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

Abstract

To provide compounds, and compositions thereof and methods of using the same, wherein the compounds are useful for modulating activin receptor-like kinase-2 (ALK2) activity and treating various diseases including cancer.SOLUTION: The present invention provides a composition for treating bone disease or anemia, comprising the compound of formula I or a pharmaceutically acceptable salt thereof, where R1 represents optionally substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or the like; R2 and R5 are selected from C6-10 aryl and 5-10 membered heteroaryl; R3 and R4 represent H, D, halo, CN, optionally substituted C1-6 alkyl or the like; A represents N or CRA; RA is selected from H, D, optionally substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and the like.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure provides compounds, as well as compositions and methods of use thereof, that modulate activin receptor-like kinase-2 (ALK2) activity and are useful in the treatment of various diseases, including cancer. [Background technology]

[0002] Bone morphogenetic protein (BMP) signaling belongs to the transforming growth factor beta (TGF-β) superfamily, and TGF-β signaling ligands include over 25 different ligands: TGF-β growth and differentiation factors, BMPs, and activins. BMP ligand binding leads to the assembly of a tetrameric receptor complex consisting of two constitutively active type II receptor serine / threonine kinases (BMPRII, ACTRIIA, or ACTRIIB), which activate two type I receptor serine / threonine kinases (ALK1, ALK2, ALK3, or ALK6). Furthermore, activated type I receptors phosphorylate BMP receptor-responsive SMAD proteins 1, 5, and 8, which then translocate to the nucleus and regulate gene transcription in association with co-SMAD4. (Ross, SL, et al. Cell Metabolism 2012, 15, 905-917; Blobe, GC, et al. New England Journal of Medicine 2000, 342, 1350-1358).

[0003] The BMPR kinase activin A receptor, type I (ACVR1), also known as activin receptor-like kinase-2 (ALK2), consists of a ligand-binding extracellular domain and a cytoplasmic domain with serine / threonine specificity. ALK2 has been reported to mediate several human diseases (Massague, J., et al. Cell 2000, 103, 295-309; Taylor, KR, et al. Cancer Research 2014, 74, 4565-4570). ALK2 and ALK3 have been shown to play an important role in regulating hepcidin levels and influencing anemia of chronic disease (Andriopoulos, B., et al. Nature Genetics 2009 41, 482-487; Steinbicker, AU, et al. Blood 2011, 118, 4224-4230; Steinbicker, AU, et al. Blood 2011, 117, 4915-4923). Hepcidin, a small peptide hormone primarily synthesized in hepatocytes, binds to the iron exporter ferroportin (FPN1) and induces its internalization and degradation, thereby reducing both duodenal iron absorption and iron transport from monocytes / macrophages (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, leading to reduced iron availability and iron-limited erythropoiesis. Inappropriately elevated hepcidin expression causes severe functional iron deficiency anemia in humans and is central to the pathophysiology of anemia of chronic disease (ACD) (Weiss, G. et al. New England Journal of Medicine 2005, 352, 1011-1023). Therefore, there is a need for novel compounds that modulate ALK2 activity. Summary of the Invention

[0004] The present disclosure relates in particular to compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the variable components are defined herein.

[0005] The present disclosure further provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0006] The present disclosure further provides a method of inhibiting ALK2 activity, comprising administering to a patient a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0007] The present disclosure further provides a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0008] The disclosure further provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to prepare a medicament for use in any of the methods described herein. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present disclosure provides compounds of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 Cy 1 , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, Halo, CN, NO2, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , OC(O)NR c Rd , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NOR a )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 1 is C 3~14 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6~10aryl, and 5- to 10-membered heteroaryl; the 4- to 14-membered heterocycloalkyl and the 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; N and S may be optionally oxidized; the ring-forming carbon atoms of the 5- to 10-membered heteroaryl and the 4- to 14-membered heterocycloalkyl may be optionally substituted with oxo to form a carbonyl group; C 3~14 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 2 is C 6~10 is selected from aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 20 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 2 The two adjacent R's above 20 The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C 3~7fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 3 H, D, Halo, CN, C 1~6 Alkyl, OR a7 , and NR c7 R d7 Selected from; C 1~6 Alkyl is R g each optionally substituted with 1, 2, or 3 substituents independently selected from R 4 H, D, Halo, CN, C 1~6 Alkyl, OR a8 , and NR c8 R d8 Selected from; C 1~6 Alkyl is R g each optionally substituted with 1, 2, or 3 substituents independently selected from R 5 is C 6~10 is selected from aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 50each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 5 The two adjacent R's above 50 The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C 3~7 fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CR A and; R A H, D, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, Halo, CN, NO2, OR a12 , S.R. 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 , N.R. c12 R d12 , N.R. c12 C(O)R b12 , N.R. c12 C(O)OR a12 , N.R. c12 C(O)NR c12 R d12 , N.R. c12 S(O)R b12 , N.R. c12 S(O)2Rb12 , N.R. c12 S(O)NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O)2R b12 , and S(O)NR c12 R d12 C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 10 is 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 a1 , S.R. 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 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NORa1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 Independently selected from the group consisting of 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 R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or two R's 10 The substituents, together with the carbon atoms to which they are attached, form a spiro 4- to 7-membered heterocycloalkyl ring or spiro C 3~6each spiro 4- to 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; ... a ring-forming carbon atom of each spiro 4- to 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the spiro 4- to 7-membered heterocycloalkyl ring and the spiro C 3~6 The cycloalkyl ring is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 11 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3, and S(O)NR c3 R d3 Independently selected from the group consisting of 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 R 12 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 12 is 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, 4-7 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 , S.R. a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 S(O)R b5 , N.R. c5 S(O)2R b5, N.R. c5 S(O)NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 , and S(O)NR c5 R d5 Independently selected from the group consisting of 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Alkylene is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 is 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 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 Rd2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NOR a2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; 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 R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R21 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)OR a4 , N.R. c4 S(O)R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , and S(O)NR c4 R d4 Independently selected from the group consisting of 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-C1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Alkylene is R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 is 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a6 , S.R. a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , N.R. c6 R d6 , N.R. c6 C(O)R b6 , N.R. c6 C(O)OR a6 , N.R. c6 S(O)R b6 , N.R. c6 S(O)2R b6 , N.R. c6 S(O)NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 , and S(O)NR c6 R d6 Independently selected from the group consisting of 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-C1~3 Alkylene, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 50 is 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 a9 , S.R. 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 , N.R. c9 R d9 , N.R. c9 C(O)R b9 , N.R. c9 C(O)OR a9 , N.R. c9 C(O)NR c9 R d9 , C(=NR e9 )R b9 , C(=NOR a9 )R b9 , C(=NR e9 )NR c9 R d9 , N.R. c9 C(=NR e9 )NR c9 Rd9 , N.R. c9 S(O)R b9 , N.R. c9 S(O)2R b9 , N.R. c9 S(O)NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 , and S(O)NR c9 R d9 Independently selected from the group consisting of 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 R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a10 , S.R. a10 , C(O)R b10 , C(O)NR c10R d10 , C(O)OR a10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , N.R. c10 C(O)OR a10 , N.R. c10 S(O)R b10 , N.R. c10 S(O)2R b10 , N.R. c10 S(O)NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O)2R b10 , and S(O)NR c10 R d10 Independently selected from the group consisting of 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 R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 is 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C1~3 Alkylene, Halo, D, CN, OR a11 , S.R. a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 S(O)R b11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O)2R b11 , and S(O)NR c11 R d11 Independently selected from the group consisting of 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a , R c , and R d is 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, C3~10 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; 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 R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b is 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 1~3alkylene; 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 R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a1 , R c1 , and R d1 is 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 1~3Alkylene and 5-10 membered heteroaryl-C 1~3 alkylene; 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 R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c1 and R d1 together with the N atom to which they are attached, R 11 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b1 is 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6~10 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 R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e1 are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a2 , R c2 , and R d2 is 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10Cycloalkyl, 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 R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b2 is 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; 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-C1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Alkylene is R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e2 are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a3 , R c3 , and R d3 is 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C1~3 Alkylene is R 12 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c3 and R d3 together with the N atom to which they are attached, R 12 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b3 is 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 12 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a4 , R c4 , and R d4 is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Haloalkyl, C 3~6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 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; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c4 and R d4 together with the N atom to which they are attached, R 22 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b4 is 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene;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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a5 , R c5 , and R d5 is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c5 and R d5 together with the N atom to which they are attached, R g forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b5 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a6 , R c6 , and R d6 is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c6 and R d6 together with the N atom to which they are attached, R g forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b6 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a7 , R c7 , and R d7 is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a8 , Rc8 , and R d8 is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a9 , R c9 , and R d9 is 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; 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 R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atomc9 and R d9 together with the N atom to which they are attached, R 51 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b9 is 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; 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 R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e9 are H, CN, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a10 , R c10 , and R d10 is 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c10 and R d10 together with the N atom to which they are attached, R 52 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b10 is C 1~6 Alkyl, C 2~6Alkenyl, 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a11 , R c11 , and R d11 is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c11 and R d11 together with the N atom to which they are attached, R gforming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b11 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a12 , R c12 , and R d12 is 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; 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 R geach optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c12 and R d12 together with the N atom to which they are attached, R g forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b12 is 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; 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 R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R g OH, NO2, CN, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C1~6 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1~6 Alkylaminosulfonylamino, di(C 1~6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1~6 Alkylaminocarbonylamino, and di(C 1~6 alkyl)aminocarbonylamino. however, 1) Cy 1 C 6~10 In the case of aryl, R 10 is other than substituted cyclobutyl; 2) The compound of formula I is other than 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.

[0010] In some embodiments, the compound of formula I is R 1 But Cy 1 , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, Halo, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NOR a )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R. c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b, and S(O)NR c R d C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Cy 1 But C 3~14 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6~10 aryl, and 5- to 10-membered heteroaryl; wherein the 4- to 14-membered heterocycloalkyl and the 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; N and S may be optionally oxidized; and the ring-forming carbon atoms of the 5- to 10-membered heteroaryl and the 4- to 14-membered heterocycloalkyl may be optionally substituted with oxo to form a carbonyl group; C 3~14 Cycloalkyl, 4-14 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 2 C 6~10 aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 20 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 2 The two adjacent R's above 20The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C 3~7 fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 3 But, H, D, Halo, CN, C 1~6 Alkyl, OR a7 , and NR c7 R d7 Selected from; C 1~6 The alkyl is R g each optionally substituted with 1, 2, or 3 substituents independently selected from R 4 But, H, D, Halo, CN, C 1~6 Alkyl, OR a8 , and NR c8 R d8 Selected from; C 1~6 The alkyl is R g each optionally substituted with 1, 2, or 3 substituents independently selected from R 5 But C 6~10 aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10Aryl and 5- to 10-membered heteroaryl are R 50 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 5 The two adjacent R's above 50 The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C 3~7 fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CR A and; R A But H, D, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, Halo, CN, NO2, OR a12 , S.R. 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 , N.R. c12 R d12 , N.R. c12 C(O)R b12 , N.R. c12 C(O)OR a12 , N.R. c12 C(O)NR c12 R d12 , N.R. c12 S(O)Rb12 , N.R. c12 S(O)2R b12 , N.R. c12 S(O)NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O)2R b12 , and S(O)NR c12 R d12 C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 10 But 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, Halo, D, CN, NO2, OR a1 , S.R. 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 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NRe1 )R b1 , C(=NOR a1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , and S(O)NR c1 R d1 Independently selected from the group consisting of 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 R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or two R's 10 The substituents, together with the carbon atoms to which they are attached, form a spiro 4- to 7-membered heterocycloalkyl ring or spiro C 3~6each spiro 4- to 7-membered heterocycloalkyl ring having at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S; a ring-forming carbon atom of each spiro 4- to 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the spiro 4- to 7-membered heterocycloalkyl ring and the spiro C 3~6 The cycloalkyl ring is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 11 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3, and S(O)NR c3 R d3 Independently selected from the group consisting of 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 R 12 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 12 But 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, 4-7 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 , S.R. a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 S(O)R b5 , N.R. c5 S(O)2R b5, N.R. c5 S(O)NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 , and S(O)NR c5 R d5 Independently selected from the group consisting of 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Alkylene is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 But 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 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 Rd2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NOR a2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 wherein a ring-forming carbon atom of the 4- to 10-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; 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 R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R21 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)OR a4 , N.R. c4 S(O)R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , and S(O)NR c4 R d4 Independently selected from the group consisting of 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-C1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Alkylene is R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a6 , S.R. a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , N.R. c6 R d6 , N.R. c6 C(O)R b6 , N.R. c6 C(O)OR a6 , N.R. c6 S(O)R b6 , N.R. c6 S(O)2R b6 , N.R. c6 S(O)NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 , and S(O)NR c6 R d6 Independently selected from the group consisting of 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-C1~3 Alkylene, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 50 But 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 a9 , S.R. 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 , N.R. c9 R d9 , N.R. c9 C(O)R b9 , N.R. c9 C(O)OR a9 , N.R. c9 C(O)NR c9 R d9 , C(=NR e9 )R b9 , C(=NOR a9 )R b9 , C(=NR e9 )NR c9 R d9 , N.R. c9 C(=NR e9 )NR c9 Rd9 , N.R. c9 S(O)R b9 , N.R. c9 S(O)2R b9 , N.R. c9 S(O)NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 , and S(O)NR c9 R d9 Independently selected from the group consisting of 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 R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a10 , S.R. a10 , C(O)R b10 , C(O)NR c10R d10 , C(O)OR a10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , N.R. c10 C(O)OR a10 , N.R. c10 S(O)R b10 , N.R. c10 S(O)2R b10 , N.R. c10 S(O)NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10 , S(O)2R b10 , and S(O)NR c10 R d10 Independently selected from the group consisting of 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 R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C1~3 Alkylene, Halo, D, CN, OR a11 , S.R. a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 S(O)R b11 , N.R. c11 S(O)2R b11 , N.R. c11 S(O)NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O)2R b11 , and S(O)NR c11 R d11 Independently selected from the group consisting of 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a , R c , and R d But 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, C3~10 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; 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 R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b But 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 1~3alkylene; 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 R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a1 , R c1 , and R d1 But 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 1~3Alkylene and 5-10 membered heteroaryl-C 1~3 alkylene; 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 R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c1 and R d1 together with the N atom to which they are attached, R 11 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b1 But 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6~10 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 R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e1 But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a2 , R c2 , and R d2 But 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; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10Cycloalkyl, 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 R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b2 But 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; 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-C1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 Alkylene is R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e2 But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a3 , R c3 , and R d3 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C1~3 Alkylene is R 12 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c3 and R d3 together with the N atom to which they are attached, R 12 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b3 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 12 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a4 , R c4 , and R d4 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Haloalkyl, C 3~6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 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; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c4 and R d4 together with the N atom to which they are attached, R 22 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b4 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene;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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a5 , R c5 , and R d5 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c5 and R d5 together with the N atom to which they are attached, R g forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b5 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a6 , R c6 , and R d6 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c6 and R d6 together with the N atom to which they are attached, R g forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b6 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a7 , R c7 , and R d7 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a8 , Rc8 , and R d8 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a9 , R c9 , and R d9 But 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; 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 R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atomc9 and R d9 together with the N atom to which they are attached, R 51 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b9 But 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; 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 R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e9 But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a10 , R c10 , and R d10 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c10 and R d10 together with the N atom to which they are attached, R 52 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b10 But C 1~6 Alkyl, C 2~6Alkenyl, 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a11 , R c11 , and R d11 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c11 and R d11 together with the N atom to which they are attached, R gforming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b11 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a12 , R c12 , and R d12 But 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; 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 R geach optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c12 and R d12 together with the N atom to which they are attached, R g forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b12 But 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; 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 R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R g OH, NO2, CN, Halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C1~6 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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1~6 Alkylaminosulfonylamino, di(C 1~6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1~6 Alkylaminocarbonylamino, and di(C 1~6 alkyl)aminocarbonylamino; It is a compound.

[0011] In some embodiments, the compound of formula I is R 1 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Haloalkyl, 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 Independently selected from the group consisting of C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 2 C 6~10 aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 20 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 2 The two adjacent R's above 20 The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C 3~7 fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C3~7 The cycloalkyl ring is R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 3 But, H, D, Halo, CN, C 1~6 Alkyl, OR a7 , and NR c7 R d7 Selected from; C 1~6 The alkyl is R g each optionally substituted with 1, 2, or 3 substituents independently selected from R 4 But, H, D, Halo, CN, C 1~6 Alkyl, OR a8 , and NR c8 R d8 Selected from; C 1~6 The alkyl is R g each optionally substituted with 1, 2, or 3 substituents independently selected from R 5 But C 6~10 aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 50 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 5 The two adjacent R's above 50 The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C 3~7fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CR A and; R A But H, D, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, Halo, CN, NO2, OR a12 , S.R. 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 , N.R. c12 R d12 , N.R. c12 C(O)R b12 , N.R. c12 C(O)OR a12 , N.R. c12 C(O)NR c12 R d12 , N.R. c12 S(O)R b12 , N.R. c12 S(O)2R b12 , N.R. c12 S(O)NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O)2R b12 , and S(O)NR c12 R d12C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 10 But 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, Halo, D, CN, NO2, OR a1 , S.R. 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 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NOR a1 )R b1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 S(O)R b1 , N.R.c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , and S(O)NR c1 R d1 Independently selected from the group consisting of 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 R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or two R's 10 The substituents, together with the carbon atoms to which they are attached, form a spiro 4- to 7-membered heterocycloalkyl ring or spiro C 3~6 each spiro 4- to 7-membered heterocycloalkyl ring having at least one ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms independently selected from N, O, and S; a ring-forming carbon atom of each spiro 4- to 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the spiro 4- to 7-membered heterocycloalkyl ring and the spiro C 3~6 The cycloalkyl ring is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 11 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , and S(O)NR c3 R d3 are independently selected from; 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 R 12each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 12 But 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, 4-7 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 , S.R. a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , N.R. c5 R d5 , N.R. c5 C(O)R b5 , N.R. c5 C(O)OR a5 , N.R. c5 S(O)R b5 , N.R. c5 S(O)2R b5 , N.R. c5 S(O)NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O)2R b5 , and S(O)NR c5 R d5 Independently selected from the group consisting of 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 1~3Alkylene, 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 is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 But 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 , S.R. 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 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NOR a2 )R b2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 Rd2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 wherein a ring-forming carbon atom of the 4- to 10-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; 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 R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 But 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, ORa4 , S.R. a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , N.R. c4 R d4 , N.R. c4 C(O)R b4 , N.R. c4 C(O)OR a4 , N.R. c4 S(O)R b4 , N.R. c4 S(O)2R b4 , N.R. c4 S(O)NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , and S(O)NR c4 R d4 Independently selected from the group consisting of 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 R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 But 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 1~3Alkylene, 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 , S.R. a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)OR a6 , N.R. c6 R d6 , N.R. c6 C(O)R b6 , N.R. c6 C(O)OR a6 , N.R. c6 S(O)R b6 , N.R. c6 S(O)2R b6 , N.R. c6 S(O)NR c6 R d6 , S(O)R b6 , S(O)NR c6 R d6 , S(O)2R b6 , and S(O)NR c6 R d6 Independently selected from the group consisting of 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 50 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10Cycloalkyl, 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 a9 , S.R. 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 , N.R. c9 R d9 , N.R. c9 C(O)R b9 , N.R. c9 C(O)OR a9 , N.R. c9 C(O)NR c9 R d9 , C(=NR e9 )R b9 , C(=NOR a9 )R b9 , C(=NR e9 )NR c9 R d9 , N.R. c9 C(=NR e9 )NR c9 R d9 , N.R. c9 S(O)R b9 , N.R. c9 S(O)2R b9 , N.R. c9 S(O)NR c9 R d9 , S(O)R b9 , S(O)NR c9 R d9 , S(O)2R b9 , and S(O)NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, 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 R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a10 , S.R. a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , N.R. c10 C(O)R b10 , N.R. c10 C(O)OR a10 , N.R. c10 S(O)R b10 , N.R. c10 S(O)2R b10 , N.R. c10 S(O)NR c10 R d10 , S(O)R b10 , S(O)NR c10 R d10, S(O)2R b10 , and S(O)NR c10 R d10 Independently selected from the group consisting of 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 R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a11 , S.R. a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , N.R. c11 R d11 , N.R. c11 C(O)R b11 , N.R. c11 C(O)OR a11 , N.R. c11 S(O)R b11 , N.R. c11 S(O)2R b11 , N.R.c11 S(O)NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O)2R b11 , and S(O)NR c11 R d11 Independently selected from the group consisting of 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a , R c , and R d But 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; 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 3~10Cycloalkyl-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 R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b But 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; 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 R 10each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a1 , R c1 , and R d1 But 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; 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-C1~3 Alkylene is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c1 and R d1 together with the N atom to which they are attached, R 11 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b1 But 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; 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 R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e1 But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a2 , R c2 , and R d2 But 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; 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 R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c2 and Rd2 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b2 But 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; 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 R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e2 But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a3 , R c3 , and R d3 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 12 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c3 and R d3 together with the N atom to which they are attached, R 12 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b3 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 12 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a4 , R c4 , and R d4 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, C3~6 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 is R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c4 and R d4 together with the N atom to which they are attached, R 22 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b4 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Ra5 , R c5 , and R d5 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c5 and R d5 together with the N atom to which they are attached, R g forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b5 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a6 , R c6 , and R d6 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c6and R d6 together with the N atom to which they are attached, R g forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b6 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a7 , R c7 , and R d7 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a8 , R c8 , and R d8 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a9 , R c9 , and R d9 But H, C 1~6Alkyl, 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; 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 R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c9 and R d9 together with the N atom to which they are attached, R 51 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b9 But 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 3~10Cycloalkyl-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; 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 R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R e9 But H, CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkylthio, C 1~6 Alkylsulfonyl, C 1~6 Alkyl carbonyl, C 1~6 Alkylaminosulfonyl, Carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl)carbamyl, aminosulfonyl, C 1~6 Alkylaminosulfonyl, and di(C 1~6 alkyl)aminosulfonyl; Each R a10 , R c10 , and R d10 But 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, C3~6 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; 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c10 and R d10 together with the N atom to which they are attached, R 52 forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b10 But 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, 4-7 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 alkylene; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 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 is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a11 , R c11 , and R d11 But H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c11 and R d11 together with the N atom to which they are attached, R g forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R b11 But C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C 1~6 haloalkyl; 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a12 , R c12 , and R d12But 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; 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 R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c12 and R d12 together with the N atom to which they are attached, R g forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b12 But 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 heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene and 5-10 membered heteroaryl-C 1~3 alkylene; 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 R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R g 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-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 Alkyl sulfonyl, carbamyl, C 1~6 Alkylcarbamyl, di(C 1~6 Alkyl) carbamyl, carboxy, C 1~6 Alkyl carbonyl, C 1~6 Alkoxycarbonyl, C 1~6 Alkylcarbonylamino, C 1~6 Alkyl sulfonyl amino, amino sulfonyl, C 1~6 Alkylaminosulfonyl, di(C 1~6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1~6 Alkylaminosulfonylamino, di(C 1~6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1~6 Alkylaminocarbonylamino, and di(C 1~6 alkyl)aminocarbonylamino; It is a compound.

[0012] In some embodiments, R 1 Cy 1 , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, NO2, OR a , S.R. 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 , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O)2R b , N.R.c S(O)NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b , and S(O)NR c R d C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R 10 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0013] In some embodiments, R 1 Cy 1 , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, CN, OR a , S.R. 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 , N.R. c R d , N.R. c C(O)R b , and NR c C(O)OR a C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R 10 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0014] In some embodiments, R 1 Cy 1 , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6Haloalkyl, CN, OR a , C(O)R b , C(O)NR c R d , C(O)OR a ,OC(O)R b , N.R. c R d , and NR c C(O)R b C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R 10 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0015] In some embodiments, R 1 is 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 C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R 10 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0016] In some embodiments, R 1 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)NRc R d , and C(O)OR a C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R 10 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0017] In some embodiments, R 1 is 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 C is selected from 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl is R 10 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0018] In some embodiments, R 1 is C 1~6 Alkyl, CN, C(O)NR c R d , C(O)R b , and C(O)OR a C is selected from 1~6 Alkyl is R 10 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0019] In some embodiments, R 1 is C 1~6 Alkyl, CN, C(O)NR c R d , and C(O)OR a C is selected from 1~6 Alkyl is R 10Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0020] In some embodiments, R 1 is C 1~6 In some embodiments, R 1 is methyl.

[0021] In some embodiments, R 1 is C(O)OR a is.

[0022] In some embodiments, R 1 is C(O)R b is.

[0023] In some embodiments, R 1 is C(O)NR c R d is.

[0024] In some embodiments, R 1 is 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.

[0025] In some embodiments, each R 10 is 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, NO2, OR a1 , S.R. 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 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O)2R b1 , N.R. c1 S(O)NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)NR c1 R d1 C is selected from 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- to 10-membered heteroaryl are R 11 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0026] In some embodiments, each R 10 is 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 a1 , C(O)OR a1 , N.R. c1 R d1 , and S(O)NR c1 R d1 C is selected from 1~6 Alkyl, C2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 11 Each may be optionally substituted with one or two substituents independently selected from:

[0027] In some embodiments, each R 10 is 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 , N.R. c1 R d1 , and S(O)NR c1 R d1 C is selected from 1~6 Alkyl is R 11 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0028] In some embodiments, each R 10 is C 1~6 Alkyl, OR a1 , and C(O)OR a1 C is selected from 1~6 Alkyl is R 11 Each may be optionally substituted with one or two substituents independently selected from:

[0029] In some embodiments, each R 10 is C 1~6 alkyl; 1~6 Alkyl is R 11 Each may be optionally substituted with one or two substituents independently selected from:

[0030] In some embodiments, each R 10 is C(O)R b1and C(O)OR a1 In some embodiments, each R 10 is OR a1 In some embodiments, each R 10 is C(O)OR a1 is.

[0031] In some embodiments, each R 10 is selected from methyl, OH, methoxy, and ethoxycarbonyl.

[0032] In some embodiments, R 10 two of the substituents together with the carbon atoms to which they are attached form a spiro 4- to 7-membered heterocycloalkyl ring; each spiro 4- to 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, and the ring-forming carbon atoms of each spiro 4- to 7-membered heterocycloalkyl ring are optionally substituted by oxo to form a carbonyl group; and the spiro 4- to 7-membered heterocycloalkyl ring is R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0033] In some embodiments, R 10 Two of the substituents, together with the carbon atoms to which they are attached, form a spiro C 3~6 Forms a cycloalkyl ring; spiro C 3~6 The cycloalkyl ring is R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0034] In some embodiments, each R 11 is 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 6~10Aryl, 5-10 membered heteroaryl, halo, D, CN, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , N.R. c3 R d3 , and NR c3 C(O)R b3 Independently selected from the group consisting of 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- to 10-membered heteroaryl are R 12 Each may be optionally substituted with one or two substituents independently selected from:

[0035] In some embodiments, each R 11 is C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a3 , and NR c3 R d3 Independently selected from the group consisting of C 1~6 Alkyl is R 12 It may be optionally substituted with one or two substituents independently selected from:

[0036] In some embodiments, each R 11 is C 1~6 alkyl.

[0037] In some embodiments, R 1 Cy 1 is.

[0038] In some embodiments, Cy 1 is R 15 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 3~14 It is cycloalkyl.

[0039] In some embodiments, Cy 1 is a 4- to 14-membered heterocycloalkyl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S may optionally be oxidized; a ring-forming carbon atom of the 4- to 14-membered heterocycloalkyl may optionally be substituted by oxo to form a carbonyl group; and the 4- to 14-membered heterocycloalkyl may be R 15 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0040] In some embodiments, Cy 1 is R 15 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 6~10 It is aryl.

[0041] In some embodiments, Cy 1 is a 5-10 membered heteroaryl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; N and S may be optionally oxidized; a ring-forming carbon atom of the 5-10 membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; the 5-10 membered heteroaryl may be R 10 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0042] In some embodiments, R 2 is R 20 C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 6~10 It is aryl.

[0043] In some embodiments, R 2is a 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; the 5- to 10-membered heteroaryl is R 20 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0044] In some embodiments, R 2 is selected from phenyl and 5- to 6-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 6-membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; the phenyl and 5- to 6-membered heteroaryl are selected from R 20 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0045] In some embodiments, R 2 is a 5- to 6-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 6-membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; the 5- to 6-membered heteroaryl is R 20 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0046] In some embodiments, R 2 is R 20and phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0047] In some embodiments, R 2 is R 20 and phenyl optionally substituted with one or two substituents independently selected from:

[0048] In some embodiments, R 2 The para rank is R 20 is phenyl substituted with

[0049] In some embodiments, R 2 is R in the meta position 20 is phenyl substituted with

[0050] In some embodiments, R 2 is R in the ortho position 20 is phenyl substituted with

[0051] In some embodiments, R 2 is R 20 and R is a pyrazole optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0052] In some embodiments, R 2 is R 20 and R is a pyrazole optionally substituted with one or two substituents independently selected from:

[0053] In some embodiments, R 2 is selected from phenyl and pyrazole, and phenyl and pyrazole are 20 Each may be optionally substituted with one or two substituents independently selected from:

[0054] In some embodiments, each R 20 is C 1~6 Alkyl, C 2~6Alkenyl, 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 a2 , S.R. 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 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 Independently selected from the group consisting of 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- to 10-membered heteroaryl are R 21 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0055] In some embodiments, each R 20 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , N.R. c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 21 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0056] In some embodiments, each R 20 is C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 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 by oxo to form a carbonyl group; 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are R 21 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0057] In some embodiments, each R 20 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6~10 Aryl, 5-10 membered heteroaryl, C 3~10 Cycloalkyl-C 1~3 Alkylene, 4-10 membered heterocycloalkyl-C 1~3 Alkylene, C 6~10 Aryl-C 1~3 Alkylene, 5-10 membered heteroaryl-C 1~3 Alkylene, Halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , N.R. c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 wherein the ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; 1~6 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 is R 21 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0058] In some embodiments, each R 20 is 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 d2wherein ring-forming carbon atoms of the 4- to 10-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; 1~6 Alkyl, C 3~10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl-C 1~3 Alkylene is R 21 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0059] In some embodiments, each R 20 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 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 , N.R. c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 wherein the ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R 21Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0060] In some embodiments, each R 20 is 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 ring-forming carbon atoms of the 4- to 6-membered heterocycloalkyl are optionally substituted by oxo to form a carbonyl group; 1~6 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene is R 21 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0061] In some embodiments, R 20 is R 21 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 1~6 It is alkyl.

[0062] In some embodiments, R 20 is R 21 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 3~10 It is cycloalkyl.

[0063] In some embodiments, R 20 is R 21 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 3~6 It is cycloalkyl.

[0064] In some embodiments, R20 is R 21 and a ring-forming carbon atom of the 4- to 10-membered heterocycloalkyl may be optionally substituted by oxo to form a carbonyl group.

[0065] In some embodiments, R 20 is R 21 and a ring-forming carbon atom of the 4- to 10-membered heterocycloalkyl may be optionally substituted by oxo to form a carbonyl group.

[0066] In some embodiments, R 20 is R 21 4 to 10-membered heterocycloalkyl-C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 1~3 alkylene, and 4- to 10-membered heterocycloalkyl-C 1~3 A ring-forming carbon atom of an alkylene may be optionally substituted by oxo to form a carbonyl group.

[0067] In some embodiments, R 20 is R 21 4- to 6-membered heterocycloalkyl-C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 1~3 alkylene, and 4- to 6-membered heterocycloalkyl-C 1~3 A ring-forming carbon atom of an alkylene may be optionally substituted by oxo to form a carbonyl group.

[0068] In some embodiments, R 20 is a halo.

[0069] In some embodiments, R 20 is NR c2 R d2is.

[0070] In some embodiments, R 20 is C(O)NR c2 R d2 is.

[0071] In some embodiments, R 20 is selected from fluoro, piperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-methyl-2-oxopiperazin-1-yl, piperazin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, (2-methylpyrrolidin-1-yl)methyl (e.g., (2-(R)-methylpyrrolidin-1-yl)methyl), tetrahydro-2H-pyran-4-yl, 4-hydroxycyclohexyl, and piperidin-4-ylmethyl.

[0072] 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.

[0073] In some embodiments, R 20is fluoro, 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 (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.

[0074] In some embodiments, R 20 is 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.

[0075] In some embodiments, R 20are fluoro, 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 (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, (4-hydroxy-4-methylpiperidin-1-yl)methyl, (3-hydroxy- and (dimethylamino)methyl.

[0076] In some embodiments, each R 21 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a4 , C(O)NR c4 R d4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are R 22 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0077] In some embodiments, each R 21is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a4 , C(O)NR c4 R d4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are R 22 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0078] In some embodiments, each R 21 is C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, OR a4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are R 22 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0079] In some embodiments, each R 21 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, OR a4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are R 22 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0080] In some embodiments, each R 21 is C 1~6Alkyl, 4-10 membered heterocycloalkyl, and OR a4 Independently selected from the group consisting of C 1~6 Alkyl and 4- to 10-membered heterocycloalkyl are R 22 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0081] In some embodiments, R 21 is R 22 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 1~6 It is alkyl.

[0082] In some embodiments, R 21 is R 22 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 3~6 It is cycloalkyl.

[0083] In some embodiments, R 21 is R 22 and cyclohexyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0084] In some embodiments, R 21 is R 22 is a 4- to 10-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0085] In some embodiments, R 21 is R 22 is a 4- to 6-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0086] In some embodiments, R 21 is OR a4 is.

[0087] In some embodiments, R21 is NR c4 R d4 is.

[0088] In some embodiments, R 21 is a halo.

[0089] 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).

[0090] In some embodiments, R 21 is selected from methyl, F, OH, dimethylamino, hydroxy-ethyl, piperazinyl, piperidinyl, methylpyrrolidinyl, azetidinyl, mopholino, hydroxypiperidinyl, difluoroazetidinyl, methylmorpholino, hydroxymethylmorpholino, hydroxymethylpyrrolidinyl, and pyrrolidinyl.

[0091] 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, mopholino, 4-hydroxypiperidin-1-yl, 3,3-difluoroazetidin-1-yl, 2-methylmorpholino, 2-(hydroxymethyl)morpholino, 3-hydroxy-3-methylpyrrolidin-1-yl, and pyrrolidin-1-yl.

[0092] In some embodiments, R 21is selected from methyl, F, OH, dimethylamino, hydroxy-ethyl, piperazinyl, piperidinyl, methylpyrrolidinyl, azetidinyl, morpholino, hydroxypiperidinyl, hydroxymethylpiperidinyl, hydroxymethylazetidinyl, methylpiperazinyl, difluoroazetidinyl, methylmorpholino, hydroxymethylmorpholino, hydroxymethylpyrrolidinyl, and pyrrolidinyl.

[0093] 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, 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.

[0094] In some embodiments, each R 22 is C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a6 , and NR c6 R d6 Independently selected from the group consisting of C 1~6 Alkyl is R g Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0095] In some embodiments, each R 22 is C 1~6 Alkyl and OR a6 Independently selected from the group consisting of C 1~6 Alkyl is R gEach may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0096] In some embodiments, each R 22 Ha, Halo, C 1~6 Alkyl and OR a6 Independently selected from the group consisting of C 1~6 Alkyl is R g Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0097] In some embodiments, R 22 is R g C, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from 1~6 In some embodiments, R 22 is OR a6 is.

[0098] In some embodiments, R 22 is OH or methyl.

[0099] In some embodiments, R 22 is F, OH, or methyl.

[0100] In some embodiments, R 2are 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.

[0101] In some embodiments, R 2are 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-methylpiperazin-1-yl)phenyl, 4-((2R-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-pyrazolinone, 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, and 4-((dimethylamino)methyl)phenyl.

[0102] In some embodiments, R 2are 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-((2 R-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) ethyl)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-methyl 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.

[0103] In some embodiments, R 3 H, D, Halo, CN, C 1~6 Alkyl, OR a7 , and NR c7 R d7 is selected from.

[0104] In some embodiments, R 3 H, D, halo, CN, and C 1~6 alkyl.

[0105] In some embodiments, R 3 is selected from H and D.

[0106] In some embodiments, R 3 is H.

[0107] In some embodiments, R 4 H, D, Halo, CN, C 1~6 Alkyl, OR a7 , and NR c7 R d7 is selected from.

[0108] In some embodiments, R 4 H, D, halo, CN, and C 1~6 alkyl.

[0109] In some embodiments, R 4 is selected from H and D.

[0110] In some embodiments, R 4 is H.

[0111] In some embodiments, R 3 and R 4 are both H.

[0112] In some embodiments, R 5 is R 50 C, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 6~10 It is aryl.

[0113] In some embodiments, R 5is a 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; the 5- to 10-membered heteroaryl is R 50 Each may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0114] In some embodiments, R 5 is selected from quinolinyl, naphthyridinyl, pyridinyl, and phenyl, and quinolinyl, naphthyridinyl, pyridinyl, and phenyl are selected from R 50 Each may be optionally substituted with 1, 2, or 3 substituents independently selected from:

[0115] In some embodiments, R 5are 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]octan-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-methylpiperazin-1-ylcarbonyl)quinolin-4-yl 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]heptan-2-yl)quinolin-4-yl (e.g., 7-((1 S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-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.

[0116] In some embodiments, R 5are 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]octan-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-methylpiperazin-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]heptan-2-yl)quinolin-4-yl (e.g., 7-((1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-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-pyrazolinone), The aryl group is selected from 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.

[0117] In some embodiments, each R 50 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, 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)OR a9 , N.R. c9 R d9 , S(O)2R b9 , and S(O)NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 51Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0118] In some embodiments, each R 50 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, 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)OR a9 , N.R. c9 R d9 , S(O)2R b9 , and S(O)NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0119] In some embodiments, each R 50 is C 1~6 Alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halo, CN, C(O)R b9 , C(O)NR c9 R d9 , and NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 Each may be optionally substituted with 1, 2, or 3 substituents independently selected from:

[0120] In some embodiments, each R 50 is C 1~6 Alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halo, CN, C(O)R b9 , C(O)NR c9 R d9 , and NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, or 3 substituents independently selected from:

[0121] In some embodiments, each R 50 is R 51 C, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from 1~6 It is alkyl.

[0122] In some embodiments, each R 50 is R 51 and 4 to 10-membered heterocycloalkyl, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0123] In some embodiments, each R 50 is R 51 and a ring-forming carbon atom of the 4- to 10-membered heterocycloalkyl may be optionally oxidized to form a carbonyl group.

[0124] In some embodiments, each R 50 is R 51 and 5-10 membered heteroaryl, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0125] In some embodiments, each R 50 , Halo, CN, OR a9 , C(O)R b9 , C(O)NR c9 R d9 , C(O)OR a9 , and NR c9 R d9 is selected from.

[0126] In some embodiments, each R 50 is a halo.

[0127] In some embodiments, each R 50 is CN.

[0128] In some embodiments, each R 50 is C(O)R b9 is.

[0129] In some embodiments, each R 50 is C(O)NR c9 R d9 is.

[0130] In some embodiments, each R 50 is NR c9 R d9 is.

[0131] In some embodiments, each R 50is fluoro, hydroxyethyl, cyano, carbamoyl, methylcarbamoyl, pyridinyl, morpholino, morpholinomethyl, pyrazolyl, 6-oxaspiro[3.4]octanyl, pyridinylamino, benzyl, piperazinyl, piperazin-1-ylcarbonyl, pyrimidinyl, pyrazinyl, (2-hydroxyethyl)carbamoyl, hexahydropyrrolo[1,2-a]pyrazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, triazolyl, imidazolyl, and pyrazinyl, and methylcarbamoyl, pyridinyl, morpholino, morpholinomethyl, pyrazolyl, 6-oxaspiro[3.4]octanyl, pyridinylamino, benzyl, piperazinyl, piperazin-1-ylcarbonyl, pyrimidinyl, pyrazinyl, (2-hydroxyethyl)carbamoyl, hexahydropyrrolo[1,2-a]pyrazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, triazolyl, imidazolyl, and pyrazinyl are independently selected from R 51 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0132] 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]octan-2-yl, pyridin-3-ylamino, (3,5-difluorophenyl)(hydroxyl)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]heptan-2-yl (e.g., (1S,4S)-5-acetyl-2,5-diazabicyclo[2.2.1]heptan-2-yl).

[0133] In some embodiments, R 50are 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]octan-2-yl, pyridin-3-ylamino, (3,5-difluorophenyl)(hydroxyl)methyl, 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-ylcarbonyl, (2-hydroxyethyl)carbamoyl, 6-oxohexahydropyrrolo[1,2-a]pyrazine-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.

[0134] In some embodiments, R 5 is a symmetrical ... 50 and the fused 5- or 6-membered heterocycloalkyl rings are substituted with substituents which, together with the atoms to which they are attached, form a fused 5- or 6-membered heterocycloalkyl ring; the fused 5- or 6-membered heterocycloalkyl rings 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; the ring-forming carbon atoms of each fused 5- or 6-membered heterocycloalkyl ring are optionally substituted with oxo to form a carbonyl group; and the fused 5- or 6-membered heterocycloalkyl ring is optionally substituted with R 51 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0135] In some embodiments, R 5 is a symmetrical ...50 2,3-dihydrodioxine substituted with substituents, together with the atoms to which they are attached; and 1-isonicotinoylpyrrolidine: [ka] The heterocycloalkyl rings are formed by condensing the heterocycloalkyl rings selected from:

[0136] In some embodiments, R 5 is selected from pyridinyl and phenyl, and pyridinyl and phenyl are selected from R 50 each optionally substituted with 1, 2, or 3 substituents independently selected from At least two adjacent R 50 The substituents, together with the atoms to which they are attached, are: 2,3-dihydrodioxine; and 1-isonicotinoylpyrrolidine: [ka] and forming a fused heterocycloalkyl ring selected from:

[0137] In some embodiments, each R 51 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , S(O)2R b10 , and S(O)NR c10 R d10 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 52Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0138] In some embodiments, each R 51 is C 1~6 Alkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, OR a10 , and C(O)R b10 Independently selected from the group consisting of C 1~6 Alkyl, 4-10 membered heterocycloalkyl, and C 6~10 Aryl is R 52 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0139] In some embodiments, each R 51 is C 1~6 alkyl; 1~6 Alkyl is R 52 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0140] In some embodiments, each R 51 is a 4- to 10-membered heterocycloalkyl; said 4- to 10-membered heterocycloalkyl is R 52 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0141] In some embodiments, each R 51 is C 6~10 aryl; 6~10 Aryl is R 52 In some embodiments, each R 51 is OR a10 is.

[0142] In some embodiments, each R 51 is C(O)R b10 is.

[0143] In some embodiments, each R 51 is C 1~6 Alkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, OH, and C(O)R b10 Independently selected from the group consisting of C 1~6 Alkyl, 4-10 membered heterocycloalkyl, and C 6~10 Aryl is R 52 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0144] 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.

[0145] In some embodiments, each R 52 is C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a11 , and NR c11 R d11 are independently selected from

[0146] In some embodiments, each R 52 Halo and OR a11 are independently selected from

[0147] In some embodiments, each R 52 is independently selected from halo and OH.

[0148] In some embodiments, each R 52 is selected from fluoro and OH.

[0149] In some embodiments, A is N.

[0150] In some embodiments, A is CR Aand R A H, D, and C 1~6 alkyl.

[0151] In some embodiments, A is CH.

[0152] In some embodiments, each R a , R c , and R d is H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, and 4- to 10-membered heteroalkyl; 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heteroalkyl are R 10 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0153] In some embodiments, each R a , R c , and R d is H, C 1~6 Alkyl, and C 3~10 cycloalkyl, wherein C 1~6 Alkyl and C 3~10 Cycloalkyl is R 10 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0154] In some embodiments, each R a are independently selected from H and methyl.

[0155] In some embodiments, R a is methyl.

[0156] In some embodiments, R c and R d is H or C 5~6 It is cycloalkyl.

[0157] In some embodiments, Rc is H.

[0158] In some embodiments, R d is H or cyclohexyl. In some embodiments, any R c and R d together with the N atom to which they are attached, R 10 In some embodiments, R 1 and R 2 are bonded to the same N atom, forming a 4- to 10-membered heterocycloalkyl group that is optionally substituted with 1, 2, 3, or 4 substituents independently selected from c and R d together with the N atom to which they are attached form a 5- to 6-membered heterocycloalkyl.

[0159] In some embodiments, R c and R d together with the N atom to which they are attached to form perazinyl.

[0160] In some embodiments, each R b is C 1~6 Alkyl and C 1~6 haloalkyl.

[0161] In some embodiments, each R b is C 1~6 Alkyl, C 1~6 and independently selected from haloalkyl, and 4 to 10 membered heterocycloalkyl.

[0162] In some embodiments, each R a1 , R c1 , and R d1 H, and C 1~6 alkyl, 1~6 Alkyl is R 11 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0163] In some embodiments, Ra1 is H or C 1~6 It is alkyl.

[0164] In some embodiments, R a1 is H or methyl.

[0165] In some embodiments, each R b1 is C 1~6 Alkyl and C 1~6 haloalkyl.

[0166] In some embodiments, each R a2 , R c2 , and R d2 is H, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0167] In some embodiments, any R attached to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 2

[0168] In some embodiments, R c2 and R d2 together with the N atom to which they are attached form a 5- to 6-membered heterocycloalkyl group.

[0169] In some embodiments, R c2 and R d2 together with the N atom to which they are attached to form a piperazinyl.

[0170] In some embodiments, each R b is C 1~6 Alkyl and C 1~6 haloalkyl.

[0171] In some embodiments, each R a4 , R c4 , and R d4 is H and C 1~6 alkyl.

[0172] In some embodiments, each R b4 is C 1~6 Alkyl and C 1~6 haloalkyl.

[0173] In some embodiments, each R a6 , R c6 , and R d6 is H and C 1~6 alkyl.

[0174] In some embodiments, each R a6 , R c6 , and R d6 is H.

[0175] In some embodiments, each R a9 , R c9 , and R d9 is H, C 1~6 Alkyl, C 1~6 independently selected from haloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0176] In some embodiments, each R a9 , R c9 , and R d9 is H, C 1~6 alkyl, and 5- to 10-membered heteroaryl; 1~6 Alkyl and 5- to 10-membered heteroaryl are R 51 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0177] In some embodiments, any R attached to the same N atom c9 and R d9 together with the N atom to which they are attached, R 51 and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 2

[0178] In some embodiments, each R b9 is C 1~6 Alkyl and C 1~6 haloalkyl.

[0179] In some embodiments, each R a10 , R c10 , and R d10 is H and C 1~6 alkyl.

[0180] In some embodiments, each R b10 is C 1~6 Alkyl, C 1~6 independently selected from haloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; 1~6 Alkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are R 52 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0181] In some embodiments, each R a11 , R c11 , and R d11 is H and C 1~6 alkyl.

[0182] In some embodiments, each R g OH, CN, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, Amino, C 1~6Alkylamino and di(C 1~6 alkyl)amino.

[0183] In some embodiments, the compound is a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof.

[0184] In some embodiments, the compound is a compound of formula III: [ka] or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the compound is a compound of formula IVa, formula IVb: [ka] or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the compound is a compound of Formula Va, Formula Vb, or Formula Vc: [ka] or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, the compound is a compound of Formula VIa or Formula VIb: [ka] or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the compound is a compound of Formula VIIa, Formula VIIb, Formula VIIc, or Formula VIId: [ka] or a pharmaceutically acceptable salt thereof, wherein: Each X is CH, N, or CR 50 are independently selected from; Each Y is CH and CR 50 are independently selected from

[0189] In some embodiments, the compound is a compound of Formula VIIIa or Formula VIIIb: [ka] or a pharmaceutically acceptable salt thereof, wherein: Each X is CH, N, or CR 50 are independently selected from; Each Y is CH and CR 50 are independently selected from

[0190] In some embodiments, the compound of formula I is R 1 But 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 , N.R. c R d , S(O)2R b , and S(O)NR c R d C is selected from 1~6 The alkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 2 But C 6~10aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 20 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 3 H, D, halo, CN, and C 1~6 alkyl; R 4 H, D, halo, CN, and C 1~6 alkyl; R 5 But C 6~10 aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 50 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 5 The two adjacent R's above 50 The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C 3~7fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CR A and; R A But H, D, and C 1~6 is alkyl; Each R 10 But 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 , N.R. c1 R d1 , and S(O)NR c1 R d1 Independently selected from the group consisting of C 1~6 The alkyl is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, D, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , N.R. c2 R d2 , S(O)2Rb2 , and S(O)NR c2 R d2 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, D, CN, OR a4 , C(O)NR c4 R d4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 But C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a6 , and NR c6 R d6 Independently selected from the group consisting of C 1~6 The alkyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 50 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, 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)OR a9 , N.R.c9 R d9 , S(O)2R b9 , and S(O)NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , S(O)2R b10 , and S(O)NR c10 R d10 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 But C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a11 , and NR c11 R d11 are independently selected from; Each R a , R c , and R d But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10cycloalkyl, and 4 to 10 membered heterocycloalkyl; 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b But C 1~6 Alkyl and C 1~6 independently selected from haloalkyl; Each R a1 , R c1 , and R d1 However, H and C 1~6 independently selected from alkyl; Each R b1 But C 1~6 Alkyl and C 1~6 independently selected from haloalkyl; Each R a2 , R c2 , and R d2 But H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b2 But C 1~6 Alkyl and C 1~6 independently selected from haloalkyl; Each R a4 , R c4 , and R d4 However, H and C1~6 independently selected from alkyl; Each R b4 But C 1~6 Alkyl and C 1~6 independently selected from haloalkyl; Each R a6 , R c6 , and R d6 However, H and C 1~6 independently selected from alkyl; Each R a9 , R c9 , and R d9 But H, C 1~6 Alkyl, C 1~6 independently selected from haloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c9 and R d9 together with the N atom to which they are attached, R 51 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b9 But C 1~6 Alkyl and C 1~6 independently selected from haloalkyl; Each R a10 , R c10 , and R d10 However, H and C 1~6 independently selected from alkyl; Each R b10 But C 1~6 Alkyl, C 1~6 independently selected from haloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; 1~6 alkyl 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are R 52each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a11 , R c11 , and R d11 However, H and C 1~6 independently selected from alkyl; Each R g 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; It is a compound of formula I.

[0191] In some embodiments, the compound of formula I is R 1 But C 1~6 Alkyl, C 1~6 Haloalkyl, CN, C(O)R b , C(O)NR c R d , and C(O)OR a C is selected from 1~6 The alkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 2 But C 6~10 aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 20 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 3H, D, halo, CN, and C 1~6 alkyl; R 4 H, D, halo, CN, and C 1~6 alkyl; R 5 But C 6~10 aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 50 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 5 The two adjacent R's above 50 The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C 3~7 fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CR A and; R A But H, D, and C 1~6 is alkyl; Each R 10 But C 1~6 Alkyl, C1~6 Haloalkyl, Halo, D, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , N.R. c1 R d1 , and S(O)NR c1 R d1 Independently selected from the group consisting of C 1~6 The alkyl is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene, 5-6 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 , N.R. c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 wherein a ring-forming carbon atom of the 4- to 6-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3~6 Cycloalkyl-C 1~3 Alkylene, 4-6 membered heterocycloalkyl-C 1~3 Alkylene, Phenyl-C 1~3 Alkylene and 5-6 membered heteroaryl-C 1~3 Alkylene is R21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR a4 , C(O)NR c4 R d4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 But C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a6 , and NR c6 R d6 Independently selected from the group consisting of C 1~6 The alkyl is R g each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 50 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, 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)OR a9 , N.R. c9 R d9 , S(O)2R b9 , and S(O)NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C6~10 Aryl and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 But C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, halo, D, CN, OR a10 , C(O)R b10 , C(O)NR c10 R d10 , C(O)OR a10 , N.R. c10 R d10 , S(O)2R b10 , and S(O)NR c10 R d10 Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl and 5- to 10-membered heteroaryl are R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 But C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, D, CN, OR a11 , and NR c11 R d11 are independently selected from; Each R a , R c , and R d But H, C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 cycloalkyl, and 4 to 10 membered heterocycloalkyl; 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b But C 1~6 Alkyl, C 1~6 haloalkyl, and 4- to 10-membered heterocycloalkyl; and 4- to 10-membered heterocycloalkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 , R c1 , and R d1 However, H and C 1~6 independently selected from alkyl; Each R b1 But C 1~6 Alkyl and C 1~6 independently selected from haloalkyl; Each R a2 , R c2 , and R d2 But H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b2 But C 1~6 Alkyl and C 1~6 independently selected from haloalkyl; Each R a4 , R c4 , and R d4 However, H and C 1~6 independently selected from alkyl; Each R b4 But C 1~6Alkyl and C 1~6 independently selected from haloalkyl; Each R a6 , R c6 , and R d6 However, H and C 1~6 independently selected from alkyl; Each R a9 , R c9 , and R d9 But H, C 1~6 Alkyl, C 1~6 independently selected from haloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c9 and R d9 together with the N atom to which they are attached, R 51 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b9 But C 1~6 Alkyl and C 1~6 independently selected from haloalkyl; Each R a10 , R c10 , and R d10 However, H and C 1~6 independently selected from alkyl; Each R b10 But C 1~6 Alkyl, C 1~6 independently selected from haloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; 1~6 alkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a11 , R c11 , and R d11But H, and C 1~6 independently selected from alkyl; Each R g 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; It is a compound of formula I.

[0192] In some embodiments, the compound of formula I is R 1 But C 1~6 Alkyl, CN, C(O)NR c R d , and C(O)OR a C is selected from 1~6 The alkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 2 But C 6~10 aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 20 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 3 is H; R 4 is H; R 5 But C 6~10aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 50 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 5 The two adjacent R's above 50 the substituents, together with the atoms to which they are attached, form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CH; Each R 10 But C 1~6 Alkyl, OR a1 , and C(O)OR a1 Independently selected from the group consisting of C 1~6 The alkyl is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 But C 1~6 Alkyl, C 3~10 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, and C(O)NR c2 R d2Independently selected from the group consisting of C 1~6 Alkyl, C 3~10 Cycloalkyl and 4- to 10-membered heterocycloalkyl are R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 But C 1~6 independently selected from alkyl, 4- to 10-membered heterocycloalkyl, and OH; 1~6 alkyl and 4- to 10-membered heterocycloalkyl are R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 But C 1~6 independently selected from alkyl and OH; Each R 50 But C 1~6 Alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halo, CN, C(O)NR c9 R d9 , and NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 But C 1~6 Alkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, OH, and C(O)R b10 Independently selected from the group consisting of C 1~6 Alkyl, 4-10 membered heterocycloalkyl, and C 6~10 Aryl is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 are independently selected from halo and OH; Each R a , R c , and R d But H, C1~6 Alkyl, and C 3~10 cycloalkyl; 1~6 Alkyl and C 3~10 Cycloalkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R a1 However, H and C 1~6 independently selected from alkyl; Each R a2 , R c2 , and R d2 But H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R c9 and R d9 But H, C 1~6 alkyl, and 5- to 10-membered heteroaryl; 1~6 Alkyl and 5-10 membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c9 and R d9 together with the N atom to which they are attached, R 51 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b10 But C 1~6 independently selected from alkyl and 5- to 6-membered heteroaryl; 1~6 Alkyl and 5-6 membered heteroaryl are R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from It is a compound of formula I.

[0193] In some embodiments, the compound of formula I is R 1 But C 1~6 Alkyl, CN, C(O)NR c R d , C(O)R b , and C(O)OR a C is selected from 1~6 The alkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 2 is selected from phenyl and 5- to 6-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 6-membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; the phenyl and 5- to 6-membered heteroaryl are selected from R 20 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 3 is H; R 4 is H; R 5 But C 6~10aryl and 5- to 10-membered heteroaryl; 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; N and S may be optionally oxidized; a ring-forming carbon atom of the 5- to 10-membered heteroaryl may be optionally substituted with oxo to form a carbonyl group; C 6~10 Aryl and 5- to 10-membered heteroaryl are R 50 each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R 5 The two adjacent R's above 50 the substituents, together with the atoms to which they are attached, form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CH; Each R 10 But C 1~6 Alkyl, OR a1 , and C(O)OR a1 Independently selected from the group consisting of C 1~6 The alkyl is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 But C 1~6 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl-C 1~3Alkylene, Halo, NR c2 R d2 , and C(O)NR c2 R d2 wherein a ring-forming carbon atom of the 4- to 6-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; 1~6 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene is R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 But C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, OR a4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 But C 1~6 independently selected from alkyl, halo, and OH; Each R 50 But C 1~6 Alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halo, CN, C(O)NR c9 R d9 , and NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 But C 1~6 Alkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, OH, and C(O)Rb10 Independently selected from the group consisting of C 1~6 Alkyl, 4-10 membered heterocycloalkyl, and C 6~10 Aryl is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 are independently selected from halo and OH; Each R a , R c , and R d But H, C 1~6 Alkyl, and C 3~10 cycloalkyl; 1~6 Alkyl and C 3~10 Cycloalkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b But C 1~6 Alkyl, C 1~6 haloalkyl, and 4- to 10-membered heterocycloalkyl; and 4- to 10-membered heterocycloalkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 However, H and C 1~6 independently selected from alkyl; Each R a2 , R c2 , and R d2 But H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R a4 , R c4 , and R d4 But H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c4 and R d4 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R c9 and R d9 But H, C 1~6 alkyl, and 5- to 10-membered heteroaryl; 1~6 Alkyl and 5-10 membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c9 and R d9 together with the N atom to which they are attached, R 51 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b10 But C 1~6 independently selected from alkyl and 5- to 6-membered heteroaryl; 1~6 Alkyl and 5-6 membered heteroaryl are R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from It is a compound.

[0194] In some embodiments, the compound of formula I is R 1 But C 1~6Alkyl, CN, C(O)NR c R d , C(O)R b , and C(O)OR a C is selected from 1~6 The alkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 2 is selected from phenyl and pyrazolyl; phenyl and pyrazolyl are selected from R 20 each optionally substituted with 1 or 2 substituents independently selected from R 3 is H; R 4 is H; R 5 is selected from quinolinyl, naphthyridinyl, pyridinyl, and phenyl; quinolinyl, naphthyridinyl, pyridinyl, and phenyl are selected from R 50 each optionally substituted with 1, 2, or 3 substituents independently selected from Or R 5 The two adjacent R's above 50 the substituents, together with the atoms to which they are attached, form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CH; Each R 10 But C 1~6 Alkyl, OR a1 , and C(O)ORa1 Independently selected from the group consisting of C 1~6 The alkyl is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 But 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 a ring-forming carbon atom of the 4- to 6-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; 1~6 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl-C 1~3 Alkylene is R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 But C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, OR a4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 But C 1~6 independently selected from alkyl, halo, and OH; Each R 50 But C 1~6 Alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halo, CN, C(O)NR c9 R d9 , and NR c9 R d9Independently selected from the group consisting of C 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 But C 1~6 Alkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, OH, and C(O)R b10 Independently selected from the group consisting of C 1~6 Alkyl, 4-10 membered heterocycloalkyl, and C 6~10 Aryl is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 are independently selected from halo and OH; Each R a , R c , and R d But H, C 1~6 Alkyl, and C 3~10 cycloalkyl; 1~6 Alkyl and C 3~10 Cycloalkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b are independently selected from 4- to 6-membered heterocycloalkyl; and 4- to 6-membered heterocycloalkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 However, H and C 1~6 independently selected from alkyl; Each Ra2 , R c2 , and R d2 But H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R a4 , R c4 , and R d4 But H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c4 and R d4 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R c9 and R d9 But H, C 1~6 alkyl, and 5- to 10-membered heteroaryl; 1~6 Alkyl and 5-10 membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c9 and R d9 together with the N atom to which they are attached, R 51 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b10 But C 1~6 independently selected from alkyl and 5- to 6-membered heteroaryl; 1~6 Alkyl and 5-6 membered heteroaryl are R 52each optionally substituted with 1, 2, 3, or 4 substituents independently selected from It is a compound.

[0195] In some embodiments, the compound is a compound of Formula VIa or Formula VIb: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 1~6 Alkyl, CN, C(O)NR c R d , C(O)R b , and C(O)OR a C is selected from 1~6 Alkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 is selected from quinolinyl, naphthyridinyl, pyridinyl, and phenyl; quinolinyl, naphthyridinyl, pyridinyl, and phenyl are selected from R 50 each optionally substituted with 1, 2, or 3 substituents independently selected from Or R 5 The two adjacent R's above 50 The substituents, together with the atoms to which they are attached, form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring; each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CH; Each R 10 is C 1~6 Alkyl, OR a1 , and C(O)OR a1 Independently selected from the group consisting of C 1~6 Alkyl is R 11 optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 is 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 by oxo to form a carbonyl group; 1~6 Alkyl, C 3~6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C 1~3 Alkylene is R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-6 membered heterocycloalkyl, halo, OR a4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 6-membered heterocycloalkyl are R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 is C 1~6 independently selected from alkyl, halo, and OH; Each R 50 is C 1~6Alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halo, CN, C(O)NR c9 R d9 , and NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 is C 1~6 Alkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, OH, and C(O)R b10 Independently selected from the group consisting of C 1~6 Alkyl, 4-10 membered heterocycloalkyl, and C 6~10 Aryl is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 are independently selected from halo and OH; Each R a , R c , and R d is H, C 1~6 Alkyl, and C 3~10 cycloalkyl; 1~6 Alkyl and C 3~10 Cycloalkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b are independently selected from 4- to 6-membered heterocycloalkyl, and the 4- to 6-membered heterocycloalkyl is selected from R 10each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 is H and C 1~6 independently selected from alkyl; Each R a2 , R c2 , and R d2 is H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R a4 , R c4 , and R d4 is H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c4 and R d4 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R c9 and R d9 is H, C 1~6 alkyl, and 5- to 10-membered heteroaryl groups; 1~6 Alkyl and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c9 and R d9 together with the N atom to which they are attached, R 51forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b10 is C 1~6 independently selected from alkyl and 5- to 6-membered heteroaryl; 1~6 Alkyl and 5-6 membered heteroaryl are R 52 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0196] In some embodiments, the present disclosure provides a compound of Formula VIIa, Formula VIIb, Formula VIIc, or Formula VIId: [ka] or a pharmaceutically acceptable salt thereof, wherein: Each X is CH, N, or CR 50 are independently selected from; Each Y is CH and CR 50 are independently selected from; R 1 is C 1~6 Alkyl, CN, C(O)NR c R d , C(O)R b , and C(O)OR a C is selected from 1~6 Alkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CH; Each R 10 is C 1~6 Alkyl, OR a1 , and C(O)OR a1 Independently selected from the group consisting of C 1~6 Alkyl is R 11 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 20 is C 1~6 Alkyl, C 3~10Cycloalkyl, 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 by oxo to form a carbonyl group; 1~6 Alkyl, C 3~10 Cycloalkyl, 4- to 10-membered heterocycloalkyl, and 4- to 10-membered heterocycloalkyl-C 1~3 Alkylene is R 21 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 21 is C 1~6 Alkyl, C 3~6 Cycloalkyl, 4-10 membered heterocycloalkyl, halo, OR a4 , and NR c4 R d4 Independently selected from the group consisting of C 1~6 Alkyl, C 3~6 Cycloalkyl and 4- to 10-membered heterocycloalkyl are R 22 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 22 is C 1~6 independently selected from alkyl, halo, and OH; Each R 50 is C 1~6 Alkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halo, CN, C(O)NR c9 R d9 , and NR c9 R d9 Independently selected from the group consisting of C 1~6 Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or R 5The two adjacent R's above 50 the substituents, together with the atoms to which they are attached, form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C 3~7 The cycloalkyl ring is R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 51 is C 1~6 Alkyl, 4-10 membered heterocycloalkyl, C 6~10 Aryl, OH, and C(O)R b10 Independently selected from the group consisting of C 1~6 Alkyl, 4-10 membered heterocycloalkyl, and C 6~10 Aryl is R 52 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 52 are independently selected from halo and OH; Each R a , R c , and R d is H, C 1~6 Alkyl, and C 3~10 cycloalkyl; 1~6 Alkyl and C 3~10 Cycloalkyl is R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c and R d together with the N atom to which they are attached, R 10forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b are independently selected from 4- to 6-membered heterocycloalkyl; and the 4- to 6-membered heterocycloalkyl is selected from R 10 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 is H and C 1~6 independently selected from alkyl; Each R a2 , R c2 , and R d2 is H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c2 and R d2 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R a4 , R c4 , and R d4 is H, C 1~6 Alkyl, and C 1~6 independently selected from haloalkyl; Or any R bonded to the same N atom c4 and R d4 together with the N atom to which they are attached, R 21 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R c9 and R d9 is H, C 1~6 alkyl, and 5- to 10-membered heteroaryl; 1~6 Alkyl and 5- to 10-membered heteroaryl are R 51 each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom c9 and R d9 together with the N atom to which they are attached, R 51 forming a 4-10 membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R b10 is C 1~6 independently selected from alkyl and 5- to 6-membered heteroaryl; 1~6 Alkyl and 5-6 membered heteroaryl are R 52 Each may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0197] 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.

[0198] The present disclosure further provides pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0199] The present disclosure further provides a method of inhibiting ALK2 activity, said method comprising administering to a patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0200] The present disclosure further provides a method of treating a disease or disorder associated with inhibition of ALK2 interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0201] The present disclosure further provides a method of treating cancer in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0202] The present disclosure further provides a method of treating a myeloproliferative disorder in a patient, said method comprising administering to the patient therapeutically effective amounts of a compound of the invention or a pharmaceutically acceptable salt thereof and ruxolitinib or a pharmaceutically acceptable salt thereof.

[0203] It is further understood that certain features of the disclosure that are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (wherein multiple embodiments are intended to be combined as if described in multiple sub-formulas). Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. Accordingly, it is contemplated that features described as embodiments of compounds of formula (I) can be combined in any suitable combination.

[0204] At various places in the present specification, certain features of compounds are disclosed in groups or ranges. It is expressly intended that such disclosure also include every individual subcombination of the members of such groups and ranges. For example, "C 1~6 The term "alkyl" is expressly intended to individually disclose, but not be limited to, methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0205] The term "n-membered," where n is an integer, typically refers to the number of ring-forming atoms at the moiety where n is the number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0206] At various places in this specification, variables defining divalent linking groups may be described. Each linking substituent is expressly intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R") n-NR(CR'R") n -and-(CR'R") n Both NR- and NR- are included and each individual form is intended to be disclosed. If a structure requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if a structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl," it is understood that "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, which is the linking group.

[0207] The term "substituted" means that an atom or group of atoms formally replaces hydrogen as a "substituent" attached to another group. The term "substituted" refers to any level of substitution, e.g., mono-, di-, tri-, tetra-, or penta-substitution, unless otherwise indicated, where such substitution is permitted. Substituents are independently selected, and substitution may be at any chemically understood possible position. It should be understood that substitution at a given atom is limited by valency. It should be understood that substitution at a given atom results in a chemically stable molecule. The phrase "optionally substituted" means unsubstituted or substituted. The term "substituted" means that a hydrogen atom has been removed and replaced with a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.

[0208] "C n~m " refers to an inclusive range, where n and m are integers and indicate the number of carbons. Examples include C 1~4 , C 1~6 Examples include:

[0209] The term "alkyl," used alone or in combination with other terms, refers to a saturated hydrocarbon group which may be straight-chained or branched. n~mThe term "alkyl" refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C-H bond replaced at the point of attachment of the alkyl group to the remainder 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; and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc.

[0210] The term "alkenyl," used alone or in combination with other terms, refers to a straight-chain or branched 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 at the point of attachment of the alkenyl group to the rest of the compound. n~m The term "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, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0211] The term "alkynyl," used alone or in combination with other terms, refers to a straight-chain or branched 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 at the point of attachment of the alkyl group to the rest of the compound. n~m The term "alkynyl" refers to an alkynyl group having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0212] The term "alkylene," used alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C-H bonds replaced by points of attachment of the alkylene group to the rest of the compound. n~m The term "alkylene" refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups 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.

[0213] The term "alkoxy", used alone or in combination with other terms, refers to a radical of the formula -O-alkyl, wherein the alkyl radical is as defined above. n~m The term "alkoxy" refers to an alkoxy group, where the alkyl group has n to m carbons. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0214] The term "alkoxylene," used alone or in combination with other terms, refers to a divalent alkoxy linking group. An alkoxylene group formally corresponds to a group of the formula -O-alkyl, in which the C-H bond is replaced by the point of attachment of the alkoxylene group to the remainder of the compound. n~m The term "alkoxylene" refers to an alkoxylene group having n to m carbon atoms.

[0215] The term "amino" refers to a group of formula -NH2.

[0216] The term "carbonyl," used alone or in combination with other terms, refers to a -C(=O)- group, which can also be written as C(O).

[0217] As used herein, the terms "carbamoyl" and "carbamyl" are interchangeable and refer to a group of formula -C(O)NH2.

[0218] As used herein, the term "carboxy" refers to a group of formula -C(O)OH.

[0219] The term "cyano" or "nitrile" refers to a group of formula -C≡N, which can also be written -CN.

[0220] As used herein, "C 1~3 Alkoxy-C 1~3 The term "alkyl" refers to a group of the formula -(C 1~3 alkylene)-(C 1~3 It refers to the group (alkoxy).

[0221] As used herein, "C 1~3 Alkoxy-C 1~3 The term "alkoxy" refers to a group of the formula -(C 1~3 Alkoxylene)-(C 1~3 It refers to the group (alkoxy).

[0222] As used herein, "HO-C" 1~3 The term "alkoxy" refers to a group of the formula -(C 1~3 It refers to the group alkoxylene)-OH.

[0223] As used herein, "HO-C" 1~3 The term "alkyl" refers to a group of the formula -(C 1~3 refers to the group alkylene-OH.

[0224] As used herein, "cyano-C" 1~3 The term "alkyl" refers to a group of the formula -(C 1~3 refers to the group alkylene-CN.

[0225] As used herein, "H2N-C 1~3 The term "alkyl" refers to a group of the formula -(C 1~3 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, the halo group is F.

[0226] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced with halogen atoms.

[0227] "C n~m The term "haloalkyl" refers to a C alkyl group having n to m carbon atoms and at least 1 and at most {2(n to m)+1} halogen atoms. n~m "haloalkyl" refers to alkyl groups, which may be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, haloalkyl groups have 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like. In some embodiments, the haloalkyl groups are fluoroalkyl groups.

[0228] The term "haloalkoxy," used alone or in combination with other terms, refers to a radical of the formula -O-haloalkyl, wherein the haloalkyl group is as defined above. n~m The term "haloalkoxy" refers to a haloalkoxy group, where the haloalkyl group has n to m carbon atoms. Exemplary haloalkoxy groups include trifluoromethoxy, and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0229] The term "oxo" refers to an oxygen atom as a divalent substituent, which when attached to a carbon forms a carbonyl group, or when attached to a heteroatom forms a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, heterocyclic groups can be optionally substituted with one or two oxo (=O) substituents.

[0230] The term "sulfide" refers to a divalent sulfur atom which, when attached to carbon, forms a thiocarbonyl group (C=S).

[0231] As used herein, "C n~m The term "alkylamino" refers to a group of formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0232] As used herein, "C n~m The term "alkoxycarbonyl" refers to a group of formula -C(O)O-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0233] As used herein, "C n~m The term "alkylcarbonyl" refers to a group of formula -C(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0234] As used herein, "C n~m The term "alkylcarbonylamino" refers to a group of formula -NHC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0235] As used herein, "C n~mThe term "alkylsulfonylamino" refers to a group of formula -NHS(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0236] The term "aminosulfonyl," as used herein, refers to a group of formula -S(O)2NH2.

[0237] As used herein, "C n~m The term "alkylaminosulfonyl" refers to a group of formula -S(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0238] As used herein, "di(C n~m The term "(alkyl)aminosulfonyl" refers to a group of formula -S(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0239] The term "aminosulfonylamino" as used herein refers to a group of formula -NHS(O)2NH2.

[0240] As used herein, "C n~m The term "alkylaminosulfonylamino" refers to a group of formula -NHS(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0241] As used herein, "di(C n~m The term "NHS(O)N(alkyl)aminosulfonylamino" refers to a group of formula -NHS(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0242] As used herein, the term "aminocarbonylamino," used alone or in combination with other terms, refers to a group of formula -NHC(O)NH2.

[0243] As used herein, "C n~m The term "alkylaminocarbonylamino" refers to a group of formula -NHC(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0244] As used herein, "di(C n~m The term "NHC(O)N(alkyl)aminocarbonylamino" refers to a group of formula -NHC(O)N(alkyl), where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0245] As used herein, "C n~m The term "alkylcarbamyl" refers to a group of formula -C(O)-NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0246] As used herein, "di(C n~m The term "(-alkyl)carbamyl" refers to a group of formula -C(O)N(alkyl), where the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0247] As used herein, the term "thio" refers to a group of formula -SH.

[0248] As used herein, "C n~mThe term "alkylthio" refers to a group of formula -S-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0249] As used herein, "C n~m The term "alkylsulfinyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0250] As used herein, "C n~m The term "alkylsulfonyl" refers to a group of formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0251] 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).

[0252] The term "aryl," used alone or in combination with other terms, refers to an aromatic hydrocarbon group that may be monocyclic or polycyclic (e.g., having two fused rings). n~m The term "aryl" refers to an aryl group having n to m ring carbon atoms. Examples of aryl groups include phenyl, naphthyl, and the like. In some embodiments, an aryl group has 6 to about 10 carbon atoms. In some embodiments, an aryl group has 6 carbon atoms. In some embodiments, an aryl group has 10 carbon atoms. In some embodiments, an aryl group is phenyl. In some embodiments, an aryl group is naphthyl.

[0253] The terms "heteroaryl" or "heteroaromatic," used alone or in combination with other terms, refer 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 may be an N-oxide. In some embodiments, the heteroaryl has 5 to 10 ring atoms, including 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 to 6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl ring. In other embodiments, the heteroaryl is an 8-, 9-, or 10-membered fused bicyclic heteroaryl ring. Exemplary heteroaryl groups include, but are not limited to, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,4-diphenyl-2,5-dione), phenyl, ... ,6-naphthyridine), indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, pyrazolopyrimidinyl (including pyrazolo[1,5-a]pyrimidine and pyrazolo[4,3-d]pyrimidinyl), imidazopyrindinyl (i.e., imidazo[1,2-a]pyridinyl), and the like. In some embodiments, the heteroaryl group is a pyridone (e.g., 2-pyridone).Exemplary 5-membered 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 6-membered heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

[0254] The term "cycloalkyl," used alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic) containing cyclized alkyl and alkenyl groups. n~m The term "cycloalkyl" refers to a cycloalkyl having n to m ring carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, or 7 ring carbon atoms (C 3~7 Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring carbons (C 3~10 In some embodiments, the cycloalkyl group has 3 to 6 ring atoms, 3 to 5 ring atoms, or 3 to 4 ring atoms. 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 3~6Monocyclic cycloalkyl groups. Ring-forming carbon atoms of a cycloalkyl group may be optionally oxidized to form oxo or sulfido groups. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. The definition of cycloalkyl also includes moieties having one or more aromatic rings fused to the cycloalkyl ring (i.e., sharing a common bond with the cycloalkyl ring), such as benzo or thienyl derivatives such as cyclopentane and cyclohexane. Cycloalkyl groups containing fused aromatic rings can be bonded through any ring-forming atom, including the ring-forming atoms of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, the cyclopropyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0255] 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 having at least one heteroatom ring component independently selected from nitrogen, sulfur, oxygen, and phosphorus, and having 4 to 10 ring atoms, 4 to 7 ring atoms, or 4 to 6 ring atoms. The term "heterocycloalkyl" includes monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include monocyclic or bicyclic (e.g., having two fused or bridged rings) or spiro ring systems. In some embodiments, heterocycloalkyl groups are monocyclic groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally oxidized to form oxo or sulfido groups or other oxidized bonds (e.g., C(O), S(O), C(S), or S(O)2, N-oxide, etc.), or the nitrogen atom may be quaternized. A heterocycloalkyl group can be bonded through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, a heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, a heterocycloalkyl group contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as benzo- or thienyl derivatives, e.g., piperidine, morpholine, azepine, etc. Heterocycloalkyl groups containing fused aromatic rings may be bonded through any ring-forming atom, including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, 2,5λ 2-diazabicyclo[2.2.1]heptan-2-yl, 6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, 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 thiomorpholino.

[0256] In certain positions, multiple definitions or embodiments refer to certain rings (for example, azetidine rings, pyridine rings, etc.). Unless otherwise specified, these rings can be bonded to any ring atom, as long as the valence of the atom is not exceeded. For example, the azetidine ring can be bonded at any position on the ring, while the azetidin-3-yl ring is bonded at the 3-position.

[0257] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0258] Resolution of racemic mixtures of compounds can be achieved by any of a number of methods known in the art. One method involves fractional crystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Resolving agents suitable for fractional crystallization include, for example, optically active acids such as D- and L-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, and lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization include stereomerically pure α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0259] Resolution of racemic mixtures can also be achieved by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Appropriate elution solvent compositions can be determined by one skilled in the art.

[0260] In some embodiments, the compounds of the present disclosure have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with two or more chiral centers, unless otherwise specified, each chiral center of the compound may independently be (R) or (S). Compounds with two chiral centers can have, for example, the (R,R), (R,S), (S,R), or (S,S) configuration.

[0261] The compounds of the present disclosure also include tautomeric forms. Tautomeric forms are obtained by the exchange of a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Exemplary prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position on a heterocyclic ring 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 may be in equilibrium or sterically locked into one form by appropriate substitution.

[0262] The compounds of the present disclosure may also include all isotopes of atoms present in intermediate or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present disclosure can be replaced or substituted with an isotope of the atom in a natural or unnatural abundance ratio. In some embodiments, the compounds contain 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 contain two or more deuterium atoms. In some embodiments, the compounds contain 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 by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic studies, and / or assays.

[0263] Substitution with heavier isotopes, such as deuterium, can confer certain therapeutic advantages, such as greater metabolic stability, increased in vivo half-life, or reduced dosage requirements, and therefore may be preferable in some circumstances (A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

[0264] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structures. The term is also intended to refer to compounds of the present disclosure regardless of their method of preparation, for example, by synthesis, by biological process (e.g., metabolic or enzymatic transformation), or by a combination thereof.

[0265] All compounds and pharmaceutically acceptable salts thereof may exist together with other substances, such as water and solvents (e.g., hydrates and solvates), or may be isolated. When in the solid state, the compounds described herein and their salts may exist in various forms and may be in the form of solvates, such as hydrates. Because the compounds may be in any solid form, such as polymorphs or solvates, unless expressly indicated otherwise, references herein to compounds and their salts should be understood to encompass any solid form of the compound.

[0266] In some embodiments, the disclosed compounds or salts thereof are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the disclosed compounds. Substantial separation can include a composition comprising at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the disclosed compounds or salts thereof.

[0267] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosages that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0268] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature about the same as the temperature of the room in which the reaction is carried out, e.g., from about 20°C to about 30°C, e.g., the reaction temperature.

[0269] 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 modified by converting an existing acid or basic moiety in the parent compound 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 or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 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.

[0270] synthesis 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 many possible synthetic routes, such as the following schemes.

[0271] The reactions to prepare the compounds provided herein can be carried out in a suitable solvent that can be easily selected by one skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, 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 two or more solvents. Depending on the specific reaction step, one skilled in the art can select a solvent suitable for the specific reaction step.

[0272] The preparation of the compounds provided herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, for example, in T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0273] The reaction can be followed according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), can be followed by spectroscopic means such as 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).

[0274] As used herein, the expressions "ambient temperature," "room temperature," and "rt" are art-recognized and generally refer to a temperature about the same as the room temperature in which a reaction is carried out, e.g., from about 20°C to about 30°C, e.g., the reaction temperature.

[0275] The compounds disclosed herein can be prepared by those skilled in the art according to preparation routes known in the literature and various possible synthetic routes. Exemplary synthetic methods for preparing the compounds of the present application are shown in the following schemes.

[0276] 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 diphenylmethanimine (Tetrahedron Lett. 1997, 38, 6367-6370) followed by hydrolysis under acidic conditions. Cycloaddition of aminopyridazine 3 with 2-chloroacetaldehyde gives imidazo[1,2-b]pyridazine 4, which can be converted to the corresponding imidazo[1,2-b]pyridazine iodide 5 by treatment with NIS. Boronic acid or ester R 5 Suzuki coupling with B(OR')2 (J. Am. Chem. Soc. 2010, 132, 14073-14075) gives compound 6, which can be synthesized by the appropriate boronic acid or ester R 2 Further Suzuki coupling with B(OR')2 can be carried out to convert to the desired imidazo[1,2-b]pyridazine derivative 7. Alternatively, the boronic acid or ester R 2 Suzuki coupling of imidazo[1,2-b]pyridazine 4 with B(OR')2 gives compound 8, which can be converted to compound 9 by treatment with NIS. The imidazo[1,2-b]pyridazine iodide 9 can then be reacted with the appropriate boronic acid or ester R 5 Suzuki coupling with B(OR')2 can convert it to the desired imidazo[1,2-b]pyridazine derivative 7. Scheme 1 [ka]

[0277] 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-carboxylates 10, prepared according to the procedure outlined in Scheme 1, can be converted to the corresponding acids 11 by hydrolysis. Acid 11 can then be converted to the desired imidazo[1,2-b]pyridazine-6-carboxamide derivative 12 by coupling with an appropriate amine using an amidating coupling reagent such as, but not limited to, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium 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). Scheme 2 [ka]

[0278] 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 can give compound 16, which can then be converted to the corresponding iodide 17 by treatment with NIS. The appropriate boronic acid or ester R 5 Suzuki coupling with B(OR')2 affords the desired imidazo[1,2-b]pyridazine-6-carbonitrile derivative 18. Scheme 3 [ka]

[0279] 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. Alcohol 20 can then be converted to the corresponding boronic acid or ester R. 2 B(OR')2 can be converted to compound 21 by Suzuki coupling. Treatment of compound 21 with NIS gives the corresponding iodide 22, which can be converted to the appropriate boronic acid or ester R 5 Suzuki coupling with B(OR')2 can convert it to the desired imidazo[1,2-b]pyridazine derivative 23. Scheme 4 [ka]

[0280] A series of imidazo[1,2-a]pyridine derivatives 28 can be prepared according to the procedure outlined in Scheme 5. Cycloaddition of aminopyridine 24 with 2-chloroacetaldehyde gives compound 25, which can be reacted with boronic acids or esters R 2 The compound 26 can be converted to compound 26 by Suzuki coupling with B(OR')2. Treatment of compound 26 with NIS gives the corresponding iodide 27, which can be converted to the appropriate boronic acid or ester R 5 Suzuki coupling with B(OR')2 can convert to the desired imidazo[1,2-a]pyridine derivative 28. Scheme 5 [ka]

[0281] The present invention will be described in detail with specific examples.The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way.Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to produce essentially the same results.Example compounds are listed below.

[0282] Preparative LC-MS purification of some of the prepared compounds was performed on a Waters mass spectrometer. The basic instrument configuration, 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). To confirm purity, the isolated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) under the following conditions: Instrument: Agilent 1100 series LC / MSD; Column: Waters Sunfire™ C 18 Particle size 5 μm, 2.1×5.0 mm, buffer: Mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient from 2% to 80% of B in 3 minutes at a flow rate of 2.0 mL / min.

[0283] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with MS detection, as shown in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows: Purification at pH=2: Waters Sunfire™ C 18The column was 5 μm in particle size, 30 × 100 mm, and eluted with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 60 mL / min. The separation gradient was optimized for each compound using a 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)]. Purification at pH=10: Waters XBridge C 18 The column was 5 μm particle size, 30 × 100 mm, and eluted with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the flow rate was 60 mL / min. The elution gradient was optimized for each compound using a 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)].

[0284] How to use The present disclosure provides a method for modulating (e.g., inhibiting) ALK2 activity, the method 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 drugs or therapies, or as adjuvants or neoadjuvants for the treatment of diseases or disorders, including cancer. Any compound of the present disclosure, including any embodiment thereof, can be used for the uses described herein.

[0285] In myelofibrosis (MF), a significant 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). Increased serum hepcidin levels in MF patients have been shown to be associated with increased hemoglobin (Hb) levels, increased RBC transfusion requirements, and decreased survival (Pardanani, A. et al. American Journal of Hematology 2013, 88, 312-316). BMP signaling plays a central role in promoting hepcidin transcriptional induction by activating SMAD signaling. In an anemic mouse model, liver-specific deletion of ALK2 or ALK3 can prevent hepcidin production and the induction of iron overload (Steinbicker, A.U. et al. Blood 2011, 118, 4224-4230). Therefore, hepcidin-mediated internalization and degradation of FPN1 may not require the action of JAK2, and ALK2 inhibition may be useful in combination with ruxolitinib in the treatment of MF patients (Ross, SL, et al. Cell Metabolism 2012, 15, 905-917). ALK2 inhibition may block the adverse effects of hepcidin on iron metabolism and improve anemia in MF patients (As shoff, M. et al. Blood 2017, 129, 1823-1830).

[0286] Fibrodysplasia ossificans progressiva (FOP) is a rare genetic bone disease characterized by extraskeletal bone formation due to endochondral ossification (Yu, P.B., et al. Nature Medicine 2008, 14, 1363-1369; Fukuda, T. et al. Journal of Biological Chemistry 2009, 284, 7149-7156). Ninety-five percent of FOP patients harbor point mutations in ACVR1 / ALK2, and the typical FOP-associated mutation 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 in patients with atypical FOP are also found in the GS domain or other amino acids in the protein kinase domain (Fukuda, T. et al. Biochemical and Biophysical Research Communications 2008, 377, 905-909). Various ALK2 mutants have been shown to constitutively activate BMP signaling without exogenous BMP ligands, and these ALK2 mutants are able to constitutively activate BMP signaling upon ligand stimulation (Van Dinther, M. et al. Journal of Bone and Mineral Research 2010, 25, 1208-1215).

[0287] Activating mutations in ALK2 have also been identified in diffuse pontine glioma (DIPG), a highly aggressive glial neoplasm of the pontine ventral region in pediatric patients. ALK2 was reported to be one of the most frequently mutated genes in DIPG. ALK2 was found to harbor nonsynonymous heterozygous somatic mutations at five specific residues in 46 of 195 cases (24%). Patients with ALK2 mutations were predominantly female (approximately 2:1) and had a younger age at onset (approximately 5 years) and longer overall survival (approximately 15 months) compared with wild-type IDPG. These ALK2 mutations are highly specific to DIPG, and the ALK2 inhibitor LDN-19318917 significantly inhibits the viability of these ALK2 mutant DIPG cells (Taylor, K. et al. Nature Genetics 2014, 46, 457-461; Buczkowicz, P. et al. Nature Genetics 2014, 46, 451-456).

[0288] Methods for treating diseases or disorders associated with inhibition of 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 using 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, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, uterine 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 (acute myeloid leukemia), and other cancers. cancers, such as leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, childhood solid tumors, chronic lymphocytic leukemia, bladder cancer, cancer of the kidney or urethra, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers such as those induced by asbestos, and combinations of the foregoing cancers.

[0289] In some embodiments, cancers treatable using the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate cancer), breast cancer, triple-negative breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer and small cell lung cancer). In addition, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0290] In some embodiments, cancers treatable using 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.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (such as relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of the foregoing cancers.

[0291] In some embodiments, diseases and conditions treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0292] Exemplary hematological cancers include lymphomas and leukemias (such as acute lymphocytic 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's lymphomas (such as relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic leukemia (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0293] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma. Exemplary sarcomas also include lymphosarcoma and leiomyosarcoma.

[0294] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma. Exemplary lung cancers also include small cell and non-small cell carcinoma, bronchial adenoma, and pleuropulmonary blastoma.

[0295] Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyoma), pancreatic cancer (exocrine pancreatic cancer, tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer. Exemplary gastrointestinal cancers also include gallbladder cancer and anal cancer.

[0296] Exemplary genitourinary tract cancers include kidney cancer (adenocarcinoma, Wilms' tumor (nephroblastoma)), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma). Exemplary genitourinary tract cancers also include renal cell carcinoma and urothelial carcinoma.

[0297] Exemplary liver cancers include hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0298] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyofibroma, osteoid osteoma, and giant cell tumor.

[0299] Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), cancers of the meninges (meningiomas, meningeal sarcomas, gliomatosis), cancers of the brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and cancers of the spinal cord (neurofibromas, meningiomas, gliomas, sarcomas), as well as neuroblastoma and Lhermitte-Dacros disease. Exemplary nervous system cancers also include neuroectodermal tumors and pineal tumors.

[0300] Exemplary gynecological cancers include cancer of the uterus (endometrial carcinoma), cancer of the cervix (cervical carcinoma, preneoplastic cervical dysplasia), cancer of the ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydegg cell tumor, dysgerminoma, malignant teratoma), cancer of the vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), cancer of the vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), and cancer (carcinoma) of the fallopian tubes. Exemplary cancers of the nervous system also include neuroectodermal tumors and pineal tumors.

[0301] Exemplary skin cancers include malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, lentigineous dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids. In some embodiments, diseases and conditions 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, bile duct cancer, esophageal cancer, and urothelial cancer.

[0302] Exemplary head and neck cancers include glioblastoma, malignant melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal and paranasal sinus cancer, thyroid and parathyroid cancer. Exemplary head and neck cancers also include eye tumors, lip and mouth tumors, and squamous cell head and neck cancers.

[0303] The compounds of the present disclosure may also be useful in inhibiting tumor metastasis. In some embodiments, the compounds provided herein can be used to treat tumors that produce PGE2 (e.g., Cox-2-overexpressing tumors) and / or adenosine (CD73- and CD39-overexpressing tumors). Cox-2 overexpression has been detected in many tumors, including colorectal, breast, pancreatic, and lung cancers, and correlates with poor prognosis. Cox-2 overexpression has been reported in hematological cancer models, such as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia), and in patient blasts. CD73 is upregulated in various human cancers, including colon, lung, pancreatic, and ovarian. Importantly, higher CD73 expression levels are associated with tumor angiogenesis, invasiveness, and metastasis, and shorter patient survival in breast cancer.

[0304] The terms "individual" or "patient" are used interchangeably and refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0305] The phrase "therapeutically effective amount" refers to that amount of an active compound or agent that produces the biological or medical response in a tissue, system, animal, individual, or human that is found by a researcher, veterinarian, physician, or other clinician.

[0306] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the symptoms or pathology of the disease, condition, or disorder (i.e., preventing further progression of the symptoms and / or pathology); and (2) ameliorating a disease, such as reducing the severity of the disease, e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting the symptoms or pathology of the disease, condition, or disorder (i.e., causing the symptoms and / or pathology to improve).

[0307] As used herein, the term "contacting" refers to bringing together indicated compounds in an in vitro system or an in vivo system so that they are in sufficient physical proximity to interact.

[0308] In some embodiments, the compounds of the present disclosure are useful for preventing or reducing the risk of developing any of the diseases mentioned herein, for example, in individuals who may be predisposed to the disease, condition, or disorder, but who have not yet experienced or exhibited the pathology or symptoms of the disease.

[0309] Combination therapy For the treatment of an ALK2-associated disease, disorder, or condition, or a disease or condition described herein, one or more additional pharmaceutical agents or therapies, such as, for example, antiviral agents, chemotherapeutic agents or other anti-cancer agents, immunostimulatory agents, immunosuppressants, radiation, antitumor 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. The agents can be combined with the compounds in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0310] I. Immune checkpoint therapy In some embodiments, the compounds provided herein can be used in combination with one or more immune checkpoint inhibitors for the cancer treatment 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 of immune checkpoint molecules such as CD20, CD28, CD39, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, 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, TIM3, TIGIT, and VISTA. In some embodiments, the compounds of the disclosure provided herein can be used in combination with one or more agents selected from a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFRbeta inhibitor.

[0311] 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).

[0312] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0313] In some embodiments, the inhibitor of an 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 (Imfinzi®), 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-PD-1 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.

[0314] In some embodiments, compounds of the present disclosure can be used in combination with INCB086550.

[0315] In some embodiments, the inhibitor of an 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, the small molecule PD-L1 inhibitor is a PD-L1 inhibitor as described in U.S. Patent Application Publications US20170107216, US20170145025, US20170174671, US20170174679, US20170320875, US20170342060, US20170362253, US20180016260, US20180057486, US201801 or an IC of less than 1 μM, less than 100 nM, less than 10 nM, or less than 1 nM in the PD-L1 assays described in US20180177870, US20180179179, US20180179197, US20180179201, and US20180179202 (each of which is incorporated by reference in its entirety for all purposes). 50 It has.

[0316] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, 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.

[0317] In some embodiments, the inhibitor of an 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.

[0318] In some embodiments, the inhibitor is MCLA-145.

[0319] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0320] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CSF1R, such as an anti-CSF1R antibody. In some embodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.

[0321] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, IMP321, GSK2831781, or INCAGN2385.

[0322] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0323] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, 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.

[0324] 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.

[0325] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0326] 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 a TGFβ receptor.

[0327] 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.

[0328] The additional compounds, inhibitors, drugs, etc. mentioned throughout can be combined with the present compounds in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0329] II. Cancer Treatment Cancer cell growth and survival can be influenced by multiple signaling pathways, and therefore, to treat such conditions, it is useful to combine different enzyme / protein / receptor inhibitors that exhibit different selectivities in the targets whose activity they regulate.

[0330] Examples of drugs that can be combined with the compounds of the present disclosure include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of the JAK-STAT pathway, inhibitors of the beta-catenin pathway, inhibitors of the Notch pathway, inhibitors of the Hedgehog pathway, inhibitors of Pim kinase, and inhibitors of protein chaperones and cell cycle progression. Targeting multiple signaling pathways (or two or more biomolecules involved in a given signaling pathway) can reduce the likelihood of drug resistance developing in a cell population and / or reduce the toxicity of the treatment.

[0331] The compounds of the present disclosure can be used in combination with one or more other enzyme / protein / receptor inhibitors for the treatment of 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 combined with inhibitors of one or more of the following kinases for the treatment of 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, KI T, 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 combined with one or more of the following inhibitors for the treatment of cancer:Non-limiting examples of inhibitors that can be combined with compounds of the present disclosure for the treatment of cancer include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, ruxolitinib, dovitinib, TAS-120, JNJ-42756493, Debio1347, INCB54828, INCB62079, and INCB63904), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, or INCB39110), IDO inhibitors (e.g., epacadostat and NLG919), LSD1 inhibitors (e.g., GSK29795), and / or IL-111 inhibitors (e.g., IL-1111). 52, INCB59872, and INCB60003), TDO inhibitors, PI3K delta inhibitors (e.g., INCB50797 and INCB50465), PI3K-gamma inhibitors such as PI3K-gamma selective inhibitors, CSF1R inhibitors (e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinase (Tyro-3, Axl, and Mer), angiogenesis inhibitors, interleukin receptor inhibitors, bromo- and extra-terminal family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors such as OTX015, CPI-0610, INCB54329, and INCB57643), and adenosine receptor antagonists, or combinations thereof. Inhibitors of HDACs such as panobinostat and vorinostat. Inhibitors of c-Met such as onartuzumab, tivantinib, and INC-280; Inhibitors of BTK such as ibrutinib; Inhibitors of mTOR such as rapamycin, sirolimus, temsirolimus, and everolimus; Inhibitors of Raf such as vemurafenib and dabrafenib; Inhibitors of MEK such as trametinib, selumetinib, and GDC-0973; Inhibitors of Hsp90 (e.g., tanespimycin), cyclin-dependent kinases (e.g., palbociclib), PARP (e.g., olaparib), and Pim kinases (LGH447, INCB053914, and SGI-1776) can also be combined with the compounds of the present disclosure.

[0332] In some embodiments, compounds of the present disclosure can be combined with one or more JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, or INCB39110). In some embodiments, compounds of the present disclosure can be combined with one or more JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib, baricitinib, or INCB39110) for the treatment of cancer, such as a myeloproliferative disorder. For example, the myeloproliferative disorder is myelofibrosis. In some embodiments, compounds of the present disclosure can be combined with ruxolitinib, or a pharmaceutically acceptable salt thereof. In some embodiments, compounds of the present disclosure can be combined with ruxolitinib, or a pharmaceutically acceptable salt thereof, for the treatment of a myeloproliferative disorder, such as myelofibrosis.

[0333] The compounds of the present disclosure can be used in combination with one or more drugs for the treatment of diseases such as cancer. In some embodiments, the drug is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include bendamustine, nitrogen mustard, ethyleneimine derivatives, alkylsulfonates, nitrosoureas and triazenes, uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), 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 immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

[0334] The compounds of the present disclosure can also be used in combination with other methods of treating cancer, such as chemotherapy, radiation 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 booster for T cell activation, oncolytic virotherapy, and immunomodulatory small molecules such as thalidomide or JAK1 / 2 inhibitors. The compounds can be administered in combination with one or more anti-cancer agents, such as chemotherapeutic agents. Exemplary chemotherapeutic agents include any of the following: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amsacrine, anastrozole, aphidicolone, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib, buparlisib, intravenous busulfan, oral busulfan, calsterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine gin, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epinephrine Rubicin, epothilone, 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 alfa-2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, 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 ninat sodium, pentostatin, piralalisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib, reloxafin, revlimid, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triptorelin, uracil mustard, barbican, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, and zoledronate.

[0335] Other anti-cancer agents include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies against PD-1 and PD-L1, or antibodies against cytokines (such as IL-10, TGF-β, etc.). Examples of antibodies against PD-1 and / or PD-L1 that can be combined with compounds of the present disclosure for the treatment of cancer or infectious diseases (such as viral, bacterial, fungal, and parasitic infections) include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736, and SHR-1210.

[0336] Other anti-cancer agents include inhibitors of kinases associated with cell proliferation disorders, including, but not limited to, Aurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinase, CHK1, CHK2, SRC, Yes, FyN, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk, and SGK.

[0337] Other anti-cancer drugs include those that block immune cell migration, such as antagonists to chemokine receptors such as CCR2 and CCR4.

[0338] The compounds of the present disclosure may further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants, or therapeutic antibodies, including, but not limited to, 17alpha-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0339] Compounds of the present disclosure may also be used in combination with lonafarnib (SCH6636), tipifarnib (R115777), L778123, BMS214662, tezacitabine (MDL101731), Sml1, triapine, didox, trimidox, and amidox.

[0340] The compounds described herein can be combined with other immunogens, such as cancer cells, purified tumor antigens (such as recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0341] The compounds described herein can be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells can be transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses involved in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma virus (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 cell immunization to activate potent anti-tumor responses.

[0342] The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effector cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.

[0343] The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0344] Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral agents.

[0345] Exemplary NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-10652; emiricitabine [(-)-FTC]; beta-L-FD4 (also known as beta-L-D4C, also beta-L-2',3'-dicreoxy-5-fluoro-citidene); DAPD, ((-)-beta-D-2,6,-diamino-purine dioxolane); and rhodenosine (FddA). Exemplary suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (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 (+)-calanolide A (NSC-675451) and B. Exemplary suitable proteases include nevirapine (BI-RG-587); delaviradine (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 (+)-calanolide A (NSC-675451) and B. Enzyme inhibitors include saquinavir (Ro31-8959); ritonavir (ABT-538); indinavir (MK-639); nerfunavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribaribine, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0346] The compounds described herein can be combined or sequentially combined with other agents against membrane receptor kinases, particularly for patients who have developed primary or acquired resistance to targeted therapies. These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3, as well as inhibitor antibodies against cancer-associated fusion protein kinases such as Bcr-Abl and EML4-Alk. EGFR inhibitors include gefitinib and erlotinib, and EGFR / Her2 inhibitors include, but are not limited to, dacomitinib, afatinib, lapitinib, and neratinib. EGFR antibodies 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 onartumzumab, tivantinib, and INC-280. Agents directed against Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, and agents directed against Alk (or EML4-ALK) include crizotinib.

[0347] In some tumors, angiogenesis inhibitors may not be effective in combination with the compounds disclosed herein. These include antibodies against VEGF or VEGFR or VEGFR kinase inhibitors. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other antiangiogenesis inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, cediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0348] Activation of intracellular signaling pathways frequently occurs in cancer, and drugs that target components of these pathways are combined with receptor-targeting drugs to increase efficacy and reduce resistance. Examples of drugs that can be used in combination with the compounds described herein include inhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPK pathway, inhibitors of the JAK-STAT pathway, and inhibitors of protein chaperones and cell cycle progression.

[0349] Drugs against PI3 kinase include, but are not limited to, topiralisib, idelalisib, and buparlisib. mTOR inhibitors, such as rapamycin, sirolimus, temsirolimus, and everolimus, may be used in combination 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 one or more JAKs (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin-dependent kinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARPs (e.g., olaparib), and proteasomes (e.g., bortezomib, carfilzomib) may also be used in combination with the compounds described herein. In some embodiments, the JAK inhibitor is selective for JAK1 over JAK2 and JAK3.

[0350] Other suitable agents for use in combination with the compounds described herein include chemotherapeutic agent combinations such as platinum-based doublets used in lung cancer and other solid tumors (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin or carboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed), or gemcitabine plus paclitaxel-bound particles (Abraxane®).

[0351] Suitable chemotherapeutic or other anti-cancer agents include alkylating agents (including, but not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as, for example, uracil mustard, chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0352] Other suitable agents for use in combination with the compounds described herein include steroids, including 17α-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, and medroxyprogesterone acetate.

[0353] Other suitable agents for use in combination with the compounds of the invention include dacarbazine (DTIC), optionally in combination with another chemotherapy agent such as carmustine (BCNU) or cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide. The compounds according to the invention may also be used in combination with immunotherapeutic agents, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) inhibitors.

[0354] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, but not limited to, folate 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.

[0355] Suitable chemotherapeutic or other anti-cancer agents further include certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as, for example, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, interferons (especially IFN-α), etoposide, and teniposide.

[0356] Other cytotoxic agents include navelbene, CPT-11, anastrozole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.

[0357] Also suitable are cytotoxic agents such as epidophyllotoxins; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cisplatin and carboplatin; biological response modifiers; growth inhibitory agents; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0358] Other anti-cancer drugs include antibody therapeutics such as trastuzumab (Herceptin), antibodies against costimulatory molecules such as CTLA-4, 4-1BB, PD-L1, and PD-1, or antibodies against cytokines (such as IL-10 and TGF-β).

[0359] Other anti-cancer drugs include those that inhibit immune cell migration, such as antagonists to chemokine receptors such as CCR2 and CCR4.

[0360] Other anti-cancer drugs include those that boost the immune system, such as adjuvants and adoptive T-cell transfer.

[0361] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. In some embodiments, tumor vaccines include proteins from viruses involved in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma virus (KHSV). Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0362] The compounds of the present disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0363] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. Moreover, 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, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0364] When multiple agents are administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, for three or more agents).

[0365] In some embodiments, compounds of the present disclosure can be used in combination with INCB086550.

[0366] Formulation, Dosage, and Administration When used as pharmaceuticals, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. Accordingly, the present disclosure provides compositions containing a compound of Formula (I) or any of the formulae described herein, any of the compounds described in the claims and herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier or excipient. The pharmaceutical composition can include a compound described herein and one or more second therapeutic agents described herein. For example, the second therapeutic agent is a JAK inhibitor such as ruxolitinib. The compositions can be prepared by methods well known in the pharmaceutical arts and can be administered by various routes, depending on whether local or systemic treatment is indicated and the area to be treated. Administration can be topical (such as transdermal, epidermal, ocular, and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, and the like may be necessary or desirable.

[0367] The present invention also includes pharmaceutical compositions containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient, combined with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the compositions are suitable for topical administration. In preparing the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, 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. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0368] In the preparation of formulation, before being combined with other components, active compound can be pulverized to obtain suitable particle size.If active compound is substantially insoluble, it can be pulverized to particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by pulverizing to be substantially uniformly distributed in the formulation, for example, about 40 mesh.

[0369] The compounds of the present disclosure can be milled using known milling procedures, such as wet milling, to obtain particle sizes suitable for tablet formation and other formulation types. Micronized (nanoparticulate) formulations of the compounds of the present disclosure can be prepared by processes known in the art (see, for example, WO2002 / 000196).

[0370] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may additionally contain the following: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents. The compositions of the present disclosure can be formulated to release the active ingredient quickly, sustainedly, or delayed after administration to a patient by adopting procedures known in the art.

[0371] 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% by weight of microcrystalline cellulose and about 2% by weight of silicon dioxide.

[0372] In some embodiments, the composition is a sustained-release composition containing 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 contains at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition contains at least one compound described herein or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition contains at least one compound described herein or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further contains magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR1105 (e.g., Polyox WSR1105™).

[0373] In some embodiments, a wet granulation process is used to manufacture the composition. In some embodiments, a dry granulation process is used to manufacture the composition.

[0374] The compositions can be formulated in unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg 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" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0375] The ingredients used to formulate pharmaceutical compositions are highly pure and substantially free of potentially harmful contaminants (e.g., at least national food grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, compositions are preferably manufactured or formulated in accordance with good manufacturing practices as defined by applicable U.S. Food and Drug Administration regulations. For example, suitable formulations may be sterile and / or substantially isotonic and / or in full compliance with all U.S. Food and Drug Administration good manufacturing practice regulations.

[0376] The active compound may be effective over a wide dosage range and is usually administered in a therapeutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by a physician depending on the relevant circumstances, such as the condition to be treated, the selected route of administration, the compound actually administered, the age, weight, response, and severity of the patient's symptoms, etc.

[0377] Therapeutic dosages of the compounds of the present invention may vary depending, for example, on the particular application for which the treatment is being performed, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition may vary depending on many factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, for parenteral administration, the compounds of the present disclosure may be provided in an aqueous physiological buffer solution containing about 0.1% to about 10% w / v of the compound. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. Dosages are likely to depend on variables such as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0378] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When these preformulation compositions are considered homogeneous, the active ingredient is typically dispersed evenly throughout the composition, so that the composition can be easily subdivided into equally effective unit doses such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit doses of the type described above containing, for example, 0.1 mg to about 1000 mg of the active ingredient of the present invention.

[0379] The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablets or pills may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0380] Liquid forms into which the compounds and compositions of the present invention can be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions including edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar vehicles.

[0381] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable water or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. The compositions can be nebulized using an inert gas. The nebulized solution can be breathed directly from the nebulizer, or the nebulizer can be attached to a face mask, tent, or intermittent positive pressure respirator. Solution, suspension, or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate format.

[0382] Topical formulations can include one or more conventional carriers. In some embodiments, ointments can include water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. Cream carrier compositions can be aqueous-based, combining glycerol with one or more other ingredients, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, appropriately combined with other ingredients, such as glycerol and hydroxyethylcellulose. In some embodiments, topical formulations contain at least about 0.1 wt.%, at least about 0.25 wt.%, at least about 0.5 wt.%, at least about 1 wt.%, at least about 2 wt.%, or at least about 5 wt.% of a compound of the present disclosure. Topical formulations can be suitably packaged, for example, in 100 g tubes, optionally associated with instructions for the treatment of a selected condition, such as psoriasis or other skin conditions.

[0383] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration, such as prophylaxis or treatment, the condition of the patient, the mode of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to treat or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition being treated and the judgment of the attending physician depending on factors such as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0384] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can be packaged for ready use or can be lyophilized, and the lyophilized preparation can be combined with a sterile aqueous carrier prior to administration. The pH of the compound formulations is typically 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It is understood that certain use of the excipients, carriers, or stabilizers described above will result in the formation of pharmaceutical salts.

[0385] Therapeutic dosages of the compounds of the invention can vary depending, for example, on the specific application for which the treatment is being performed, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present disclosure in a pharmaceutical composition can vary depending on many factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, compounds of the present disclosure can be provided in an aqueous physiological buffer containing about 0.1% to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. Dosages are likely to depend on variables such as the type and progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0386] Labeled Compounds and Assay Methods The compounds of the present disclosure may further be useful in investigating biological processes in normal and abnormal tissues. Accordingly, another aspect of the present invention relates to the fluorescent dye, spin label, heavy metal, or radiolabeled compounds provided herein, which may be useful in assays as well as in vitro and in vivo imaging techniques for localizing and quantifying ALK2 protein in tiss...

Claims

1. 1. A composition for the treatment of bone disease or anemia, comprising a compound of formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof (In the formula: R １ is 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 C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ２ is C ６～１０ aryl and 5- to 10-membered heteroaryl; 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, and said N and S may be optionally oxidized; said 5- to 10-membered heteroaryl may optionally be substituted with oxo to form a carbonyl group; said C ６～１０ Aryl and 5- to 10-membered heteroaryl are R ２０ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R ２ The two adjacent Rs above ２０ The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C ３～７ wherein the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C ３～７ The cycloalkyl ring is R ２１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ３ H, D, Halo, CN, C １～６ Alkyl, OR ａ７ , and N.R. ｃ７ R ｄ７ C １～６ Alkyl is R ｇ each optionally substituted with 1, 2, or 3 substituents independently selected from R ４ H, D, Halo, CN, C １～６ Alkyl, OR ａ８ , and N.R. ｃ８ R ｄ８ C １～６ Alkyl is R ｇ each optionally substituted with 1, 2, or 3 substituents independently selected from R ５ is C ６～１０ aryl and 5- to 10-membered heteroaryl; 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, and said N and S may be optionally oxidized; said 5- to 10-membered heteroaryl may optionally be substituted with oxo to form a carbonyl group; said C ６～１０ Aryl and 5- to 10-membered heteroaryl are R ５０ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R ５ The two adjacent Rs above ５０ The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C ３～７ wherein the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C ３～７ The cycloalkyl ring is R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CR Ａ and R Ａ H, D, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, Halo, CN, NO ２ , OR ａ１２ , S.R. ａ１２ , C(O)R ｂ１２ , C(O)NR ｃ１２ R ｄ１２ , C(O)OR ａ１２ , O.C.(O.)R ｂ１２ , OC(O)NR ｃ１２ R ｄ１２ , N.R. ｃ１２ R ｄ１２ , N.R. ｃ１２ C(O)R ｂ１２ , N.R. ｃ１２ C(O)OR ａ１２ , N.R. ｃ１２ C(O)NR ｃ１２ R ｄ１２ , N.R. ｃ１２ S(O)R ｂ１２ , N.R. ｃ１２ S (O) ２ R ｂ１２ , N.R. ｃ１２ S (O) ２ NR ｃ１２ R ｄ１２ , S(O)R ｂ１２ , S(O)NR ｃ１２ R ｄ１２ , S(O) ２ R ｂ１２ , and S(O) ２ NR ｃ１２ R ｄ１２ C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R １０ is 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, NO ２ , OR ａ１ , S.R. ａ１ , C(O)R ｂ１ , C(O)NR ｃ１ R ｄ１ , C(O)OR ａ１ , O.C.(O.)R ｂ１ , OC(O)NR ｃ１ R ｄ１ , N.R. ｃ１ R ｄ１ , N.R. ｃ１ C(O)R ｂ１ , N.R. ｃ１ C(O)OR ａ１ , N.R. ｃ１ C(O)NR ｃ１ R ｄ１ , C(=NR ｅ１ ) R ｂ１ , C(=NOR ａ１ ) R ｂ１ , C(=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ C (=NR ｅ１ ) NR ｃ１ R ｄ１ , N.R. ｃ１ S(O)R ｂ１ , N.R. ｃ１ S (O) ２ R ｂ１ , N.R. ｃ１ S (O) ２ NR ｃ１ R ｄ１ , S(O)R ｂ１ , S(O)NR ｃ１ R ｄ１ , S(O) ２ R ｂ１ , and S(O) ２ NR ｃ１ R ｄ１ are independently selected from the group consisting of 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 R １１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or two R's １０ The substituents, together with the carbon atoms to which they are attached, form a spiro 4- to 7-membered heterocycloalkyl ring or spiro C ３～６ each spiro 4- to 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; a ring-forming carbon atom of each spiro 4- to 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the spiro 4- to 7-membered heterocycloalkyl ring and the spiro C ３～６ The cycloalkyl ring is R １１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R １１ is 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 , S.R. ａ３ , C(O)R ｂ３ , C(O)NR ｃ３ R ｄ３ , C(O)OR ａ３ , N.R. ｃ３ R ｄ３ , N.R. ｃ３ C(O)R ｂ３ , N.R. ｃ３ C(O)OR ａ３ , N.R. ｃ３ S(O)R ｂ３ , N.R. ｃ３ S (O) ２ R ｂ３ , N.R. ｃ３ S (O) ２ NR ｃ３ R ｄ３ , S(O)R ｂ３ , S(O)NR ｃ３ R ｄ３ , S(O) ２ R ｂ３ , and S(O) ２ NR ｃ３ R ｄ３ are independently selected from the group consisting of 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 R １２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R １２ is 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 １～３ alkylene, 5- to 10-membered heteroaryl-C １～３ Alkylene, Halo, D, CN, OR ａ５ , S.R. ａ５ , C(O)R ｂ５ , C(O)NR ｃ５ R ｄ５ , C(O)OR ａ５ , N.R. ｃ５ R ｄ５ , N.R. ｃ５ C(O)R ｂ５ , N.R. ｃ５ C(O)OR ａ５ , N.R. ｃ５ S(O)R ｂ５ , N.R. ｃ５ S (O) ２ R ｂ５ , N.R. ｃ５ S (O) ２ NR ｃ５ R ｄ５ , S(O)R ｂ５ , S(O)NR ｃ５ R ｄ５ , S(O) ２ R ｂ５ , and S(O) ２ NR ｃ５ R ｄ５ are independently selected from the group consisting of 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 is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２０ is 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, NO ２ , OR ａ２ , S.R. ａ２ , C(O)R ｂ２ , C(O)NR ｃ２ R ｄ２ , C(O)OR ａ２ , O.C.(O.)R ｂ２ , OC(O)NR ｃ２ R ｄ２ , N.R. ｃ２ R ｄ２ , N.R. ｃ２ C(O)R ｂ２ , N.R. ｃ２ C(O)OR ａ２ , N.R. ｃ２ C(O)NR ｃ２ R ｄ２ , C(=NR ｅ２ ) R ｂ２ , C(=NOR ａ２ ) R ｂ２ , C(=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ C (=NR ｅ２ ) NR ｃ２ R ｄ２ , N.R. ｃ２ S(O)R ｂ２ , N.R. ｃ２ S (O) ２ R ｂ２ , N.R. ｃ２ S (O) ２ NR ｃ２ R ｄ２ , S(O)R ｂ２ , S(O)NR ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ NR ｃ２ R ｄ２ wherein a ring-forming carbon atom of a 4- to 10-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; 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 R ２１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２１ is 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 ａ４ , S.R. ａ４ , C(O)R ｂ４ , C(O)NR ｃ４ R ｄ４ , C(O)OR ａ４ , N.R. ｃ４ R ｄ４ , N.R. ｃ４ C(O)R ｂ４ , N.R. ｃ４ C(O)OR ａ４ , N.R. ｃ４ S(O)R ｂ４ , N.R. ｃ４ S (O) ２ R ｂ４ , N.R. ｃ４ S (O) ２ NR ｃ４ R ｄ４ , S(O)R ｂ４ , S(O)NR ｃ４ R ｄ４ , S(O) ２ R ｂ４ , and S(O) ２ NR ｃ４ R ｄ４ are independently selected from the group consisting of 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 R ２２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２２ is 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, 5-6 membered heteroaryl-C １～３ Alkylene, Halo, D, CN, OR ａ６ , S.R. ａ６ , C(O)R ｂ６ , C(O)NR ｃ６ R ｄ６ , C(O)OR ａ６ , N.R. ｃ６ R ｄ６ , N.R. ｃ６ C(O)R ｂ６ , N.R. ｃ６ C(O)OR ａ６ , N.R. ｃ６ S(O)R ｂ６ , N.R. ｃ６ S (O) ２ R ｂ６ , N.R. ｃ６ S (O) ２ NR ｃ６ R ｄ６ , S(O)R ｂ６ , S(O)NR ｃ６ R ｄ６ , S(O) ２ R ｂ６ , and S(O) ２ NR ｃ６ R ｄ６ are independently selected from the group consisting of 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 R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ５０ is 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, NO ２ , OR ａ９ , S.R. ａ９ , C(O)R ｂ９ , C(O)NR ｃ９ R ｄ９ , C(O)OR ａ９ , O.C.(O.)R ｂ９ , OC(O)NR ｃ９ R ｄ９ , N.R. ｃ９ R ｄ９ , N.R. ｃ９ C(O)R ｂ９ , N.R. ｃ９ C(O)OR ａ９ , N.R. ｃ９ C(O)NR ｃ９ R ｄ９ , C(=NR ｅ９ ) R ｂ９ , C(=NOR ａ９ ) R ｂ９ , C(=NR ｅ９ ) NR ｃ９ R ｄ９ , N.R. ｃ９ C (=NR ｅ９ ) NR ｃ９ R ｄ９ , N.R. ｃ９ S(O)R ｂ９ , N.R. ｃ９ S (O) ２ R ｂ９ , N.R. ｃ９ S (O) ２ NR ｃ９ R ｄ９ , S(O)R ｂ９ , S(O)NR ｃ９ R ｄ９ , S(O) ２ R ｂ９ , and S(O) ２ NR ｃ９ R ｄ９ are independently selected from the group consisting of 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 R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ５１ is 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 , S.R. ａ１０ , C(O)R ｂ１０ , C(O)NR ｃ１０ R ｄ１０ , C(O)OR ａ１０ , N.R. ｃ１０ R ｄ１０ , N.R. ｃ１０ C(O)R ｂ１０ , N.R. ｃ１０ C(O)OR ａ１０ , N.R. ｃ１０ S(O)R ｂ１０ , N.R. ｃ１０ S (O) ２ R ｂ１０ , N.R. ｃ１０ S (O) ２ NR ｃ１０ R ｄ１０ , S(O)R ｂ１０ , S(O)NR ｃ１０ R ｄ１０ , S(O) ２ R ｂ１０ , and S(O) ２ NR ｃ１０ R ｄ１０ are independently selected from the group consisting of 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 R ５２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ５２ is 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, 5-6 membered heteroaryl-C １～３ Alkylene, Halo, D, CN, OR ａ１１ , S.R. ａ１１ , C(O)R ｂ１１ , C(O)NR ｃ１１ R ｄ１１ , C(O)OR ａ１１ , N.R. ｃ１１ R ｄ１１ , N.R. ｃ１１ C(O)R ｂ１１ , N.R. ｃ１１ C(O)OR ａ１１ , N.R. ｃ１１ S(O)R ｂ１１ , N.R. ｃ１１ S (O) ２ R ｂ１１ , N.R. ｃ１１ S (O) ２ NR ｃ１１ R ｄ１１ , S(O)R ｂ１１ , S(O)NR ｃ１１ R ｄ１１ , S(O) ２ R ｂ１１ , and S(O) ２ NR ｃ１１ R ｄ１１ are independently selected from the group consisting of 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 R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ , R ｃ , and R ｄ is 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; 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 R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ and R ｄ together with the N atom to which they are attached, R １０ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ is 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; 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 R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｅ are H, CN, and C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkylthio, C １～６ Alkylsulfonyl, C １～６ Alkylcarbonyl, C １～６ Alkylaminosulfonyl, carbamyl, C １～６ Alkylcarbamyl, di(C １～６ alkyl) carbamyl, aminosulfonyl, C １～６ Alkylaminosulfonyl, and di(C １～６ independently selected from: (alkyl)aminosulfonyl; Each R ａ１ , R ｃ１ , and R ｄ１ is 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; 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 R １１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ１ and R ｄ１ together with the N atom to which they are attached, R １１ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ１ is 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; 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 R １１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｅ１ are H, CN, and C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkylthio, C １～６ Alkylsulfonyl, C １～６ Alkylcarbonyl, C １～６ Alkylaminosulfonyl, carbamyl, C １～６ Alkylcarbamyl, di(C １～６ alkyl) carbamyl, aminosulfonyl, C １～６ Alkylaminosulfonyl, and di(C １～６ independently selected from: (alkyl)aminosulfonyl; Each R ａ２ , R ｃ２ , and R ｄ２ is 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; 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 R ２１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ２ and R ｄ２ together with the N atom to which they are attached, R ２１ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ２ is 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; 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 R ２１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｅ２ are H, CN, and C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkylthio, C １～６ Alkylsulfonyl, C １～６ Alkylcarbonyl, C １～６ Alkylaminosulfonyl, carbamyl, C １～６ Alkylcarbamyl, di(C １～６ alkyl) carbamyl, aminosulfonyl, C １～６ Alkylaminosulfonyl, and di(C １～６ independently selected from: (alkyl)aminosulfonyl; Each R ａ３ , R ｃ３ , and R ｄ３ is 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; 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 R １２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ３ and R ｄ３ together with the N atom to which they are attached, R １２ forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R ｂ３ is 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; 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 R １２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ４ , R ｃ４ , and R ｄ４ is 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; 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 R ２２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ４ and R ｄ４ together with the N atom to which they are attached, R ２２ forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R ｂ４ is 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; 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 R ２２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ５ , R ｃ５ , and R ｄ５ is H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C １～６ haloalkyl; １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ５ and R ｄ５ together with the N atom to which they are attached, R ｇ forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R ｂ５ is C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C １～６ haloalkyl; １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ６ , R ｃ６ , and R ｄ６ is H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C １～６ haloalkyl; １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ６ and R ｄ６ together with the N atom to which they are attached, R ｇ forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R ｂ６ is C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C １～６ haloalkyl; １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ７ , R ｃ７ , and R ｄ７ is H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C １～６ haloalkyl; １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ８ , R ｃ８ , and R ｄ８ is H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C １～６ haloalkyl; １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ９ , R ｃ９ , and R ｄ９ is 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; 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 R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ９ and R ｄ９ together with the N atom to which they are attached, R ５１ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ９ is 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; 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 R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｅ９ are H, CN, and C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkylthio, C １～６ Alkylsulfonyl, C １～６ Alkylcarbonyl, C １～６ Alkylaminosulfonyl, carbamyl, C １～６ Alkylcarbamyl, di(C １～６ alkyl) carbamyl, aminosulfonyl, C １～６ Alkylaminosulfonyl, and di(C １～６ independently selected from: (alkyl)aminosulfonyl; Each R ａ１０ , R ｃ１０ , and R ｄ１０ is 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; 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 R ５２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ１０ and R ｄ１０ together with the N atom to which they are attached, R ５２ forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R ｂ１０ is 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; 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 R ５２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ１１ , R ｃ１１ , and R ｄ１１ is H, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C １～６ haloalkyl; １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ１１ and R ｄ１１ together with the N atom to which they are attached, R ｇ forming a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from: Each R ｂ１１ is C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C １～６ haloalkyl; １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ１２ , R ｃ１２ , and R ｄ１２ is 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; 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 R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ１２ and R ｄ１２ together with the N atom to which they are attached, R ｇ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ１２ is 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; 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 R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ｇ OH NO ２ , CN, Halo, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, C ３～６ Cycloalkyl-C １－２ Alkylene, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～３ Alkoxy-C １～３ Alkyl, C １～３ Alkoxy-C １～３ Alkoxy, HO-C １～３ Alkoxy, HO-C １～３ Alkyl, cyano-C １～３ Alkyl, H ２ N-C １～３ Alkyl, amino, C １～６ Alkylamino, di(C １～６ alkyl) amino, thio, C １～６ Alkylthio, C １～６ Alkylsulfinyl, C １～６ Alkyl sulfonyl, carbamyl, C １～６ Alkylcarbamyl, di(C １～６ alkyl) carbamyl, carboxy, C １～６ Alkylcarbonyl, C １～６ Alkoxycarbonyl, C １～６ Alkylcarbonylamino, C １～６ Alkyl sulfonyl amino, amino sulfonyl, C １～６ Alkylaminosulfonyl, di(C １～６ alkyl)aminosulfonyl, aminosulfonylamino, C １～６ Alkylaminosulfonylamino, di(C １～６ alkyl)aminosulfonylamino, aminocarbonylamino, C １～６ Alkylaminocarbonylamino, and di(C １～６ alkyl)aminocarbonylamino) wherein the bone disease is fibrodysplasia ossificans progressiva.

2. (a) R １ But 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 C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl is R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (b) R １ But C １～６ Alkyl, CN, C(O)NR ｃ R ｄ , C(O)R ｂ , and C(O)OR ａ C １～６ The alkyl is R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (c) R １ is selected from methyl, methoxycarbonyl, carbamoyl, cyano, hydroxymethyl, methoxymethyl, N-(4-hydroxy-4-methylcyclohexyl)carbamoyl, and 4-ethoxycarbonyl-piperazin-1-ylcarbonyl; The composition of claim 1.

3. (a) Each R １０ But 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, 5-10 membered heteroaryl, halo, D, CN, OR ａ１ , C(O)OR ａ１ , N.R. ｃ１ R ｄ１ , and S(O) ２ NR ｃ１ R ｄ１ 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 and 5- to 10-membered heteroaryl are R １１ each optionally substituted with 1 or 2 substituents independently selected from (b) Each R １０ But 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 , N.R. ｃ１ R ｄ１ , and S(O) ２ NR ｃ１ R ｄ１ C １～６ The alkyl is R １１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (c) Each R １０ But C １～６ Alkyl, OR ａ１ , and C(O)OR ａ１ C １～６ The alkyl is R １１ each optionally substituted with 1 or 2 substituents independently selected from (d) Each R １０ is selected from methyl, OH, methoxy, and ethoxycarbonyl; The composition according to claim 1 or 2.

4. (a) R ２ is a 5- to 6-membered heteroaryl; said 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; said N and S may be optionally oxidized; a ring-forming carbon atom of said 5- to 6-membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; said 5- to 6-membered heteroaryl is R ２０ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (b) R ２ is selected from phenyl and pyrazolyl; said phenyl and pyrazolyl are selected from R ２０ each optionally substituted with 1 or 2 substituents independently selected from (c) R ２ But, R ２０ or phenyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (d) R ２ But, R ２０ or a pyrazole, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (e) R ２ 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, 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, 4-(azetidin-1-ylmethyl)phenyl, 1-ethyl-1H-pyrazol-4-yl, 1-isopropyl-1H-pyrazole 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-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; The composition according to any one of claims 1 to 3.

5. (a) Each R ２０ But 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, 5-6 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 , N.R. ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ NR ｃ２ R ｄ２ wherein a ring-forming carbon atom of said 4- to 6-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; 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 The alkylene is R ２１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (b) Each R ２０ But 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 a ring-forming carbon atom of said 4- to 6-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; １～６ Alkyl, C ３～６ Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C １～３ The alkylene is R ２１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (c) R ２０ Fluoro, 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, piperidin-4-yl, tetrahydro-2H-pyran-4-yl, 4-hydroxycyclohexyl, piperidin-4-ylmethyl, (4-hydroxypiperidin-1-yl)methyl, (4-hydroxy-4-methylpiperidinyl) the alkyl group is selected from (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-methylmorpholino)methyl, (2-(hydroxymethyl)morpholino)methyl, pyrrolidin-1-ylmethyl, (3-hydroxy-3-methylpyrrolidin-1-yl)methyl, and (dimethylamino)methyl; The composition according to any one of claims 1 to 4.

6. (a) Each R ２１ But C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR ａ４ , C(O)NR ｃ４ R ｄ４ , and N.R. ｃ４ R ｄ４ are independently selected from the group consisting of １～６ Alkyl, C ３～６ Cycloalkyl and 4- to 6-membered heterocycloalkyl are R ２２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (b) Each R ２１ But C １～６ Alkyl, C ３～６ cycloalkyl, 4- to 6-membered heterocycloalkyl, halo, OR ａ４ , and N.R. ｃ４ R ｄ４ are independently selected from the group consisting of １～６ Alkyl, C ３～６ Cycloalkyl and 4- to 6-membered heterocycloalkyl are R ２２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (c) R ２１ is selected from methyl, F, OH, dimethylamino, hydroxyethyl, piperazinyl, piperidinyl, methylpyrrolidinyl, 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; The composition according to any one of claims 1 to 5.

7. (a) Each R ２２ But C １～６ Alkyl, C １～６ Haloalkyl, Halo, D, CN, OR ａ６ , and N.R. ｃ６ R ｄ６ are independently selected from the group consisting of １～６ The alkyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (b) Each R ２２ But C １～６ Alkyl, halo, and OR ａ６ are independently selected from the group consisting of １～６ The alkyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (c) R ２２ is OH, F, or methyl; The composition according to any one of claims 1 to 6.

8. R ３ The composition of any one of claims 1 to 7, wherein is H.

9. R ４ The composition of any one of claims 1 to 7, wherein is H.

10. (a) R ５ But, R ５０ C optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from ６～１０ is aryl, or (b) R ５ is a 5- to 10-membered heteroaryl; 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; said N and S may be optionally oxidized; a ring-forming carbon atom of said 5- to 10-membered heteroaryl may be optionally substituted by oxo to form a carbonyl group; said 5- to 10-membered heteroaryl is R ５０ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from (c) R ５ is selected from quinolinyl, naphthyridinyl, pyridinyl, and phenyl, and said quinolinyl, naphthyridinyl, pyridinyl, and phenyl are selected from R ５０ each optionally substituted with 1, 2, or 3 substituents independently selected from (d) R ５ 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]octan-2-yl)quinolin-4-yl, 7-(methylcarbamoyl)quinolin-4-yl, 7-(pyridin-3-ylamino)quinolin-4-yl yl, 7-((3,5-difluorophenyl)(hydroxy)methyl)quinolin-4-yl, 7-(4-acetylpiperazin-1-yl)quinolin-4-yl, 7-(4-methylpiperazin-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]heptan-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-pyrazin-2-yl)-1,8-naphthyridin-4-yl 7-(1-methyl-1H-imidazol-4-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; (e) R ５ has at least two adjacent R ５０ is substituted with a substituent, and the two adjacent R ５０ the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered heterocycloalkyl ring; the fused 5- or 6-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 5- or 6-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 5- or 6-membered heterocycloalkyl ring is optionally substituted by R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (f) R ５ has at least two adjacent R ５０ is substituted with a substituent, and the two adjacent R ５０ Substituents, together with the atoms to which they are attached, 【Chemistry 2】 and 【Chemistry 3】 forming a fused heterocycloalkyl ring selected from The composition according to any one of claims 1 to 9.

11. (a) Each R ５０ But C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, 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)OR ａ９ , N.R. ｃ９ R ｄ９ , S(O) ２ R ｂ９ , and S(O) ２ NR ｃ９ R ｄ９ are independently selected from the group consisting of １～６ Alkyl, C ３～１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl and 5- to 10-membered heteroaryl are R ５１ a ring-forming carbon atom of said 4- to 10-membered heterocycloalkyl may be optionally oxidized to form a carbonyl group, or (b) Each R ５０ But 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 N.R. ｃ９ R ｄ９ are independently selected from the group consisting of １～６ Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R ５１ a ring-forming carbon atom of said 4- to 10-membered heterocycloalkyl may be optionally oxidized to form a carbonyl group, or (c) Each R ５０ fluoro, hydroxyethyl, cyano, carbamoyl, methylcarbamoyl, pyridinyl, morpholino, morpholinomethyl, pyrazolyl, 6-oxaspiro[3.4]octanyl, pyridinylamino, benzyl, piperazinyl, piperazin-1-ylcarbonyl, pyrimidinyl, pyrazinyl, (2-hydroxyethyl)carbamoyl, hexahydropyrrolo[1,2-a]pyrazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, triazolyl, imidazolyl, and and pyrazinyl, wherein said methylcarbamoyl, pyridinyl, morpholino, morpholinomethyl, pyrazolyl, 6-oxaspiro[3.4]octanyl, pyridinylamino, benzyl, piperazinyl, piperazin-1-ylcarbonyl, pyrimidinyl, pyrazinyl, (2-hydroxyethyl)carbamoyl, hexahydropyrrolo[1,2-a]pyrazinyl, 2,5-diazabicyclo[2.2.1]heptanyl, triazolyl, imidazolyl, and pyrazinyl are independently selected from R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Two adjacent R ５０ the substituents, together with the atoms to which they are attached, form a fused 5- or 6-membered heterocycloalkyl ring; the fused 5- or 6-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 5- or 6-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 5- or 6-membered heterocycloalkyl ring is optionally substituted by R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (d) R ５０ 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]octan-2-yl, pyridin-3-ylamino, (3,5-difluorophenyl)(hydroxyl)methyl, 4-acetylpiperazin-1-yl, 4-methylpiperazin-1-ylcarbonyl, (2-hydroxyethyl)carbamoyl, 6-oxohexa independently selected from hydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 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; The composition according to any one of claims 1 to 10.

12. (a) Each R ５１ But C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, halo, D, CN, OR ａ１０ , C(O)R ｂ１０ , C(O)NR ｃ１０ R ｄ１０ , C(O)OR ａ１０ , N.R. ｃ１０ R ｄ１０ , S(O) ２ R ｂ１０ , and S(O) ２ NR ｃ１０ R ｄ１０ are independently selected from the group consisting of １～６ Alkyl, C ３～１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl and 5- to 10-membered heteroaryl are R ５２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (b) Each R ５１ But C １～６ Alkyl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl, OR ａ１０ , and C(O)R ｂ１０ are independently selected from the group consisting of １～６ alkyl, 4- to 10-membered heterocycloalkyl, and C ６～１０ The aryl is R ５２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from (c) 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; The composition according to any one of claims 1 to 11.

13. (a) Each R ５２ But C １～６ Alkyl, C １～６ Haloalkyl, Halo, D, CN, OR ａ１１ , and N.R. ｃ１１ R ｄ１１ are independently selected from (b) Each R ５２ But halo and OR a11 are independently selected from The composition according to any one of claims 1 to 12.

14. (a) A is N, or (b) A is CR Ａ and R Ａ However, H, D, and C １～６ alkyl; or (c) A is CH; The composition according to any one of claims 1 to 13.

15. (a) the compound is a compound of Formula II: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof; (b) the compound is a compound of formula III: 【Chemistry 5】 or a pharmaceutically acceptable salt thereof; (c) the compound is a compound of formula IVa or IVb: 【Chemistry 6】 or a pharmaceutically acceptable salt thereof; (d) the compound is a compound of Formula Va, Formula Vb, or Formula Vc: 【Chemistry 7】 or a pharmaceutically acceptable salt thereof; (e) the compound is a compound of Formula VIa or Formula VIb: 【Chemistry 8】 or a pharmaceutically acceptable salt thereof, or (f) the compound is a compound of Formula VIIa, Formula VIIb, Formula VIIc, or Formula VIId: 【Chemistry 9】 or a pharmaceutically acceptable salt thereof, wherein: Each X is CH, N, or CR ５０ are independently selected from Each Y is CH and CR ５０ are independently selected from The composition of claim 1.

16. (a) R １ But C １～６ Alkyl, C １～６ Haloalkyl, CN, C(O)R ｂ , C(O)NR ｃ R ｄ , and C(O)OR ａ C １～６ The alkyl is R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ２ But C ６～１０ aryl and 5- to 10-membered heteroaryl; said 5- to 10-membered heteroaryl 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; said 5- to 10-membered heteroaryl ring-forming carbon atoms are optionally substituted with oxo to form a carbonyl group; C ６～１０ Aryl and 5- to 10-membered heteroaryl are R ２０ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ３ H, D, halo, CN, and C １～６ alkyl; R ４ H, D, halo, CN, and C １～６ alkyl; R ５ But C ６～１０ aryl and 5- to 10-membered heteroaryl; said 5- to 10-membered heteroaryl 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; said 5- to 10-membered heteroaryl ring-forming carbon atoms are optionally substituted with oxo to form a carbonyl group; said C ６～１０ Aryl and 5- to 10-membered heteroaryl are R ５０ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R ５ The two adjacent Rs above ５０ The substituents, together with the atoms to which they are attached, may form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring or a fused C ３～７ wherein the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl rings 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; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; the fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and the fused C ３～７ The cycloalkyl ring is R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CR Ａ and R Ａ However, H, D, and C １～６ is alkyl; Each R １０ But 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 , N.R. ｃ１ R ｄ１ , and S(O) ２ NR ｃ１ R ｄ１ are independently selected from the group consisting of １～６ The alkyl is R １１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２０ But 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, 5-6 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 , N.R. ｃ２ R ｄ２ , S(O) ２ R ｂ２ , and S(O) ２ NR ｃ２ R ｄ２ wherein a ring-forming carbon atom of said 4- to 6-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; 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 The alkylene is R ２１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２１ But C １～６ Alkyl, C １～６ Haloalkyl, C ３～６ Cycloalkyl, 4-6 membered heterocycloalkyl, halo, D, CN, OR ａ４ , C(O)NR ｃ４ R ｄ４ , and N.R. ｃ４ R ｄ４ are independently selected from the group consisting of １～６ Alkyl, C ３～６ Cycloalkyl and 4- to 6-membered heterocycloalkyl are R ２２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２２ But C １～６ Alkyl, C １～６ Haloalkyl, Halo, D, CN, OR ａ６ , and N.R. ｃ６ R ｄ６ are independently selected from the group consisting of １～６ The alkyl is R ｇ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ５０ But C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, 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)OR ａ９ , N.R. ｃ９ R ｄ９ , S(O) ２ R ｂ９ , and S(O) ２ NR ｃ９ R ｄ９ are independently selected from the group consisting of １～６ Alkyl, C ３～１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl and 5- to 10-membered heteroaryl are R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ５１ But C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, halo, D, CN, OR ａ１０ , C(O)R ｂ１０ , C(O)NR ｃ１０ R ｄ１０ , C(O)OR ａ１０ , N.R. ｃ１０ R ｄ１０ , S(O) ２ R ｂ１０ , and S(O) ２ NR ｃ１０ R ｄ１０ are independently selected from the group consisting of １～６ Alkyl, C ３～１０ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl and 5- to 10-membered heteroaryl are R ５２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ５２ But C １～６ Alkyl, C １～６ Haloalkyl, Halo, D, CN, OR ａ１１ , and N.R. ｃ１１ R ｄ１１ are independently selected from Each R ａ , R ｃ , and R ｄ But H, C １～６ Alkyl, C １～６ Haloalkyl, C ３～１０ cycloalkyl, and 4- to 10-membered heterocycloalkyl; １～６ Alkyl, C ３～１０ Cycloalkyl and 4- to 10-membered heterocycloalkyl are R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ and R ｄ together with the N atom to which they are attached, R １０ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ But C １～６ Alkyl, C １～６ haloalkyl, and 4- to 10-membered heterocycloalkyl; and 4- to 10-membered heterocycloalkyl is R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ１ , R ｃ１ , and R ｄ１ However, H and C １～６ independently selected from alkyl; Each R ｂ１ But C １～６ Alkyl and C １～６ independently selected from haloalkyl; Each R ａ２ , R ｃ２ , and R ｄ２ But H, C １～６ Alkyl, and C １～６ independently selected from haloalkyl; Or any R bonded to the same N atom ｃ２ and R ｄ２ together with the N atom to which they are attached, R ２１ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ２ But C １～６ Alkyl and C １～６ independently selected from haloalkyl; Each R ａ４ , R ｃ４ , and R ｄ４ However, H and C １～６ independently selected from alkyl; Each R ｂ４ But C １～６ Alkyl and C １～６ independently selected from haloalkyl; Each R ａ６ , R ｃ６ , and R ｄ６ However, H and C １～６ independently selected from alkyl; Each R ａ９ , R ｃ９ , and R ｄ９ But H, C １～６ Alkyl, C １～６ independently selected from haloalkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl; １～６ Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ９ and R ｄ９ together with the N atom to which they are attached, R ５１ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ９ But C １～６ Alkyl and C １～６ independently selected from haloalkyl; Each R ａ１０ , R ｃ１０ , and R ｄ１０ However, H and C １～６ independently selected from alkyl; Each R ｂ１０ But C １～６ Alkyl, C １～６ independently selected from haloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl; １～６ alkyl 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl are R ５２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ１１ , R ｃ１１ , and R ｄ１１ However, H and C １～６ independently selected from alkyl; Each R ｇ But, 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 or (b) R １ But C １～６ Alkyl, CN, C(O)NR ｃ R ｄ , C(O)R ｂ , and C(O)OR ａ C １～６ The alkyl is R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ２ is selected from phenyl and 5- to 6-membered heteroaryl; said 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 said N and S are optionally oxidized; said ring-forming carbon atoms of said 5- to 6-membered heteroaryl are optionally substituted by oxo to form a carbonyl group; said phenyl and 5- to 6-membered heteroaryl are optionally substituted by R ２０ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ３ is H; R ４ is H; R ５ But C ６～１０ aryl and 5- to 10-membered heteroaryl; said 5- to 10-membered heteroaryl 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; said 5- to 10-membered heteroaryl ring-forming carbon atoms are optionally substituted with oxo to form a carbonyl group; said C ６～１０ Aryl and 5- to 10-membered heteroaryl are R ５０ each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Or R ５ The two adjacent Rs above ５０ the substituents, together with the atoms to which they are attached, form a fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring; said fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S; a ring-forming carbon atom of each fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring may be optionally substituted by oxo to form a carbonyl group; said fused 4-, 5-, 6-, or 7-membered heterocycloalkyl ring and fused C ３～７ The cycloalkyl ring is R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from A is N or CH; Each R １０ But C １～６ Alkyl, OR ａ１ , and C(O)OR ａ１ are independently selected from the group consisting of １～６ The alkyl is R １１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２０ But 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 a ring-forming carbon atom of said 4- to 6-membered heterocycloalkyl is optionally substituted by oxo to form a carbonyl group; １～６ Alkyl, C ３～６ Cycloalkyl, 4- to 6-membered heterocycloalkyl, and 4- to 6-membered heterocycloalkyl-C １～３ The alkylene is R ２１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２１ But C １～６ Alkyl, C ３～６ cycloalkyl, 4- to 6-membered heterocycloalkyl, halo, OR ａ４ , and N.R. ｃ４ R ｄ４ are independently selected from the group consisting of １～６ Alkyl, C ３～６ Cycloalkyl and 4- to 6-membered heterocycloalkyl are R ２２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ２２ But C １～６ independently selected from alkyl, halo, and OH; Each R ５０ But C １～６ Alkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, halo, CN, C(O)NR ｃ９ R ｄ９ , and N.R. ｃ９ R ｄ９ are independently selected from the group consisting of １～６ Alkyl, 4- to 10-membered heterocycloalkyl, and 5- to 10-membered heteroaryl are R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ５１ But C １～６ Alkyl, 4- to 10-membered heterocycloalkyl, C ６～１０ Aryl, OH, and C(O)R ｂ１０ are independently selected from the group consisting of １～６ alkyl, 4- to 10-membered heterocycloalkyl, and C ６～１０ The aryl is R ５２ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ５２ is independently selected from halo and OH; Each R ａ , R ｃ , and R ｄ But H, C １～６ Alkyl, and C ３～１０ cycloalkyl; １～６ Alkyl and C ３～１０ Cycloalkyl is R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ and R ｄ together with the N atom to which they are attached, R １０ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ But C １～６ Alkyl, C １～６ haloalkyl, and 4- to 10-membered heterocycloalkyl; and 4- to 10-membered heterocycloalkyl is R １０ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ１ However, H and C １～６ independently selected from alkyl; Each R ａ２ , R ｃ２ , and R ｄ２ But H, C １～６ Alkyl, and C １～６ independently selected from haloalkyl; Or any R bonded to the same N atom ｃ２ and R ｄ２ together with the N atom to which they are attached, R ２１ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ａ４ , R ｃ４ , and R ｄ４ But H, C １～６ Alkyl, and C １～６ independently selected from haloalkyl; Or any R bonded to the same N atom ｃ４ and R ｄ４ together with the N atom to which they are attached, R ２１ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｃ９ and R ｄ９ But H, C １～６ alkyl, and 5- to 10-membered heteroaryl; １～６ alkyl and 5- to 10-membered heteroaryl are R ５１ each optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or any R bonded to the same N atom ｃ９ and R ｄ９ together with the N atom to which they are attached, R ５１ forming a 4- to 10-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Each R ｂ１０ But C １～６ independently selected from alkyl and 5- to 6-membered heteroaryl; １～６ Alkyl and 5- to 6-membered heteroaryl are R ５２ 10. The composition of claim 1, wherein each of the groups is optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

17. (a) the compound is 4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinoline; Methyl 7-(4-(piperazin-1-yl)phenyl)-3-(quinolin-4-yl)imidazo[1,2-b]pyridazine-6-carboxylate; N-((1R,4R)-4-hydroxy-4-methylcyclohexyl)-7-(4-(piperazin-1-yl)phenyl)-3-(quinolin-4-yl)imidazo[1,2-b]pyridazine-6-carboxamide; Ethyl 4-(7-(4-(piperazin-1-yl)phenyl)-3-(quinolin-4-yl)imidazo[1,2-b]pyridazine-6-carbonyl)piperazine-1-carboxylate; 7-(4-(piperazin-1-yl)phenyl)-3-(quinolin-4-yl)imidazo[1,2-b]pyridazine-6-carboxamide; 7-(4-(piperazin-1-yl)phenyl)-3-(quinolin-4-yl)imidazo[1,2-b]pyridazine-6-carbonitrile; (7-(4-(piperazin-1-yl)phenyl)-3-(quinolin-4-yl)imidazo[1,2-b]pyridazin-6-yl)methanol; 4-(6-(methoxymethyl)-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinoline; 4-(6-methyl-7-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)-7-(pyridin-4-yl)quinoline; (trans)-4-(4-(6-methyl-3-(7-(pyridin-4-yl)quinolin-4-yl)imidazo[1,2-b]pyridazin-7-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol; 2-(4-(4-(6-methyl-3-(7-(pyridin-4-yl)quinolin-4-yl)imidazo[1,2-b]pyridazin-7-yl)phenyl)piperazin-1-yl)ethan-1-ol; 4-methyl-1-(4-(6-methyl-3-(7-(pyridin-4-yl)quinolin-4-yl)imidazo[1,2-b]pyridazin-7-yl)phenyl)piperazin-2-one; 4-(6-methyl-7-(3-(4-methylpiperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-7-(pyridin-4-yl)quinoline; (4-(6-methyl-3-(7-(pyridin-4-yl)quinolin-4-yl)imidazo[1,2-b]pyridazin-7-yl)phenyl)(4-methylpiperazin-1-yl)methanone; (R)-4-(7-(3-fluoro-4-((2-methylpyrrolidin-1-yl)methyl)phenyl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-7-(pyridin-4-yl)quinoline; N-methyl-4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinoline-7-carboxamide; (4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)(4-methylpiperazin-1-yl)methanone; 7-(1-methyl-1H-pyrazol-3-yl)-4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinoline; (4-(4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)pyridin-2-yl)methanol; 4-(4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)morpholine; 2-(4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)-6-oxa-2-azaspiro[3.4]octane; 4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-N-(pyridin-3-yl)quinolin-7-amine; 1-(4-(4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)piperazin-1-yl)ethan-1-one; 4-((4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)methyl)morpholine; (3,5-difluorophenyl)(4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)methanol; (4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)methanol; 4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-1,8-naphthyridine; 5-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinoline-8-carbonitrile; 8-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine; 4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinoline-7-carbonitrile; N-(2-hydroxyethyl)-4-(6-methyl-7-(4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazin-3-yl)quinoline-8-carboxamide; (4-(6-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)(pyridin-4-yl)methanone; 1-((1S,4S)-5-(4-(7-(1-((1R,4R)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethan-1-one; 2-(4-(7-(1-((1R,4R)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)quinolin-7-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one; 4-(6-methyl-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)quinoline; or 2-fluoro-4-(6-methyl-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-3-yl)benzamide; or a pharmaceutically acceptable salt thereof; (b) the compound is (1R,4R)-4-(4-(6-methyl-3-(7-(pyridin-2-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol; 5-(7-(4-(azetidin-1-ylmethyl)phenyl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(pyridin-2-yl)-1,8-naphthyridine; 5-(7-(1-ethyl-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(pyridin-2-yl)-1,8-naphthyridine; 5-(7-(1-isopropyl-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(pyrimidin-2-yl)-1,8-naphthyridine; (1R,4R)-4-(4-(6-methyl-3-(7-(pyrazin-2-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)-1H-pyrazol-1-yl)cyclohexan-1-ol; 5-(7-(4-(azetidin-1-ylmethyl)phenyl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(pyrazin-2-yl)-1,8-naphthyridine; 5-(7-(1-isopropyl-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(pyrazin-2-yl)-1,8-naphthyridine; 5-(6-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)-2-(pyrazin-2-yl)-1,8-naphthyridine; 5-(7-(1-isopropyl-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(1-methyl-1H-pyrazol-3-yl)-1,8-naphthyridine; 5-(7-(4-(azetidin-1-ylmethyl)phenyl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(1-methyl-1H-pyrazol-3-yl)-1,8-naphthyridine; N,N-dimethyl-4-(6-methyl-3-(7-(1-methyl-1H-pyrazol-3-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)benzamide; 5-(7-(4-(azetidin-1-ylmethyl)phenyl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(5-methyl-1H-pyrazol-3-yl)-1,8-naphthyridine; 4-(4-(6-methyl-3-(7-(5-methyl-1H-pyrazol-3-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)benzyl)morpholine; 5-(7-(1-isopropyl-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(5-methyl-1H-pyrazol-3-yl)-1,8-naphthyridine; 5-(7-(1-isopropyl-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-1,8-naphthyridine; 2-(1-ethyl-1H-imidazol-4-yl)-5-(6-methyl-7-(4-(pyrrolidin-1-ylmethyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-1,8-naphthyridine; 4-(4-(3-(7-(1-ethyl-1H-imidazol-4-yl)-1,8-naphthyridin-4-yl)-6-methylimidazo[1,2-b]pyridazin-7-yl)benzyl)morpholine; 1-(4-(3-(7-(1-ethyl-1H-imidazol-4-yl)-1,8-naphthyridin-4-yl)-6-methylimidazo[1,2-b]pyridazin-7-yl)phenyl)-N,N-dimethylmethanamine; 2-(1-ethyl-1H-imidazol-4-yl)-5-(7-(1-isopropyl-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-1,8-naphthyridine; 5-(7-(4-(azetidin-1-ylmethyl)phenyl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(1-ethyl-1H-imidazol-4-yl)-1,8-naphthyridine; 5-(7-(4-((3,3-difluoroazetidin-1-yl)methyl)phenyl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(1-ethyl-1H-imidazol-4-yl)-1,8-naphthyridine; (S)-4-(4-(3-(7-(1-ethyl-1H-imidazol-4-yl)-1,8-naphthyridin-4-yl)-6-methylimidazo[1,2-b]pyridazin-7-yl)benzyl)-2-methylmorpholine; (S)-(4-(4-(3-(7-(1-ethyl-1H-imidazol-4-yl)-1,8-naphthyridin-4-yl)-6-methylimidazo[1,2-b]pyridazin-7-yl)benzyl)morpholin-2-yl)methanol; 2-(4-methyl-2H-1,2,3-triazol-2-yl)-5-(6-methyl-7-(4-(pyridazin-1-ylmethyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-1,8-naphthyridine; 5-(7-(1-isopropyl-1H-pyrazol-4-yl)-6-methylimidazo[1,2-b]pyridazin-3-yl)-2-(4-methyl-2H-1,2,3-triazol-2-yl)-1,8-naphthyridine; 2-(4-methyl-2H-1,2,3-triazol-2-yl)-5-(6-methyl-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl)-1,8-naphthyridine; N,N-dimethyl-1-(4-(6-methyl-3-(7-(4-methyl-2H-1,2,3-triazol-2-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)phenyl)methanamine; 4-(4-(6-methyl-3-(7-(4-methyl-2H-1,2,3-triazol-2-yl)-1,8-naphthyridin-4-yl)imidazole[1,2-b]pyridazin-7-yl)benzyl)morpholine; N,N-dimethyl-1-(4-(6-methyl-3-(7-(4-methyl-2H-1,2,3-triazol-2-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)phenyl)methanamine; (S)-3-methyl-1-(4-(6-methyl-3-(7-(4-methyl-2H-1,2,3-triazol-2-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)benzyl)pyrrolidin-3-ol; or 1-(4-(6-methyl-3-(7-(4-methyl-2H-1,2,3-triazol-2-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)benzyl)piperidin-4-ol; or a pharmaceutically acceptable salt thereof, or (c) the compound is 4-methyl-1-(4-(6-methyl-3-(7-(4-methyl-2H-1,2,3-triazol-2-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)benzyl)piperidin-4-ol; 3-methyl-1-(4-(6-methyl-3-(7-(4-methyl-2H-1,2,3-triazol-2-yl)-1,8-naphthyridin-4-yl)imidazo[1,2-b]pyridazin-7-yl)benzyl)azetidin-3-ol; 2-(4-methyl-2H-1,2,3-triazol-2-yl)-5-(6-methyl-7-(4-((4-methylpiperazin-1-yl)methyl)phenyl)imidazo[1,2-b]pyridazin-3-yl)-1,8-naphthyridine; 1-(4-(3-(7-(1-ethyl-1H-imidazol-4-yl)-1,8-naphthyridin-4-yl)-6-methylimidazo[1,2-b]pyridazin-7-yl)benzyl)piperidin-4-ol; or 1-(4-(3-(7-(1-ethyl-1H-imidazol-4-yl)-1,8-naphthyridin-4-yl)-6-methylimidazo[1,2-b]pyridazin-7-yl)benzyl)-4-methylpiperidin-4-ol; or a pharmaceutically acceptable salt thereof. The composition of claim 1.

18. a) whether the anemia is associated with myelofibrosis; b) the anemia is associated with treatment for myelofibrosis; or c) the anemia is associated with treatment of myelofibrosis with ruxolitinib; The composition according to any one of claims 1 to 17.

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