 Each alkylene group is optionally substituted by 1, 2, 3 or 4 groups independently selected from R g Substituents are substituted;

[0161] Each R a , R c and R d 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, 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; wherein the 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 1-3Each alkylene group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0162] or any R attached to the same N atom c and R d together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0163] Each R b 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0164] Each R e 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C1-6 alkyl)sulfamoyl;

[0165] 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0166] 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- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0167] 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10Aryl-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, 4-10 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 is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0168] 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl;

[0169] 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, 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; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Each alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0170] Or any R c2 and R d2 together with the N atom to which they are attached form a 4- to 10-membered heteroalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0171] Each R b2 is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Each alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0172] Each R e2 is independently selected from H, CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkylcarbonyl, C 1-6 alkylaminosulfonyl, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl;

[0173] 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 12 ;

[0174] Or any R c3 and R d3 connected to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R 12 ;

[0175] Each R b3 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 12 ;

[0176] 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 Halogenated alkyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0177] or any R c4 and R d4Together with the N atoms to which they are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R 22 ;

[0178] 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0179] 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 ;

[0180] 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 optionally substituted with 1, 2 or 3 substituents independently selected from R g ;

[0181] Each R b5 is independently selected from C1-6 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 ;

[0182] 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 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 ;

[0183] 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 optionally substituted with 1, 2 or 3 substituents independently selected from R g ;

[0184] Each R b6 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 ;

[0185] 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 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 ;

[0186] 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 ;

[0187] 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, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0188] Or any R c9 and R d9 that are attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heteroalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0189] Each R b9 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0190] Each R e9 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl;

[0191] Each R a10 , R c10 and R d10 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ;

[0192] Or any R c10 and R d10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R 52 ;

[0193] Each R b10 is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenoalkyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 Alkylene, phenyl-C 1-3 Alkylene and 5- to 6-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R52 is substituted with a substituent;

[0194] Each R a11 and R c11 and R d11 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 ;

[0195] or any R c11 and R d11 connected to the same N atom together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl optionally substituted with 1, 2, or 3 substituents independently selected from R g ;

[0196] Each R b11 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 ;

[0197] Each R a12 and R c12 and R d12 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;

[0198] Or any R c12 and R d12 together with the N atom to which they are attached form a 4- to 10-membered heteroalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ;

[0199] Each R b12 is independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Alkylene; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-3 Alkylene, 4- to 10-membered heteroalkyl-C 1-3 Alkylene, C 6-10 Aryl-C 1-3 Alkylene and 5- to 10-membered heteroaryl-C 1-3 Alkylene is each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g ; and

[0200] Each R g is independently selected from OH, NO2, CN, halogen, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-C 1-2 Alkylene, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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, H2N-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, carbamoyl, C 1-6 Alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, sulfamoyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, sulfamoylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino and di(C 1-6 alkyl)aminocarbonylamino.

[0201] In some embodiments, R 1 is selected from Cy 1 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, CN, NO2, 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 , NRc 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)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2R b and S(O)2NR c R d wherein said C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by 1, 2, 3 or 4 independently selected from R 10 substituted by a substituent.

[0202] In some embodiments, R 1 Selected from Cy 1 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, CN, 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 and NR c C(O)OR a wherein said C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by 1, 2, 3 or 4 independently selected from R 10 substituted by a substituent.

[0203] In some embodiments, R1 Selected from Cy 1 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , NR c R d and NR c C(O)R b ; 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 10 .

[0204] In some embodiments, R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, C(O)R b , C(O)NR c R d , C(O)OR a , C(=NR e )R b , C(=NOR a )R b and C(=NR e )NR c R d , 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 10 .

[0205] In some embodiments, R 1 is selected from Cy 1 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, OR a , C(O)R b , C(O)NR c R d and C(O)ORa ; 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 10 .

[0206] In some embodiments, R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, C(O)R b , C(O)NR c R d , and C(O)OR a ; 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 10 .

[0207] In some embodiments, R 1 is selected from C 1-6 alkyl, CN, C(O)NR c R d , C(O)R b , and C(O)OR a ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .

[0208] In some embodiments, R 1 is selected from C 1-6 alkyl, CN, C(O)NR c R d , and C(O)OR a ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .

[0209] In some embodiments, R 1 is C 1-6 alkyl. In some embodiments, R 1 is methyl.

[0210] In some embodiments, R 1 is C(O)OR a .

[0211] In some embodiments, R 1 is C(O)Rb .

[0212] In some embodiments, R 1 is C(O)NR c R d .

[0213] In some embodiments, R 1 is selected from methyl, methoxycarbonyl, carbamoyl, cyano, hydroxymethyl, methoxymethyl, N-(4-hydroxy-4-methylcyclohexyl)carbamoyl (e.g., N-((1R,4R)-(4-hydroxy-4-methylcyclohexyl)carbamoyl), and 4-ethoxycarbonyl-piperazin-1-ylcarbonyl.

[0214] In some embodiments, each R 10 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, halo, D, CN, NO2, 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 , NR c1 S(O)R b1 , NR c1 , S(O)2R b1 , NR c1 , NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 ; wherein the C 1-6 alkyl, C2-6 Alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4 - 10 - membered hetero cycloalkyl, 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 .

[0215] In some embodiments, each R 10 is 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 hetero cycloalkyl, C 6-10 aryl, 5 - 10 - membered heteroaryl, halo, D, CN, OR a1 , C(O)OR a1 , NR c1 R d1 and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4 - 10 - membered hetero cycloalkyl, C 6-10 aryl, and 5 - 10 - membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R 11 .

[0216] In some embodiments, each R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 .

[0217] In some embodiments, each R 10 is selected from C 1-6 alkyl, OR a1 and C(O)OR a1 ; wherein said C 1-6The alkyl group is optionally substituted by 1 or 2 substituents independently selected from R 11 .

[0218] In some embodiments, each R 10 is C 1-6 alkyl; wherein the C 1-6 alkyl is optionally substituted by 1 or 2 substituents independently selected from R 11 .

[0219] In some embodiments, each R 10 is selected from C(O)R b1 and C(O)OR a1 . In some embodiments, each R 10 is OR a1 . In some embodiments, each R 10 is C(O)OR a1 .

[0220] In some embodiments, each R 10 is selected from methyl, OH, methoxy and ethoxycarbonyl.

[0221] In some embodiments, two R 10 substituents together with the carbon atom to which they are attached form a spiro 4-7-membered heterocycloalkyl ring; wherein each spiro 4-7-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of each spiro 4-7-membered heterocycloalkyl ring are optionally substituted by oxo groups to form carbonyl groups; and wherein the spiro 4-7-membered heterocycloalkyl ring is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 11 .

[0222] In some embodiments, two R 10 substituents together with the carbon atom to which they are attached form a spiro C 3-6 cycloalkyl ring; wherein the spiro C 3-6 cycloalkyl ring is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 11 .

[0223] In some embodiments, 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, halo, D, CN, OR a3 , SR a3 , C(O)Rb3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 and NR c3 C(O)R b3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4 - 10 membered heteroalkyl, C 6-10 aryl and 5 - 10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R 12 .

[0224] In some embodiments, each R 11 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a3 and NR c3 R d3 ; wherein said C 1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from R 12 .

[0225] In some embodiments, each R 11 is independently selected from C 1-6 alkyl,

[0226] In some embodiments, R 1 is Cy 1 .

[0227] In some embodiments, Cy 1 is a C 15 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 3-14 .

[0228] In some embodiments, Cy 1 is a 4 - 14 membered heteroalkyl having at least one ring - forming carbon atom and 1, 2, 3 or 4 ring - forming heteroatoms independently selected from N, O and S; wherein said N and S are optionally oxidized; wherein the ring - forming carbon atoms of the 4 - 14 membered heteroalkyl are optionally substituted with oxo groups to form carbonyl groups; and wherein said 4 - 14 membered heteroalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 15 .

[0229] In some embodiments, Cy 1 is a C 15substituted C 6-10 aryl.

[0230] In some embodiments, Cy 1 is a 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .

[0231] In some embodiments, R 2 is a C 20 aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 6-10 aryl.

[0232] In some embodiments, R 2 is a 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 20 .

[0233] In some embodiments, R 2 is selected from phenyl and 5- to 6-membered heteroaryl; wherein the 5- to 6-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 the ring-forming carbon atoms of the 5- to 6-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the phenyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 20 .

[0234] In some embodiments, R 2 is a 5- to 6-membered heteroaryl; wherein the 5- to 6-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 the ring-forming carbon atoms of the 5- to 6-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the 5- to 6-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 20 .

[0235] In some embodiments, R2 is phenyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 20 groups.

[0236] In some embodiments, R 2 is phenyl optionally substituted with 1 or 2 substituents independently selected from R 20 groups.

[0237] In some embodiments, R 2 is phenyl substituted at the para position with R 20 group.

[0238] In some embodiments, R 2 is phenyl substituted at the meta position with R 20 group.

[0239] In some embodiments, R 2 is phenyl substituted at the ortho position with R 20 group.

[0240] In some embodiments, R 2 is pyrazole optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 20 groups.

[0241] In some embodiments, R 2 is pyrazole optionally substituted with 1 or 2 substituents independently selected from R 20 groups.

[0242] In some embodiments, R 2 is selected from phenyl and pyrazolyl; wherein the phenyl and pyrazolyl are each optionally substituted with 1 or 2 substituents independently selected from R 20 groups.

[0243] In some embodiments, each R 20 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, D, CN,, OR a2 group, SR a2 group, C(O)R b2 group, C(O)NR c2 R d2 group, C(O)OR a2 group, OC(O)R b2 group, OC(O)NR c2 R d2 group, NRc2 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)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR 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 by 1, 2, 3 or 4 independently selected R 21 substituted by a substituent.

[0244] In some embodiments, each R 20 Independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, D, CN, OR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; wherein the ring carbon atoms of the 4-10 membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 21 substituted by a substituent.

[0245] In some embodiments, each R 20 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, halo, NR c2 R d2 and C(O)NR c2 R d2 , wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 3-10 cycloalkyl and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 .

[0246] In some embodiments, each R 20 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R21 is substituted with a substituent.

[0247] In some embodiments, each R 20 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, halo, NR c2 R d2 and C(O)NR c2 R d2 , wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 .

[0248] In some embodiments, each R 20 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 6-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, 5- to 6-membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein the ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 6-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, and 5- to 6-membered heteroaryl-C 1-3Each alkylene is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 .

[0249] In some embodiments, each R 20 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl-C 1-3 alkylene, halo, NR c2 R d2 and C(O)NR c2 R d2 , where the ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; where the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 .

[0250] In some embodiments, R 20 is C 21 alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 1-6 .

[0251] In some embodiments, R 20 is C 21 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 3-10 .

[0252] In some embodiments, R 20 is C 21 cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 3-6 .

[0253] In some embodiments, R 20 is 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 , and where the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups.

[0254] In some embodiments, R 20 is 4- to 6-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 , and where the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups.

[0255] In some embodiments, R 20 is a 4- to 10-membered heterocycloalkyl-C 21 alkylene optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1-3 , and wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl-C 1-3 alkylene are optionally substituted with oxo groups to form carbonyl groups.

[0256] In some embodiments, R 20 is a 4- to 6-membered heterocycloalkyl-C 21 alkylene optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1-3 , and wherein the ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl-C 1-3 alkylene are optionally substituted with oxo groups to form carbonyl groups.

[0257] In some embodiments, R 20 is a halogen group.

[0258] In some embodiments, R 20 is NR c2 R d2 .

[0259] In some embodiments, R 20 is C(O)NR c2 R d2 .

[0260] In some embodiments, R 20 is selected from fluoro, piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-methyl-2-oxopiperazin-1-yl, piperazine-1-carbonyl, 4-methylpiperazine-1-carbonyl, (2-methylpyrrolidin-1-yl)methyl (e.g., (2-(R)-methylpyrrolidin-1-yl)methyl), tetrahydro-2H-pyran-4-yl, 4-hydroxycyclohexyl, and piperidin-4-ylmethyl.

[0261] In some embodiments, R 20 is selected from fluoro, piperazinyl, (2-hydroxyethyl)piperazinyl, methyloxopiperazinyl, methylpiperazinyl, piperazinecarbonyl, methylpiperazinecarbonyl, (methylpyrrolidinyl)methyl, piperidinyl, tetrahydropyranyl, hydroxycyclohexyl, piperidinylmethyl, hydroxypiperidinylmethyl, azetidinylmethyl, difluoroazetidinylmethyl, methyl, ethyl, isopropyl, dimethylcarbamoyl, morpholinomethyl, methylmorpholinomethyl, hydroxymethylmorpholinomethyl, pyrrolidinylmethyl, hydroxymethylpyrrolidinylmethyl, and (dimethylamino)methyl.

[0262] In some embodiments, R 20Selected from fluoro, piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-methyl-2-oxopiperazin-1-yl, 4-methylpiperazin-1-yl, piperazine-1-ylcarbonyl, 4-methylpiperazine-1-ylcarbonyl, (2-methylpyrrolidin-1-yl)methyl (e.g., (2-(R)-methylpyrrolidin-1-yl)methyl), piperidin-4-yl, tetrahydro-2H-pyran-4-yl, 4-hydroxycyclohexyl, piperidin-4-ylmethyl, (4-hydroxypiperidin-1-yl)methyl, azetidin-1-ylmethyl, (3,3-difluoroazetidin-1-yl)methyl, methyl, ethyl, isopropyl, dimethylcarbamoyl, morpholinomethyl, (2-methylmorpholino)methyl (e.g., (S)-(2-methylmorpholino)methyl), (2-(hydroxymethyl)morpholino)methyl, pyrrolidin-1-ylmethyl, (3-hydroxy-3-methylpyrrolidin-1-yl)methyl (e.g., (S)-(3-hydroxy-3-methylpyrrolidin-1-yl)methyl)) and (dimethylamino)methyl.

[0263] In some embodiments, R 20 Selected from fluoro, piperazinyl, (2-hydroxyethyl)piperazinyl, methyloxopiperazinyl, methylpiperazinyl, piperazinecarbonyl, methylpiperazinecarbonyl, (methylpyrrolidinyl)methyl, piperidinyl, tetrahydropyranyl, hydroxycyclohexyl, piperidinylmethyl, hydroxypiperidinylmethyl, hydroxymethylpiperidinylmethyl, hydroxymethylazetidinylmethyl, methylpiperazinylmethyl, azetidinylmethyl, difluoroazetidinylmethyl, methyl, ethyl, isopropyl, dimethylcarbamoyl, morpholinomethyl, methylmorpholinomethyl, hydroxymethylmorpholinomethyl, pyrrolidinylmethyl, hydroxymethylpyrrolidinylmethyl and (dimethylamino)methyl.

[0264] In some embodiments, R 20Selected from fluorine, piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-methyl-2-oxopiperazin-1-yl, 4-methylpiperazin-1-yl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, (2-methylpyrrolidin-1-yl)methyl (such as (2-(R)-methylpyrrolidin-1-yl)methyl), piperidin-4-yl, tetrahydro-2H-pyran-4-yl, 4-hydroxycyclohexyl, piperidin-4-ylmethyl, (4-hydroxypiperidin-1-yl)methyl, (4-hydroxy-4-methylpiperidin-1-yl)methyl, (3-hydroxy-3-methylazetidin-1-yl)methyl, (4-methylpiperazin-1-yl)methyl, azetidin-1-ylmethyl, (3,3-difluoroazetidin-1-yl)methyl, methyl, ethyl, isopropyl, dimethylcarbamoyl, morpholinomethyl, (2-methylmorpholinyl)methyl (such as (S)-(2-methylmorpholinyl)methyl), (2-(hydroxymethyl)morpholinyl)methyl, pyrrolidin-1-ylmethyl, (3-hydroxy-3-methylpyrrolidin-1-yl)methyl (such as (S)-(3-hydroxy-3-methylpyrrolidin-1-yl)methyl)) and (dimethylamino)methyl.

[0265] In some embodiments, each R 21 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, halogen, D, CN, OR a4 , C(O)NR c4 R d4 and NR c4 R d4 ; wherein said C 1-6 alkyl, C 3-10 cycloalkyl and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 .

[0266] In some embodiments, each R 21 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, halogen, D, CN, OR a4 , C(O)NR c4 R d4 and NR c4 R d4 ; wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 .

[0267] In some embodiments, each R 21 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, halo, OR a4 and NR c4 R d4 ; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 22 .

[0268] In some embodiments, each R 21 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, halo, OR a4 and NR c4 R d4 ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 22 .

[0269] In some embodiments, each R 21 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and OR a4 ; wherein the C 1-6 alkyl and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 22 .

[0270] In some embodiments, R 21 is a C 22 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1-6 .

[0271] In some embodiments, R 21 is a C 22 cycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 3-6 .

[0272] In some embodiments, R 21 is a cyclohexyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 22 .

[0273] In some embodiments, R 21 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R22 4- to 10-membered heterocycloalkyl substituted with substituents.

[0274] In some embodiments, R 21 is 4- to 6-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 22 4- to 6-membered heterocycloalkyl substituted with substituents.

[0275] In some embodiments, R 21 is OR a4 .

[0276] In some embodiments, R 21 is NR c4 R d4 .

[0277] In some embodiments, R 21 is a halogen group.

[0278] In some embodiments, R 21 is selected from methyl, OH, 2-hydroxyethyl, piperazin-1-yl, piperidin-4-yl, and 2-methylpyrrolidin-1-yl (e.g., 2-(R)-methylpyrrolidin-1-yl).

[0279] In some embodiments, R 21 is selected from methyl, F, OH, dimethylamino, hydroxy-ethyl, piperazinyl, piperidinyl, methylpyrrolidinyl, azetidinyl, morpholino, hydroxypiperidinyl, difluoroazetidinyl, methylmorpholino, hydroxymethylmorpholino, hydroxymethylpyrrolidinyl, and pyrrolidinyl.

[0280] In some embodiments, R 21 is selected from methyl, F, OH, dimethylamino, 2-hydroxyethyl, piperazin-1-yl, piperidin-4-yl, 2-methylpyrrolidin-1-yl (e.g., 2-(R)-methylpyrrolidin-1-yl), azetidinyl, morpholino, 4-hydroxypiperidin-1-yl, 3,3-difluoroazetidin-1-yl, 2-methylmorpholino, 2-(hydroxymethyl)morpholino, 3-hydroxy-3-methylpyrrolidin-1-yl, and pyrrolidin-1-yl.

[0281] In some embodiments, R 21 is selected from methyl, F, OH, dimethylamino, hydroxy-ethyl, piperazinyl, piperidinyl, methylpyrrolidinyl, azetidinyl, morpholino, hydroxypiperidinyl, hydroxymethylpiperidinyl, hydroxymethylazetidinyl, methylpiperazinyl, difluoroazetidinyl, methylmorpholino, hydroxymethylmorpholino, hydroxymethylpyrrolidinyl, and pyrrolidinyl.

[0282] In some embodiments, R 21Selected from methyl, F, OH, dimethylamino, 2-hydroxyethyl, piperazin-1-yl, piperidin-4-yl, 2-methylpyrrolidin-1-yl (e.g., 2-(R)-methylpyrrolidin-1-yl), azetidinyl, morpholino, 4-hydroxypiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, 4-methylpiperazin-1-yl, 3,3-difluoroazetidin-1-yl, 2-methylmorpholino, 2-(hydroxymethyl)morpholino, 3-hydroxy-3-methylpyrrolidin-1-yl, and pyrrolidin-1-yl.

[0283] In some embodiments, each R 22 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a6 and NR c6 R d6 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g .

[0284] In some embodiments, each R 22 is independently selected from C 1-6 alkyl and OR a6 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g .

[0285] In some embodiments, each R 22 is independently selected from halo, C 1-6 alkyl, and OR a6 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R g .

[0286] In some embodiments, R 22 is C g alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1-6 . In some embodiments, R 22 is OR a6 .

[0287] In some embodiments, R 22 is OH or methyl.

[0288] In some embodiments, R 22 is F, OH, or methyl.

[0289] In some embodiments, R2 Selected from 4-(piperazin-1-yl)phenyl, 4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl, 4-(4-methyl-2-oxopiperazin-1-yl)phenyl, 3-(4-methylpiperazin-1-yl)phenyl, 4-(4-methylpiperazin-1-ylcarbonyl)phenyl, 4-(piperazin-1-ylcarbonyl)phenyl, 3-fluoro-4-((2-methylpyrrolidin-1-yl)methyl)phenyl (e.g., 3-fluoro-4-((2R-methylpyrrolidin-1-yl)methyl)phenyl), 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, 1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl, and (piperidin-4-ylmethyl)-1H-pyrazol-4-yl.

[0290] In some embodiments, R 2 Selected from 4-(piperazin-1-yl)phenyl, 4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl, 4-(4-methyl-2-oxopiperazin-1-yl)phenyl, 3-(4-methylpiperazin-1-yl)phenyl, 4-(4-methylpiperazin-1-ylcarbonyl)phenyl, 4-(piperazin-1-ylcarbonyl)phenyl, 3-fluoro-4-((2-methylpyrrolidin-1-yl)methyl)phenyl (e.g., 3-fluoro-4-((2R-methylpyrrolidin-1-yl)methyl)phenyl), 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, (piperidin-4-ylmethyl)-1H-pyrazol-4-yl, (piperidin-4-yl)-1H-pyrazol-4-yl, 1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl (e.g., 1-((1R,4R)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl), 4-(azetidin-1-ylmethyl)phenyl, 1-ethyl-1H-pyrazol-4-yl, 1-isopropyl-1H-pyrazol-4-yl, 4-(dimethylcarbamoyl)phenyl, 4-(pyrrolidin-1-ylmethyl)phenyl, 4-(morpholinomethyl)phenyl, 4-((3,3-difluoroazetidin-1-yl)methyl)phenyl, 4-((2-methylmorpholin-1-yl)methyl)phenyl, 4-((2-(hydroxymethyl)morpholin-1-yl)methyl)phenyl, 4-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)phenyl, 4-((4-hydroxypiperidin-1-yl)methyl)phenyl, and 4-((dimethylamino)methyl)phenyl.

[0291] In some embodiments, R 2Selected from 4-(piperazin-1-yl)phenyl, 4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl, 4-(4-methyl-2-oxopiperazin-1-yl)phenyl, 3-(4-methylpiperazin-1-yl)phenyl, 4-(4-methylpiperazin-1-ylcarbonyl)phenyl, 4-(piperazin-1-ylcarbonyl)phenyl, 3-fluoro-4-((2-methylpyrrolidin-1-yl)methyl)phenyl (e.g., 3-fluoro-4-((2R-methylpyrrolidin-1-yl)methyl)phenyl), 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl, (piperidin-4-ylmethyl)-1H-pyrazol-4-yl, (piperidin-4-yl)-1H-pyrazol-4-yl, 1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl (e.g., 1-((1R,4R)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl), 4-(azetidin-1-ylmethyl)phenyl, 1-ethyl-1H-pyrazol-4-yl, 1-isopropyl-1H-pyrazol-4-yl, 4-(dimethylcarbamoyl)phenyl, 4-(pyrrolidin-1-ylmethyl)phenyl, 4-(morpholinomethyl)phenyl, 4-((3,3-difluoroazetidin-1-yl)methyl)phenyl, 4-((2-methylmorpholino)methyl)phenyl, 4-((2-(hydroxymethyl)morpholino)methyl)phenyl, 4-((3-hydroxy-3-methylpyrrolidin-1-yl)methyl)phenyl, 4-((4-hydroxypiperidin-1-yl)methyl)phenyl, 4-((4-hydroxy-4-methylpiperidin-1-yl)methyl)phenyl, 4-((3-hydroxy-3-methylazetidin-1-yl)methyl)phenyl, 4-((4-methylpiperazin-1-yl)methyl)phenyl, 4-((4-hydroxypiperidin-1-yl)methyl)phenyl, and 4-((dimethylamino)methyl)phenyl.

[0292] In some embodiments, R 3 is selected from H, D, halo, CN, C 1-6 alkyl, OR a7 and NR c7 R d7 .

[0293] In some embodiments, R 3 is selected from H, D, halo, CN, and C 1-6 alkyl.

[0294] In some embodiments, R 3 is selected from H and D.

[0295] In some embodiments, R 3 is H.

[0296] In some embodiments, R 4 is selected from H, D, halo, CN, C 1-6 alkyl, ORa7 and NR c7 R d7 。

[0297] In some embodiments, R 4 is selected from H, D, halogen, CN, and C 1-6 alkyl.

[0298] In some embodiments, R 4 is selected from H and D.

[0299] In some embodiments, R 4 is H.

[0300] In some embodiments, R 3 and R 4 are both H.

[0301] In some embodiments, R 5 is C 50 aryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 6-10 aryl.

[0302] In some embodiments, R 5 is a 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the 5- to 10-membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 50 substituents.

[0303] In some embodiments, R 5 is selected from quinolinyl, naphthyridinyl, pyridinyl, and phenyl, wherein the quinolinyl, naphthyridinyl, pyridinyl, and phenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 50 substituents.

[0304] In some embodiments, R 5Selected from 1,8-naphthyridin-4-yl, quinolin-4-yl, 7-(hydroxymethyl)quinolin-4-yl, 7-(pyridin-4-yl)quinolin-4-yl, 7-(2-(hydroxymethyl)pyridin-4-yl)quinolin-4-yl, 7-morpholinoquinolin-4-yl, 7-(1-methyl-1H-pyrazol-3-yl)quinolin-4-yl, 7-(6-oxa-2-azaspiro[3.4]oct-2-yl)quinolin-4-yl, 7-(methylcarbamoyl)quinolin-4-yl, 7-(pyridin-3-ylamino)quinolin-4-yl, 7-((3,5-difluorophenyl)(hydroxy)methyl)quinolin-4-yl, 7-(4-acetylpiperazin-1-yl)quinolin-4-yl, 7-(4-methylpiperazine-1-ylcarbonyl)quinolin-4-yl, 7-(morpholinomethyl)quinolin-4-yl, 7-((2-hydroxyethyl)carbamoyl)quinolin-4-yl, 7-cyanoquinolin-4-yl, 7-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)quinolin-4-yl, 7-(5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl)quinolin-4-yl (such as 7-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl)quinolin-4-yl), 8-cyanoquinolin-5-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, 1-isonicotinoyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl, and 4-carbamoyl-3-fluorophenyl.

[0305] In some embodiments, R 5Selected from 1,8-naphthyridin-4-yl, quinolin-4-yl, 7-(hydroxymethyl)quinolin-4-yl, 7-(pyridin-4-yl)quinolin-4-yl, 7-(2-(hydroxymethyl)pyridin-4-yl)quinolin-4-yl, 7-morpholinoquinolin-4-yl, 7-(1-methyl-1H-pyrazol-3-yl)quinolin-4-yl, 7-(6-oxa-2-azaspiro[3.4]oct-2-yl)quinolin-4-yl, 7-(methylcarbamoyl)quinolin-4-yl, 7-(pyridin-3-ylamino)quinolin-4-yl, 7-((3,5-difluorophenyl)(hydroxy)methyl)quinolin-4-yl, 7-(4-acetylpiperazin-1-yl)quinolin-4-yl, 7-(4-methylpiperazine-1-ylcarbonyl)quinolin-4-yl, 7-(morpholinomethyl)quinolin-4-yl, 7-((2-hydroxyethyl)carbamoyl)quinolin-4-yl, 7-cyanoquinolin-4-yl, 7-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)quinolin-4-yl, 7-(5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl)quinolin-4-yl (such as 7-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl)quinolin-4-yl), 8-cyanoquinolin-5-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, 1-isonicotinoyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl, 4-carbamoyl-3-fluorophenyl, 7-(pyridin-2-yl)-1,8-naphthyridin-4-yl, 7-(pyrimidin-2-yl)-1,8-naphthyridin-4-yl, 7-(pyrazin-2-yl)-1,8-naphthyridin-4-yl, 7-(1-methyl-1H-pyrazol-3-yl)-1,8-naphthyridin-4-yl, 7-(5-methyl-1H-pyrazol-3-yl)-1,8-naphthyridin-4-yl, 7-(1-methyl-1H-pyrazol-4-yl)-1,8-naphthyridin-4-yl, 7-(1-methyl-1H-imidazol-4-yl)-1,8-naphthyridin-4-yl, 7-(1-ethyl-1H-imidazol-4-yl)-1,8-naphthyridin-4-yl, and 7-(4-methyl-2H-1,2,3-triazol-2-yl)-1,8-naphthyridin-4-yl.

[0306] In some embodiments, each R 50 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4-10 membered heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, D, CN, OR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)ORa9 , NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 ; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 .

[0307] In some embodiments, each R 50 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, halo, D, CN, OR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 ; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ; and wherein the ring-forming carbon atoms of said 4- to 10-membered heterocycloalkyl are optionally oxidized to form a carbonyl group.

[0308] In some embodiments, each R 50 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, CN, C(O)R b9 , C(O)NR c9 R d9 and NR c9 R d9 ; wherein said C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 51 .

[0309] In some embodiments, each R 50 is independently selected from C1-6 alkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, CN, C(O)R b9 , C(O)NR c9 R d9 and NR c9 R d9 ; wherein said C 1-6 alkyl, 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each optionally substituted by 1, 2 or 3 substituents independently selected from R 51 ; and wherein the ring-forming carbon atoms of said 4- to 10-membered heterocycloalkyl are optionally oxidized to form a carbonyl group.

[0310] In some embodiments, each R 50 is a C 51 alkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 1-6 .

[0311] In some embodiments, each R 50 is a 4- to 10-membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 51 .

[0312] In some embodiments, each R 50 is a 4- to 10-membered heterocycloalkyl optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 51 , wherein the ring-forming carbon atoms of said 4- to 10-membered heterocycloalkyl are optionally oxidized to form a carbonyl group.

[0313] In some embodiments, each R 50 is independently selected from 5- to 10-membered heteroaryl optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 51 .

[0314] In some embodiments, each R 50 is selected from halo, CN, OR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 and NR c9 R d9 .

[0315] In some embodiments, each R 50 is halo.

[0316] In some embodiments, each R 50 is CN.

[0317] In some embodiments, each R50 is C(O)R b9 。

[0318] In some embodiments, each R 50 is C(O)NR c9 R d9 。

[0319] In some embodiments, each R 50 is NR c9 R d9 。

[0320] In some embodiments, each R 50 is independently selected from fluoro, hydroxyethyl, cyano, carbamoyl, methylcarbamoyl, pyridyl, morpholino, morpholinomethyl, pyrazolyl, 6-oxaspiro[3.4]octyl, pyridylamino, benzyl, piperazinyl, piperazin-1-ylcarbonyl, pyrimidinyl, pyrazinyl, (2-hydroxyethyl)carbamoyl, hexahydropyrrolo[1,2-a]pyrazinyl, 2,5-diazabicyclo[2.2.1]heptyl, triazolyl, imidazolyl, and pyrazinyl, wherein the methylcarbamoyl, pyridyl, morpholino, morpholinomethyl, pyrazolyl, 6-oxaspiro[3.4]octyl, pyridylamino, benzyl, piperazinyl, piperazin-1-ylcarbonyl, pyrimidinyl, pyrazinyl, (2-hydroxyethyl)carbamoyl, hexahydropyrrolo[1,2-a]pyrazinyl, 2,5-diazabicyclo[2.2.1]heptyl, triazolyl, imidazolyl, and pyrazinyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 。

[0321] In some embodiments, R 50 is selected from fluoro, hydroxyethyl, cyano, carbamoyl, methylcarbamoyl, pyridin-4-yl, 3-hydroxymethylpyridin-4-yl, 4-morpholino, 4-morpholinomethyl, 1-methyl-1H-pyrazol-3-yl, 6-oxaspiro[3.4]oct-2-yl, pyridin-3-ylamino, (3,5-difluorophenyl)(hydroxy)methyl, 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-ylcarbonyl, (2-hydroxyethyl)carbamoyl, 6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, and 5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl (e.g., (1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]hept-2-yl).

[0322] In some embodiments, R 50Independently selected from fluoro, 2-hydroxyethyl, cyano, carbamoyl, methylcarbamoyl, pyridin-4-yl, 3-(hydroxymethyl)pyridin-4-yl, 4-morpholino, 4-(morpholinomethyl), 1-methyl-1H-pyrazol-3-yl, 6-oxaspiro[3.4]octan-2-yl, pyridin-3-ylamino, (3,5-difluorophenyl)(hydroxy)methyl, 4-acetylpiperazin-1-yl, 4-methylpiperazine-1-carbonyl, (2-hydroxyethyl)carbamoyl, 6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl (e.g., (1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl), pyridin-2-yl, pyrazin-2-yl, pyrimidin-2-yl, 1-methyl-1H-pyrazol-3-yl, 5-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl, 1-ethyl-1H-imidazol-4-yl, and 4-methyl-2H-1,2,3-triazol-2-yl.

[0323] In some embodiments, R 5 is substituted by at least two adjacent R 50 substituents which, together with the atoms to which they are attached, form a fused 5- or 6-membered heterocycloalkyl ring; wherein each fused 5- or 6-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 the ring-forming carbon atoms of each fused 5- or 6-membered heterocycloalkyl ring are optionally substituted by oxo groups to form carbonyl groups; and wherein the fused 5- or 6-membered heterocycloalkyl ring is optionally substituted by 1, 2, 3, or 4 substituents independently selected from R 51 .

[0324] In some embodiments, R 5 is substituted by at least two adjacent R 50 substituents which, together with the atoms to which they are attached, form a fused heterocycloalkyl ring selected from: 2,3-dihydrodioxole; and 1-isonicotinoyl pyrrolidine:

[0325]

[0326] In some embodiments, R 5 is selected from pyridinyl and phenyl, wherein each of the pyridinyl and phenyl is optionally substituted by 1, 2, or 3 substituents independently selected from R 50 ; and

[0327] at least two adjacent R 50 substituents which, together with the atoms to which they are attached, form a fused heterocycloalkyl ring selected from: 2,3-dihydrodioxole; and 1-isonicotinoyl pyrrolidine:

[0328]

[0329] In some embodiments, each R 51 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , NR c10 R d10 , S(O)2R b10 and S(O)2NR c10 R d10 ; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 .

[0330] In some embodiments, each R 51 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, OR a10 and C(O)R b10 ; wherein said C 1-6 alkyl, 4- to 10-membered heterocycloalkyl and C 6-10 aryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 .

[0331] In some embodiments, each R 51 is C 1-6 alkyl; wherein said C 1-6 alkyl is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 .

[0332] In some embodiments, each R 51 is 4- to 10-membered heterocycloalkyl; wherein said 4- to 10-membered heterocycloalkyl is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 .

[0333] In some embodiments, each R 51 is C6-10 aryl; wherein said C 6-10 aryl is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 . In some embodiments, each R 51 is OR a10 .

[0334] In some embodiments, each R 51 is C(O)R b10 .

[0335] In some embodiments, each R 51 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, OH and C(O)R b10 ; wherein said C 1-6 alkyl, 4- to 10-membered heterocycloalkyl and C 6-10 aryl is each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 .

[0336] In some embodiments, each R 51 is selected from methyl, OH, hydroxymethyl, hydroxyethyl, acetyl, 4-morpholino, 4-methylpiperazin-1-yl, pyridin-3-yl, 3,5-difluorophenyl and pyridin-4-yl-carbonyl.

[0337] In some embodiments, each R 52 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a11 and NR c11 R d11 .

[0338] In some embodiments, each R 52 is independently selected from halo and OR a11 .

[0339] In some embodiments, each R 52 is independently selected from halo and OH.

[0340] In some embodiments, each R 52 is selected from fluorine and OH.

[0341] In some embodiments, A is N.

[0342] In some embodiments, A is CR A and wherein R A is selected from H, D and C 1-6 alkyl.

[0343] In some embodiments, A is CH.

[0344] In some embodiments, each R a 、R c and R d is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, and 4- to 10-membered heteroalkyl, wherein said C 1-6 alkyl, C 3-10 cycloalkyl, and 4- to 10-membered heteroalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .

[0345] In some embodiments, each R a 、R c and R d is independently selected from H, C 1-6 alkyl, and C 3-10 cycloalkyl, wherein said C 1-6 alkyl and C 3-10 cycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 .

[0346] In some embodiments, each R a is independently selected from H and methyl.

[0347] In some embodiments, R A is methyl.

[0348] In certain embodiments, R c and R d are H or C 5-6 cycloalkyl.

[0349] In certain embodiments, R c is H.

[0350] In some embodiments, R d is H or cyclohexyl. In some embodiments, any R c and R d connected to the same N atom together with the N atom to which they are connected form a 4- to 10-membered heteroalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 . In some embodiments, R c and R d connected to the same N atom together with the N atom to which they are connected form a 5- to 6-membered heteroalkyl.

[0351] In some embodiments, R connected to the same N atomc and R d together with the N atom to which they are attached form a piperazinyl group.

[0352] In some embodiments, each R b is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

[0353] In some embodiments, each R b is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and 4- to 10-membered heterocycloalkyl.

[0354] In some embodiments, each R a1 , R c1 and R d1 are independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 .

[0355] In some embodiments, R a1 is H or C 1-6 alkyl.

[0356] In some embodiments, R a1 is H or methyl.

[0357] In some embodiments, each R b1 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

[0358] In some embodiments, each R a2 , R c2 and R d2 are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0359] In some embodiments, 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- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 .

[0360] In some embodiments, R c2 and R d2 attached to the same N atom together with the N atom to which they are attached form a 5- to 6-membered heterocycloalkyl.

[0361] In some embodiments, R attached to the same N atom c2 and R d2 Together with the N atom to which they are attached they form a piperazinyl group.

[0362] In some embodiments, each R b2 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0363] In some embodiments, each R a4 , R c4 and R d4 Independently selected from H and C 1-6 alkyl.

[0364] In some embodiments, each R b4 Independently selected from C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0365] In some embodiments, each R a6 , R c6 and R d6 Independently selected from H and C 1-6 alkyl.

[0366] In some embodiments, each R a6 , R c6 and R d6 It's H.

[0367] In some embodiments, each R a9 , R c9 and R d9 Independently selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl; wherein the C 1-6 alkyl, 4-10 membered heterocycloalkyl and 5-10 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 51 substituted by a substituent.

[0368] In some embodiments, each R a9 , R c9 and R d9 Independently selected from H, C 1-6 alkyl and 5-10 membered heteroaryl; wherein the C 1-6 The alkyl and 5-10 membered heteroaryl groups are each optionally substituted by 1, 2, 3 or 4 groups independently selected from R 51 substituted by a substituent.

[0369] In some embodiments, any R attached to the same N atomc9 and R d9 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 .

[0370] In some embodiments, each R b9 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.

[0371] In some embodiments, each R a10 , R c10 and R d10 is independently selected from H and C 1-6 alkyl.

[0372] In some embodiments, each R b10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; wherein the C 1-6 alkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 .

[0373] In some embodiments, each R a11 , R c11 and R d11 is independently selected from H and C 1-6 alkyl.

[0374] In some embodiments, each R g is independently selected from OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino.

[0375] In some embodiments, the compound is a compound of formula II:

[0376]

[0377] or a pharmaceutically acceptable salt thereof.

[0378] In some embodiments, the compound is a compound of formula III:

[0379]

[0380] or a pharmaceutically acceptable salt thereof.

[0381] In some embodiments, the compound is a compound of Formula IVa or Formula IVb:

[0382]

[0383] or a pharmaceutically acceptable salt thereof.

[0384] In some embodiments, the compound is a compound of Formula Va, Formula Vb or Formula Vc:

[0385]

[0386] or a pharmaceutically acceptable salt thereof.

[0387] In some embodiments, the compound is a compound of Formula VIa or Formula VIb:

[0388]

[0389] or a pharmaceutically acceptable salt thereof.

[0390] In some embodiments, the compound is a compound of Formula VIIa, Formula VIIb, Formula VIIc or Formula VIId:

[0391]

[0392] or a pharmaceutically acceptable salt thereof, wherein

[0393] each X is independently selected from CH, N and CR 50 ; and

[0394] each Y is independently selected from CH and CR 50 .

[0395] In some embodiments, the compound is a compound of Formula VIIIa or Formula VIIIb:

[0396]

[0397] or a pharmaceutically acceptable salt thereof, wherein

[0398] each X is independently selected from CH, N and CR 50 ; and

[0399] each Y is independently selected from CH and CR 50 .

[0400] In some embodiments, the Compound of Formula I is a compound wherein:

[0401] R 1Selected from C 1-6 alkyl, C 1-6 haloalkyl, CN, OR a , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , S(O)2R b and S(O)2NR c R d ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0402] R 2 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said 5- to 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 said N and S are optionally oxidized; wherein the ring-forming carbon atoms of said 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 20 ;

[0403] R 3 is selected from H, D, halo, CN and C 1-6 alkyl;

[0404] R 4 is selected from H, D, halo, CN and C 1-6 alkyl;

[0405] R 5 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said 5- to 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 said N and S are optionally oxidized; wherein the ring-forming carbon atoms of said 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 50 ;

[0406] Or two adjacent R 5 substituents on R 50 together with the atoms to which they are attached form a fused 4-, 5-, 6- or 7-membered heteroalkyl ring, or a fused C 3-7A cycloalkyl ring; wherein each fused 4-, 5-, 6- or 7-membered heteroalkyl 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 the ring-forming carbon atoms of each fused 4-, 5-, 6- or 7-membered heteroalkyl ring are optionally substituted with oxo groups to form carbonyl groups; and wherein the fused 4-, 5-, 6- or 7-membered heteroalkyl ring and the fused C 3-7 cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0407] A is N or CR A ;

[0408] R A is selected from H, D and C 1-6 alkyl;

[0409] Each R 10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 and S(O)2NR c1 R d1 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0410] Each R 20 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10The aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0411] Each R 21 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, halo, D, CN, OR a4 , C(O)NR c4 R d4 and NR c4 R d4 ; provided that said C 1-6 alkyl, C 3-10 cycloalkyl and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0412] Each R 22 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a6 and NR c6 R d6 ; provided that said C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0413] Each R 50 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, halo, D, CN, OR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 ; provided that said C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0414] Each R51 independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , NR c10 R d10 , S(O)2R b10 and S(O)2NR c10 R d10 ; wherein said C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ;

[0415] Each R 52 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a11 and NR c11 R d11 ;

[0416] Each R a , R c and R d is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl and 4- to 10-membered heteroalkyl; wherein said C 1-6 alkyl, C 3-10 cycloalkyl and 4- to 10-membered heteroalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0417] Or any R c and R d attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heteroalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0418] Each R b is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

[0419] Each R a1 、R c1 and R d1 is independently selected from H and C 1-6 alkyl;

[0420] Each R b1 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

[0421] Each R a2 、R c2 and R d2 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0422] Or any R c2 and R d2 connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0423] Each R b2 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

[0424] Each R a4 、R c4 and R d4 is independently selected from H and C 1-6 alkyl;

[0425] Each R b4 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

[0426] Each R a6 、R c6 and R d6 is independently selected from H and C 1-6 alkyl;

[0427] Each R a9 、R c9 and R d9 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl; wherein the C 1-6 alkyl, 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0428] or any R attached to the same N atom c9 and R d9 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0429] each R b9 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

[0430] each R a10 , R c10 and R d10 is independently selected from H and C 1-6 alkyl;

[0431] each R b10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; wherein the C 1-6 alkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 ; and

[0432] each R a11 , R c11 and R d11 is independently selected from H and C 1-6 alkyl; and

[0433] each R g is independently selected from OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino.

[0434] In some embodiments, the compound of formula I is a compound wherein:

[0435] R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, CN, C(O)R b , C(O)NR c R d and C(O)OR a ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10substituted by substituents of;

[0436] R 2 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted by oxo groups to form carbonyl groups; and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 20 substituted by substituents of;

[0437] R 3 selected from H, D, halogen, CN and C 1-6 alkyl;

[0438] R 4 selected from H, D, halogen, CN and C 1-6 alkyl;

[0439] R 5 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted by oxo groups to form carbonyl groups; and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 50 substituted by substituents of;

[0440] or two adjacent R 5 on R 50 substituents together with the atoms to which they are attached form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused C 3-7 cycloalkyl ring; wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring each 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 ring-forming carbon atoms of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring are optionally substituted by oxo groups to form carbonyl groups; and wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and the fused C 3-7 cycloalkyl ring are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 51 substituted by substituents of;

[0441] A is N or CR A ;

[0442] RA Selected from H, D, and C 1-6 alkyl;

[0443] Each R 10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 and S(O)2NR c1 R d1 ; provided that the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ;

[0444] Each R 20 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 6-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, 5- to 6-membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; provided that the ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl are optionally substituted with an oxo group to form a carbonyl; provided that the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 6-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, and 5- to 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0445] Each R 21 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 4- to 6-membered heteroalkyl, halogen, D, CN, OR a4 , C(O)NR c4 R d4 and NR c4 R d4 ; provided that said C 1-6 alkyl, C 3-6 cycloalkyl and 4- to 6-membered heteroalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0446] Each R 22 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halogen, D, CN, OR a6 and NR c6 R d6 ; provided that said C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ;

[0447] Each R 50 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, halogen, D, CN, OR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 ; provided that said C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0448] Each R 51 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C3-10 Cycloalkyl, 4-10 membered heteroalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, halogen, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , NR c10 R d10 , S(O)2R b10 and S(O)2NR c10 R d10 ; wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heteroalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ;

[0449] Each R 52 Is independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, halogen, D, CN, OR a11 and NR c11 R d11 ;

[0450] Each R a , R c and R d Is independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl and 4-10 membered heteroalkyl; wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl and 4-10 membered heteroalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0451] Or any R c and R d Connected to the same N atom together with the N atom to which they are attached form a 4-10 membered heteroalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0452] Each R b Is independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl and 4-10 membered heteroalkyl, wherein said 4-10 membered heteroalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0453] Each R a1 、R c1 and R d1 is independently selected from H and C 1-6 alkyl;

[0454] Each R b1 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

[0455] Each R a2 、R c2 and R d2 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0456] Or any R c2 and R d2 connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0457] Each R b2 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

[0458] Each R a4 、R c4 and R d4 is independently selected from H and C 1-6 alkyl;

[0459] Each R b4 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

[0460] Each R a6 、R c6 and R d6 is independently selected from H and C 1-6 alkyl;

[0461] Each R a9 、R c9 and R d9 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl; wherein the C 1-6 alkyl, 4- to 10-membered heterocycloalkyl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0462] or any R attached to the same N atom c9 and R d9 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0463] Each R b9 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl;

[0464] Each R a10 , R c10 and R d10 are independently selected from H and C 1-6 alkyl;

[0465] Each R b10 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; wherein the C 1-6 alkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 ; and

[0466] Each R a11 , R c11 and R d11 are independently selected from H and C 1-6 alkyl; and

[0467] Each R g is independently selected from OH, CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, and di(C 1-6 alkyl)amino.

[0468] In some embodiments, the compound of formula I is a compound wherein:

[0469] R 1 is selected from C 1-6 alkyl, CN, C(O)NR c R d and C(O)OR a ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0470] R2 Selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 20 ;

[0471] R 3 is H;

[0472] R 4 is H;

[0473] R 5 Selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 50 ;

[0474] or two adjacent R 5 substituents on R 50 together with the atoms to which they are attached form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring; wherein the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring each 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 ring-forming carbon atoms of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring are optionally substituted with oxo groups to form carbonyl groups; and wherein the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3-7 cycloalkyl ring are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0475] A is N or CH;

[0476] Each R 10 is independently selected from C 1-6 alkyl, OR a1 and C(O)OR a1 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11is substituted with a substituent;

[0477] Each R 20 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, halogen, and C(O)NR c2 R d2 ; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0478] Each R 21 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and OH; wherein the C 1-6 alkyl and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 22 ;

[0479] Each R 22 is independently selected from C 1-6 alkyl and OH;

[0480] Each R 50 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halogen, CN, C(O)NR c9 R d9 and NR c9 R d9 ; wherein the C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0481] Each R 51 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, OH, and C(O)R b10 ; wherein the C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and C 6-10 aryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 ;

[0482] Each R 52 is independently selected from halogen and OH;

[0483] Each R a , R c and R dIndependently selected from H, C 1-6 alkyl and C 3-10 cycloalkyl; wherein said C 1-6 alkyl and C 3-10 cycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0484] or any R c and R d attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0485] Each R a1 is independently selected from H and C 1-6 alkyl;

[0486] Each R a2 , R c2 and R d2 are independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0487] 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- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0488] Each R c9 and R d9 are independently selected from H, C 1-6 alkyl and 5- to 10-membered heteroaryl; wherein said C 1-6 alkyl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0489] or any R c9 and R d9 attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0490] Each R b10 is independently selected from C 1-6 alkyl and 5- to 6-membered heteroaryl; wherein said C 1-6 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ;

[0491] In some embodiments, the compound of Formula I is a compound wherein:

[0492] R 1 is selected from C 1-6 alkyl, CN, C(O)NR c R d , C(O)R b and C(O)OR a ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0493] R 2 is selected from phenyl and 5- or 6-membered heteroaryl; wherein the 5- or 6-membered heteroaryl has at least one ring carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; wherein the N and S are optionally oxidized; wherein the ring carbon atoms of the 5- or 6-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the phenyl and 5- or 6-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 20 ;

[0494] R 3 is H;

[0495] R 4 is H;

[0496] R 5 is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the 5- to 10-membered heteroaryl has at least one ring carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; wherein the N and S are optionally oxidized; wherein the ring carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 50 ;

[0497] or two adjacent R 5 substituents on R 50 together with the atom to which they are attached form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring; wherein each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring has at least one ring carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S; wherein the ring carbon atoms of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring are optionally substituted with oxo groups to form carbonyl groups; and wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused C 3-7The cycloalkyl rings are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0498] A is N or CH;

[0499] Each R 10 is independently selected from C 1-6 alkyl, OR a1 and C(O)OR a1 ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0500] Each R 20 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl-C 1-3 alkylene, halo, NR c2 R d2 and C(O)NR c2 R d2 , wherein the ring-forming carbon atoms of said 4- to 6-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein said C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0501] Each R 21 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, halo, OR a4 and NR c4 R d4 ; wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0502] Each R 22 is independently selected from C 1-6 alkyl, halo and OH;

[0503] Each R 50 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, CN, C(O)NR c9 R d9 and NR c9R d9 ; wherein said C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0504] Each R 51 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, OH, and C(O)R b10 ; wherein said C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and C 6-10 aryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 ;

[0505] Each R 52 is independently selected from halo and OH;

[0506] Each R a , R c , and R d are independently selected from H, C 1-6 alkyl, and C 3-10 cycloalkyl; wherein said C 1-6 alkyl and C 3-10 cycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0507] or any R c and R d connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0508] Each R b is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, and 4- to 10-membered heterocycloalkyl, wherein said 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0509] Each R a1 is independently selected from H and C 1-6 alkyl;

[0510] Each R a2 , R c2 , and R d2 are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0511] or any R attached to the same N atom c2 and R d2 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0512] each R a4 、R c4 and R d4 are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0513] or any R attached to the same N atom c4 and R d4 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0514] each R c9 and R d9 are independently selected from H, C 1-6 alkyl, and 5- to 10-membered heteroaryl; wherein the C 1-6 alkyl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0515] or any R attached to the same N atom c9 and R d9 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0516] each R b10 is independently selected from C 1-6 alkyl and 5- to 6-membered heteroaryl; wherein the C 1-6 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 ;

[0517] In some embodiments, the compound of formula I is a compound wherein:

[0518] R 1 is selected from C 1-6 alkyl, CN, C(O)NR c R d 、C(O)R b and C(O)OR a ; wherein the C1-6 The alkyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0519] R 2 is selected from phenyl and pyrazolyl; wherein the phenyl and pyrazolyl are each optionally substituted by 1 or 2 substituents independently selected from R 20 ;

[0520] R 3 is H;

[0521] R 4 is H;

[0522] R 5 is selected from quinolinyl, naphthyridinyl, pyridyl and phenyl, wherein the quinolinyl, naphthyridinyl, pyridyl and phenyl are each optionally substituted by 1, 2 or 3 substituents independently selected from R 50 ;

[0523] or two adjacent R 5 substituents on R 50 together with the atoms to which they are attached form a fused 4-, 5-, 6- or 7-membered heteroalkyl ring; wherein the fused 4-, 5-, 6- or 7-membered heteroalkyl ring each 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 each ring-forming carbon atom of the fused 4-, 5-, 6- or 7-membered heteroalkyl ring is optionally substituted by an oxo group to form a carbonyl group; and wherein the fused 4-, 5-, 6- or 7-membered heteroalkyl ring and the fused C 3-7 cycloalkyl ring are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0524] A is N or CH;

[0525] Each R 10 is independently selected from C 1-6 alkyl, OR a1 and C(O)OR a1 ; wherein the C 1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0526] Each R 20 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4-6 membered heteroalkyl, 4-6 membered heteroalkyl-C 1-3 alkylene, halo, NR c2 R d2 and C(O)NR c2 Rd2 , wherein the ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0527] Each R 21 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, halo, OR a4 , and NR c4 R d4 ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 22 ;

[0528] Each R 22 is independently selected from C 1-6 alkyl, halo, and OH;

[0529] Each R 50 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, CN, C(O)NR c9 R d9 , and NR c9 R d9 ; wherein the C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0530] Each R 51 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, OH, and C(O)R b10 ; wherein the C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and C 6-10 aryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 ;

[0531] Each R 52 is independently selected from halo and OH;

[0532] Each R a , R c and Rd independently selected from H, C 1-6 alkyl, and C 3-10 cycloalkyl; wherein said C 1-6 alkyl and C 3-10 cycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0533] or any R c and R d attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0534] each R b is independently selected from 4- to 6-membered heterocycloalkyl, wherein said 4- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0535] each R a1 is independently selected from H and C 1-6 alkyl;

[0536] each R a2 , R c2 and R d2 are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0537] 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- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0538] each R a4 , R c4 and R d4 are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0539] 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- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0540] each R c9 and R d9 are independently selected from H, C 1-6alkyl and 5- to 10-membered heteroaryl; wherein said C 1-6 alkyl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0541] or any R c9 and R d9 attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0542] Each R b10 is independently selected from C 1-6 alkyl and 5- to 6-membered heteroaryl; wherein said C 1-6 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 .

[0543] In some embodiments, the compound is a compound of formula VIa or formula VIb:

[0544]

[0545] or a pharmaceutically acceptable salt thereof; wherein

[0546] R 1 is selected from C 1-6 alkyl, CN, C(O)NR c R d , C(O)R b and C(O)OR a ; wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0547] R 5 is selected from quinolinyl, naphthyridinyl, pyridinyl, and phenyl, wherein said quinolinyl, naphthyridinyl, pyridinyl, and phenyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R 50 ;

[0548] or two adjacent R 5 on R 50The substituents, together with the atoms to which they are attached, form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring; wherein each of the fused 4-, 5-, 6- or 7-membered heterocycloalkyl rings 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 ring-forming carbon atoms of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring are optionally substituted with oxo groups to form carbonyl groups; and wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and the fused C 3-7 cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0549] A is N or CH;

[0550] Each R 10 is independently selected from C 1-6 alkyl, OR a1 and C(O)OR a1 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ;

[0551] Each R 20 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl-C 1-3 alkylene, halo, NR c2 R d2 and C(O)NR c2 R d2 , wherein the ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0552] Each R 21 is independently selected from C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, halo, OR a4 and NR c4 R d4 ; wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4- to 6-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0553] Each R 22 is independently selected from C 1-6 alkyl, halo, and OH;

[0554] Each R 50 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, CN, C(O)NR c9 R d9 and NR c9 R d9 ; wherein the C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0555] Each R 51 is independently selected from C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, OH, and C(O)R b10 ; wherein the C 1-6 alkyl, 4- to 10-membered heterocycloalkyl, and C 6-10 aryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 ;

[0556] Each R 52 is independently selected from halo and OH;

[0557] Each R a , R c and R d are independently selected from H, C 1-6 alkyl, and C 3-10 cycloalkyl; wherein the C 1-6 alkyl and C 3-10 cycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0558] Or any R c and R d connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0559] Each R b is independently selected from 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0560] Each R a1Independently selected from H and C 1-6 alkyl;

[0561] Each R a2 、R c2 and R d2 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0562] or any R c2 and R d2 connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0563] Each R a4 、R c4 and R d4 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0564] or any R c4 and R d4 connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0565] Each R c9 and R d9 is independently selected from H, C 1-6 alkyl and 5- to 10-membered heteroaryl; wherein the C 1-6 alkyl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0566] or any R c9 and R d9 connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0567] Each R b10 is independently selected from C 1-6 alkyl and 5- to 6-membered heteroaryl; wherein the C 1-6 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 .

[0568] In some embodiments, the present disclosure provides compounds of Formula VIIa, Formula VIIb, Formula VIIc, or Formula VIId:

[0569]

[0570] or a pharmaceutically acceptable salt thereof, wherein:

[0571] Each X is independently selected from CH, N, and CR 50 ;

[0572] Each Y is independently selected from CH and CR 50 ;

[0573] R 1 is selected from C 1-6 alkyl, CN, C(O)NR c R d , C(O)R b and C(O)OR a ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ;

[0574] A is N or CH;

[0575] Each R 10 is independently selected from C 1-6 alkyl, OR a1 and C(O)OR a1 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ;

[0576] Each R 20 is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, halo, NR c2 R d2 and C(O)NR c2 R d2 , wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ;

[0577] Each R 21 is independently selected from C1-6 alkyl, C 3-6 cycloalkyl, 4-10 membered heteroalkyl, halo, OR a4 and NR c4 R d4 ; wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4-10 membered heteroalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ;

[0578] Each R 22 is independently selected from C 1-6 alkyl, halo and OH;

[0579] Each R 50 is independently selected from C 1-6 alkyl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, halo, CN, C(O)NR c9 R d9 and NR c9 R d9 ; wherein said C 1-6 alkyl, 4-10 membered heteroalkyl and 5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0580] or two adjacent R 5 substituents on R 50 together with the atoms to which they are attached form a fused 4-, 5-, 6- or 7-membered heteroalkyl ring; wherein said fused 4-, 5-, 6- or 7-membered heteroalkyl ring each 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 each ring-forming carbon atom of said fused 4-, 5-, 6- or 7-membered heteroalkyl ring is optionally substituted with an oxo group to form a carbonyl group; and wherein said fused 4-, 5-, 6- or 7-membered heteroalkyl ring and fused C 3-7 cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ;

[0581] Each R 51 is independently selected from C 1-6 alkyl, 4-10 membered heteroalkyl, C 6-10 aryl, OH and C(O)R b10 ; wherein said C 1-6 alkyl, 4-10 membered heteroalkyl and C 6-10 aryl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ;

[0582] Each R52 Independently selected from a halogen group and OH;

[0583] Each R a 、R c and R d is independently selected from H, C 1-6 alkyl, and C 3-10 cycloalkyl; wherein the C 1-6 alkyl and C 3-10 cycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0584] Or any R c and R d connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0585] Each R b is independently selected from 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ;

[0586] Each R a1 is independently selected from H and C 1-6 alkyl;

[0587] Each R a2 、R c2 and R d2 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0588] Or any R c2 and R d2 connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ;

[0589] Each R a4 、R c4 and R d4 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0590] Or any R c4 and R d4 connected to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21a 4- to 10-membered heterocycloalkyl substituted with substituents;

[0591] Each R c9 and R d9 is independently selected from H, C 1-6 alkyl, and 5- to 10-membered heteroaryl; wherein said C 1-6 alkyl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0592] or any R c9 and R d9 attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 51 ;

[0593] Each R b10 is independently selected from C 1-6 alkyl and 5- to 6-membered heteroaryl; wherein said C 1-6 alkyl and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 52 .

[0594] In some embodiments, the compound is a compound of formula VIIa. In some embodiments, the compound is a compound of formula VIIb. In some embodiments, the compound is a compound of formula VIIc. In some embodiments, the compound is a compound of formula VIId.

[0595] The present disclosure further provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0596] The present disclosure further provides a method of inhibiting ALK2 activity, wherein the method comprises administering to a patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0597] The present disclosure further provides a method of treating a disease or disorder associated with inhibition of ALK2 interaction, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0598] The present disclosure further provides a method of treating cancer in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0599] The present disclosure further provides a method for treating a myeloproliferative disease in a patient, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and ruxolitinib or a pharmaceutically acceptable salt thereof.

[0600] It should be further understood that certain features of the present disclosure described in the context of individual embodiments for clarity may also be provided in combination in a single embodiment (and the embodiment is intended to be combined as if written in multiple dependent forms). Conversely, various features of the present disclosure described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination. Thus, it is contemplated that the features described for embodiments of the compound of formula (I) may be combined in any suitable combination.

[0601] Throughout this specification, certain features of the compounds are disclosed in groups or ranges. In particular, it is contemplated that such disclosure includes every individual sub-combination of the members of such groups and ranges. For example, the term "C 1-6 alkyl" is specifically intended to disclose (but is not limited to) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl independently.

[0602] The term "n-membered" (where n is an integer) typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl ring.

[0603] Throughout this specification, variables defining divalent linking groups may be described. In particular, it is contemplated that each linking substituent includes the forward and reverse forms of the linking substituent. For example, -NR(CR'R”) n - includes -NR(CR'R”) n - and -(CR'R”) n NR- and each of these forms is intended to be disclosed independently. In cases where a linking group is required by the structure, the Markush variables listed for such group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", then it should be understood that "alkyl" or "aryl" represents a connecting alkylene or arylene, respectively.

[0604] The term "substituted" means that an atom or group formally replaces a hydrogen with a "substituent" attached to another group. Unless otherwise indicated, the term "substituted" refers to any level of substitution, such as mono-substitution, di-substitution, tri-substitution, tetra-substitution, or penta-substitution, provided that such substitution is permissible. The substituents are independently selected, and the substitution can occur at any chemically accessible position. It is understood that substitution at a given atom is limited by valence. It is understood that substitution at a given atom results in a stable molecule of the chemical formula. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as an oxo group, can replace two hydrogen atoms.

[0605] The term "C n-m " indicates a range including the endpoints, where n and m are integers and indicate the number of carbon atoms. Examples include C 1-4 、C 1-6 and similar forms.

[0606] The term "alkyl", used alone or in combination with other terms, refers to a straight-chain or branched-chain saturated hydrocarbon group. The term "C n-m alkyl" refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane in which one C-H bond is replaced by the point of attachment of the alkyl group to the rest of the compound. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and similar groups.

[0607] The term "alkenyl", used alone or in combination with other terms, refers to a straight-chain or branched-chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon double bonds. An alkenyl group formally corresponds to an alkene in which one C-H bond is replaced by the point of attachment of the alkenyl group to the rest of the compound. The term "C n-m alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Exemplary alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and similar groups.

[0608] The term "alkynyl", used alone or in combination with other terms, refers to a straight-chain or branched-chain hydrocarbon group corresponding to an alkyl group having one or more carbon-carbon triple bonds. An alkynyl group formally corresponds to an alkyne in which one C-H bond is replaced by the point of attachment of the alkynyl group to the rest of the compound. The term "C n-m"Alkynyl" refers to an alkynyl group having from n to m carbons. Exemplary alkynyl groups include, but are not limited to, ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, and the like. In some embodiments, the alkynyl moiety contains from 2 to 6, from 2 to 4, or from 2 to 3 carbon atoms.

[0609] The term "alkylene", used alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene formally corresponds to an alkane in which two C-H bonds are replaced by the points of attachment of the alkylene to the remainder of the compound. The term "C n-m alkylene" refers to an alkylene having from n to m carbon atoms. Examples of alkylene include, but are not limited to, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl, and the like.

[0610] The term "alkoxy", used alone or in combination with other terms, refers to a group of the formula -O-alkyl, where the alkyl is as defined above. The term "C n-m alkoxy" refers to an alkoxy in which the alkyl has from n to m carbon atoms. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0611] The term "alkoxylene", used alone or in combination with other terms, refers to a divalent alkoxy linking group. An alkoxylene formally corresponds to a group of the formula -O-alkyl in which a C-H bond is replaced by the point of attachment of the alkoxylene to the remainder of the compound. The term "C n-m alkoxylene" refers to an alkoxylene having from n to m carbon atoms.

[0612] The term "amino" refers to a group of the formula –NH2.

[0613] The term "carbonyl", used alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O).

[0614] As used herein, the terms "carbamoyl" and "carbamyl" are used interchangeably to refer to a group of the formula –C(O)NH2.

[0615] As used herein, the term "carboxyl" refers to a group of the formula -C(O)OH.

[0616] The term "cyano" or "nitrile" refers to a group of the formula –C≡N, which may also be written as -CN.

[0617] As used herein, the term "C 1-3Alkoxy-C 1-3 “alkyl” refers to a group of the formula -(C 1-3 alkylene)-(C 1-3 alkoxy).

[0618] As used herein, the term “C 1-3 alkoxy-C 1-3 alkoxy” refers to a group of the formula -(C 1-3 alkyleneoxy)-(C 1-3 alkoxy).

[0619] As used herein, the term “HO-C 1-3 alkoxy” refers to a group of the formula -(C 1-3 alkyleneoxy)-OH.

[0620] As used herein, the term “HO-C 1-3 alkyl” refers to a group of the formula -(C 1-3 alkylene)-OH.

[0621] As used herein, the term “cyano-C 1-3 alkyl” refers to a group of the formula -(C 1-3 alkylene)-CN.

[0622] As used herein, the term “H2N-C 1-3 alkyl” refers to a group of the formula -(C 1-3 alkylene)-NH2. The term “halo” or “halogen,” used alone or in combination with other terms, refers to fluoro, chloro, bromo, and iodo. In some embodiments, “halo” refers to a halogen atom selected from F, Cl, or Br. In some embodiments, halo is F.

[0623] As used herein, the term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by halogen atoms. The term “C n-m haloalkyl” refers to a C n-m alkyl having from n to m carbon atoms and from at least one to {2(n to m)+1} identical or different halogen atoms. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the haloalkyl has from 1 to 6 or from 1 to 4 carbon atoms. Exemplary haloalkyls include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and like groups. In some embodiments, the haloalkyl is a fluoroalkyl.

[0624] The term “haloalkoxy,” used alone or in combination with other terms, refers to a group of the formula -O-haloalkyl, wherein haloalkyl is as defined above. The term “C n-m"Halogenated alkoxy" refers to a halogenated alkoxy group in which the halogenated alkyl has n to m carbons. Exemplary halogenated alkoxy groups include trifluoromethoxy and similar groups. In some embodiments, the halogenated alkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0625] The term "oxo group" refers to an oxygen atom as a divalent substituent that forms a carbonyl group when attached to a carbon atom, or forms a sulfoxide or sulfone group when attached to a heteroatom, or an N-oxide group. In some embodiments, the heterocyclic group may optionally be substituted with 1 or 2 oxo group (=O) substituents.

[0626] The term "sulfide group" refers to a sulfur atom as a divalent substituent that forms a thiocarbonyl group (C=S) when attached to a carbon atom.

[0627] As used herein, the term "C n-m alkylamino" refers to a group of the formula -NH(alkyl), where the alkyl has n to m carbon atoms. In some embodiments, the alkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0628] As used herein, the term "C n-m alkoxycarbonyl" refers to a group of the formula -C(O)O-alkyl, where the alkyl has n to m carbon atoms. In some embodiments, the alkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0629] As used herein, the term "C n-m alkylcarbonyl" refers to a group of the formula -C(O)-alkyl, where the alkyl has n to m carbon atoms. In some embodiments, the alkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0630] As used herein, the term "C n-m alkylcarbonylamino" refers to a group of the formula -NHC(O)-alkyl, where the alkyl has n to m carbon atoms. In some embodiments, the alkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0631] As used herein, the term "C n-m alkylsulfonylamino" refers to a group of the formula -NHS(O)2-alkyl, where the alkyl has n to m carbon atoms. In some embodiments, the alkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0632] As used herein, the term "aminosulfonyl" refers to a group of the formula -S(O)2NH2.

[0633] As used herein, the term "C n-m"Alkylsulfamoyl" refers to a group of the formula -S(O)2NH(alkyl), wherein the alkyl has from n to m carbon atoms. In some embodiments, the alkyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0634] As used herein, the term "di(C n-m alkyl)sulfamoyl" refers to a group of the formula -S(O)2N(alkyl)2, wherein each alkyl independently has from n to m carbon atoms. In some embodiments, each alkyl independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0635] As used herein, the term "sulfamoylamino" refers to a group of the formula -NHS(O)2NH2.

[0636] As used herein, the term "C n-m alkylsulfamoylamino" refers to a group of the formula -NHS(O)2NH(alkyl), wherein the alkyl has from n to m carbon atoms. In some embodiments, the alkyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0637] As used herein, the term "di(C n-m alkyl)sulfamoylamino" refers to a group of the formula -NHS(O)2N(alkyl)2, wherein each alkyl independently has from n to m carbon atoms. In some embodiments, each alkyl independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0638] As used herein, the term "aminocarbonylamino", used alone or in combination with other terms, refers to a group of the formula -NHC(O)NH2.

[0639] As used herein, the term "C n-m alkylaminocarbonylamino" refers to a group of the formula -NHC(O)NH(alkyl), wherein the alkyl has from n to m carbon atoms. In some embodiments, the alkyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0640] As used herein, the term "di(C n-m alkyl)aminocarbonylamino" refers to a group of the formula -NHC(O)N(alkyl)2, wherein each alkyl independently has from n to m carbon atoms. In some embodiments, each alkyl independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0641] As used herein, the term "C n-m alkylcarbamoyl" refers to a group of the formula -C(O)-NH(alkyl), wherein the alkyl has from n to m carbon atoms. In some embodiments, the alkyl has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0642] As used herein, the term "di(C n-m alkyl)carbamoyl" refers to a group of the formula –C(O)N(alkyl)2, where each of the two alkyl groups independently has from n to m carbon atoms. In some embodiments, each alkyl group independently has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0643] As used herein, the term "sulfanyl" refers to a group of the formula -SH.

[0644] As used herein, the term "C n-m alkylthio" refers to a group of the formula -S-alkyl, where the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0645] As used herein, the term "C n-m alkylsulfinyl" refers to a group of the formula -S(O)-alkyl, where the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0646] As used herein, the term "C n-m alkylsulfonyl" refers to a group of the formula -S(O)2-alkyl, where the alkyl group has from n to m carbon atoms. In some embodiments, the alkyl group has from 1 to 6, from 1 to 4, or from 1 to 3 carbon atoms.

[0647] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings with aromatic character (i.e., having (4n + 2) delocalized π (pi) electrons, where n is an integer).

[0648] The term "aryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2 fused rings). The term "C n-m aryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, and similar groups. In some embodiments, the aryl group has from 6 to about 10 carbon atoms. In some embodiments, the aryl group has 6 carbon atoms. In some embodiments, the aryl group has 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.

[0649] The term "heteroaryl" or "heteroaromatic", used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, nitrogen, and phosphorus. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-10 ring atoms, which include carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five- or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-, nine-, or ten-membered fused bicyclic heteroaryl ring. Exemplary heteroaryls include, but are not limited to, pyridinyl / pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furyl, benzothienyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3-, and 2,6-naphthyridin), indolyl, isoindolyl, benzobenzothienyl, benzofuryl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, pyrazolopyrimidinyl (including pyrazolo[1,5-a]pyrimidine and pyrazolo[4,3-d]pyrimidinyl), imidazopyridinyl (i.e., imidazo[1,2-a]pyridinyl), and similar groups. In some embodiments, the heteroaryl is pyridone (e.g., 2-pyridone). Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. Exemplary six-membered ring heteroaryls are pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0650] The term "cycloalkyl", used alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), including cycloalkyl and alkenyl. The term "C n-m cycloalkyl" refers to a cycloalkyl having n to m ring member carbon atoms. Cycloalkyl can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spiro rings. Cycloalkyl can have 3, 4, 5, 6, or 7 ring-forming carbons (C 3-7 ). Cycloalkyl can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C 3-10)。In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6 monocyclic cycloalkyl group. The ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form oxo groups or sulfide groups. The cycloalkyl group also includes cycloalkylene groups. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The definition of the cycloalkyl group also includes moieties having one or more aromatic rings fused (i.e., forming a shared bond) with the cycloalkyl ring, such as benzo- or thienyl derivatives of cyclopentane, cyclohexane, and the like. The cycloalkyl group containing a fused aromatic ring may be linked through any ring-forming atom including the ring-forming atoms of the fused aromatic ring. Examples of the cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaranyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and similar groups. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0651] The term "heterocycloalkyl", used alone or in combination with other terms, refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure, has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus, and has 4 - 10 ring members, 4 - 7 ring members, or 4 - 6 ring members. Monocyclic 4-membered, 5-membered, 6-membered, and 7-membered heterocycloalkyl groups are included within the term "heterocycloalkyl". The heterocycloalkyl group may include monocyclic or bicyclic (e.g., having two fused or bridged rings) or spiro ring systems. In some embodiments, the heterocycloalkyl group is monocyclic with 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be oxidized to form oxo groups or sulfide groups or other oxidized linkages (such as C(O), S(O), C(S), or S(O)2, N-oxides, etc.) or the nitrogen atom may be quaternized. The heterocycloalkyl group may be linked through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. The definition of the heterocycloalkyl group also includes moieties having one or more aromatic rings fused (i.e., forming a shared bond) with the heterocycloalkyl ring, such as benzo- or thienyl derivatives of piperidine, morpholine, azepane, etc. The heterocycloalkyl group containing a fused aromatic ring may be linked through any ring-forming atom including the ring-forming atoms of the fused aromatic ring. Examples of the heterocycloalkyl group include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, 2,5λ 2-diazabicyclo[2.2.1]hept-2-yl, 6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 6-oxa-2-azaspiro[3.4]oct-2-yl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-inden-5-yl, isoindolinyl, tropanyl and thiomorpholinyl.

[0652] In certain instances, the definition or embodiment refers to a specific ring (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise indicated, the ring can be attached to any ring member, provided that the valence of the atoms is not exceeded. For example, the azetidine ring can be attached at any position of the ring, while the azetidin-3-yl ring is attached at the 3-position.

[0653] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers are encompassed, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are encompassed in the present invention. The cis and trans geometric isomers of the compounds of the present invention have been described and can be isolated as a mixture of isomers or in separate isomer forms.

[0654] The resolution of a racemic mixture of a compound can be carried out by any of a variety of methods known in the art. One method involves fractional recrystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Resolving agents suitable for the fractional recrystallization method are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for the fractional crystallization method include α-methylbenzylamine (e.g., the S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norpseudoephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and stereoisomerically pure forms of analogs.

[0655] The resolution of a racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoyl phenylglycine). The suitable elution solvent composition can be determined by those skilled in the art.

[0656] In some embodiments, the compounds of the present disclosure have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds having multiple chiral centers, each chiral center in the compound can independently be (R) or (S) unless otherwise indicated. Compounds having two chiral centers can have, for example, the (R,R), (R,S), (S,R), or (S,S) configuration.

[0657] The compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond along with an accompanying proton migration. Tautomeric forms include proton-transfer tautomers, which are isomeric protonation states having the same empirical formula and total charge. Exemplary proton-transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactone-lactam pairs, enamine-imine pairs, and cyclic forms where a proton can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazole; 1H-, 2H-, and 4H-1,2,4-triazole; 1H- and 2H-isoindole; and 1H- and 2H-pyrazole. Tautomeric forms can exist in equilibrium or be spatially locked in one form by appropriate substitution.

[0658] The compounds of the present disclosure can also include all isotopes of atoms that occur in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more of the constituent atoms of the compounds of the present disclosure can be replaced or substituted with isotopes of the atoms in natural or non-natural abundances. In some embodiments, the compounds include at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced or substituted with deuterium. In some embodiments, the compounds include two or more deuterium atoms. In some embodiments, the compounds include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry, Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange, Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765). Isotope-labeled compounds can be used in various studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0659] Replacement with an isotope such as deuterium can provide certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dose requirements, and can thus be preferred in some cases. (A. Kerekes et al., J. Med. Chem. 2011, 54, 201 - 210; R. Xu et al., J. Label Compd. Radiopharm. 2015, 58, 308 - 312).

[0660] As used herein, the term “compound” is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. The term is also intended to refer to the compounds of the present disclosure regardless of their method of preparation, e.g., synthetic preparation, preparation by biological methods (e.g., metabolic or enzymatic transformation), or combinations thereof.

[0661] All compounds and their pharmaceutically acceptable salts can exist with other substances such as water and solvents (e.g., hydrates and solvates), or can be isolated. When in solid form, the compounds and salts described herein can exist in various forms and can, for example, be in solvate form, including hydrates. The compounds can be in any solid form, such as polymorphs or solvates, and thus, unless otherwise indicated, the compounds and salts referred to in this specification should be understood to encompass any solid form of the compounds.

[0662] In some embodiments, the compounds or salts of the present disclosure are substantially isolated. “Substantially isolated” means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, compositions that enrich the compounds of the present disclosure. Substantially isolated can include compositions containing at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 95 wt%, at least about 97 wt%, or at least about 99 wt% of the compounds or salts of the present disclosure.

[0663] The phrase “pharmaceutically acceptable” is used herein to refer to compounds, materials, compositions, and / or dosage forms that are within the scope of reasonable medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0664] As used herein, the expressions “ambient temperature” and “room temperature” are as understood herein and generally refer to a temperature approximately equal to the indoor temperature at which a reaction is carried out, e.g., the reaction temperature, e.g., a temperature of about 20 °C to about 30 °C.

[0665] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; in general, non-aqueous media such as diethyl ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, (Mack Publishing Company, Easton, 1985), page 1418; Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19; and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include N-oxide forms.

[0666] Synthesis

[0667] The compounds of the present disclosure, including their salts, can be prepared using known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, such as the routes in the following schemes.

[0668] The reactions used to prepare the compounds provided herein can be carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents do not substantially react with the starting materials (reactants), intermediates or products at the temperature at which the reaction proceeds, e.g., at a temperature within the range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, the solvent suitable for the particular reaction step can be selected by a skilled person.

[0669] The preparation of the compounds provided herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the choice of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0670] The reaction can be monitored according to any suitable method known in the art. By way of example, product formation can be monitored spectroscopically, such as by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0671] As used herein, the expressions “ambient temperature,” “room temperature,” and “r.t.” are as understood herein and generally refer to a temperature approximately equal to the temperature of the room in which the reaction is carried out, e.g., the reaction temperature, e.g., a temperature of about 20 °C to about 30 °C.

[0672] The compounds disclosed herein can be prepared by those skilled in the art according to the preparation routes known in the literature and according to various possible synthetic routes. Exemplary synthetic methods for preparing the compounds of the present application are provided in the following schemes.

[0673] A series of imidazo[1,2-b]pyridazine derivatives 7 can be prepared according to the procedure outlined in Scheme 1. Aminopyridazine 3 can be obtained by palladium-catalyzed amination of dichloropyridazine 1 with diphenylketimine (Tetrahedron Lett. 1997, 38, 6367-6370), followed by hydrolysis under acidic conditions. The aminopyridazine 3 undergoes a cycloaddition with 2-chloroacetaldehyde to give imidazo[1,2-b]pyridazine 4, which can be converted to the corresponding imidazo[1,2-b]pyridazine iodide 5 by treatment with NIS. Suzuki coupling (J. Am. Chem. Soc. 2010, 132, 14073-14075) with boric acid or ester R 5 B(OR’)2 gives compound 6, which can be converted to the desired imidazo[1,2-b]pyridazine derivative 7 by further Suzuki coupling with a suitable boric acid or ester R 2 B(OR’)2. Alternatively, imidazo[1,2-b]pyridazine 4 is reacted with boric acid or ester R 2The Suzuki coupling of B(OR’)2 gives compound 8, which can be converted to compound 9 by treatment with NIS. Imidazo[1,2-b]pyridazine iodide 9 can then be converted to the desired imidazo[1,2-b]pyridazine derivative 7 by Suzuki coupling with a suitable boric acid or ester R 5 B(OR’)2.

[0674] Scheme 1

[0675]

[0676] A series of imidazo[1,2-b]pyridazine-6-carboxamide derivatives 12 can be prepared according to the procedure outlined in Scheme 2. Methyl imidazo[1,2-b]pyridazine-6-carboxylate 10 prepared according to the procedure outlined in Scheme 1 can be converted to the corresponding acid 11 by hydrolysis. Acid 11 can then be converted to the desired imidazo[1,2-b]pyridazine-6-carboxamide derivative 12 by coupling with a suitable amine using an amidation coupling reagent such as, but not limited to, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) or N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU).

[0677] Scheme 2

[0678]

[0679] A series of imidazo[1,2-b]pyridazine-6-carbonitrile derivatives 18 can be prepared according to the procedure outlined in Scheme 3. Methyl imidazo[1,2-b]pyridazine-6-carboxylate 13 prepared according to the procedure outlined in Scheme 1 can be converted to the corresponding acid 14 by hydrolysis. Acid 14 can then be converted to imidazo[1,2-b]pyridazine-6-carboxamide 15 by coupling with ammonium chloride using an amidation coupling reagent such as HATU. Treatment of compound 15 with oxalyl chloride in the presence of triethylamine and triphenylphosphine oxide gives compound 16, which can then be converted to the corresponding iodide 17 by treatment with NIS. Suzuki coupling with a suitable boric acid or ester R 5 B(OR’)2 gives the desired imidazo[1,2-b]pyridazine-6-carbonitrile derivative 18. Scheme 3

[0680]

[0681] A series of imidazo[1,2-b]pyridazine derivatives 23 can be prepared according to the procedure outlined in Scheme 4. Methyl 7-chloroimidazo[1,2-b]pyridazine-6-carboxylate 19, prepared according to the procedure outlined in Scheme 1, can be converted to the corresponding alcohol 20 by reduction. The alcohol 20 can then be converted to compound 21 via Suzuki coupling with boric acid or ester R 2 B(OR’)2. Treatment of compound 21 with NIS gives the corresponding iodide 22, which can be converted to the desired imidazo[1,2-b]pyridazine derivative 23 via Suzuki coupling with a suitable boric acid or ester R 5 B(OR’)2.

[0682] Scheme 4

[0683]

[0684] A series of imidazo[1,2-a]pyridine derivatives 28 can be prepared according to the procedure outlined in Scheme 5. The aminopyridine 24 undergoes a cycloaddition with 2-chloroacetaldehyde to give compound 25, which can be converted to compound 26 via Suzuki coupling with boric acid or ester R 2 B(OR’)2. Treatment of compound 26 with NIS gives the corresponding iodide 27, which can be converted to the desired imidazo[1,2-b]pyridine derivative 28 via Suzuki coupling with a suitable boric acid or ester R 5 B(OR’)2.

[0685] Scheme 5

[0686]

[0687] The present invention will be described in more detail by way of specific examples. The examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize that various non-critical parameters can be changed or modified to obtain substantially the same results. The compounds of the examples are described below.

[0688] Preparative LC-MS purification of some of the compounds prepared was carried out on a Waters mass-directed fractionation system. The basic equipment settings, protocols, and control software for operating these systems are described in detail in the literature. See, for example, “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and “Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874 - 883 (2004). The isolated compounds typically undergo analytical liquid chromatography mass spectrometry (LCMS) for purity checks under the following conditions: Instrument: Agilent 1100 series, LC / MSD; Column: Waters Sunfire TM C 18 5 μm particle size, 2.1×5.0 mm; Buffer: Mobile phase A: water containing 0.025% TFA and mobile phase B: acetonitrile; Gradient 2% to 80% B in 3 minutes, and flow rate: 2.0 mL / min.

[0689] Some of the compounds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) using an MS detector as indicated in the examples, or by flash chromatography (silica gel). Typical preparative reverse-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0690] pH = 2 purification: Waters Sunfire TM C 185 μm particle size, 30 × 100 mm column, eluted with the following: mobile phase A: water containing 0.1% TFA (trifluoroacetic acid) and mobile phase B: acetonitrile; flow rate is 60 mL / min, and the separation gradient is optimized for each compound using the Compound Specific Method Optimization protocol described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874 - 883 (2004)].

[0691] pH = 10 purification: Waters XBridge C 18 5 μm particle size, 30 × 100 mm column, eluted with the following: mobile phase A: water containing 0.15% NH4OH and mobile phase B: acetonitrile; flow rate is 60 mL / min, and the separation gradient is optimized for each compound using the Compound Specific Method Optimization protocol described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874 - 883 (2004)].

[0692] Usage

[0693] The present disclosure provides methods for modulating (e.g., inhibiting) ALK2 activity, the methods comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure can be used alone, in combination with other agents or therapies, or as an adjuvant or neo - adjuvant to treat diseases or disorders, including cancer. For the uses described herein, any of the compounds of the present disclosure can be used, including any of its embodiments.

[0694] In myelofibrosis (MF), a substantial proportion of patients develop anemia and become dependent on frequent red blood cell (RBC) transfusions (Tefferi, A. et al., Mayo Clinic Proceedings 2012 87, 25 - 33). Elevated levels of serum hepcidin in patients with MF have been shown to be associated with hemoglobin (Hb) levels, increased need for RBC transfusions, and reduced survival (Pardanani, A. et al., American Journal of Hematology 2013, 88, 312 - 316). BMP signaling plays a key role in driving the induction of hepcidin transcription by activating SMAD signaling. In anemic mouse models, liver - specific deletion of ALK2 or ALK3 blocks the induction of hepcidin production and iron overload (Steinbicker, A.U. et al., Blood 2011, 118, 4224 - 4230). Thus, ALK2 inhibition can be combined with ruxolitinib for the treatment of patients with MF because hepcidin - mediated internalization and degradation of FPN1 may not require JAK2 activity (Ross, S.L. et al., Cell Metabolism 2012, 15, 905 - 917). ALK2 inhibition can block the negative effects of hepcidin on iron metabolism and improve anemia in patients with MF (Asshoff, M. et al., Blood 2017, 129, 1823 - 1830).

[0695] Progressive fibrodysplasia ossificans (FOP) is a rare human genetic bone disease characterized by extraskeletal bone formation to endochondral ossification in patients (Yu, P.B. et al., Nature Medicine 2008, 14, 1363 - 1369; Fukuda, T. et al., Journal of Biological Chemistry 2009 284, 7149 - 7156). 95% of FOP patients carry point mutations in ACVR1 / ALK2 and the reactive mutation in classic FOP is 617G>A (R206H) in the intracellular glycine- and serine-rich (GS) domain of ALK2 (Shen, Q. et al., Journal of Clinical Investigation 2009, 119, 3462 - 3472). ALK2 mutations have also been found in other amino acids in the GS domain or the protein kinase domain of patients with atypical FOP (Fukuda, T. et al., Biochemical and Biophysical Research Communications 2008, 377, 905 - 909). Different ALK2 mutants have been shown to activate BMP signaling without constitutively activating exogenous BMP ligands and these ALK2 mutants can transmit significantly stronger BMP signaling after ligand stimulation (Van Dinther, M. et al., Journal of Bone and Mineral Research 2010, 25, 1208 - 1215).

[0696] Activating mutations in ALK2 have also been identified in diffuse intrinsic pontine gliomas (DIPG; a highly invasive ventral pontine glioma in the pediatric population). ALK2 has been reported to be one of the most frequently mutated genes in DIPG. In 46 of 195 cases (24%), ALK2 was found to carry nonsynonymous heterozygous somatic mutations at five specific residues. Patients with ALK2 mutations were predominantly female (approx. 2:1) and had a younger age of onset (approx. 5 years) and a longer overall survival time (approx. 15 months) compared to wild-type IDPG. The ALK2 mutants are highly specific for DIPG and the ALK2 inhibitor LDN-19318917 causes significant inhibition of the survival of ALK2 mutant DIPG cells (Taylor, K.R. et al., Nature Genetics 2014, 46, 457 - 461; Buczkowicz, P. et al., Nature Genetics 2014, 46, 451 - 456).

[0697] Methods for treating a disease or disorder associated with inhibiting ALK2 activity can include administering to a patient in need thereof a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or disorder is cancer. Examples of cancers that can be treated with the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, kidney cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, carcinoma of the endometrium, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, pediatric solid tumors, lymphocytic lymphoma, bladder cancer, kidney cancer or urethral cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal cord axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T cell lymphoma, environmentally induced cancers, including cancers induced by asbestos, and combinations of the foregoing cancers.

[0698] In some embodiments, cancers that can be treated with the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), kidney cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, triple-negative breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer and small cell lung cancer). Additionally, the present disclosure includes refractory or recurrent malignancies, the growth of which can be inhibited using the compounds of the present disclosure.

[0699] In some embodiments, cancers that can be treated with the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular NHL), Hodgkin lymphoma, or multiple myeloma), and combinations of the foregoing cancers.

[0700] In some embodiments, diseases and indications that can be treated using the compounds of the present disclosure include, but are not limited to, blood cancers, sarcomas, lung cancers, gastrointestinal cancers, urogenital cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0701] Exemplary blood cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular NHL), Hodgkin lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglobulinemia, hairy cell lymphoma, chronic granulocytic lymphoma, and Burkitt lymphoma.

[0702] Exemplary sarcomas include chondrosarcoma, Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxosarcoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, hamartoma, and teratoma. Exemplary sarcomas also include lymphosarcoma and leiomyosarcoma.

[0703] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell bronchial carcinoma, undifferentiated small cell bronchial carcinoma, undifferentiated large cell bronchial carcinoma, bronchial adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma. Exemplary lung cancers also include small cell carcinoma and non-small cell carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0704] Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (exocrine pancreatic cancer, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, enteroglucagonoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer. Exemplary gastrointestinal cancers also include gallbladder cancer and anal cancer.

[0705] Exemplary urogenital cancers include kidney cancers (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethral cancers (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancers (adenocarcinoma, sarcoma), and testicular cancers (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma). Exemplary urogenital cancers also include renal cell carcinoma and urothelial carcinoma.

[0706] Exemplary liver cancers include hepatomas (hepatocellular carcinoma), cholangiocarcinomas, hepatoblastomas, angiosarcomas, hepatocellular adenomas, and hemangiomas.

[0707] Exemplary bone cancers include, for example, osteosarcomas (osteogenic sarcoma), fibrosarcomas, malignant fibrous histiocytomas, chondrosarcomas, Ewing's sarcoma, malignant lymphomas (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumors, chordomas, osteochondromas (osteochondroma) (osteochondral exostosis), benign chondromas, chondroblastomas, chondromyxoid fibromas, osteoid osteomas, and giant cell tumors.

[0708] Exemplary nervous system cancers include skull cancers (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meningeal cancers (meningioma, meningeal sarcoma, gliomatosis), brain cancers (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord cancers (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte - Duclos disease. Exemplary nervous system cancers also include neuroectodermal tumors and pineal tumors.

[0709] Exemplary gynecological cancers include uterine cancers (endometrial carcinoma), cervical cancers (cervical carcinoma, pre - neoplastic cervical cell lesions), ovarian cancers (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa - theca cell tumors, Sertoli–Leydig cell tumors, dysgerminoma, malignant teratoma), vulvar cancers (squamous cell carcinoma, epithelioma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancers (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma)), and fallopian tube cancers (carcinoma). Exemplary nervous system cancers also include neuroectodermal tumors and pineal tumors.

[0710] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloid. In some embodiments, the diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, cholangiocarcinoma, esophageal cancer, and urothelial carcinoma.

[0711] Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, sinus and paranasal sinus cancer, thyroid and parathyroid cancer. Exemplary head and neck cancers also include ocular tumors, lip and mouth tumors, and squamous head and neck cancers.

[0712] The compounds of the present disclosure are useful for inhibiting tumor metastasis. In some embodiments, the compounds provided herein can be used to treat tumors that produce PGE2 (e.g., tumors overexpressing Cox-2) and / or adenosine (tumors overexpressing CD73 and CD39). Overexpression of Cox-2 has been detected in a variety of tumors, such as colorectal cancer, breast cancer, pancreatic cancer, and lung cancer, where it is associated with poor prognosis. Overexpression of Cox-2 has been reported in hematological cancer models, such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia), and in blasts from patients. CD73 is upregulated in various human carcinomas, including colon cancer, lung cancer, pancreatic cancer, and ovarian cancer. Importantly, higher expression levels of CD73 are associated with tumor neovascularization, invasiveness, and metastasis, and shorter survival in breast cancer patients.

[0713] The terms "individual" or "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0714] The phrase "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medical response sought by a researcher, veterinarian, medical doctor, or other clinician in a tissue, system, animal, individual, or human.

[0715] As used herein, the term "treating / treatment" refers to one or more of the following: (1) inhibiting a disease; e.g., inhibiting a disease, disorder, or condition in an individual who is experiencing or displaying a lesion or symptom of the disease, disorder, or condition (i.e., arresting the further development of the lesion and / or symptom); and (2) ameliorating the disease; e.g., ameliorating a disease, disorder, or condition in an individual who is experiencing or displaying a lesion or symptom of the disease, disorder, or condition (i.e., reversing the lesion and / or symptom), such as reducing the severity of the disease.

[0716] As used herein, the term "contacting" means bringing a specified compound together in an in vitro or in vivo system such that they are physically close enough to interact with each other.

[0717] In some embodiments, the compounds of the present disclosure can be used to prevent any of the diseases mentioned herein or reduce the risk of developing any of the diseases mentioned herein; for example, to prevent a disease, disorder or condition in an individual who is predisposed to develop a disease, disorder or condition but has not yet experienced or exhibited a lesion or symptom of the disease, or to reduce the risk of the individual developing the disease, disorder or condition.

[0718] Combination therapy

[0719] One or more additional pharmaceutical agents or therapeutic methods, such as antiviral agents, chemotherapeutic agents or other anti-cancer agents, immunomodulators, immunosuppressants, radiation, anti-tumor and antiviral vaccines, cytokine therapy (e.g., IL2, GM-CSF, etc.) and / or tyrosine kinase inhibitors can be used in combination with the compounds described herein to treat ALK2-related diseases, conditions or disorders, or diseases or disorders as described herein. The agents can be combined with the compounds of the invention in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0720] I. Immune checkpoint therapy

[0721] In some embodiments, the compounds provided herein can be used in combination with one or more immune checkpoint inhibitors for treating cancer as described herein. The compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD28, CD39, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM, arginase, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from: CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from: A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM-3, TIGIT, and VISTA. In some embodiments, the compounds of the present disclosure provided herein can be used in combination with one or more agents selected from: KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFRβ inhibitors.

[0722] In some embodiments, the compounds provided herein can be used in combination with one or more agonists of immune checkpoint molecules such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0723] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0724] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), durvalumab Pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD-1 antibody is SHR-1210. Other anti-cancer agents include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab). In some embodiments, the anti-PD-1 monoclonal antibody is ipilumimab.

[0725] In some embodiments, the compounds of the present disclosure can be used in combination with INCB086550.

[0726] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-small molecule PD-L1 antibody, or an anti-CTLA-4 antibody inhibitor. In some embodiments, in the PD-L1 assays described in U.S. Patent Publication Nos. US20170107216, US20170145025, US 20170174671, US20170174679, US20170320875, US20170342060, US20170362253, US20180016260, US20180057486, US 20180177784, US20180177870, US20180179179, US20180179197, US20180179201, and US20180179202, the IC 50 is less than 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM, each of which is incorporated by reference for all purposes.

[0727] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

[0728] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1 and PD-L1, such as an anti-PD-1 / PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 / PD-L1 is MCLA-136.

[0729] In some embodiments, the inhibitor is MCLA-145.

[0730] In some embodiments, the inhibitor of the immune checkpoint molecule is a CTLA-4 inhibitor, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884 or CP-675,206.

[0731] In some embodiments, the inhibitor of the immune checkpoint molecule is a CSF1R inhibitor, such as an anti-CSF1R antibody. In some embodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.

[0732] In some embodiments, the inhibitor of the immune checkpoint molecule is a LAG3 inhibitor, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, IMP321, GSK2831781 or INCAGN2385.

[0733] In some embodiments, the inhibitor of the immune checkpoint molecule is a TIM3 inhibitor, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453 or TSR-022.

[0734] In some embodiments, the inhibitor of the immune checkpoint molecule is a GITR inhibitor, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323 or MEDI1873.

[0735] In some embodiments, the inhibitor of the immune checkpoint molecule is an OX40 agonist, such as an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, MEDI6469, MOXR-0916, PF-04518600, GSK3174998 or BMS-986178. In some embodiments, the OX40L fusion protein is MEDI6383.

[0736] In some embodiments, the inhibitor of the immune checkpoint molecule is a CD20 inhibitor, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0737] The compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one domain of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or the TGFβ receptor.

[0738] In some embodiments, the compounds of the present disclosure can be used in combination with one or more metabolic enzyme inhibitors. In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO or arginase. Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196. An example of an arginase inhibitor is CB-1158.

[0739] As provided throughout, the additional compounds, inhibitors, agents, etc. can be combined with the compounds of the present invention in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0740] II. Cancer Therapies

[0741] The growth and survival of cancer cells can be affected by multiple signaling pathways. Thus, it is useful to combine different enzyme / protein / receptor inhibitors that exhibit different preferences among the targets whose activity they regulate and can be used to treat such disorders. Examples of agents that can be combined with the compounds of the present disclosure include PI3K-AKT-mTOR pathway inhibitors, Raf-MAPK pathway inhibitors, JAK-STAT pathway inhibitors, β-catenin pathway inhibitors, notch pathway inhibitors, hedgehog pathway inhibitors, Pim kinase inhibitors, and protein chaperone and cell cycle progression inhibitors. Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the likelihood of developing drug resistance in a cell population and / or reduce treatment toxicity.

[0742] The compounds of the present disclosure can be used in combination with one or more other enzyme / protein / receptor inhibitors to treat diseases such as cancer. Examples of cancer include solid tumors and liquid tumors such as blood cancers. For example, the compounds of the present disclosure can be used in combination with one or more inhibitors of the following kinases for treating cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG, PKC, CaM kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, HPK, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL and B-Raf. In some embodiments, the compounds of the present disclosure can be used in combination with one or more of the following inhibitors for treating cancer.Non-limiting examples of inhibitors that can be used in combination with the compounds of the present disclosure for treating cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, such as AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JNJ-42756493, Debio1347, INCB54828, INCB62079, and INCB63904), JAK inhibitors (JAK1 and / or JAK2, such as ruxolitinib, baricitinib, or INCB39110), IDO inhibitors (such as epacadostat and NLG919), LSD1 inhibitors (such as GSK2979552, INCB59872, and INCB60003), TDO inhibitors, PI3K-δ inhibitors (such as INCB50797 and INCB50465), PI3K-γ inhibitors such as PI3K-γ selective inhibitors, CSF1R inhibitors (such as PLX3397 and LY3022855), TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer), angiogenesis inhibitors, interleukin receptor inhibitors, bromodomain and extra-terminal domain family member inhibitors (such as bromodomain inhibitors or BET inhibitors, such as OTX015, CPI-0610, INCB54329, and INCB57643), and adenosine receptor antagonists or combinations thereof. HDAC inhibitors such as panobinostat and vorinostat. c-Met inhibitors such as onartumzumab, tivantinib, and INC-280. BTK inhibitors such as ibrutinib. mTOR inhibitors such as rapamycin, sirolimus, temsirolimus, and everolimus. Raf inhibitors such as vemurafenib and dabrafenib. MEK inhibitors such as trametinib, selumetinib, and GDC-0973. Inhibitors of Hsp90 (such as tanespimycin), cyclin-dependent kinases (such as palbociclib), PARP (such as olaparib), and Pim kinases (LGH447, INCB053914, and SGI-1776) can also be combined with the compounds of the present disclosure.

[0743] In some embodiments, the compounds of the present disclosure can be combined with one or more JAK inhibitors (JAK1 and / or JAK2, such as ruxolitinib, baricitinib, or INCB39110). In some embodiments, the compounds of the present disclosure can be combined with one or more JAK inhibitors (JAK1 and / or JAK2, such as ruxolitinib, baricitinib, or INCB39110) for the treatment of cancers such as myeloproliferative diseases. By way of example, a myeloproliferative disease is myelofibrosis. In some embodiments, the compounds of the present disclosure can be combined with ruxolitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present disclosure can be combined with ruxolitinib or a pharmaceutically acceptable salt thereof for the treatment of myeloproliferative diseases such as myelofibrosis. The compounds of the present disclosure can be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include bendamustine, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes, uracil mustard, chlormethine, cyclophosphamide (CytoxanTM), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0744] The compounds of the present disclosure can be further used in combination with other cancer treatment methods, such as chemotherapy, irradiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, adoptive T cell transfer, CAR (chimeric antigen receptor) T cell therapy as a T cell activation enhancer, oncolytic virus therapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, and similar therapies. The compounds can be administered in combination with one or more anticancer drugs such as chemotherapeutic agents. Exemplary chemotherapeutic agents include any of the following: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amsacrine, anastrozole, aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparlisib, intravenous busulfan, oral busulfan, calusterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparinsodium), dasatinib, actinomycin D, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon α2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetateacetate), levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab, nelarabine, neratinib, nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafine, revlimid, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib malatemaleate), tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, and zoledronate.

[0745] Other anti-cancer agents include antibody therapeutics such as trastuzumab (Herceptin); antibodies against co-stimulatory molecules such as CTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, PD-1, and PD-L1; or antibodies against cytokines (IL-10, TGF-β, etc.). Examples of antibodies against PD-1 and / or PD-L1 that can be combined with the compounds of the present disclosure for treating cancer or infections such as viral, bacterial, fungal, and parasitic infections include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736, and SHR-1210.

[0746] Other anti-cancer agents include inhibitors of kinase-related cell proliferation disorders. The kinases include, but are not limited to, Aurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk, and SGK.

[0747] Other anti-cancer agents also include those that block the migration of immune cells, such as antagonists against chemokine receptors including CCR2 and CCR4.

[0748] The compounds of the present disclosure can also be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressive agents, or therapeutic antibodies. Steroids include, but are not limited to, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0749] The compounds of the present disclosure can also be used in combination with lonafarnib (SCH6636), tipifarnib (R115777), L778123, BMS214662, tezacitabine (MDL 101731), Sml1, triapine, didox, trimidox, and amidox.

[0750] The compounds described herein can be combined with another immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines include peptides of melanoma antigens, such as gp100, MAGE antigens, Trp-2, MART1, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0751] The compounds described herein can be used in combination with vaccination regimens to treat cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, the tumor vaccine includes proteins from viruses involved in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma herpesvirus (KHSV). In some embodiments, the compounds of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the compounds described herein can be combined with dendritic cells for activating a potent anti-tumor response.

[0752] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target effector cells expressing Feα or Feβ receptors to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate the host immunoreactivity.

[0753] The compounds of the present disclosure can be used in combination with bone marrow grafts to treat various tumors of hematopoietic origin.

[0754] Antiviral agents expected to be suitable for use in combination with the compounds of the present disclosure can include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

[0755] Exemplary suitable NRTIs include zidovudine (AZT); didanosine (ddI); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and named β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD ((-)-β-D-2,6-diamino-purine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-ketolactone coumarin A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Ismuth project number 11607.

[0756] The compounds described herein can be used in combination with or sequentially with other agents directed against membrane receptor kinases, particularly for patients who have developed primary or acquired resistance to targeted therapies. The therapeutic agents include inhibitors or antibodies directed against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1 or Flt-3 and against cancer-related fusion protein kinases such as Bcr-Abl and EML4-Alk. Inhibitors of EGFR include gefitinib and erlotinib, and inhibitors of EGFR / Her2 include, but are not limited to, dacomitinib, afatinib, lapatinib and neratinib. Antibodies against EGFR include, but are not limited to, cetuximab, panitumumab and necitumumab. c-Met inhibitors can be used in combination with the compounds disclosed herein. These include orantinib, tivantinib and INC-280. Agents against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib and ponatinib and agents against Alk (or EML4-ALK) include crizotinib.

[0757] Angiogenesis inhibitors can be combined with the compounds disclosed herein and are effective for some tumors. These include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other anti-angiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib and vandetanib.

[0758] Activation of intracellular signaling pathways is frequently seen in cancer, and agents that target components of these pathways have been combined with receptor-targeted agents to enhance efficacy and reduce resistance. Examples of agents that can be combined with the compounds described herein include inhibitors of the PI3K-AKT-mTOR pathway, Raf-MAPK pathway, JAK-STAT pathway and inhibitors of protein chaperones and cell cycle progression.

[0759] Agents against PI3 kinase include but are not limited to topilaralisib, idelalisib, and buparlisib. mTOR inhibitors such as rapamycin, sirolimus, temsirolimus, and everolimus can be combined with the compounds of the present invention. Other suitable examples include but are not limited to vemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetinib, and GDC-0973 (MEK inhibitors). Inhibitors of the following can also be combined with the compounds described herein: one or more JAK (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin-dependent kinase (e.g., palbociclib), HDAC (e.g., panobinostat), PARP (e.g., olaparib), and proteasome (e.g., bortezomib, carfilzomib). In some embodiments, the JAK inhibitor is selective for JAK1 relative to JAK2 and JAK3.

[0760] Other suitable agents for use in combination with the compounds described herein include chemotherapy combinations such as platinum doublets (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed) for lung cancer and other solid tumors or gemcitabine plus paclitaxel bound particles

[0761] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, alkylating agents (including but not limited to nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, nitrogen mustard, cyclophosphamide (Cytoxan TM )), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0762] Other suitable agents for use in combination with the compounds described herein include steroids, including 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0763] Other suitable agents for use in combination with the compounds described herein include: dacarbazine (DTIC), optionally in combination with other chemotherapeutic drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen", which consists of DTIC, BCNU, cisplatin and tamoxifen; a combination of cisplatin, vinblastine and DTIC; or temozolomide. The compounds described herein may also be combined with immunotherapy drugs, which include cytokines such as interferon α, interleukin 2 and tumor necrosis factor (TNF) inhibitors.

[0764] Suitable chemotherapeutic agents or other anti-cancer agents include, for example, antimetabolites (including but not limited to folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin and gemcitabine.

[0765] Suitable chemotherapeutic agents or other anti-cancer agents also include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, actinomycin D, daunomycin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL TM ), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-a)), etoposide and teniposide.

[0766] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, cyclophosphamide, ifosfamide and droloxifene.

[0767] Cytotoxic agents are also suitable, such as epipodophyllotoxins; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biologic response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0768] Other anti-cancer agents include antibody therapeutic agents, such as trastuzumab (Herceptin); antibodies against co-stimulatory molecules such as CTLA-4, 4-1BB, PD-1 and PD-L1; or antibodies against cytokines (IL-10, TGF-β, etc.).

[0769] Other anti-cancer agents also include those that block the migration of immune cells, such as antagonists against chemokine receptors including CCR2 and CCR4.

[0770] Other anti-cancer agents also include those that enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0771] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. In some embodiments, the tumor vaccine includes proteins from viruses involved in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). Non-limiting examples of available tumor vaccines include melanoma antigen peptides, such as peptides of gp100, MAGE antigens, Trp-2, MART1, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0772] The compounds of the present disclosure can be used in combination with bone marrow grafts to treat a variety of tumors of hematopoietic origin.

[0773] Most methods for the safe and effective administration of the chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, N.J.), the disclosure of which is incorporated herein by reference in its entirety.

[0774] When more than one pharmaceutical agent is administered to a patient, it can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents).

[0775] In some embodiments, the compounds of the present disclosure can be used in combination with INCB086550.

[0776] Formulations, Dosage Forms, and Administration

[0777] When used as a medicine, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. Accordingly, the present disclosure provides a composition comprising a compound of formula (I) or any of the formulas described herein, a compound as described in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any one of its embodiments, and at least one pharmaceutically acceptable carrier or excipient. The pharmaceutical composition may comprise a compound described herein and one or more second therapeutic agents as described herein. By way of example, the second therapeutic agent is a JAK inhibitor such as ruxolitinib. The composition can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including using a nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, by continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickening agents, and the like may be necessary or desirable.

[0778] The present invention also includes pharmaceutical compositions containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the composition is suitable for topical administration. In preparing the compositions of the present disclosure, the active ingredient is typically admixed with an excipient, diluted with an excipient, or enclosed within a carrier such as in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Accordingly, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0779] In preparing the formulations, the active compound can be comminuted to provide an appropriate particle size before being combined with the other ingredients. If the active compound is substantially insoluble, it can be comminuted to a particle size less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by comminution to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[0780] The compounds of the present disclosure can be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for forming tablets and for other dosage forms. Fine particle (nanoparticle) formulations of the compounds of the present disclosure can be prepared by methods known in the art, see for example WO 2002 / 000196.

[0781] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally contain: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylparaben and propylparaben; sweetening agents; and flavoring agents. The compositions of the present disclosure can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by procedures known in the art.

[0782] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silica (w / w).

[0783] In some embodiments, the composition is a sustained release composition that comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from: microcrystalline cellulose, lactose monohydrate, hydroxypropylmethylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropylmethylcellulose. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silica. In some embodiments, the microcrystalline cellulose is Avicel PH102 TM . In some embodiments, the lactose monohydrate is Fast-flo 316 TM . In some embodiments, the hydroxypropylmethylcellulose is hydroxypropylmethylcellulose 2208K4M (e.g., Methocel K4M Premier TM ) and / or hydroxypropylmethylcellulose 2208K100LV (e.g., Methocel K00LVTM )。In some embodiments, the polyethylene oxide is Polyethylene Oxide WSR 1105 (e.g., Polyox WSR 1105 TM )。

[0784] In some embodiments, the composition is produced using a wet granulation method. In some embodiments, the composition is produced using a dry granulation method.

[0785] The composition may be formulated into unit dosage forms, each dosage containing from about 5 to about 1,000 mg (1 g), more typically from about 100 to about 500 mg of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a single dosage for a human individual and other mammals, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect and a pharmaceutically suitable excipient.

[0786] The components used to formulate the pharmaceutical composition have high purity and are substantially free of contaminants that may be harmful (e.g., at least National Formulary (NF) grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, the composition is preferably manufactured or formulated according to the standards of Good Manufacturing Practice as defined in the applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations may be sterile and / or substantially isotonic, and / or fully compliant with all Good Manufacturing Practice regulations of the U.S. Food and Drug Administration.

[0787] The active compound can be effective over a wide dosage range and is generally administered in a therapeutically effective amount. However, it should be understood that the amount of the compound actually administered will usually be determined by the physician based on relevant circumstances, including the disorder to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms and the like.

[0788] The therapeutic dosage of the compounds of the present invention can vary depending on, for example, the specific use for which the treatment is carried out, the mode of administration of the compound, the health condition and disease of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds disclosed herein in the pharmaceutical composition can vary depending on various factors including the dosage, chemical characteristics (such as hydrophobicity), and route of administration. For example, the compounds disclosed herein can be provided in the form of an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is from 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage may depend on variables such as the type and progression of the disease or disorder, the overall health condition of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. The effective dosage can be extrapolated from the dose-response curve obtained from in vitro or animal model test systems.

[0789] For preparing solid compositions such as tablets, the principal active ingredient is admixed with a pharmaceutical excipient to form a solid preformulation composition that contains a homogeneous mixture of the compounds of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically uniformly dispersed throughout the composition, whereby the composition can be readily redivided into equal effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then redivided into unit dosage forms of the above type containing, for example, about 0.1 to about 1000 mg of the...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, C(O)R b , C(O)NR c R d , C(O)OR a , C(=NR e )R b , C(=NOR a )R b and C(=NR e )NR c R d , 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 10 ; R 2 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein said 5- to 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 said N and S are optionally oxidized; wherein the ring-forming carbon atoms of said 5- to 10-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein said C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 20 ; or R 2 two adjacent Rs on 20 the substituents together with the atoms to which they are attached form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused C 3-7 cycloalkyl ring; wherein each of said fused 4-, 5-, 6- or 7-membered heterocycloalkyl rings 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 ring-forming carbon atoms of each of said fused 4-, 5-, 6- or 7-membered heterocycloalkyl rings are optionally substituted with oxo groups to form carbonyl groups; and wherein said fused 4-, 5-, 6- or 7-membered heterocycloalkyl rings and fused C 3-7 cycloalkyl rings are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ; R 3 Selected from H, D, halogen, CN, C 1-6 alkyl, OR a7 and NR c7 R d7 ; wherein said C 1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from R g ; R 4 Selected from H, D, halogen, CN, C 1-6 alkyl, OR a8 and NR c8 R d8 ; wherein said C 1-6 alkyl is optionally substituted by 1, 2 or 3 substituents independently selected from R g ; R 5 selected from C 6-10 aryl and 5- to 10-membered heteroaryl; wherein the 5- to 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 the ring-forming carbon atoms of the 5- to 10-membered heteroaryl are optionally substituted by oxo groups to form carbonyl groups; and wherein the C 6-10 aryl and 5- to 10-membered heteroaryl are each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from R 50 ; or R 5 two adjacent Rs on 50 the substituents, together with the atoms to which they are attached, form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused C 3-7 cycloalkyl ring; wherein each of the fused 4-, 5-, 6- or 7-membered heterocycloalkyl rings 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 ring-forming carbon atoms of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring are optionally substituted with oxo groups to form carbonyl groups; and wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl rings and the fused C 3-7 cycloalkyl rings are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ; A is N or CR A ; R A Selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, halo, CN, NO2, OR a12 , SR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)OR a12 , OC(O)R b12 , OC(O)NR c12 R d12 , NR c12 R d12 , NR c12 C(O)R b12 , NR c12 C(O)OR a12 , NR c12 C(O)NR c12 R d12 , NR c12 S(O)R b12 , NR c12 S(O)2R b12 , NR c12 S(O)2NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O)2R b12 and S(O)2NR c12 R d12 ; 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 10 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 5-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halo, D, CN, NO2, 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)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 each alkylene is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 11 ; or two Rs 10 The substituent, together with the carbon atom to which it is attached, forms a spiro 4-7-membered heterocycloalkyl ring, or a spiro C 3-6 cycloalkyl ring; wherein each spiro 4-7-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2 or 3 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of each spiro 4-7-membered heterocycloalkyl ring are optionally substituted with oxo groups to form carbonyl groups; and wherein said spiro 4-7-membered heterocycloalkyl rings and spiro C 3-6 cycloalkyl rings are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 substituents; 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 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)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 and S(O)2NR c3 R d3 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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, C 3-6 cycloalkyl-C 1-3 alkylene, 4-7 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 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)2R b5 , NR c5 S(O)2NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 and S(O)2NR 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, 4-7 membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4-7 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 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 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halogen, D, CN, NO2, 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(=NOR a2 )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)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted with oxo groups to form carbonyl groups; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 21 ; Each R 21 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- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , 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)2R b4 , NR c4 S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 and S(O)2NR c4 R d4 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ; Each R 22 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, 5- or 6-membered heteroaryl-C 1-3 alkylene, 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)2R b6 , NR c6 S(O)2NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 and S(O)2NR c6 R d6 ; provided that said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ; Each R 50 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halo, D, CN, NO2, OR a9 , SR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , OC(O)R b9 , OC(O)NR c9 R d9 , NR c9 R d9 , NR c9 C(O)R b9 , NR c9 C(O)OR a9 , NR c9 C(O)NR c9 R d9 , C(=NR e9 )R b9 , C(=NOR a9 )R b9 , C(=NR e9 )NR c9 R d9 , NR c9 C(=NR e9 )NR c9 R d9 , NR c9 S(O)R b9 , NR c9 S(O)2R b9 , NR c9 S(O)2NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 and S(O)2NR c9 R d9 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ; Each R 51 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene, 5- to 10-membered heteroaryl-C 1-3 alkylene, halogen, D, CN, OR a10 , SR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , NR c10 R d10 , NR c10 C(O)R b10 , NR c10 C(O)OR a10 , NR c10 S(O)R b10 , NR c10 S(O)2R b10 , NR c10 S(O)2NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O)2R b10 and S(O)2NR c10 R d10 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ; Each R 52 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene, 5- or 6-membered heteroaryl-C 1-3 alkylene, halo, D, CN, OR a11 , SR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 S(O)R b11 , NR c11 S(O)2R b11 , NR c11 S(O)2NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O)2R b11 and S(O)2NR c11 R d11 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ; Each R a 、R c and R d are 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ; or any R attached to the same N atom c and R d together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ; Each R b 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ; Each R e 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl; Each R a1 、R c1 and R d1 are 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 ; or any R attached to the same N atom c1 and R d1 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl; Each R a2 、R c2 and R d2 are 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 21 ; or any R attached to the same N atom c2 and R d2 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 21 ; 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 heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5-10 membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4-10 membered heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-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 by 1, 2, 3 or 4 substituents independently selected from R 21 ; Each R e2 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl; Each R a3 、R c3 and R d3 are 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 12 ; or any R attached to the same N atom c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 12 ; Each R a4 、R c4 and R d4 are 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ; or any R attached to the same N atom c4 and R d4 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R 22 ; 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- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- or 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 22 ; 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 attached to the same N atom c5 and R d5 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 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 are 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 attached to the same N atom c6 and R d6 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R g ; Each R b6 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 a7 , R c7 and R d7 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 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 a9 、R c9 and R d9 are 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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- to 10-membered heterocycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heterocycloalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 51 ; or any R attached to the same N atom c9 and R d9 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ; Each R b9 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- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 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- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 51 ; Each R e9 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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, aminosulfonyl, C 1-6 alkylaminosulfonyl and di(C 1-6 alkyl)aminosulfonyl; Each R a10 , R c10 and R d10 are 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- to 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- to 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ; or any R attached to the same N atom c10 and R d10 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R 52 ; Each R b10 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- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- to 6-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C 3-6 cycloalkyl-C 1-3 alkylene, 4- to 7-membered heterocycloalkyl-C 1-3 alkylene, phenyl-C 1-3 alkylene and 5- to 6-membered heteroaryl-C 1-3 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 52 ; Each R a11 、R c11 and R d11 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 attached to the same N atom c11 and R d11 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl optionally substituted with 1, 2 or 3 substituents independently selected from R g ; Each R b11 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 a12 、R c12 and R d12 are 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- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene; wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4- to 10-membered heteroalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4- to 10-membered heteroalkyl-C 1-3 alkylene, C 6-10 aryl-C 1-3 alkylene and 5- to 10-membered heteroaryl-C 1-3 alkylene are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R g ; or any R attached to the same N atom c12 and R d12 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from R g ; Each R b12 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 heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-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, 4-10 membered heteroalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-3 alkylene, 4-10 membered heteroalkyl-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 g ; and Each R g is independently selected from OH, NO2, CN, halogen, 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, H2N-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, carbamoyl, C 1-6 alkylcarbamoyl, di(C 1-6 alkyl)carbamoyl, carboxyl, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, sulfamoyl, C 1-6 alkylaminosulfonyl, di(C 1-6 alkyl)aminosulfonyl, sulfamoylamino, 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 according to claim 1, wherein R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, C(O)R b , C(O)NR c R d and C(O)OR a ; wherein the C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted by 1, 2, 3 or 4 substituents independently selected from R 10 .

3. The compound according to claim 1, wherein R 1 is selected from C 1-6 alkyl, CN, C(O)NR c R d , C(O)R b and C(O)OR a ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 10 .

4. The compound according to claim 1, wherein R 1 is selected from methyl, methoxycarbonyl, carbamoyl, cyano, hydroxymethyl, methoxymethyl, N-(4-hydroxy-4-methylcyclohexyl)carbamoyl and 4-ethoxycarbonyl-piperazin-1-ylcarbonyl.

5. A compound according to any one of claims 1 - 3, wherein each R 10 is 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 heteroalkyl, C 6-10 aryl, 5 - 10 membered heteroaryl, halo, D, CN, OR a1 , C(O)OR a1 , NR c1 R d1 and S(O)2NR c1 R d1 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 4 - 10 membered heteroalkyl, C 6-10 aryl and 5 - 10 membered heteroaryl are each optionally substituted with 1 or 2 substituents independently selected from R 11 .

6. The compound according to any one of claims 1 - 3, wherein each R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 and S(O)2NR c1 R d1 ; wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 .

7. The compound according to any one of claims 1-3, wherein each R 10 is selected from C 1-6 alkyl, OR a1 and C(O)OR a1 ; wherein the C 1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from R 11 .

8. The compound according to any one of claims 1-3, wherein each R 10 is selected from methyl, OH, methoxy and ethoxycarbonyl.

9. The compound according to any one of claims 1-8, wherein R 2 is a 5- or 6-membered heteroaryl; wherein the 5- or 6-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 the ring-forming carbon atoms of the 5- or 6-membered heteroaryl are optionally substituted with oxo groups to form carbonyl groups; and wherein the 5- or 6-membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 20 .

10. The compound according to any one of claims 1-8, wherein R 2 is selected from phenyl and pyrazolyl; wherein the phenyl and pyrazolyl are each optionally substituted with 1 or 2 substituents independently selected from R 20 and the substituents are as defined above.

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