TYK-2 inhibitors

Abstract

Disclosed herein are compounds of formula (I) for inhibiting TYK2 and treating diseases associated with unwanted tyk-2 activity (tyk-2 associated diseases), methods of using the compounds disclosed herein for treating inflammatory or autoimmune diseases, and pharmaceutical compositions comprising the same.

Description

[Technical Field]

[0001] Disclosed herein are compounds of formula (I) for inhibiting TYK2 and treating diseases associated with unwanted tyk-2 activity (tyk-2 associated diseases), methods of using the compounds disclosed herein for treating inflammatory or autoimmune diseases, and pharmaceutical compositions comprising the same. [Background technology]

[0002] The Janus kinase family, which includes JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2), is a non-receptor tyrosine kinase that binds to the intracellular portion of cell surface cytokine receptors. In response to stimulation of these receptors, Janus kinases phosphorylate signal transducers and activators of transcription (STAT) proteins, which then dimerize, translocate to the nucleus, and activate gene transcription. Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases and has been reported in mice (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12 / TH1 and IL-23 / TH17 Axes in vivo", J. Immunol., 187:181-189 (2011); Prchal-Murphyl, M. et al., "TYK2 kinase activity is required for functional type I interferon responses in vivo", PloS one, 7:e39141 (2012)) and humans (Minegishi, Y. et al., "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate acquired Tyk2 has been shown to be crucial in regulating the signaling cascade downstream of the receptors for IL-12, IL-23, and type I interferons in both IL-12 and IL-23-dependent inflammatory responses ...Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, demonstrating the importance of Tyk2-mediated signaling in autoimmune and related disorders (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12 / TH1 and IL-23 / TH17 Axes in Vivo", J. Immunol., 187:181-189 (2011); Oyamada, A. et al., "Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis", J. Immunol., 2009, 183, 7539-7546).

[0003] To date, most of the known small molecule JAK inhibitors that have reached development are active site-specific inhibitors that bind to the adenosine triphosphate (ATP) site in the catalytic domain of the JAK protein (also known as the JH1 or "Janus homolog 1" domain), which prevents the catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and resulting pathway signaling (Bryan, M. et al., "Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances", J. Med. Chem. 2018, 61, 9030-9058). JAK2 is involved in hematopoiesis (Neubauer, H.; et al., "JAK2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis", Cell 1998, 93, 397-409), and inhibition of JAK2 may cause side effects such as anemia, neutropenia, and increased risk of infection and lipid abnormalities (Wollenhaupt, J., et al., "Safety and efficacy of tofacitinib, an oral Janus Kinase Inhibitor, for the treatment of rheumatoid arthritis in open-label. J. Rheumatol. 2014, 41, 837-852; He, Y., et al., Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systematic review and meta-analysis. BMC Musculoskelet. Disord. 2013, 14, 298; Zerbini, CA, et al., Tofacitinib for the treatment of rheumatoid arthritis. Expert Rev. Clin. Immunol. 2012, 8, 319-331).

[0004] Small molecule inhibitors of the TYK2-JH2 domain are being developed for the treatment of autoimmune diseases. BMS986165 (WO2014074661A1, WO2018183649A1, WO2018183656A1, and WO2019232138A1) is a first-in-class TYK2-JH2 inhibitor currently undergoing multiple clinical trials for psoriasis, ulcerative colitis (UC), lupus, and systemic lupus erythematosus. Another TYK2-JH2 inhibitor in clinical trials is ABBV-712 (see, for example, WO2019178079A1, WO2019178079A9, JP6557436B1, and US2019276450A1), which is currently undergoing clinical trials for psoriasis. Summary of the Invention

[0005] Disclosed herein are a series of compounds that inhibit the TYK2 pseudokinase (JH2) domain. These compounds exhibit picomolar to nanomolar biochemical activity in TYK2-JH2 binding assays and nanomolar activity in cellular assays. Meanwhile, these compounds exhibit excellent selectivity over JAK1 in biochemical assays and excellent selectivity over JAK2 in cellular assays.

[0006] In the present disclosure, compounds bind to the TYK2 pseudokinase (JH2) domain and inhibit its function via an allosteric mechanism, while possessing significantly improved selectivity over other JAK family members (JAK1, JAK2, and JAK3).

[0007] In a first aspect, there is provided a compound of formula (I) [ka] During the ceremony, X is N or CH; Y is N, NR 3 , or CR 3 and L 1 is a direct bond, -(CR a Rb ) q -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -, -O-(CR a R b ) q -, -S-(CR a R b ) q -, -S(O)-(CR a R b ) q -, -SO2-(CR a R b ) q -, -C(O)-(CR a R b ) q -, C(O)O-(CR a R b ) q -, -OC(O)-(CR a R b ) q -, -NR a -(CR a R b ) q -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)O-, -NR a C(O)NR b -,-SO2NR a -, -NR a SO2-, -NR a S(O)NR b -, -NR a S(O)NR b -, -C(O)NR a SO2-, -C(O)NR a SO-, or -C(=NR a )NR b wherein q is a number from 1 to 7; R a and R b are independently hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R1 But -C 1-6 Alkyl, -haloC 1-6 Alkyl, -C 1-6 Alkoxy, -haloC 1-6 Alkoxyl, -C 3-6 Cycloalkyl, aryl, or -NR c R d and R 2 , R 3 , and R 4 are each independently hydrogen, cyano, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -NO2, -OR e , -SO2R e , -COR e , -CO2R e , -CONR e R f , -C(=NR e )NR f R g , -NR e R f , -NR e COR f , -NR e CONR f R g , -NR e CO2R f , -NR e SONR f R g , -NR e SO2NR f R g , or -NR e SO2R f and where -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl each i) cyano, -oxo-, halogen, -NR m R n , -ORh , -C(O)NR m R n , ii) cyano, -oxo, halogen, hydroxy, -NR m R n , substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 1-6 Alkoxy, or -C(O)NR m heterocyclyl optionally substituted with at least one substituent independently selected from R, or iii) cyano, halogen, hydroxy, -NH2, or C 1-6 C optionally substituted with at least one substituent independently selected from alkoxy 1-6 alkyl, In the formula, R h But hydrogen, hydroxy, -NH2, -C 1-6 C substituted with alkyl, hydroxy 1-6 alkyl, or heterocyclyl; R e , R f , and R g are each independently hydrogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may each be cyano; -oxo-; halogen; hydroxy; -NR m R n ;-C 1-6 Alkyl;-C 1-6 Alkoxy; halogen, hydroxy, or -C 1-6 -C optionally substituted with alkoxy 3-6 Cycloalkyl; -C(O)NR m R nor heterocyclyl; R 5 is hydrogen or C 1-6 is alkyl, Cy 1 is a 6- to 12-membered aryl or a 5- to 14-membered heteroaryl, or a 5- to 14-membered heterocyclyl, each of which is substituted with at least one substituent R i optionally substituted with R i are independently halogen, cyano, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, cyano (-CN), -NO2, -OR j , -SO2R j , -COR j , -CO2R k , -CONR j R k , -C(=NR j )NR k R l , -NR j R k , -NR j COR k , -NR j CONR k R l , -NR j CO2R k , -NR j SONR k R l , -NR j SO2NR k R l , or -NR j SO2R k and where -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, -OR m , -C(O)R m , -NRm R n , -C 1-6 Alkyl, C 1-6 Alkoxy-, -C 1-6 Alkoxy-substituted C 1-6 optionally substituted with alkyl, or -oxo-; R j , R k , R l , R m , R n are each independently hydrogen, -C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl-, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R 1 and R 2 ), or (R 2 and R 3 ), or (R 3 and R 4 ), taken together with the atom to which they are attached, form a fused ring system, said fused ring system containing 0-4 heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s), halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, halogen-substituted C 1-6 C substituted with alkyl and halogen 1-6 Alkoxy, or -C 3-6 optionally substituted independently by cycloalkyl; Disclosed herein are compounds, or stereoisomers or pharmaceutically acceptable salts thereof, wherein either said alkyl or said alkoxy is optionally deuterium enriched.

[0008] In some embodiments, the compound of formula (IA) is [ka] During the ceremony, X is N or CH; L1 is a direct bond, -(CR a R b ) q -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -, -O-(CR a R b ) q -, -S-(CR a R b ) q -, -S(O)-(CR a R b ) q -, -SO2-(CR a R b ) q -, -C(O)-(CR a R b ) q -, C(O)O-(CR a R b ) q -, -OC(O)-(CR a R b ) q -, -NR a -(CR a R b ) q -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)O-, -NR a C(O)NR b -,-SO2NR a -, -NR a SO2-, -NR a S(O)NR b -, -NR a S(O)NR b -, -C(O)NR a SO2-, -C(O)NR a SO-, or -C(=NR a )NR b wherein q is a number from 1 to 7; R a and R b are independently hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 1 But -C 1-6 Alkyl, -haloC 1-6 Alkyl, -C 1-6 Alkoxy, -haloC 1-6 Alkoxyl, -C 3-6 Cycloalkyl, aryl, or -NR m R n and R 2 , R 3 , and R 4 are each independently hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -oxo-, -CN, -NO2, -OR e , -SO2R e , -COR e , -CO2R e , -CONR e R f , -C(=NR e )NR f R g , -NR e R f , -NR e COR f , -NR e CONR f R g , -NR e CO2R f , -NR e SONR f R g , -NR e SO2NR f R g , or -NR e SO2R f and where -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8cycloalkyl, heterocyclyl, aryl, or heteroaryl, each optionally substituted with cyano, oxo, halogen, halogen; 1-6 C substituted with alkyl, hydroxy (preferably hydroxymethyl, hydroxyethyl) 1-6 Alkyl, -OR h , -C(O)NR m R n , -NH2, -C substituted with -NH2 1-6 Alkyl, or -C 1-6 Alkoxy-substituted -C 1-6 and optionally substituted independently with at least one substituent selected from alkyl, In the formula, R h but hydrogen, alkyl, hydroxy-C 1-6 alkyl, or heterocyclyl; R e , R f , and R g are each independently hydrogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each selected from the group consisting of halogen, hydroxy, cyano, or -C 1-6 Alkoxy; halogen, hydroxy, or C 1-6 -C optionally substituted with alkoxy 3-6 cycloalkyl; or heterocyclyl; R 5 is hydrogen or C 1-6 is alkyl, Cy 1 is a 6- to 12-membered aryl or a 5- to 14-membered heteroaryl, or a 5- to 14-membered heterocyclyl, each of which is substituted with at least one substituent R i optionally substituted with R i are independently halogen, cyano, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR j , -SO2R j , -COR j , -CO2R k , -CONR j R k , -C(=NR j )NR k R l , -NR j R k , -NR j COR k , -NR j CONR k R l , -NR j CO2R k , -NR j SONR k R l , -NR j SO2NR k R l , or -NR j SO2R k and Here, the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, OR m , C(O)R m , -NR m R n , -C 1-6 Alkyl, C 1-6 Alkoxy-, C 1-6 Alkoxy-C 1-6 optionally substituted with alkyl- or oxo; R j , R k , R l , R m , R n are each independently hydrogen, -C1-6 Alkyl, C 1-6 -C substituted with alkoxy 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R 1 and R 2 ), or (R 2 and R 3 ), or (R 3 and R 4 ), taken together with the atom to which they are attached, form a fused ring system, said fused ring system containing 0 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur as ring member(s), halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -haloC 1-6 Alkyl, -haloC 1-6 Alkoxy, or -C 3-6 optionally substituted independently by cycloalkyl; Disclosed herein are compounds, or stereoisomers or pharmaceutically acceptable salts thereof, wherein either said alkyl or said alkoxy is optionally deuterium enriched.

[0009] In some embodiments, X is N and Y is CR 3 In some embodiments, X is N and Y is N. In some embodiments, X is CH and Y is N.

[0010] In some embodiments, R 1 -C 1-3 Alkyl, -NR c R d , or -C 3-6 It is cycloalkyl, preferably -NH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclopentyl.

[0011] In some embodiments, R 2 and R 4 are each independently hydrogen, halogen, or -C1-6 Alkyl, or -C 1-6 Alkoxy is preferably hydrogen, fluoro, methyl, methoxy, ethoxy, or isopropoxy.

[0012] In some embodiments, R 3 teeth, - hydrogen or -Cyano or - is halogen or -halogen, 3- to 6-membered heterocyclyl, or -OR h -C optionally substituted with at least one substituent independently selected from 1-4 alkyl, A 3- to 6-membered heterocyclyl contains one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (O) as ring member(s), and is optionally substituted with cyano, -oxo, halogen, hydroxy, -NR m R n , C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; R h is hydrogen, alkyl, or heterocyclyl; 1-4 Is it alkyl? -cyano, -oxo, halogen, -NR m R n , hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with at least one substituent independently selected from 3-6 cycloalkyl, where -C 1-6Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; 3-6 is cycloalkyl, or -cyano, -oxo-, halogen, hydroxy, C 1-6 Alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n and a heterocyclyl containing one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s), optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 heterocyclyl substituted with at least one substituent independently selected from alkoxy; --OR e wherein R e But -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, or aryl; I C 1-6 Alkyl is cyano; -oxo-; halogen; hydroxy; -NR m R n ;-C 1-6 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with 3-6 Cycloalkyl; cyano, halogen, hydroxy, C 1-6 Alkyl or C 1-6optionally substituted by 4- to 6-membered heterocyclyl optionally substituted by alkoxy; ii)-C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is selected from the group consisting of cyano, -oxo, halogen, hydroxy, -NR m R n , C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; e Or --C 5-10 is aryl, or -cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and wherein: -C is a heteroaryl containing one oxygen (O), nitrogen (N), or sulfur (S) heteroatom as a ring member, optionally substituted with at least one substituent independently selected from 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 heteroaryl, substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or C 1-3 alkyl, Either the alkyl or the alkoxy is optionally deuterium enriched.

[0013] In some embodiments, R3 teeth, - hydrogen or -Cyano or - is halogen or -halogen, 3- to 6-membered heterocyclyl, or -OR h -C optionally substituted with at least one substituent independently selected from 1-4 alkyl, The 3- to 6-membered heterocyclyl contains one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (O) as ring members or ring members, and is optionally substituted with cyano, -oxo, halogen, hydroxy, -NR m R n , C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; R h is hydrogen, alkyl, or heterocyclyl (preferably 3- to 6-membered heterocyclyl, for example, tetrahydrofuranyl, thiazolidinyl); 1-4 Is it alkyl? -cyano, -oxo, halogen, -NR m R n , hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with at least one substituent independently selected from 3-6 cycloalkyl, where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6substituted with at least one substituent independently selected from alkoxy; 3-6 is cycloalkyl, or -cyano, -oxo, halogen, hydroxy, -C 1-6 Alkyl, alkoxy, -NR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 heterocyclyl substituted with at least one substituent independently selected from alkoxy; --OR e wherein R e But -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl (preferably 4- to 6-membered monocyclic saturated heterocyclyl containing one oxygen heteroatom as a ring member), or aryl; I C 1-6 Alkyl is cyano; -oxo-; halogen; hydroxy; -NR m R n ;-C 1-6 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with3-6 Cycloalkyl; cyano, halogen, hydroxy, -C 1-6 Alkyl or -C 1-6 optionally substituted by 4- to 6-membered heterocyclyl optionally substituted by alkoxy; ii)-C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is cyano, -oxo, halogen, hydroxy, NR m R n , C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; e Or --C 5-10 is aryl, or -cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n Heteroaryl, preferably a 5-6 membered heteroaryl, containing one oxygen (O), nitrogen (N), or sulfur (S) heteroatom as a ring member, optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 heteroaryl, substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or C 1-3 alkyl.

[0014] In some embodiments, R 3 teeth, - hydrogen, cyano, halogen, -halogen, 3- to 6-membered heterocyclyl, or -OR h -C optionally substituted with at least one substituent independently selected from 1-4 alkyl, The 3- to 6-membered heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, thiazolidinyl, and azetidinyl, each of which is selected from cyano, -oxo, halogen, hydroxy, -NR m R n , C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; h But hydrogen, C 1-6 alkyl, or 3- to 6-membered heterocyclyl (e.g., tetrahydrofuranyl or thiazolidinyl), 1-4 Is it alkyl? -cyano, -oxo, halogen, NR m R n , hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n , hydroxy, or C 1-6 -C optionally substituted with at least one substituent independently selected from alkoxy 3-6 cycloalkyl, where -C 1-6 Alkyl or C 1-6Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; 3-6 is cycloalkyl, or -heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, and is selected from cyano, -oxo, halogen, hydroxy, C 1-6 Alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 substituted with at least one substituent independently selected from alkoxy; --OR e wherein R e But -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 4-6 membered monocyclic saturated heterocyclyl containing one oxygen heteroatom as a ring member, or C 6-10 is aryl, I C 1-6 Alkyl is cyano; -oxo-; halogen; hydroxy; -NR m R n ;-C 1-6 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with 3-6 Cycloalkyl; cyano, halogen, hydroxy, -C 1-6 Alkyl or -C 1-6optionally substituted by 4- to 6-membered heterocyclyl optionally substituted by alkoxy; ii)-C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is cyano, -oxo, halogen, hydroxy, NR m R n , C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; e Or --C 6-10 is aryl, or -5-6 membered heteroaryl selected from pyridinyl, pyridazinyl, pyrazinyl, thiazolyl, and isoxazolyl, each of which is cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 5-6 membered heteroaryl substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or -C 1-3 alkyl.

[0015] In some embodiments, R 3 teeth, - hydrogen, cyano, halogen, -cyano, -oxo, halogen, hydroxy, -NR m R n , or -C 1-3 optionally substituted with at least one substituent independently selected from alkyl, halogen, hydroxy, C 1-3 -C optionally substituted with at least one substituent independently selected from alkoxy, thiazolidin-3-yl 1-4 Is it alkyl? -cyano, -oxo, halogen, -NR m R n , hydroxy, -C 1-6 Alkyl, or -C 1-6 -C optionally substituted with at least one substituent independently selected from alkoxy 3-6 cycloalkyl, where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-3 substituted with at least one substituent independently selected from alkoxy; 3-6 is cycloalkyl, or -heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, and is selected from cyano, -oxo, halogen, hydroxy, C 1-6 Alkyl, alkoxy, -NR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 substituted with at least one substituent independently selected from alkoxy; --OR e wherein Re But -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 4-6 membered monocyclic saturated heterocyclyl containing one oxygen heteroatom as a ring member, or C 6-10 is aryl, I C 1-6 Alkyl is cyano; -oxo-; halogen; hydroxy; -NR m R n ;-C 1-6 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with 3-6 Cycloalkyl; cyano, halogen, hydroxy, -C 1-6 Alkyl or -C 1-6 optionally substituted by 4- to 6-membered heterocyclyl optionally substituted by alkoxy; ii)-C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is selected from the group consisting of cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n where -C 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 substituted with at least one substituent independently selected from alkoxy; e Or --C 6-10 is aryl, or -5-6 membered heteroaryl selected from pyridinyl, pyridazinyl, pyrazinyl, thiazolyl, and isoxazolyl, each of which is cyano, -oxo, halogen, hydroxy, -NR m Rn , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 5-6 membered heteroaryl substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or -C 1-3 alkyl.

[0016] In some embodiments, R 3 teeth, - hydrogen, cyano, halogen, -methyl, ethyl, propyl, or butyl, each of which is optionally substituted with at least one substituent independently selected from halogen, hydroxy, methoxy, ethoxy, propoxy, or 2,4-dioxothiazolidin-3-yl; -cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is selected from the group consisting of cyano, -oxo, halogen, -NR m R n , hydroxy, -C 1-3 Alkyl, or -C 1-3 Optionally substituted with at least one substituent independently selected from alkoxy, wherein 1-3 Alkyl or C 1-3 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-3 Alkyl, or -C 1-3 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with at least one substituent independently selected from alkoxy; -heterocyclyl is selected from morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 5-azaspiro[2.4]heptanyl, 3-azabicyclo[3.1.0]hexan-3-yl, or 2-azabicyclo[3.1.0]hexan-2-yl, each of which is selected from cyano, -oxo, halogen, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -NR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 substituted with at least one substituent independently selected from alkoxy; --OR e wherein R e but, i) methyl, ethyl, propyl (isopropyl), butyl, pentyl, or hexyl, each of which is selected from the group consisting of deuterium, cyano, -oxo-, halogen, hydroxy, and -NR m R n ;-C 1-3 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-3 Alkyl, -C 1-3 Alkoxy, or -C(O)NR m R n -C optionally substituted with 3-6cycloalkyl; or cyano, halogen, hydroxy, -C 1-3 Alkyl or -C 1-3 optionally substituted by a 4- to 6-membered heterocyclyl optionally substituted by an alkoxy; or ii) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl, azetidin-2-yl, or azetidin-3-yl, each of which is selected from the group consisting of cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-3 Alkyl, -C 1-3 Alkoxy, or -C(O)NR m R n where -C 1-3 Alkyl or -C 1-3 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-3 Alkyl, or -C 1-3 substituted with at least one substituent independently selected from alkoxy; e Or --C 6-10 is aryl, or -5-6 membered heteroaryl selected from pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-1-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-1-yl, pyrazin-2-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4-yl, isoxazol-2-yl, isoxazol-3-yl, and isoxazol-4-yl, each of which is selected from cyano, -oxo, halogen, hydroxy, -NRm R n , -C 1-3 Alkyl, -C 1-3 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-3 Alkyl or -C 1-3 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-3 Alkyl, or C 1-3 5-6 membered heteroaryl substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or -C 1-3 alkyl.

[0017] In some embodiments, R 3 teeth, -hydrogen, -methyl, 1-methoxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, or (2,4-dioxothiazolidin-3-yl)methyl, -isopropoxy, methoxy-d3, methoxy, ethoxy, difluoromethoxy, 2-methoxyethoxy, 2-methoxy-2-methylpropoxy, 2-hydroxy-2-methylpropoxy, cyclopropylmethoxy, (1,4-dioxan-2-yl)methoxy, (4-hydroxycyclohexyl)oxy, (cis-4-hydroxycyclohexyl)oxy, (trans-4-hydroxycyclohexyl)oxy, (4-methoxycyclohexyl)oxy, (cis-4-methoxycyclohexyl)oxy, (trans-4-methoxycyclohexyl)oxy, or (3-methyloxetan-3-yl)methoxy, -Cyano, -3-methoxycyclobutyl, (trans)-3-methoxycyclobutyl, (cis)-3-methoxycyclobutyl, 2,2-dichlorocyclopropyl, or 1-cyanocyclopropyl, -morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, 3(S)-methyl-morpholino, 3,3-dimethylmorpho, -tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, (R)-tetrahydro-2H-pyran-3-yl, (S)-tetrahydro-2H-pyran-3-yl, 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl, -3-methoxypyrrolidin-1-yl, 3(R)-methoxypyrrolidin-1-yl, 3(S)-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, 3-(2-hydroxyethoxy)pyrrolidin-1-yl, 3-(trifluoromethoxy)pyrrolidin-1-yl, 3(R)-(trifluoromethoxy)pyrrolidin-1-yl, 3(S)-(trifluoromethoxy)pyrrolidin-1-yl, 2-(aminocarbonyl)pyrrolidin-1-yl, 2(R)-(aminocarbonyl)pyrrolidin-1-yl, 2(S)-(aminocarbonyl)pyrrolidin-1-yl, 3-(methoxymethyl)pyrrolidin-1-yl, 3(R)-(methoxymethyl)pyrrolidin-1-yl, 3(S)-(methoxymethyl)pyrrolidin-1-yl pyrolidin-1-yl, 3-cyano-4-hydroxypyrrolidin-1-yl, cis-3-cyano-4-hydroxypyrrolidin-1-yl, trans-3-cyano-4-hydroxypyrrolidin-1-yl, 3-cyano-4-methoxypyrrolidin-1-yl, cis-3-cyano-4-methoxypyrrolidin-1-yl, trans-3-cyano-4-methoxypyrrolidin-1-yl, 2-(methoxymethyl)pyrrolidin-1-yl, 2(R)-(methoxymethyl)pyrrolidin-1-yl, 2(S)-(methoxymethyl)pyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, 3(R)-methylpyrrolidin-1-yl, 3(S)-methylpyrrolidin-1-yl, pyrrolidin-1-yl, 3-(cyanomethoxy)pyrrolidin-1-yl, -5-azaspiro[2.4]heptan-5-yl, -tetrahydrofuran-3-yl, -3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, -1,4-dioxan-2-yl, -4-aminotetrahydro-2H-pyran-4-yl, 4-(aminomethyl)tetrahydro-2H-pyran-4-yl, -4-methoxypiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 3-methoxypiperidin-1-yl, 3(R)-methoxypiperidin-1-yl, 3(S)-methoxypiperidin-1-yl, 3-ethoxypiperidin-1-yl, 3(R)-ethoxypiperidin-1-yl, 3(S)-ethoxypiperidin-1-yl, -3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 4-methylpyridin-3-yl, 5-methylpyridazin-4-yl, 5-methoxypyridazin-4-yl, 3,5-dimethylisoxazol-4-yl, 4-methoxypyridin-3-yl, 4-(2-hydroxypropyl)-2-azabicyclo[3.1.0]hexan-2 ...(2-hydroxypropyl)-2-azabicyclo[3.1.0]hexan-2-yl, 4-(2-hydroxypropyl)-2-azabicyclo[3.1.0]hexan-3-yl, 4-(2-hydroxypropyl)-2-azabicyclo[3.1.0]hexan-3-yl, 4-(2-hydroxypropyl)-2-azabicyclo[3.1.0]hexan-3-yl, 4-(2-hydroxypropyl)- 4-(1-hydroxyethyl)pyridin-3-yl, 4-(1-methoxyethyl)pyridin-3-yl, pyridin-2-yl, or thiazol-4-yl.

[0018] In some embodiments, (R 1 and R 2 ), or (R 2 and R 3 ), or (R 3 and R 4 ) together with the atom to which they are attached form a fused 5-7 membered ring system, said fused ring system containing 0-2 oxygen heteroatoms as ring member(s), halogen, -C 1-6 Alkyl, -C1-6 Alkoxy, -haloC 1-6 Alkyl, -haloC 1-6 Alkoxy, or -C 3-6 Optionally, independently substituted cycloalkyl.

[0019] In some embodiments, R 1 and R 2 together with the atoms to which they are attached, [ka] or R 2 and R 3 together with the atoms to which they are attached form a fused ring system [ka] Form R 3 and R 4 together with the atoms to which they are attached, [ka] and forming a fused ring system selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -haloC 1-6 Alkyl, -haloC 1-6 Alkoxy, or -C 3-6 Optionally, independently substituted cycloalkyl.

[0020] In some embodiments, Cy 1 teeth, - a 5-7 membered monocyclic heterocyclyl or heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen, or sulfur as ring member(s); or - a 7-14 membered bicyclic or tricyclic heterocyclyl or heteroaryl having 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur as ring member(s); Each of these has at least one substituent Ri is optionally replaced by

[0021] In some embodiments, Cy 1 teeth, - the 5-7 membered monocyclic heteroaryl containing 1, 2, 3 or 4 heteroatom(s) selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s), preferably pyrazolyl, triazolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl, wherein the monocyclic heteroaryl is i. halogens, ii. Cyano, iii. Halogen, hydroxy, -C 1-6 Alkoxy, -C(O)R m (Preferably, R m is morpholinyl), or -NR m R n -C optionally substituted with 1-6 Alkyl, iv.Halogen, C 1-6 Alkyl-, -C 1-6 -C substituted with alkoxy 1-6 heterocyclyl optionally substituted by alkyl or oxo, preferably said heterocyclyl selected from tetrahydrofuranyl (preferably tetrahydrofuran-3-yl), morpholinyl (preferably morpholino), 2-oxa-5-azabicyclo[2.2.1]heptanyl (preferably 2-oxa-5-azabicyclo[2.2.1]heptan-2-yl), 8-oxa-3-azabicyclo[3.2.1]octanyl (preferably 8-oxa-3-azabicyclo[3.2.1]octan-8-yl), isoindolinyl (preferably isoindolin-2-yl), each of which is optionally substituted by methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-butyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, or oxo; v. Halogen, -oxo, -C 1-6 Alkyl, C1-6 Alkoxy- or -C 1-6 -C substituted with alkoxy 1-6 -C optionally substituted with alkyl 3-6 cycloalkyl, or vi.-OR j wherein R j But -C 1-6 Alkyl, -C 1-6 -C substituted with alkoxy 1-6 alkyl, or heterocyclyl, -OR j , vii. oxo, -the 7- to 14-membered bicyclic or tricyclic heteroaryl containing 1, 2, or 3 heteroatom(s) as ring member(s), preferably benzimidazolyl, imidazopyrimidinyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, benzothiophenyl, benzothiazolyl, benzisoxazolyl, benzoxazolyl, benzisothiazolyl, imidazopyridazinyl, imidazopyridazinyl, dihydro-4H-furo[3,2-c]pyranyl, 6,7-dihydro-4H- Thieno[3,2-c]pyranyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl, 6,7-dihydro-4H-pyrano[4,3-d]thiazolyl, [1,3]dioxolo[4,5-c]pyridinyl, 2, 3-dihydro-[1,4]dioxino[2,3-c]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazinyl, or 2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl, each of which is selected from the group consisting of halogen, —C 1-6 Alkyl, -NH2, or -C(O)R m wherein R m But C 1-6 The 7-14 membered bicyclic or tricyclic heteroaryl is alkyl.

[0022] In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridinyl, pyrazolyl, thienyl, or thiazolyl ring fused to a 5- or 6-membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring contains one or two heteroatoms selected from oxygen or nitrogen as ring member(s), and the 5- or 6-membered heterocyclyl ring is fused to one or two C 1-6 alkyl or oxo, preferably two C 1-6 In some embodiments, Cy is optionally substituted with alkyl, more preferably with two methyls, and most preferably with two methyls. 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridinyl ring fused to a 5- or 6-membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring contains one or two heteroatoms selected from oxygen (O) or nitrogen (N) as ring member(s), and the 5- or 6-membered heterocyclyl ring is fused to one or two C 1-6 alkyl or oxo, preferably two C 1-6 In some embodiments, Cy is optionally substituted with alkyl, more preferably with two methyls, and most preferably with two methyls. 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridinyl ring fused to a 5- or 6-membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring contains two oxygen atoms as ring member(s), and the 5- or 6-membered heterocyclyl ring is fused to one or two C 1-6 Alkyl, preferably two C 1-6 In some embodiments, Cy is optionally substituted with alkyl, more preferably with two methyls, and most preferably with two methyls. 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridinyl ring fused to a 1,4-dioxane ring, and the 1,4-dioxane ring is fused to one or two C 1-6 Alkyl, preferably two C 1-6Optionally substituted with alkyl, more preferably with two methyls, most preferably with two methyls, either of which is optionally deuterium enriched. In some preferred embodiments, Cy 1 teeth, [ka] and preferably [ka] is.

[0023] In some embodiments, Cy 1 teeth, [ka] [ka] [ka] [ka] [ka] [ka] is.

[0024] In one embodiment, a compound of formula (IB) [ka] During the ceremony, X is N or CH; L 1 is a direct bond, -(CR a R b ) q -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -, -O-(CRa R b ) q -, -S-(CR a R b ) q -, -S(O)-(CR a R b ) q -, -SO2-(CR a R b ) q -, -C(O)-(CR a R b ) q -, C(O)O-(CR a R b ) q -, -OC(O)-(CR a R b ) q -, -NR a -(CR a R b ) q -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)O-, -NR a C(O)NR b -,-SO2NR a -, -NR a SO2-, -NR a S(O)NR b -, -NR a S(O)NR b -, -C(O)NR a SO2-, -C(O)NR a SO-, or -C(=NR a )NR b wherein q is a number from 1 to 7; R a and R b are independently hydrogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 1 But -C 1-6 Alkyl, -haloC 1-6 Alkyl, -C 1-6 Alkoxy, -haloC 1-6Alkoxyl, -C 3-6 Cycloalkyl, aryl, or -NR c R d and R 2 , R 3 , and R 4 are each independently hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl (preferably morpholin-4-yl, tetrahydrofuran-3-yl), aryl, heteroaryl, -oxo-, -CN, -NO2, -OR e , -SO2R e , -COR e , -CO2R e , -CONR e R f , -C(=NR e )NR f R g , -NR e R f , -NR e COR f , -NR e CONR f R g , -NR e CO2R f , -NR e SONR f R g , -NR e SO2NR f R g , or -NR e SO2R f and where -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, hydroxy-C 1-6 alkyl (preferably hydroxymethyl), -OR h , or C 1-6 Alkoxy-C 1-6and optionally substituted independently with at least one substituent selected from alkyl-, R h is hydrogen, alkyl, or heterocyclyl; R e , R f , and R g are each independently hydrogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each selected from the group consisting of halogen, hydroxy, cyano, and -C 1-6 Alkoxy; halogen, hydroxy, or C 1-6 -C optionally substituted with alkoxy 3-6 optionally substituted with 1 to 3 independently selected from cycloalkyl; R 5 is hydrogen or C 1-6 is alkyl, Cy 1 is a 6- to 12-membered aryl or a 5- to 14-membered heteroaryl, or a 5- to 14-membered heterocyclyl, each of which is substituted with at least one substituent R i optionally substituted with R i are independently halogen, cyano, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR j , -SO2R j , -COR j , -CO2R k , -CONR j R k , -C(=NR j )NR k Rl , -NR j R k , -NR j COR k , -NR j CONR k R l , -NR j CO2R k , -NR j SONR k R l , -NR j SO2NR k R l , or -NR j SO2R k and Here, the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, OR m , C(O)R m , -NR m R n , -C 1-6 Alkyl, C 1-6 Alkoxy-, C 1-6 Alkoxy-C 1-6 optionally substituted with alkyl- or oxo; R j , R k , R l , R m , R n are each independently hydrogen, -C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl-, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R 1 and R 2 ), or (R 2 and R 3 ), or (R 3 and R 4), taken together with the atom to which they are attached, form a fused ring system, said fused ring system containing 0 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur as ring member(s), halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -haloC 1-6 Alkyl, -haloC 1-6 Alkoxy, or -C 3-6 optionally substituted independently by cycloalkyl; Disclosed herein are compounds, or stereoisomers or pharmaceutically acceptable salts thereof, wherein either said alkyl or said alkoxy may be optionally deuterium enriched.

[0025] In some embodiments, the compound of formula (IC) is [ka] During the ceremony, X is N or CH; L 1 is a direct bond, R 1 But -C 1-6 Alkyl or -haloC 1-6 is alkyl, R 2 and R 4 are each independently hydrogen, halogen, -C 1-6 Alkyl, or -C 1-6 is an alkoxy; R 3 are independently hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -oxo-, -CN, -NO2, -OR e , -SO2R e , -COR e , -CO2R e , -CONR e R f , -C(=NR e )NR f Rg , -NR e R f , -NR e COR f , -NR e CONR f R g , -NR e CO2R f , -NR e SONR f R g , -NR e SO2NR f R g , or -NR e SO2R f and where -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl each i) Cyano, -oxo-, halogen, -NH2, -OR h , -C(O)NR m R n , ii) cyano, -oxo, halogen, hydroxy, -NR m R n , substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 1-6 Alkoxy, or -C(O)NR m heterocyclyl optionally substituted with at least one substituent independently selected from R, or iii) C optionally substituted with halogen 1-6 -C substituted with alkyl, hydroxy (preferably hydroxymethyl, hydroxyethyl) 1-6 Alkyl, -C substituted with -NH 1-6 Alkyl, -NH2, or C 1-6 -C substituted with alkoxy 1-6 and optionally substituted independently with at least one substituent selected from alkyl, In the formula, R h is hydrogen, hydroxy, hydroxy-substituted alkyl, or heterocyclyl; R e , R f , and R g are each independently hydrogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may each be halogen; hydroxy; cyano; -oxo-; -NR m R n ;-C 1-6 Alkyl;-C 1-6 Alkoxy; halogen, hydroxy, or C 1-6 -C optionally substituted with alkoxy 3-6 Cycloalkyl; -C(O)NR m R n or heterocyclyl; R 5 is hydrogen or C 1-6 is alkyl, Cy 1 is a 7-14 membered bicyclic or tricyclic heterocyclyl or heteroaryl having 1, 2, or 3 heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s), which is / are selected from at least one substituent R i optionally substituted with R i are independently halogen, cyano, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR j , -SO2R j , -COR j , -CO2R k , -CONR j Rk , -C(=NR j )NR k R l , -NR j R k , -NR j COR k , -NR j CONR k R l , -NR j CO2R k , -NR j SONR k R l , -NR j SO2NR k R l , or -NR j SO2R k and Here, the -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, OR m , C(O)R m , -NR m R n , -C 1-6 Alkyl, C 1-6 Alkoxy-, -C 1-6 Alkoxy-substituted C 1-6 optionally substituted with alkyl, or oxo; R j , R k , R l , R m , R n are each independently hydrogen, -C 1-6 Alkyl, C 1-6 -C substituted with alkoxy 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R 1 and R 2 ), or (R 2 and R 3 ), or (R 3 and R4 ), taken together with the atom to which they are attached, form a fused ring system, said fused ring system containing 0-4 heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s), halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -haloC 1-6 Alkyl, -haloC 1-6 Alkoxy, or -C 3-6 optionally substituted independently by cycloalkyl; Disclosed herein are compounds, or stereoisomers or pharmaceutically acceptable salts thereof, wherein either said alkyl or said alkoxy is optionally deuterium enriched.

[0026] In some embodiments, R 1 -C 1-3 It is alkyl, preferably methyl, ethyl, propyl, or isopropyl.

[0027] In some embodiments, R 2 and R 4 are each independently hydrogen, halogen, or -C 1-3 Alkyl, or -C 1-3 Alkoxy is preferably hydrogen, fluoro, methyl, methoxy, ethoxy, or isopropoxy.

[0028] In some embodiments, R 3 teeth, - hydrogen or -Cyano or - is halogen or -halogen, 3- to 6-membered heterocyclyl, or -OR h -C optionally substituted with at least one substituent independently selected from 1-4 alkyl, A 3- to 6-membered heterocyclyl contains one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (O) as ring member(s), and is optionally substituted with cyano, -oxo, halogen, hydroxy, -NR m Rn , C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; R h is hydrogen, alkyl, or heterocyclyl; 1-4 Is it alkyl? -cyano, -oxo, halogen, -NR m R n , hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with at least one substituent independently selected from 3-6 cycloalkyl, where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; 3-6 is cycloalkyl, or -cyano, -oxo-, halogen, hydroxy, C 1-6 Alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n and a heterocyclyl containing one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s), optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C1-6 Alkyl, or C 1-6 heterocyclyl substituted with at least one substituent independently selected from alkoxy; --OR e wherein R e But -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, or aryl; I C 1-6 Alkyl is cyano; -oxo-; halogen; hydroxy; -NR m R n ;-C 1-6 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with 3-6 Cycloalkyl; cyano, halogen, hydroxy, C 1-6 Alkyl or C 1-6 optionally substituted by 4- to 6-membered heterocyclyl optionally substituted by alkoxy; ii)-C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is selected from the group consisting of cyano, -oxo, halogen, hydroxy, -NR m R n , C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; e Or --C 5-10 is aryl, or -cyano, -oxo, halogen, hydroxy, -NRm R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and wherein: -C is a heteroaryl containing one oxygen (O), nitrogen (N), or sulfur (S) heteroatom as a ring member, optionally substituted with at least one substituent independently selected from 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 heteroaryl, substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or C 1-3 alkyl, Either the alkyl or the alkoxy is optionally deuterium enriched. In some preferred embodiments, R 3 is cyano, -oxo-, halogen, hydroxy, C 1-6 Alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n and a heterocyclyl containing 1 or 2 heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s), optionally substituted with at least one substituent independently selected from 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 and substituted with at least one substituent independently selected from alkoxy.

[0029] In some embodiments, R 3 teeth, - hydrogen or -Cyano or - is halogen or -halogen, 3- to 6-membered heterocyclyl, or -OR h -C optionally substituted with at least one substituent independently selected from 1-4 alkyl, The 3- to 6-membered heterocyclyl contains one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (O) as ring members or ring members, and is optionally substituted with cyano, -oxo, halogen, hydroxy, -NR m R n , C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; R h is hydrogen, alkyl, or heterocyclyl (preferably 3- to 6-membered heterocyclyl, for example, tetrahydrofuranyl, thiazolidinyl); 1-4 Is it alkyl? -cyano, -oxo, halogen, -NR m R n , hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with at least one substituent independently selected from 3-6 cycloalkyl, where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; 3-6 is cycloalkyl, or -cyano, -oxo, halogen, hydroxy, -C 1-6 Alkyl, alkoxy, -NR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 heterocyclyl substituted with at least one substituent independently selected from alkoxy; --OR e wherein R e But -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl (preferably 4- to 6-membered monocyclic saturated heterocyclyl containing one oxygen heteroatom as a ring member), or aryl; I C 1-6 Alkyl is cyano; -oxo-; halogen; hydroxy; -NR m R n ;-C 1-6 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with 3-6 Cycloalkyl; cyano, halogen, hydroxy, -C 1-6 Alkyl or -C 1-6optionally substituted by 4- to 6-membered heterocyclyl optionally substituted by alkoxy; ii)-C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is cyano, -oxo, halogen, hydroxy, NR m R n , C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; e Or --C 5-10 is aryl, or -cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n Heteroaryl, preferably a 5-6 membered heteroaryl, containing one oxygen (O), nitrogen (N), or sulfur (S) heteroatom as a ring member, optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 heteroaryl, substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or C 1-3 alkyl. In some preferred embodiments, R 3 is cyano, -oxo, halogen, hydroxy, -C 1-6Alkyl, alkoxy, -NR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 and substituted with at least one substituent independently selected from alkoxy.

[0030] In some embodiments, R 3 teeth, - hydrogen, cyano, halogen, -halogen, 3- to 6-membered heterocyclyl, or -OR h -C optionally substituted with at least one substituent independently selected from 1-4 alkyl, The 3- to 6-membered heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, thiazolidinyl, and azetidinyl, each of which is selected from cyano, -oxo, halogen, hydroxy, -NR m R n , C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; h But hydrogen, C 1-6 alkyl, or 3- to 6-membered heterocyclyl (e.g., tetrahydrofuranyl or thiazolidinyl), 1-4 Is it alkyl? -cyano, -oxo, halogen, NR m R n , hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n , hydroxy, or C 1-6 -C optionally substituted with at least one substituent independently selected from alkoxy 3-6 cycloalkyl, where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; 3-6 is cycloalkyl, or -heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, and is selected from cyano, -oxo, halogen, hydroxy, C 1-6 Alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 substituted with at least one substituent independently selected from alkoxy; --ORe wherein R e But -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 4-6 membered monocyclic saturated heterocyclyl containing one oxygen heteroatom as a ring member, or C 6-10 is aryl, I C 1-6 Alkyl is cyano; -oxo-; halogen; hydroxy; -NR m R n ;-C 1-6 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with 3-6 Cycloalkyl; cyano, halogen, hydroxy, -C 1-6 Alkyl or -C 1-6 optionally substituted by 4- to 6-membered heterocyclyl optionally substituted by alkoxy; ii)-C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is cyano, -oxo, halogen, hydroxy, NR m R n , C 1-6 Alkyl, C 1-6 Alkoxy, or -C(O)NR m R n where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 substituted with at least one substituent independently selected from alkoxy; e Or --C 6-10 is aryl, or -5-6 membered heteroaryl selected from pyridinyl, pyridazinyl, pyrazinyl, thiazolyl, and isoxazolyl, each of which is cyano, -oxo, halogen, hydroxy, -NRm R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or C 1-6 5-6 membered heteroaryl substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or -C 1-3 alkyl. In some preferred embodiments, R 3 is heterocyclyl and is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, and is selected from cyano, -oxo, halogen, hydroxy, C 1-6 Alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 and substituted with at least one substituent independently selected from alkoxy.

[0031] In some embodiments, R 3 teeth, - hydrogen, cyano, halogen, -cyano, -oxo, halogen, hydroxy, -NR m R n , or -C 1-3optionally substituted with at least one substituent independently selected from alkyl, halogen, hydroxy, C 1-3 -C optionally substituted with at least one substituent independently selected from alkoxy, thiazolidin-3-yl 1-4 Is it alkyl? -cyano, -oxo, halogen, -NR m R n , hydroxy, -C 1-6 Alkyl, or -C 1-6 -C optionally substituted with at least one substituent independently selected from alkoxy 3-6 cycloalkyl, where -C 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-3 substituted with at least one substituent independently selected from alkoxy; 3-6 is cycloalkyl, or -heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, and is selected from cyano, -oxo, halogen, hydroxy, C 1-6 Alkyl, alkoxy, -NR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 substituted with at least one substituent independently selected from alkoxy; --OR e wherein R e But -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 4-6 membered monocyclic saturated heterocyclyl containing one oxygen heteroatom as a ring member, or C 6-10is aryl, I C 1-6 Alkyl is cyano; -oxo-; halogen; hydroxy; -NR m R n ;-C 1-6 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n -C optionally substituted with 3-6 Cycloalkyl; cyano, halogen, hydroxy, -C 1-6 Alkyl or -C 1-6 optionally substituted by 4- to 6-membered heterocyclyl optionally substituted by alkoxy; ii)-C 3-6 Cycloalkyl or 3- to 6-membered heterocyclyl is selected from the group consisting of cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R n where -C 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 substituted with at least one substituent independently selected from alkoxy; e Or --C 6-10 is aryl, or -5-6 membered heteroaryl selected from pyridinyl, pyridazinyl, pyrazinyl, thiazolyl, and isoxazolyl, each of which is cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-6 Alkyl, -C 1-6 Alkoxy, or -C(O)NR m R nand optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or -C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 5-6 membered heteroaryl substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or -C 1-3 alkyl. In some preferred embodiments, R 3 is heterocyclyl and is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, and is selected from cyano, -oxo, halogen, hydroxy, C 1-6 Alkyl, alkoxy, -NR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 and substituted with at least one substituent independently selected from alkoxy.

[0032] In some embodiments, R 3 teeth, - hydrogen, cyano, halogen, -methyl, ethyl, propyl, or butyl, each of which is optionally substituted with at least one substituent independently selected from halogen, hydroxy, methoxy, ethoxy, propoxy, or 2,4-dioxothiazolidin-3-yl; -cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is selected from the group consisting of cyano, -oxo, halogen, -NR m R n , hydroxy, -C 1-3 Alkyl, or -C 1-3 Optionally substituted with at least one substituent independently selected from alkoxy, wherein 1-3 Alkyl or C 1-3 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-3 Alkyl, or -C 1-3 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with at least one substituent independently selected from alkoxy; -heterocyclyl is selected from morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 5-azaspiro[2.4]heptanyl, 3-azabicyclo[3.1.0]hexan-3-yl, or 2-azabicyclo[3.1.0]hexan-2-yl, each of which is selected from cyano, -oxo, halogen, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -NR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 substituted with at least one substituent independently selected from alkoxy; --OR e wherein R e but, i) methyl, ethyl, propyl (isopropyl), butyl, pentyl, or hexyl, each of which is selected from the group consisting of deuterium, cyano, -oxo-, halogen, hydroxy, and -NR m R n ;-C 1-3 Alkoxy-; Cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-3 Alkyl, -C 1-3 Alkoxy, or -C(O)NR m R n -C optionally substituted with 3-6 cycloalkyl; or cyano, halogen, hydroxy, -C 1-3 Alkyl, or -C 1-3 optionally substituted by a 4- to 6-membered heterocyclyl optionally substituted by an alkoxy; or ii) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl, azetidin-2-yl, or azetidin-3-yl, each of which is selected from the group consisting of cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-3 Alkyl, -C 1-3 Alkoxy, or -C(O)NR m R n where -C 1-3 Alkyl or -C 1-3 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-3 Alkyl, or -C 1-3substituted with at least one substituent independently selected from alkoxy; e Or --C 6-10 is aryl, or -5-6 membered heteroaryl selected from pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-1-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-1-yl, pyrazin-2-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4-yl, isoxazol-2-yl, isoxazol-3-yl, and isoxazol-4-yl, each of which is selected from cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-3 Alkyl, -C 1-3 Alkoxy, or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-3 Alkyl or -C 1-3 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-3 Alkyl, or C 1-3 5-6 membered heteroaryl substituted with at least one substituent independently selected from alkoxy; In the formula, R m and R n are independently hydrogen or -C 1-3 alkyl. In some preferred embodiments, R 3is heterocyclyl and is selected from the group consisting of morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1 -yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 5-azaspiro[2.4]heptanyl, 3-azabicyclo[3.1.0]hexan-3-yl, or 2-azabicyclo[3.1.0]hexan-2-yl, each of which is selected from cyano, -oxo, halogen, hydroxy, -C 1-6 Alkyl, -C 1-6 Alkoxy, -NR m R n , or -C(O)NR m R n and optionally substituted with at least one substituent independently selected from: 1-6 Alkyl or C 1-6 Alkoxy is cyano, halogen, hydroxy, -NH2, -C 1-6 Alkyl, or -C 1-6 and substituted with at least one substituent independently selected from alkoxy.

[0033] In some embodiments, R 3 teeth, -hydrogen, -methyl, 1-methoxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, or (2,4-dioxothiazolidin-3-yl)methyl, -isopropoxy, methoxy-d3, methoxy, ethoxy, difluoromethoxy, 2-methoxyethoxy, 2-methoxy-2-methylpropoxy, 2-hydroxy-2-methylpropoxy, cyclopropylmethoxy, (1,4-dioxan-2-yl)methoxy, (4-hydroxycyclohexyl)oxy, (cis-4-hydroxycyclohexyl)oxy, (trans-4-hydroxycyclohexyl)oxy, (4-methoxycyclohexyl)oxy, (cis-4-methoxycyclohexyl)oxy, (trans-4-methoxycyclohexyl)oxy, or (3-methyloxetan-3-yl)methoxy, -Cyano, -3-methoxycyclobutyl, (trans)-3-methoxycyclobutyl, (cis)-3-methoxycyclobutyl, 2,2-dichlorocyclopropyl, or 1-cyanocyclopropyl, -morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, 3(S)-methyl-morpholino, -tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, (R)-tetrahydro-2H-pyran-3-yl, (S)-tetrahydro-2H-pyran-3-yl, 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl, 3,3-dimethylmorpho, -3-methoxypyrrolidin-1-yl, 3(R)-methoxypyrrolidin-1-yl, 3(S)-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, 3-(2-hydroxyethoxy)pyrrolidin-1-yl, 3-(trifluoromethoxy)pyrrolidin-1-yl, 3(R)-(trifluoromethoxy)pyrrolidin-1-yl, 3(S)-(trifluoromethoxy)pyrrolidin-1-yl, 2-(aminocarbonyl)pyrrolidin-1-yl, 2(R)-(aminocarbonyl)pyrrolidin-1-yl, 2(S)-(aminocarbonyl)pyrrolidin-1-yl, 3-(methoxymethyl)pyrrolidin-1-yl, 3(R)-(methoxymethyl)pyrrolidin-1-yl, 3(S)-(methoxymethyl)pyrrolidin-1-yl pyrolidin-1-yl, 3-cyano-4-hydroxypyrrolidin-1-yl, cis-3-cyano-4-hydroxypyrrolidin-1-yl, trans-3-cyano-4-hydroxypyrrolidin-1-yl, 3-cyano-4-methoxypyrrolidin-1-yl, cis-3-cyano-4-methoxypyrrolidin-1-yl, trans-3-cyano-4-methoxypyrrolidin-1-yl, 2-(methoxymethyl)pyrrolidin-1-yl, 2(R)-(methoxymethyl)pyrrolidin-1-yl, 2(S)-(methoxymethyl)pyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, 3(R)-methylpyrrolidin-1-yl, 3(S)-methylpyrrolidin-1-yl, pyrrolidin-1-yl, 3-(cyanomethoxy)pyrrolidin-1-yl, -5-azaspiro[2.4]heptan-5-yl, -tetrahydrofuran-3-yl, -3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, -1,4-dioxan-2-yl, -4-aminotetrahydro-2H-pyran-4-yl, 4-(aminomethyl)tetrahydro-2H-pyran-4-yl, -4-methoxypiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 3-methoxypiperidin-1-yl, 3(R)-methoxypiperidin-1-yl, 3(S)-methoxypiperidin-1-yl, 3-ethoxypiperidin-1-yl, 3(R)-ethoxypiperidin-1-yl, 3(S)-ethoxypiperidin-1-yl, -3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 4-methylpyridin-3-yl, 5-methylpyridazin-4-yl, 5-methoxypyridazin-4-yl, 3,5-dimethylisoxazol-4-yl, 4-methoxypyridin-3-yl, 4-(2-hydroxypropan-2-yl)pyridin-3-yl, 6-cyanopyridin-3-yl, 4-cyanopyridin-3-yl, 2-cyanopyridin-3-yl, 3-methylpyrazin-2-yl, 5-cyanopyridazin-4-yl, 5-fluoropyridazin-4-yl, 4-fluoropyridin-3-yl, 4-isopropylpyridin-3-yl, 4-(1-hydroxyethyl)pyridin-3-yl, 4-(1-methoxyethyl)pyridin-3-yl, pyridin-2-yl, or thiazol-4-yl.

[0034] In some preferred embodiments, R 3 teeth, -morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, 3(S)-methyl-morpholino, -tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, (R)-tetrahydro-2H-pyran-3-yl, (S)-tetrahydro-2H-pyran-3-yl, 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl, -3-methoxypyrrolidin-1-yl, 3(R)-methoxypyrrolidin-1-yl, 3(S)-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, 3-(2-hydroxyethoxy)pyrrolidin-1-yl, 3-(trifluoromethoxy)pyrrolidin-1-yl, 3(R)-(trifluoromethoxy)pyrrolidin-1-yl, 3(S)-(trifluoromethoxy)pyrrolidin-1-yl, 2-(aminocarbonyl)pyrrolidin-1-yl, 2(R)-(aminocarbonyl)pyrrolidin-1-yl, 2(S)-(aminocarbonyl)pyrrolidin-1-yl, 3-(methoxymethyl)pyrrolidin-1-yl, 3(R)-(methoxymethyl)pyrrolidin-1-yl, 3(S)-(methoxymethyl)pyrrolidin-1-yl pyrolidin-1-yl, 3-cyano-4-hydroxypyrrolidin-1-yl, cis-3-cyano-4-hydroxypyrrolidin-1-yl, trans-3-cyano-4-hydroxypyrrolidin-1-yl, 3-cyano-4-methoxypyrrolidin-1-yl, cis-3-cyano-4-methoxypyrrolidin-1-yl, trans-3-cyano-4-methoxypyrrolidin-1-yl, 2-(methoxymethyl)pyrrolidin-1-yl, 2(R)-(methoxymethyl)pyrrolidin-1-yl, 2(S)-(methoxymethyl)pyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, 3(R)-methylpyrrolidin-1-yl, 3(S)-methylpyrrolidin-1-yl, pyrrolidin-1-yl, 3-(cyanomethoxy)pyrrolidin-1-yl, -5-azaspiro[2.4]heptan-5-yl, -tetrahydrofuran-3-yl, -3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, -1,4-dioxan-2-yl, -4-aminotetrahydro-2H-pyran-4-yl, 4-(aminomethyl)tetrahydro-2H-pyran-4-yl, -4-methoxypiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 3-methoxypiperidin-1-yl, 3(R)-methoxypiperidin-1-yl, 3(S)-methoxypiperidin-1-yl, 3-ethoxypiperidin-1-yl, 3(R)-ethoxypiperidin-1-yl, 3(S)-ethoxypiperidin-1-yl, -3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, or 3-azabicyclo[3.1.0]hexan-3-yl. In some further preferred embodiments, R 3 is morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, or 3(S)-methyl-morpholino.

[0035] In some embodiments, (R 1 and R 2 ), or (R 2 and R 3 ), or (R 3 and R 4 ) together with the atom to which they are attached form a fused 5-7 membered ring system, said fused ring system containing 0-2 oxygen heteroatoms as ring member(s), halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -haloC 1-6 Alkyl, -haloC 1-6 Alkoxy, or -C 3-6 Optionally, independently substituted cycloalkyl.

[0036] In some embodiments, R 1 and R 2 together with the atoms to which they are attached, [ka] or R 2 and R3 together with the atoms to which they are attached form a fused ring system [ka] Form R 3 and R 4 together with the atoms to which they are attached, [ka] and forming a fused ring system selected from the group consisting of halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -haloC 1-6 Alkyl, -haloC 1-6 Alkoxy, or -C 3-6 Optionally, independently substituted cycloalkyl.

[0037] In some embodiments, Cy 1 teeth, - the 7-14 membered bicyclic or tricyclic heteroaryl containing 1, 2 or 3 heteroatom(s) selected from oxygen, nitrogen or sulfur as ring member(s), preferably benzimidazolyl, imidazopyrimidinyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, benzothiophenyl, benzothiazolyl, benzisoxazolyl, benzoxazolyl, benzisothiazolyl, imidazopyridazinyl, imidazopyridazinyl, dihydro-4H-furo[3,2-c]pyranyl, 6,7-Dihydro-4H-thieno[3,2-c]pyranyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl Hydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 2,3-dihydropyrazolo[5,1-b]oxazolyl, 1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazolyl, 6,7-dihydro-4H-pyrano[4,3-d]thiazolyl, [1,3]dioxolo[4,5-c]pyridinyl 2,3-dihydro-[1,4]dioxino[2,3-c]pyridinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridinyl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazinyl, or 2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl, each of which is selected from the group consisting of halogen, —C 1-6 Alkyl, -NH2, or -C(O)R m wherein R m But C 1-6alkyls, any of which is optionally deuterium enriched.

[0038] In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridinyl, pyrazolyl, thienyl, or thiazolyl ring fused to a 5- or 6-membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring contains one or two heteroatoms selected from oxygen or nitrogen as ring member(s), and the 5- or 6-membered heterocyclyl ring is fused to one or two C 1-6 alkyl or oxo, preferably two C 1-6 In some embodiments, Cy is optionally substituted with alkyl, more preferably with two methyls, and most preferably with two methyls. 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridinyl ring fused to a 5- or 6-membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring contains one or two heteroatoms selected from oxygen or nitrogen as ring member(s), and the 5- or 6-membered heterocyclyl ring is fused to one or two C 1-6 alkyl or oxo, preferably two C 1-6 In some embodiments, Cy is optionally substituted with alkyl, more preferably with two methyls, and most preferably with two methyls. 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridinyl ring fused to a 5- or 6-membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring contains two oxygen atoms as ring member(s), and the 5- or 6-membered heterocyclyl ring is fused to one or two C 1-6 Alkyl, preferably two C 1-6 In some embodiments, Cy is optionally substituted with alkyl, more preferably with two methyls, and most preferably with two methyls. 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridinyl ring fused to a 1,4-dioxane ring, and the 1,4-dioxane ring is fused to one or two C 1-6Alkyl, preferably two C 1-6 In some preferred embodiments, Cy is optionally substituted with alkyl, more preferably with two methyls, and most preferably with two methyls. 1 teeth, [ka] and preferably [ka] is.

[0039] In some embodiments, Cy 1 teeth, [ka] [ka]

[0040] [ka] is.

[0041] In some embodiments, the compound is selected from the compounds exemplified in the Examples.

[0042] In a second aspect, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure, or stereoisomers or pharmaceutically acceptable salts thereof, as disclosed herein, and a pharmaceutically acceptable excipient.

[0043] In a third aspect, there is provided a method for treating a disease associated with undesired TYK2 activity (TYK2-associated disease), as disclosed herein, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of the present disclosure, or a stereoisomer or pharmaceutically acceptable salt thereof.

[0044] In one embodiment, the disease is an inflammatory disease or an autoimmune disease. DETAILED DESCRIPTION OF THE INVENTION

[0045] definition The following terms have the indicated meanings throughout this specification.

[0046] As used in this specification, including the appended claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0047] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0048] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 18, such as 1 to 12, further such as 1 to 10, and even further such as 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6 Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups. Alkyl groups may optionally be enriched with deuterium, eg, -CD3, -CD2CD3, and the like.

[0049] The term "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0050] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms, such as fluoro, chloro, bromo, and iodo. Examples of haloalkyl include haloC 1-8 Alkyl, HaloC 1-6 Alkyl or haloC 1-4 Alkyl includes, but is not limited to, -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, and the like.

[0051] The term "alkyloxy" or "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. 1-6 Alkyloxy or C 1-4 Examples of alkyloxy include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0052] The term "alkoxy-alkyl-" refers to an alkyl group as defined above that is further substituted with an alkoxy group as defined above. Alkoxy-alkyl-, for example, C alkoxy-C alkyl- or C alkoxy-C 1-6 Examples of alkyl- include, but are not limited to, methoxymethyl, ethoxymethyl, ethoxyethyl, isopropoxymethyl, or propoxymethyl, and the like.

[0053] The term "amino" refers to -NH2. The term "alkylamino" refers to -NH(alkyl). The term "dialkylamino" refers to -N(alkyl).

[0054] The term "alkenyl," as used herein, refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18, for example, 2 to 8, further for example, 2 to 6, carbon atoms. Examples of alkenyl groups, e.g., C2-6 alkenyl, include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0055] The term "alkynyl," as used herein, refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Examples of alkynyl groups, e.g., C2-6 alkynyl, include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0056] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0057] For example, the cycloalkyl group can contain 3 to 12, such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Still further, for example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12, such as 3 to 10, further such as 3 to 8, or 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclodecyl groups. Specifically, saturated monocyclic cycloalkyl groups, such as C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl is a monocyclic ring (C) containing 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0058] The term "cycloalkenyl" refers to a non-aromatic cyclic alkyl group of 3 to 10 carbon atoms having a single ring or multiple rings and having at least one double bond, preferably one to two double bonds. In one embodiment, cycloalkenyl is cyclopentenyl or cyclohexenyl, preferably cyclohexenyl.

[0059] The term "cycloalkynyl" refers to a non-aromatic cycloalkyl group of from 5 to 10 carbon atoms having a single ring or multiple rings and having at least one triple bond.

[0060] The term "deuterated" is used herein to modify a chemical structure or organic group or radical in which one or more carbon-bonded hydrogen(s) are replaced with one or more deuterium(s), such as, for example, "deuterated alkyl," "deuterated cycloalkyl," "deuterated heterocycloalkyl," "deuterated aryl," "deuterated morpholinyl," etc. For example, the term "deuterated alkyl," as defined above, refers to an alkyl group, as defined herein, in which at least one hydrogen atom bonded to a carbon is replaced with a deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium, and it is possible for a carbon atom to be bonded to more than one deuterium, and it is also possible for more than one carbon atom in an alkyl group to be bonded to deuterium.

[0061] The term "aryl," used alone or in combination with other terms, refers to a group selected from: 5- and 6-membered carbocyclic aromatic rings, for example phenyl groups, bicyclic ring systems, such as 7-12 membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl, and - Tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0062] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0063] As used herein, the term "heteroaryl" refers to a group selected from: a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4, or in some embodiments 1 to 3, and in some embodiments 1 to 2 heteroatoms, and the remaining ring atoms are carbon; - 7-12 membered bicyclic rings containing at least one heteroatom, e.g., 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), with the remaining ring atoms being carbon, wherein at least one ring is aromatic and at least one heteroatom is in the aromatic ring; and - An 11-14 membered tricyclic ring containing at least one heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur as a ring member(s), e.g., 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, and the remaining ring atoms are carbon, wherein at least one ring is aromatic and at least one heteroatom is in the aromatic ring.

[0064] When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide.

[0065] As used herein, the term "optionally oxidized sulfur" refers to S, SO, or SO.

[0066] The terms "heteroaromatic ring" and "heteroaryl" are used interchangeably throughout this disclosure. In some embodiments, a monocyclic or bicyclic heteroaromatic ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O), and has 5, 6, 7, 8, 9, or 10 ring members, with the remaining ring members being carbon. In some embodiments, a monocyclic or bicyclic heteroaromatic ring is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic heteroaromatic ring is a 5- to 6-membered heteroaryl ring that is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, the monocyclic or bicyclic aromatic heterocycle is an 8-10 membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0067] Examples of heteroaryl groups or monocyclic or bicyclic heteroaromatic rings include (when numbered from the attachment position assigned priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl). azolyl), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3, 4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2, Examples include, but are not limited to, 4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (e.g., furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0068] Additionally, a "heteroaryl" further fused with a "heterocyclyl" is defined as a "heteroaryl."

[0069] "Heterocyclyl," "heterocycle," or "heterocyclic ring" are interchangeable and refer to a non-aromatic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings, i.e., including monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0070] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle may be saturated or partially saturated.

[0071] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include (when numbered from the attachment position assigned priority 1): pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholine, and the like. -2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, phosphatidyl, mopiperazinyl, homopiperidinyl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azatianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, Examples include, but are not limited to, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0072] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl having rings connected via one common carbon atom (called a spiro atom), with the remaining ring members containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur. One or more rings in a spiroheterocyclyl group may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the spiroheterocyclyl has 6 to 14 members, more preferably 7 to 12 members. According to the number of common spiro atoms, spiroheterocyclyl is divided into monospiroheterocyclyl, dispiroheterocyclyl, or polyspiroheterocyclyl, preferably monospiroheterocyclyl or dispiroheterocyclyl, more preferably 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl.

[0073] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclyl group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, in which each ring shares an adjacent pair of atoms (carbon atom and carbon atom or carbon atom and nitrogen atom) with another ring. One or more rings of a fused heterocyclic group may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, the fused heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. According to the number of membered rings, the fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, and preferably refers to a bicyclic or tricyclic fused heterocyclyl, more preferably refers to a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocycles include, but are not limited to, the following groups: octahydrocyclopenta[c]pyrrole (e.g., octahydrocyclopenta[c]pyrrol-2-yl), octahydropyrrolo[3,4-c]pyrrolyl, octahydroisoindolyl, isoindolinyl (e.g., isoindolin-2-yl), octahydro-benzo[b][1,4]dioxine.

[0074] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic alkyl group containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, sharing two disconnecting atoms for every two rings in the system. One or more rings of a bridged heterocyclyl group may contain one or more double bonds, but neither ring has a fully conjugated π-electron system. Preferably, the bridged heterocyclyl has 6 to 14 members, more preferably 7 to 10 members. According to the number of membered rings, the bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, and more preferably refers to bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyls include, but are not limited to, the following groups: 2-azabicyclo[2.2.1]heptyl, azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.2.2]octyl, and 2-azabicyclo[3.3.2]decyl.

[0075] The compounds disclosed herein may have asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All possible stereoisomers are intended to be included, including substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specifically stated, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0076] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, such as no more than 30% by weight, further such as no more than 25% by weight, and even further such as no more than 20% by weight of any other stereoisomer(s). In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, such as no more than 5% by weight, such as no more than 1% by weight of any other stereoisomer(s).

[0077] When the compounds disclosed herein contain olefinic double bonds, unless specified otherwise, it is intended that such double bonds include both E and Z geometric isomers.

[0078] When the compounds disclosed herein contain a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can be in cis and trans configurations, where cis means that both substituents are found above the two substituent positions on the carbon, while trans means that they are on opposite sides.

[0079] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse-phase and normal-phase, size exclusion, ion exchange, high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed ("SMB"), and preparative thin- or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art will apply the technique most likely to achieve the desired separation.

[0080] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0081] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as the formation of diastereomers using optically active resolving agents [Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H. et al., "Chromatographic resolution of enantiomers: Selective review," J. Chromatogr., 113(3)(1975): pp. 283-302]. Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) the formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) the formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) the direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0082] "Pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or can be prepared separately by reacting a free base function with a suitable organic acid, or by reacting an acidic group with a suitable base.

[0083] In addition, if the compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, for example, a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0084] As defined herein, "pharmaceutically acceptable salts thereof" includes salts of at least one compound of formula (I), as well as salts of stereoisomers, e.g., enantiomeric and / or diastereomeric salts, of compounds of formula (I).

[0085] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with a cell as well as contact of a reagent with a biological fluid, where the biological fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell, with a reagent, diagnostic, binding compound, or another cell. As used herein, the term "subject" includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human.

[0086] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case will be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof disclosed herein, effective to "treat" a disease or disorder in a subject as defined above. In the case of a combination therapy, a "therapeutically effective amount" refers to the total amount of the combined entities for effective treatment of a disease, disorder, or condition.

[0087] Pharmaceutical compositions comprising the compounds disclosed herein can be administered to subjects in need thereof by oral, inhalation, rectal, parenteral, or topical administration.For oral administration, pharmaceutical compositions can be conventional solid formulations such as tablets, powders, granules, capsules, etc., liquid formulations such as water or oil suspensions, or other liquid formulations such as syrups, solutions, suspensions, etc.For parenteral administration, pharmaceutical compositions can be solutions, aqueous solutions, oil suspension concentrates, freeze-dried powders, etc.Preferably, the formulation of the pharmaceutical composition is selected from tablets, coated tablets, capsules, suppositories, nasal sprays, or injection solutions, and more preferably selected from tablets or capsules.The pharmaceutical composition can be a single unit administration with a precise dosage.In addition, the pharmaceutical composition can further contain additional active ingredients.

[0088] All formulations of the pharmaceutical compositions disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients to produce the desired formulation. "Pharmaceutically acceptable excipients" refers to conventional pharmaceutical carriers suitable for the desired pharmaceutical formulation, such as diluents, vehicles such as water and various organic solvents, fillers such as starch and sucrose, binders such as cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone (PVP), humectants such as glycerol, disintegrants such as agar, calcium carbonate, and sodium bicarbonate, absorption enhancers such as quaternary ammonium compounds, surfactants such as hexadecanol, absorption carriers such as kaolin and soap clay, and lubricants such as talc, calcium stearate, magnesium stearate, and polyethyl glycol. In addition, the pharmaceutical composition may further contain other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, permeation enhancers, polymers, aromatic compounds, sweeteners, and dyes.

[0089] The term "disease" refers to any disease, ailment, illness, symptom, or indication, and may be used interchangeably with the terms "disorder" or "condition."

[0090] Throughout this specification and the claims that follow, unless the context requires otherwise, the term "comprise," as well as variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the term "comprising" can be interchanged with "containing," "including," or occasionally "having."

[0091] Throughout this specification and the claims that follow, the term "C" denotes an inclusive range, where n and m are integers and indicate the number of carbons. Examples include C, C, etc.

[0092] Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. [Example]

[0093] The following examples are intended to be purely illustrative and should not be considered limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for. Temperatures are in degrees Celsius unless otherwise specified. Reagents were purchased from commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise indicated.

[0094] Unless otherwise indicated, reactions described below were carried out in anhydrous solvents under a positive pressure of nitrogen or argon or using drying tubes, reaction flasks fitted with rubber septa for the introduction of substrates and reagents via syringe, and glassware was oven-dried and / or heat-dried.

[0095] Unless otherwise indicated, reactions described below were carried out in anhydrous solvents under a positive pressure of nitrogen or argon or using drying tubes, reaction flasks fitted with rubber septa for the introduction of substrates and reagents via syringe, and glassware was oven-dried and / or heat-dried.

[0096] Unless otherwise indicated, column chromatography purifications were performed on a Biotage system (manufacturer: Dyax Corporation) with a silica gel column or silica SepPak cartridges (Waters), or on a Teledyne Isco Combiflash purification system using prepacked silica gel cartridges.

[0097] 1 1 H NMR spectra were recorded on a Varian instrument operating at 400 MHz. 1 H-NMR spectra were acquired using CDCl3, CD2Cl2, CD3OD, DO, d6-DMSO, d6-acetone, or (CD3)2CO as solvents, using tetramethylsilane (0.00 ppm) or residual solvent (CDCl3: 7.25 ppm, CD3OD: 3.31 ppm, DO: 4.79 ppm, d6-DMSO: 2.50 ppm, d6-acetone: 2.05 ppm, (CD3)2CO: 2.05 ppm) as a reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broadened), dd (double doublet), and dt (double triplet). Coupling constants, when given, are reported in Hertz (Hz). Non-reagent compound names were generated by ChemDraw version 12.0.

[0098] [Table 1]

[0099] Example BB1: Synthesis of 2-bromo-4-(methoxymethyl)-6-(methylsulfonyl)pyridine [ka] Step 1: 2,6-Dibromo-4-(bromomethyl)pyridine [ka] A mixture of 2,6-dibromo-4-methylpyridine (10.0 g, 39.85 mmol), CCl (100 mL), AIBN (1.31 g, 7.98 mmol), and NBS (10.64 g, 59.78 mmol) was stirred at 80 °C for 15 h. After cooling to room temperature, DCM (100 mL) was added, and the resulting mixture was washed with H O (150 mL × 3). The mixture was dried over anhydrous Na SO and concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-20%) to give 2,6-dibromo-4-(bromomethyl)pyridine (10.0 g, 76%). LCMS (ESI) m / e [M+1] + 328.

[0100] Step 2: 2,6-Dibromo-4-(methoxymethyl)pyridine [ka] A mixture of 2,6-dibromo-4-(bromomethyl)pyridine (10.0 g, 30.32 mmol), MeOH (100 mL), and K2CO3 (8.38 g, 60.63 mmol) was stirred at room temperature for 2 hours. Upon completion of the reaction, EA (200 mL) was added, and the resulting mixture was washed with H2O (200 mL x 3). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-25%) to give 2,6-dibromo-4-(methoxymethyl)pyridine (2.00 g, 23%). LCMS (ESI) m / e [M+1] + 280.

[0101] Step 3: 2-Bromo-4-(methoxymethyl)-6-(methylsulfanyl)pyridine [ka] A mixture of 2,6-dibromo-4-(methoxymethyl)pyridine (2.00 g, 7.12 mmol), DMF (20 mL), and NaSCH (0.50 g, 7.14 mmol) was stirred at room temperature for 1 hour. Upon completion of the reaction, EA (100 mL) was added, and the resulting mixture was washed with HO (200 mL × 3). The organic layer was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-25%) to give 2-bromo-4-(methoxymethyl)-6-(methylsulfanyl)pyridine (1.40 g, 79%). LCMS (ESI) m / e [M+1] + 248.

[0102] Step 4: 2-Bromo-6-methanesulfonyl-4-(methoxymethyl)pyridine [ka] A mixture of 2-bromo-4-(methoxymethyl)-6-(methylsulfanyl)pyridine (1.40 g, 5.64 mmol), THF (10 mL), HO (10.00 mL), NaIO (2.41 g, 11.26 mmol), and RuCl.HO (127.19 mg, 0.56 mmol) was stirred at 0 °C for 1 h. Upon completion of the reaction, EA (100 mL) was added, and the resulting mixture was washed with HO (200 mL × 3). The organic layer was dried over anhydrous NaSO, concentrated, and purified by Combiflash (EA / PE = 0-30%) to give 2-bromo-6-methanesulfonyl-4-(methoxymethyl)pyridine (1.10 g, 69%). 1 H NMR(300 MHz,CDCl3)δ 7.99(s,1H),7.74(s,1H),4.56(s,2H),3.50(s,3H),3.27(s,3H).LCMS(ESI)m / e[M+1] + 280.

[0103] Example BB2: Synthesis of 2-bromo-4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]-6-methanesulfonylpyridine [ka] Step 1: 2-Bromo-6-(methylthio)pyridin-4-ol [ka] A mixture of 2,6-dibromopyridin-4-ol (10.00 g, 39.542 mmol), DIEA (10.22 g, 0.079 mmol), Xantphos (0.23 g, 0.39 mmol), NaSCH (2.93 g, 39.54 mmol), and Pd(dba) (0.18 g, 0.20 mmol) in 1,4-dioxane (200 mL) was stirred overnight at 75 °C under a nitrogen atmosphere. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with water and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo, and the crude product, 2-bromo-6-(methylthio)pyridin-4-ol, was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 220.

[0104] Step 2: 2-Bromo-6-methanesulfonylpyridin-4-ol [ka] To a stirred solution of 2-bromo-6-(methylsulfanyl)pyridin-4-ol (6.00 g, 27.26 mmol) in HO (100 mL) / THF (100 mL) was added dropwise a solution of RuCl3.HO (0.18 g, 0.82 mmol) in water (30 mL) at 0 °C, followed by successive dropwise addition of NaIO4 (11.66 g, 0.055 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 min. Upon completion of the reaction, the resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 12:1) to give 2-bromo-6-methanesulfonylpyridin-4-ol (3 g, 44%). LCMS(ESI)m / e[M+1] + 252.

[0105] Step 3: 2-Bromo-4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]-6-methanesulfonylpyridine [ka] A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), K2CO3 (1.10 g, 79.59 mmol), and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.90 g, 79.42 mmol) in DMF (20 mL) was stirred at 60 °C for 3 h. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (hexane / EA = 5:1) to give the product (1.08 g, 68%). 1 H NMR(300 MHz,DMSO-d6)δ 7.62(s 1H),7.54(s 1H),4.30-4.25(m,2H),3.90-3.87(m,2H),3.28(s,3H),0.85(s,9H),0.06(s,6H).LCMS(ESI)m / e[M+1] + 410.

[0106] Example BB3: Synthesis of 2-bromo-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-(methylsulfonyl)pyridine [ka] A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (200 mg, 0.79 mmol), CsCO (517.01 mg, 1.59 mmol), and (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (272.62 mg, 0.95 mmol) in DMF (5 mL) was stirred at 80 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with water and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (PE / EA = 5:1) to give 2-bromo-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6-(methylsulfonyl)pyridine (260 mg, 89%). 1 H NMR(300 MHz,MeOD-d4)δ 7.64(s,1H),7.49(s,1H),4.59-4.40(m,1H),4.32-4.13(m,3H),3.89(d,J = 8.6 Hz,1H),3.23(s,3H),1.41(s,3H),1.37(s,3H).LCMS(ESI)m / e[M+1] + 366.

[0107] Example BB4: Synthesis of 2-bromo-4-(2-((tert-butyldimethylsilyl)oxy)propoxy)-6-(methylsulfonyl)pyridine [ka] Step 1: 1-((2-bromo-6-(methylsulfonyl)pyridin-4-yl)oxy)propan-2-ol [ka] A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol), 2-propanol-1-bromo (4.14 g, 29.75 mmol), and K2CO3 (548 mg, 3.97 mmol) in DMF (5 mL) was stirred at 70 °C for 12 h. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to give the crude product 1-((2-bromo-6-(methylsulfonyl)pyridin-4-yl)oxy)propan-2-ol, which was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 310.

[0108] Step 2: 2-Bromo-4-(2-((tert-butyldimethylsilyl)oxy)propoxy)-6-(methylsulfonyl)pyridine [ka] A solution of 1-[(2-bromo-6-methanesulfonylpyridin-4-yl)oxy]propan-2-ol (600 mg, 1.93 mmol), TBSCl (437.4 mg, 2.90 mmol), and DIEA (500 mg, 3.87 mmol) in DCM (10 mL) was stirred at room temperature for 12 hours. Upon completion of the reaction, the solvent was removed, and the residue was purified by preparative TLC (EA / PE=1:3) to give 2-bromo-4-[2-[(tert-butyldimethylsilyl)oxy]propoxy]-6-methanesulfonylpyridine (635 mg, 77%). 1 H NMR(300 MHz,DMSO-d6)δ 7.61(s,1H),7.52(s,1H),4.24-4.05(m,1H),3.35(s,3H),3.28(d,J = 4.4 Hz,2H),1.25-1.20(m,3H),0.82(s,9H),0.08(s,6H).LCMS(ESI)m / e[M+1] + 425.

[0109] Example BB5: Synthesis of 2-[(2-bromo-6-methanesulfonylpyridin-4-yl)oxy]acetonitrile [ka] To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol) and 2-bromoacetonitrile (475 mg, 3.97 mmol) in DMF (10 mL) was added KCO (548 mg, 3.97 mmol) in small portions at room temperature, and the resulting mixture was then stirred at 80 °C overnight. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (40 mL × 3). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous NaSO, concentrated, and purified by preparative TLC (PE / EA = 3:1) to give 2-[(2-bromo-6-methanesulfonylpyridin-4-yl)oxy]acetonitrile (254.3 mg, 44%). 1 H NMR(300 MHz,MeOD-d4)δ 7.73(s,1H),7.63(s,1H),5.27(s,2H),3.27(s,3H).LCMS(ESI)m / e[M+1] + 291.

[0110] Example BB6: Synthesis of 2-bromo-4-isopropoxy-6-methanesulfonylpyridine [ka] To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (600 mg, 2.38 mmol) and 2-iodopropane (809 mg, 4.76 mmol) in DMF (10 mL) was added K2CO3 (658 mg, 4.76 mmol) in small portions at room temperature. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (40 mL × 3). The combined organic layers were washed with brine (30 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (PE / EA = 3:1) to give the product (570 mg, 82%). 1H NMR(400 MHz,MeOD-d4)δ 7.54(s,1H),7.41(s,1H),4.96-4.85(m,1H),3.24(s,3H),1.40(d,J = 6.1 Hz,6H).LCMS(ESI)m / e[M+1] + 294.

[0111] Example BB7: Synthesis of 2-bromo-6-methanesulfonyl-4-[(trans)-3-[(tert-butyldimethylsilyl)oxy]cyclobutoxy]pyridine [ka] A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (2.00 g, 7.93 mmol), PPh3 (3.12 g, 11.89 mmol), DIAD (2.41 g, 11.92 mmol), and trans-3-[(tert-butyldimethylsilyl)oxy]cyclobutan-1-ol (1.61 g, 7.95 mmol) in THF (100 mL) was stirred at 50 °C overnight. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (40 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (hexane / EA = 5:1) to give the product (2.06 g, 60%). 1 H NMR(300 MHz,MeOD-d4)δ 7.48(s,1H),7.29(s,1H),5.03(t,J = 6.3 Hz,1H),4.70-4.52(m,1H),3.23(s,3H),2.59-2.37(m,4H),0.92(s,9H),0.08(s,6H).LCMS(ESI)m / e[M+1] + 436.

[0112] Example BB8: Synthesis of 2-bromo-6-methanesulfonylpyridine-4-carbonitrile [ka] Step 1: 2-Bromo-6-(methylsulfanyl)pyridine-4-carbonitrile [ka] A mixture of 2,6-dibromopyridine-4-carbonitrile (4.00 g, 15.27 mmol), DMF (40 mL), and CHClSNa (1.28 g, 18.33 mmol) was stirred at room temperature overnight. Upon completion of the reaction, water was added, and the resulting solution was extracted with EA (60 mL × 3). The combined organic layers were washed with brine and dried over anhydrous NaSO. The solid was filtered off, and the resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-5%) to give the product (1.50 g, 43%). GCMS (ESI) [M] 228.

[0113] Step 2: 2-Bromo-6-methanesulfonylpyridine-4-carbonitrile [ka] To a solution of 2-bromo-6-(methylsulfanyl)pyridine-4-carbonitrile (1.50 g, 6.55 mmol) in THF (15 mL) was added a solution of NaIO (2.80 g, 13.10 mmol) in HO (20 mL) in small portions at 0 °C, followed by the addition of a solution of RuCl.HO (147.60 mg, 0.655 mmol) in HO (10 mL) in small portions at 0 °C. The resulting solution was stirred at room temperature for 2 h. Upon completion of the reaction, the resulting solution was extracted with EA (60 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous NaSO. The solid was filtered off, the resulting mixture was concentrated in vacuo, and the residue was purified by preparative TLC (EA / PE = 1:2) to give the product (1.06 g, 62%). 1 H NMR(300 MHz,DMSO-d6)δ 8.65(s,1H),8.55(s,1H),3.40(s,3H); GC-MS(ESI)[M] 260.

[0114] Example BB9: Synthesis of 2-bromo-6-methanesulfonyl-4-methoxypyridine [ka] To a mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (5.00 g, 19.84 mmol) and K2CO3 (5.49 g, 0.04 mmol) in DMF (100 mL) was added CHI (4.20 g, 29.59 mmol) dropwise at 60 °C for 2 h. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (150 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 25-35%) to give the product (4.00 g, 76%). 1 H NMR(300 MHz,CDCl3)δ 7.56(s,1H),7.18(s,1H),3.95(s,3H),3.24(s,3H).LCMS(ESI)m / e[M+1] + 266.

[0115] Example BB10: Synthesis of 6-bromo-4-methylpyridine-2-sulfonamide [ka] Step 1: 2-(benzylsulfanyl)-6-bromo-4-methylpyridine [ka] A mixture of 2,6-dibromo-4-methylpyridine (2.00 g, 7.97 mmol), DMF (30 mL), benzyl mercaptan (1.09 g, 8.78 mmol), and CsCO (5.19 g, 15.93 mmol) was stirred at room temperature for 2 hours. Upon completion of the reaction, EA (100 mL) was added, and the resulting mixture was washed with water (100 mL × 3). The mixture was then dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-25%) to give the product (2.30 g, 98%). LCMS (ESI) m / e [M+1] + 294.

[0116] Step 2: 6-Bromo-4-methylpyridine-2-sulfonyl chloride [ka] A mixture of 2-(benzylsulfanyl)-6-bromo-4-methylpyridine (2.30 g, 7.82 mmol), AcOH (36 mL), HO (4 mL), and NCS (3.65 g, 27.33 mmol) was stirred at room temperature for 1 hour. Upon completion of the reaction, EA (100 mL) was added, and the resulting mixture was washed with water (100 mL × 3). The mixture was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-25%) to give the product (2.00 g, 94%).

[0117] Step 3: 4-Methylpyridine-2-sulfonamide [ka] To a solution of 6-bromo-4-methylpyridine-2-sulfonyl chloride (2.00 g, 7.39 mmol) in THF (20 mL), ammonium (10 mL, 33 wt%) was added dropwise at 0 °C and stirred at room temperature for 1 h. Upon completion of the reaction, EA (100 mL) was added, and the resulting mixture was washed with water (100 mL × 3). The mixture was dried over anhydrous Na2SO4 and concentrated. The residue was purified by Combiflash (EA / PE = 0-50%) to give the product (1.02 g, 55%). 1 H NMR(300 MHz,DMSO-d6)δ 7.84(s,1H),7.62(s,2H),7.37(s,1H),2.43(s,3H).LCMS(ESI)m / e[M+1] + 251.

[0118] Example BB11: Synthesis of 6-bromo-4-(2-methoxyethoxy)pyridine-2-sulfonamide [ka] Step 1: 2,6-Dibromo-4-(2-methoxyethoxy)pyridine [ka] A mixture of 2,6-dibromopyridin-4-ol (2.02 g, 7.90 mmol), 2-bromoethyl methyl ether (1.65 g, 11.86 mmol), and K2CO3 (2.19 g, 15.82 mmol) in DMF (10.00 mL) was stirred at 80 °C for 3 h. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (150 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo to give the crude product. The crude product was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 310.

[0119] Step 2: 6-Bromo-4-(2-methoxyethoxy)pyridine-2-sulfonyl chloride [ka] To a stirred solution of 2,6-dibromo-4-(2-methoxyethoxy)pyridine (1.90 g, 6.11 mmol) in THF (10 mL) was added i-PrMgCl (4.0 mL, 8.00 mmol, 2 M) dropwise at 0 °C, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. A solution of SO2Cl2 (1.2 mL) in hexane (3 mL) was added dropwise at 0 °C, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Upon completion of the reaction, the reaction was quenched with cold water. The resulting mixture was concentrated in vacuo to give the crude product, 6-bromo-4-(2-methoxyethoxy)pyridine-2-sulfonyl chloride (2.0 g), which was used directly in the next step without purification.

[0120] Step 3: 6-Bromo-4-(2-methoxyethoxy)pyridine-2-sulfonamide [ka] A mixture of 6-bromo-4-(2-methoxyethoxy)pyridine-2-sulfonyl chloride (1.80 g, 5.44 mmol) in NH3 / THF (0.5 M, 33 mL) was stirred at room temperature for 1 h. Upon completion of the reaction, the solvent was removed under vacuum, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX, phase: A-HO, B-acetonitrile, B%: 15%-25% over 15 min) to give the product (128 mg, 81%). 1 H NMR(300 MHz,DMSO-d6)δ 7.63(s,2H),7.52(s,1H),7.43(s,1H),4.34-4.32(m,2H),3.68-3.66(m,2H),3.31(s,3H).LCMS(ESI)m / e[M+1] + 312.

[0121] Example BB12: Synthesis of 2-bromo-4-(difluoromethyl)-6-(methylsulfonyl)pyridine [ka] Step 1: (2,6-Dibromopyridin-4-yl)methanol [ka] To a solution of 2,6-dibromopyridine-4-carboxylic acid (2.00 g, 7.12 mmol) in THF (20 mL) was added BH3.THF (14 mL, 14.00 mmol, 1 M THF solution) dropwise, and the resulting mixture was stirred at room temperature for 48 h. Upon completion of the reaction, water was slowly added to quench the reaction, and the resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude product was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 266.

[0122] Step 2: 2,6-Dibromoisonicotinaldehyde [ka] A solution of (2,6-dibromopyridin-4-yl)methanol (1.50 g, 5.62 mmol) and DMP (3.58 g, 8.43 mmol) in DCM (15 mL) was stirred at room temperature for 12 hours. Upon completion of the reaction, water was added, and the resulting mixture was extracted with DCM (200 mL × 3). The combined organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM / PE = 1:1) to give the product (900 mg, 60%).

[0123] Step 3: 2,6-Dibromo-4-(difluoromethyl)pyridine [ka] To a stirred solution of 2,6-dibromopyridine-4-carbaldehyde (850 mg, 3.21 mmol) in DCM (8.5 mL) was added DAST (1.55 g, 9.63 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for an additional hour. Upon completion of the reaction, EtOH was added and the resulting mixture was concentrated in vacuo. The crude product was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 286.

[0124] Step 4: 2-Bromo-4-(difluoromethyl)-6-(methylthio)pyridine [ka] A solution of 2,6-dibromo-4-(difluoromethyl)pyridine (1.00 g, 3.49 mmol) and MeSNa (195 mg, 2.79 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. Upon completion of the reaction, water was added and the resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The crude product was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 254.

[0125] Step 5: 2-Bromo-4-(difluoromethyl)-6-(methylsulfonyl)pyridine [ka] To a stirred solution of 2-bromo-4-(difluoromethyl)-6-(methylsulfanyl)pyridine (450 mg, 1.77 mmol) in HO (5 mL) and THF (5 mL) was added dropwise a solution of RuCl3.HO (12 mg, 0.053 mmol) in water (2 mL) at 0 °C. To the above mixture, NaIO4 (1515 mg, 7.08 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for another 30 min. Upon completion of the reaction, the resulting mixture was extracted with EA (3 × 100 mL), and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (EA / PE = 1:4) to give the product (317 mg, 63%). 1 H NMR(300 MHz,DMSO-d6)δ 8.28(s,1H),8.21(s,1H),7.40-7.05(m,1H),3.37(s,3H).LCMS(ESI)m / e[M+1] + 286.

[0126] Example BB13: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxetan-3-ylmethoxy)pyridine [ka] A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), PPh3 (3.12 g, 11.89 mmol), DIAD (2.41 g, 11.92 mmol), and oxetan-3-ylmethanol (0.35 g, 3.97 mmol) in THF (20 mL) was stirred at 50 °C overnight. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (hexane / EA = 5:1) to give the product (996 mg, 78%).1 H NMR(300 MHz,DMSO-d6)δ 7.65(s,1H),7.58(s,1H),4.71(d,J = 7.9 Hz,2H),4.52-4.37(m,4H),3.49-3.37(m,1H),2.54(s,3H).LCMS(ESI)m / e[M+1] + 322.

[0127] Example BB14: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxetan-3-yloxy)pyridine [ka] A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (826 mg, 3.27 mmol), PPh3 (3.12 g, 11.89 mmol), DIAD (2.41 g, 11.92 mmol), and oxetan-3-ol (0.59 g, 7.93 mmol) in THF (20 mL) was stirred at 50 °C overnight. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (hexane / EA = 5:1) to give the product (899 mg, 89%). 1 H NMR(300 MHz,DMSO-d6)δ 7.50(s,1H),7.45(s,1H),5.59-5.50(m,1H),4.99-4.95(m,2H),4.60-4.55(m,2H),3.29(s,3H).LCMS(ESI)m / e[M+1] + 308.

[0128] Example BB15: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxetan-3-ylmethoxy)pyridine [ka] A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), PPh3 (3.12 g, 11.89 mmol), DIAD (2.41 g, 11.92 mmol), and 2-methoxypropan-1-ol (0.44 g, 3.97 mmol) in THF (20 mL) was stirred at 50 °C overnight. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (hexane / EA = 5:1) to give the product (900 mg, 70%). 1 H NMR(300 MHz,DMSO-d6)δ 7.63(s,1H),7.56(s,1H),4.31-4.14(m,2H),3.70-3.65(m,1H),3.39(m,3H),3.25(m,3H),1.17-1.14(m,3H).LCMS(ESI)m / e[M+1] + 324.

[0129] Example BB16: Synthesis of 2-bromo-6-methanesulfonyl-3-methoxypyridine [ka] Step 1: 2-Bromo-3-methoxy-6-(methylsulfanyl)pyridine [ka] A mixture of 2-bromo-6-iodo-3-methoxypyridine (4.00 g, 12.74 mmol), (methylsulfanyl)sodium (0.80 g, 11.41 mmol), Pd(dba) (0.58 g, 0.63 mmol), and Xantphos (0.74 g, 1.27 mmol) in dioxane (64 mL) was stirred at 75 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (200 mL × 3). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo and purified by Combiflash (EA / PE = 0-4%) to give the product (1.72 g, 52%). LCMS (ESI, m / e) [M+1] + 234.

[0130] Step 2: 2-Bromo-6-methanesulfonyl-3-methoxypyridine [ka] To a mixture of 2-bromo-3-methoxy-6-(methylsulfanyl)pyridine (1.72 g, 7.34 mmol) in THF (15 mL) was added dropwise a solution of NaIO (4.73 g, 22.14 mmol) and RuCl (0.05 g, 0.22 mmol) in HO (15 mL) at 0 °C. The resulting solution was stirred at room temperature for 1 h. Upon completion of the reaction, the resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-39%) to give the product (1.78 g, 82%). 1 H NMR(300 MHz,DMSO-d6)δ 8.06(d,J = 8.5 Hz,1H),7.75(d,J = 8.5 Hz,1H),4.01(s,3H),3.24(s,3H).LCMS(ESI,m / e)[M+1] + 266.

[0131] Example BB17: Synthesis of 1-bromo-3-methanesulfonyl-5-(2-methoxyethoxy)benzene [ka] Step 1: 1,3-Dibromo-5-(2-methoxyethoxy)benzene [ka] A mixture of 3,5-dibromophenol (11.00 g, 43.66 mmol), 2-bromoethyl methyl ether (15.17 g, 109.14 mmol), and CsCO (28.46 g, 87.33 mmol) in DMF (165 mL) was stirred at 80 °C for 4 h. After cooling to room temperature, water was added, followed by extraction with EA (500 mL × 3). The combined organic layer was washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated to give the crude product, which was used directly in the next step without further purification. LCMS (ESI, m / e) [M+1] + 311.

[0132] Step 2: 1-Bromo-3-(2-methoxyethoxy)-5-(methylsulfanyl)benzene [ka] A mixture of 1,3-dibromo-5-(2-methoxyethoxy)benzene (15.00 g, 48.39 mmol), (methylsulfanyl)sodium (2.71 g, 38.67 mmol), Pd2(dba)3 (2.22 g, 2.42 mmol), and Xantphos (2.80 g, 4.83 mmol) in dioxane (150 mL) was stirred overnight at 75 °C under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-1%) to give the product (5.71 g, 38%). LCMS (ESI, m / e) [M+1] + 277.

[0133] Step 3: 1-Bromo-3-methanesulfonyl-5-(2-methoxyethoxy)benzene [ka] To a mixture of 1-bromo-3-(2-methoxyethoxy)-5-(methylsulfanyl)benzene (5.71 g, 20.60 mmol) in THF (60 mL) and HO (30 mL) was added a solution of NaIO (13.22 g, 61.81 mmol) in HO (15 mL) in small portions at 0 °C. Then, to this mixture was added a solution of RuCl (0.14 g, 0.62 mmol) in HO (15 mL) in small portions at 0 °C. The resulting solution was stirred at room temperature for 1 h. Upon completion of the reaction, the resulting solution was extracted with EA (50 mL × 3). The solvent was removed under vacuum, and the residue was purified by Combiflash (EA / PE = 0-31%) to give the product (4.99 g, 71%). 1 H NMR(300 MHz,DMSO-d6)δ 7.65(s,1H),7.56(s,1H),7.46(s,1H),4.30-4.22(m,2H),3.70-3.65(m,2H),3.31(s,3H),3.29(s,3H).LCMS(ESI,m / e)[M+1] + 309.

[0134] Example BB18: Synthesis of [2-(3-bromo-5-methanesulfonylphenoxy)ethoxy](tert-butyl)dimethylsilane [ka] Step 1: tert-butyl[2-(3,5-dibromophenoxy)ethoxy]dimethylsilane [ka] A mixture of 3,5-dibromophenol (5.00 g, 19.85 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (7.12 g, 29.77 mmol), and Cs2CO3 (12.93 g, 39.69 mmol) in DMF (50 mL) was stirred at 80 °C for 2 h. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (80 mL × 3). The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-20%) to give the product (5.00 g, 61%).

[0135] Step 2: [2-[3-bromo-5-(methylsulfanyl)phenoxy]ethoxy](tert-butyl)dimethylsilane [ka] A mixture of tert-butyl[2-(3,5-dibromophenoxy)ethoxy]dimethylsilane (5.00 g, 12.19 mmol), (methylsulfanyl)sodium (768 mg, 10.97 mmol), Xantphos (705 mg, 1.22 mmol), DIEA (3.15 g, 24.38 mmol), Pd2(dba)3 (558 mg, 0.61 mmol), and 1,4-dioxane (50 mL) was stirred at 90 °C overnight under a nitrogen atmosphere. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (120 mL × 3). The combined organic layers were washed with brine (50 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-10%) to give the product (2.80 g, 60%). LCMS(ESI,m / e)[M+1] + 377.

[0136] Step 3: [2-(3-bromo-5-methanesulfonylphenoxy)ethoxy](tert-butyl)dimethylsilane [ka] To a stirred solution of [2-[3-bromo-5-(methylsulfanyl)phenoxy]ethoxy](tert-butyl)dimethylsilane (2.80 g, 7.41 mmol) in THF (30 mL) was added a solution of RuCl3.HO (50 mg, 0.22 mmol) and NaIO4 (3.17 g, 14.84 mmol) in HO (20 mL) at 0 °C, and the resulting solution was stirred at this temperature for 2 h. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-30%) to give the product (1.07 g, 35%). 1 H NMR(300 MHz,DMSO-d6)δ 7.64(s,1H),7.57-7.52(m,1H),7.44(s,1H),4.20-4.15(m,2H),3.96-3.90(m,2H),3.29(s,3H),0.86(s,9H),0.07(s,6H).LCMS(ESI)m / e[M+1] + 409.

[0137] Example BB19: Synthesis of 1-bromo-3-isopropoxy-5-(methylsulfonyl)benzene Step 1: 1,3-Dibromo-5-isopropoxybenzene [ka] A mixture of 3,5-dibromophenol (10 g, 39.69 mmol), DMF (200 mL), 2-iodopropane (20.24 g, 119.06 mmol), and K2CO3 (10.97 g, 79.38 mmol) was stirred at 80 °C for 2 h. After cooling to room temperature, EA (200 mL) was added, and the resulting mixture was washed with HO (200 mL × 3). The mixture was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-15%) to give the product (7.6 g, 65%).

[0138] Step 2: 1-Bromo-3-isopropoxy-5-(methylsulfanyl)benzene [ka] A mixture of 1,3-dibromo-5-isopropoxybenzene (7.60 g, 25.85 mmol), dioxane (100 mL), Pd(dba) (1.18 g, 1.29 mmol), Xantphos (1.50 g, 2.59 mmol), and MeSNa (1.81 g, 25.85 mmol) was stirred at 75 °C for 3 h. After cooling to room temperature, EA (200 mL) was added, and the resulting mixture was washed with HO (200 mL × 3). The mixture was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-15%) to give the product (7.1 g, crude). GCMS (ESI) m / e [M+1] 260.

[0139] Step 3: 1-Bromo-3-isopropoxy-5-(methylsulfonyl)benzene [ka] A mixture of 1-bromo-3-isopropoxy-5-(methylsulfanyl)benzene (7.10 g, 27.18 mmol), THF (60 mL), HO (60 mL), NaIO (23.26 g, 108.75 mmol), and RuCl.HO (1.23 g, 5.46 mmol) was stirred at 0 °C for 1 h. Upon completion of the reaction, the resulting solution was diluted with EA (200 mL). The resulting mixture was washed with HO (100 mL × 3). The mixture was dried over anhydrous NaSO and concentrated. The residue was purified by Combiflash (EA / PE = 0-25%) to give the product (4.25 g, 53%). 1 H NMR(300 MHz,CDCl3)δ 7.63(s,1H),7.37(s,1H),7.30(s,1H),4.62(q,J = 6.1 Hz,1H),3.08(s,3H),1.38(d,J = 6.0 Hz,6H).GCMS(ESI)m / e[M] 292.

[0140] Example BB20: Synthesis of 1-bromo-3-methoxy-5-(methylsulfonyl)benzene [ka] Step 1: (3-Bromo-5-methoxyphenyl)(methyl)sulfane [ka] A mixture of 1,3-dibromo-5-methoxybenzene (9.00 g, 33.16 mmol), dioxane (100 mL), NaSCH (3.19 g, 33.19 mmol), Pd(dba) (1.52 g, 1.66 mmol), and Xantphos (1.92 g, 3.31 mmol) was stirred overnight at 75 °C under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-10%) to give the product (3.2 g, 39%). GCMS (ESI) m / e [M] 232.

[0141] Step 2: 1-Bromo-3-methoxy-5-(methylsulfonyl)benzene [ka] To a mixture of 1-bromo-3-methoxy-5-(methylsulfanyl)benzene (3.10 g, 12.63 mmol) in THF (30 mL) and HO (30 mL) was added a solution of NaIO (10.81 g, 50.54 mmol) in HO (15 mL) in small portions at 0 °C, followed by the addition of a solution of RuCl (0.14 g, 0.62 mmol) in HO (15 mL) in successive small portions at 0 °C. The resulting solution was stirred at room temperature for 1 h. The resulting solution was diluted with HO (50 mL) and extracted with EA (30 mL × 3). The organic layer was concentrated and purified by Combiflash (EA / PE = 0-30%) to give the product (3.22 g, 91%). 1 H NMR(300 MHz,DMSO-d6)δ 7.66(s,1H),7.54(s,1H),7.45(s,1H),3.89(s,3H),3.30(s,3H).GCMS(ESI)m / e[M] 264.

[0142] Example BB21: Synthesis of 1-bromo-3-methyl-5-(methylsulfonyl)benzene [ka] Step 1: (3-bromo-5-methylphenyl)(methyl)sulfane [ka] A mixture of 1,3-dibromo-5-methylbenzene (11.00 g, 43.13 mmol), dioxane (150 mL), NaSCH (3.02 g, 43.14 mmol), Pd(dba) (1.97 g, 2.15 mmol), and Xantphos (2.50 g, 4.32 mmol) was stirred overnight at 75 °C under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-8%) to give the product (4.40 g, 42%). GCMS (ESI) m / e [M] 216

[0143] Step 2: 1-Bromo-3-methyl-5-(methylsulfonyl)benzene [ka] To a mixture of 1-bromo-3-methyl-5-(methylsulfanyl)benzene (4.30 g, 17.82 mmol) in THF (20 mL) was added a solution of NaIO (15.25 g, 71.29 mmol) in HO (10 mL) in small portions at 0 °C, followed by the addition of a solution of RuCl (0.20 g, 0.89 mmol) in HO (10 mL) in successive small portions at 0 °C. The resulting solution was stirred at room temperature for 1 h. Upon completion of the reaction, the resulting solution was diluted with HO (50 mL) and extracted with EA (3 × 30 mL). The organic layers were combined and concentrated. The residue was purified by Combiflash (EA / PE = 0-20%) to give the product (4.51 g, 96%). 1 H NMR(300 MHz,DMSO-d6)δ 7.91(s,1H),7.84-7.72(m,2H),3.28(s,3H),2.46-2.40(m,3H).GCMS(ESI)m / e[M] 248.

[0144] Example BB22: Synthesis of 1-bromo-3-methanesulfonyl-5-(methoxymethyl)benzene [ka] Step 1: 1,3-Dibromo-5-(methoxymethyl)benzene [ka] A mixture of 1,3-dibromo-5-(bromomethyl)benzene (7.00 g, 21.28 mmol), MeONa (5.75 g, 106.40 mmol) and MeOH (70 mL) was stirred at 70 °C for 1 h. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water. The resulting solution was extracted with EA (100 mL × 3), and the combined organic layers were washed with brine. The organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-5%) to give the product (5.00 g, 84%). GCMS (ESI) m / e [M] 280.

[0145] Step 2: 1-Bromo-3-(methoxymethyl)-5-(methylsulfanyl)benzene [ka] A mixture of 1,3-dibromo-5-(methoxymethyl)benzene (5.00 g, 17.86 mmol), DMF (50 mL), and CHClSNa (1.50 g, 21.43 mmol) was stirred at room temperature overnight. Upon completion of the reaction, water (20 mL) was added, and the resulting solution was extracted with EA (100 mL × 3). The combined organic layers were washed with brine and dried over anhydrous NaSO. The solid was filtered off, and the resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-2%) to give the product (3.50 g, 79%). GCMS (ESI) m / e [M] 246.

[0146] Step 3: 1-Bromo-3-methanesulfonyl-5-(methoxymethyl)benzene [ka] A mixture of 1-bromo-3-(methoxymethyl)-5-(methylsulfanyl)benzene (3.50 g, 14.16 mmol), RuCl3.HO (319.26 mg, 1.416 mmol), and NaIO4 (6.06 g, 28.32 mmol) in THF (35 mL) and HO (35 mL) was stirred at room temperature for 2 h. Upon completion of the reaction, the resulting solution was extracted with EA (100 mL × 3), and the organic layers were combined. The resulting mixture was washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated in vacuo, and the residue was purified by Combiflash (EA / PE = 0-10%) to give the product (2.21 g, 56%). 1 H NMR(300 MHz,DMSO-d6)δ 8.05(s,1H),7.75(s,1H),7.70(s,1H),4.50(s,2H),3.45(s,3H),3.03(s,3H).GCMS(ESI)m / e[M] 278.

[0147] Example BB23: Synthesis of 1-bromo-3-(difluoromethyl)-5-methanesulfonylbenzene [ka] Step 1: 1-Bromo-3-(difluoromethyl)-5-(methylsulfanyl)benzene [ka] A mixture of 1,3-dibromo-5-(difluoromethyl)benzene (4.20 g, 14.69 mmol), (methylsulfanyl)sodium (927 mg, 13.22 mmol), DIEA (3.80 g, 29.38 mmol), Xantphos (849.97 mg, 1.47 mmol), Pd(dba) (672.58 mg, 0.74 mmol), and 1,4-dioxane (50 mL) was stirred overnight at 80 °C under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was extracted with EA (150 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-10%) to give the product (2.60 g, 69%). GCMS (ESI) m / e [M] 252

[0148] Step 2: 1-Bromo-3-(difluoromethyl)-5-methanesulfonylbenzene [ka] To a stirred solution of 1-bromo-3-(difluoromethyl)-5-(methylsulfanyl)benzene (2.60 g, 10.27 mmol) in THF (40 mL) and HO (40 mL) was added RuCl.HO (69.48 mg, 0.31 mmol) and NaIO (4.39 g, 20.55 mmol) in small portions at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. Upon completion of the reaction, the resulting mixture was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-40%) to give the product (1.79 g, 61%). 1 H NMR(300 MHz,DMSO-d6)δ 8.31(s,1H),8.19(s,1H),8.13(s,1H),7.20-7.10(m,1H),3.37(s,3H).

[0149] Example BB24: Synthesis of 3-bromo-5-methanesulfonylbenzonitrile [ka] Step 1: 3-Bromo-5-(methylsulfanyl)benzonitrile [ka] A mixture of 3,5-dibromobenzonitrile (10.00 g, 38.32 mmol), dioxane (160 mL), (methylsulfanyl)sodium (2.42 g, 34.53 mmol), Pd2(dba)3 (1.75 g, 1.91 mmol), and Xantphos (2.22 g, 3.83 mmol) was stirred overnight at 75 °C in an oil bath. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (100 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-9%) to give the product (8.52 g, 88%). LCMS (ESI, m / e) [M+1] + 228.

[0150] Step 2: 3-Bromo-5-methanesulfonylbenzonitrile [ka] To a mixture of 3-bromo-5-(methylsulfanyl)benzonitrile (8.52 g, 37.35 mmol) in THF (75 mL), a solution of NaIO (23.97 g, 112.06 mmol) in HO (35 mL) and a solution of RuCl (0.25 g, 1.12 mmol) in HO (35 mL) were added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 1 h. Upon completion of the reaction, the resulting solution was extracted with EA (100 mL × 3) and then concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-38%) to give the product (4.40 g, 40%). 1 H NMR(300 MHz,DMSO-d6)δ 8.55(s,1H),8.45-8.32(m,2H),3.36(s,3H).LCMS(ESI,m / e)[M+1] + 260.

[0151] Example BB25: Synthesis of 1-bromo-3-methanesulfonyl-5-(trifluoromethoxy)benzene [ka] Step 1: 1-Bromo-3-(methylsulfanyl)-5-(trifluoromethoxy)benzene [ka] A mixture of 1,3-dibromo-5-(trifluoromethoxy)benzene (5.00 g, 15.63 mmol), 1,4-dioxane (50 mL), CHClSNa (984.67 mg, 14.07 mmol), Pd(dba) (715.62 mg, 0.78 mmol), and XantPhos (904.37 mg, 1.56 mmol) was stirred at 75 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed and the residue was diluted with water. The resulting solution was extracted with EA (150 mL), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-5%) to give the product (3.00 g, 67%). GCMS (ESI) m / e [M] 286.

[0152] Step 2: 1-Bromo-3-methanesulfonyl-5-(trifluoromethoxy)benzene [ka] A mixture of 1-bromo-3-(methylsulfanyl)-5-(trifluoromethoxy)benzene (3.00 g, 10.45 mmol), RuCl3.HO (235.58 mg, 1.05 mmol), NaIO4 (6.71 g, 31.35 mmol), HO (30 mL) and THF (30 mL) was stirred at room temperature for 2 h. Upon completion of the reaction, the resulting solution was extracted with EA (100 mL × 3) and the organic layers were combined. The resulting mixture was washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated in vacuo, and the residue was purified by Combiflash (EA / PE = 0-15%) to give the product (2.31 g, 69%). 1 H NMR(300 MHz,DMSO-d6)δ 8.05(s,1H),7.75(s,1H),7.70(s,1H),3.10(s,3H).GCMS(ESI)m / e[M] 318.

[0153] Example BB26: Synthesis of 2-bromo-4-[(2R)-2-[(tert-butyldimethylsilyl)oxy]propoxy]-6-methanesulfonylpyridine [ka] A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), (2R)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate (2.73 g, 7.94 mmol), and CsCO (2.59 g, 7.90 mmol) in DMF (10 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed and the residue was diluted with water. The resulting solution was extracted with EA (50 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by preparative TLC (PE / EA = 5:1) to give the product (644 mg, 82%). 1H NMR(300 MHz,CDCl3)δ 7.55(s,1H),7.18(s,1H),4.26-4.11(m,1H),4.03-3.89(m,2H),3.24(s,3H),1.24(d,J = 6.3 Hz,3H),0.88(s,9H),0.11(s,3H),0.08(s,3H).LCMS(ESI)m / e[M+1] + 424.

[0154] Example BB27: Synthesis of 7-bromo-2H,3H-[1,4]dioxino[2,3-c]pyridine [ka] Step 1: 2-[(6-bromo-4-iodopyridin-3-yl)oxy]ethanol [ka] To a mixture of 2-bromo-5-fluoro-4-iodopyridine (11.00 g, 36.43 mmol) in NMP (135 mL) was added ethylene glycol (10.81 g, 174.16 mmol), and a solution of t-BuOK (4.50 g, 40.08 mmol) in NMP (30 mL) was added dropwise at 0 °C. The resulting solution was stirred at 80 °C for 1 h. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (300 mL). The resulting solution was extracted with EA (200 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-41%) to give the product (12.00 g, 86%). LCMS (ESI, m / e) [M+1] + 344.

[0155] Step 2: 7-Bromo-2H,3H-[1,4]dioxino[2,3-c]pyridine [ka] A mixture of 2-[(6-bromo-4-iodopyridin-3-yl)oxy]ethanol (12.00 g, 34.89 mmol), i-PrOH (180.00 mL), 3,4,7,8-tetramethyl-1,10-phenanthroline (0.68 g, 2.88 mmol), CuI (0.41 g, 2.13 mmol), and t-BuOK (5.48 g, 48.85 mmol) was stirred at 80 °C for 1 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (300 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-7%) to give the product (1.36 g, 16%). 1 H NMR(300 MHz,DMSO-d6)δ 7.95(s,1H),7.19(s,1H),4.44-4.24(m,4H).LCMS(ESI,m / e)[M+1] + 216.

[0156] Example BB29: Synthesis of 2-bromo-4-chloro-6-(methylsulfonyl)pyridine [ka] Step 1: 2-Bromo-6-(methylthio)pyridin-4-amine [ka] A mixture of 2,6-dibromopyridin-4-amine (5.00 g, 19.85 mmol), CsCO (9.70 g, 29.77 mmol), and MeSNa (1.53 g, 21.83 mmol) in DMSO (50 mL) was stirred at 80 °C for 12 h. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (500 mL × 3). The combined organic layers were washed with brine and dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo, and the residue was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 219.

[0157] Step 2: 2-Bromo-6-(methylsulfonyl)pyridin-4-amine [ka] To a solution of 2-bromo-6-(methylsulfanyl)pyridin-4-amine (2.50 g, 11.41 mmol) in THF (25 mL) was added RuCl3.HO (77.17 mg, 0.34 mmol), NaIO4 (9.76 g, 45.64 mmol), and HO (25 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the resulting mixture was extracted with EA (300 mL × 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 1:1) to give the product (1.02 g, 35%). LCMS (ESI) m / e [M+1] + 251.

[0158] Step 3: 2-Bromo-4-chloro-6-(methylsulfonyl)pyridine [ka] To a solution of 2-bromo-6-methanesulfonylpyridin-4-amine (800 mg, 3.18 mmol) in HCl (12 M, 14.4 mL) was added NaNO (1.10 g, 15.93 mmol) at 0 °C, and the mixture was stirred at this temperature for 1 h. Upon completion of the reaction, the resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (EA / PE = 1:4) to give the product (468 mg, 54%). 1 H NMR(300 MHz,DMSO-d6)δ 8.33(s,1H),8.17(s,1H),3.33(s,3H).LCMS(ESI)m / e[M+1] + 270.

[0159] Example BB30: Synthesis of 1-bromo-3-fluoro-5-methanesulfonylbenzene [ka] Step 1: 1-Bromo-3-fluoro-5-(methylsulfanyl)benzene [ka] A mixture of 1-bromo-3,5-difluorobenzene (5.00 g, 25.91 mmol), (methylsulfanyl)sodium (1.82 g, 25.91 mmol) and DMF (50 mL) was stirred at room temperature for 2 hours. Upon completion of the reaction, water was added, and the resulting solution was extracted with EA (100 mL × 3), and the organic layers were combined. The resulting mixture was washed with brine and dried over anhydrous Na2SO4. The solid was filtered off, and the resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-2%) to give the product (4.80 g, 84%). GCMS (ESI) m / e [M] 220.

[0160] Step 2: 1-Bromo-3-fluoro-5-methanesulfonylbenzene [ka] To a mixture of 1-bromo-3-fluoro-5-(methylsulfanyl)benzene (4.80 g, 21.71 mmol) in THF (50 mL) and HO (50 mL) was added RuCl3.HO (489 mg, 2.17 mmol) and NaIO4 (13.93 g, 65.13 mmol) in portions at 0 °C. The resulting solution was stirred at room temperature for 2 h. Upon completion of the reaction, water was added, and the resulting solution was extracted with EA (100 mL × 3). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-15%) to give the product (4.60 g, 80%). 1 H NMR(300 MHz,CDCl3)δ 7.91(s,1H),7.60-7.50(m,2 H),3.13(s,3H).GCMS(ESI)m / e[M] 252.

[0161] Example BB31: Synthesis of 1-bromo-3-chloro-5-(methylsulfonyl)benzene [ka] Step 1: 1-Bromo-3-chloro-5-(methylsulfanyl)benzene [ka] A mixture of 1,3-dibromo-5-chlorobenzene (10.00 g, 36.98 mmol), DMF (200 mL), and MeSNa (2.59 g, 37.00 mmol) was stirred at room temperature for 1 hour. Upon completion of the reaction, the resulting solution was diluted with EA (200 mL), and the resulting mixture was washed with HO (200 mL × 3). The mixture was dried over anhydrous NaSO and concentrated. The residue was purified by Combiflash (EA / PE = 0-15%) to give the product (7.6 g, 87%). GCMS (ESI) m / e [M] 236.

[0162] Step 2: 1-Bromo-3-chloro-5-methanesulfonylbenzene [ka] A mixture of 1-bromo-3-chloro-5-(methylsulfanyl)benzene (7.60 g, 31.99 mmol), THF (60 mL), HO (60 mL), NaIO (27.37 g, 127.96 mmol), and RuCl.HO (1.44 g, 6.39 mmol) was stirred at 0 °C for 1 h. Upon completion of the reaction, the resulting solution was diluted with EA (200 mL), and the resulting mixture was washed with HO (200 mL × 3). The mixture was dried over anhydrous NaSO and concentrated. The residue was purified by Combiflash (EA / PE = 0-30%) to give the product (1.13 g, 13%). 1 H NMR(400 MHz,CDCl3)δ 7.91(s,1H),7.81(s,1H),7.73(s,1H),3.02(s,3H).GCMS(ESI)m / e[M] 268.

[0163] Example BB32: Synthesis of 1-bromo-3-cyclopropoxy-5-methanesulfonylbenzene [ka] Step 1: 1,3-Dibromo-5-cyclopropoxybenzene [ka] A mixture of 3,5-dibromophenol (5.00 g, 19.85 mmol), potassium cyclopropyltrifluorolambda 4-borane (11.75 g, 79.40 mmol), K2CO3 (5.49 g, 39.70 mmol), 1,10-phenanthroline (357.69 mg, 1.99 mmol), and Cu(OAc)2 (360.5 mg, 1.985 mmol) in toluene (45 mL) and HO (15 mL) was stirred overnight at 70 °C under a nitrogen atmosphere. After cooling to room temperature, water was added, and the resulting solution was extracted with EA (200 mL × 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The solids were filtered off, and the resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-5%) to give the product (1.00 g, 17%). GCMS(ESI)m / e[M] 290.

[0164] Step 2: 1-Bromo-3-cyclopropoxy-5-(methylsulfanyl)benzene [ka] A mixture of 1,3-dibromo-5-cyclopropoxybenzene (1.00 g, 3.43 mmol), 1,4-dioxane (10 mL), CHClSNa (191.8 mg, 2.74 mmol), Xantphos (396.35 mg, 0.69 mmol), and Pd(dba) (313.6 mg, 0.34 mmol) was stirred at 75 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (40 mL). The resulting solution was extracted with EA (60 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-5%) to give the product (300 mg, 34%). GCMS (ESI) m / e [M] 258.

[0165] Step 3: 1-Bromo-3-cyclopropoxy-5-methanesulfonylbenzene [ka] To a mixture of 1-bromo-3-cyclopropoxy-5-(methylsulfanyl)benzene (300 mg, 1.16 mmol) in THF (5 mL) and HO (5 mL) was added RuCl3.HO (26 mg, 0.12 mmol) at 0 °C. Then, NaIO4 (742.79 mg, 3.47 mmol) was added in portions at 0 °C. The resulting solution was stirred at room temperature for 2 h. Upon completion of the reaction, water was added, and the resulting solution was extracted with EA (30 mL × 3), and the organic layers were combined. The resulting mixture was washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated in vacuo, and the residue was purified by preparative TLC (EA / PE = 1:2) to give the product (165 mg, 49%). 1 H NMR(300 MHz,CDCl3)δ 7.69(s,1H),7.55(s,1H),7.49(s,1H),3.85-3.81(m,1H),3.09(s,3H),0.94-0.76(m,4H).GCMS(ESI)m / e[M] 290.

[0166] Example BB33: Synthesis of 2-bromo-3-isopropoxy-6-methanesulfonylpyridine [ka] Step 1: 2-Bromo-6-iodo-3-isopropoxypyridine [ka] A mixture of 2-bromo-6-iodopyridin-3-ol (10.00 g, 33.34 mmol), DMF (150 mL), 2-iodopropane (13.04 g, 76.70 mmol), and CsCO (21.73 g, 66.69 mmol) was stirred at 80 °C for 3 h. After cooling to room temperature, water was added, and the resulting solution was extracted with EA (100 mL × 3). The resulting mixture was concentrated in vacuo to give the product (11.08 g, 87%). LCMS (ESI, m / e) [M+1] + 342.

[0167] Step 2: 2-Bromo-3-isopropoxy-6-(methylsulfanyl)pyridine [ka] A mixture of 2-bromo-6-iodo-3-isopropoxypyridine (11.08 g, 32.40 mmol), 1,4-dioxane (166 mL), (methylsulfanyl)sodium (1.82 g, 25.97 mmol), Pd2(dba)3 (1.48 g, 1.62 mmol), and Xantphos (1.87 g, 3.24 mmol) was stirred at 75 °C for 3 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 10:1) to give the product (8.00 g, 84%). LCMS (ESI, m / e) [M+1] + 262.

[0168] Step 3: 2-Bromo-3-isopropoxy-6-methanesulfonylpyridine [ka] To a mixture of 2-bromo-3-isopropoxy-6-(methylsulfanyl)pyridine (5.00 g, 19.07 mmol) in THF (50.00 mL) was added dropwise a solution of NaIO (12.24 g, 57.22 mmol) and RuCl (0.13 g, 0.57 mmol) in HO (30 mL) at 0 °C, and the resulting solution was stirred at room temperature for 1 h. Upon completion of the reaction, the resulting solution was extracted with EA (30 mL × 3), and the combined organic layers were concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-24%) to give the product (3.10 g, 50%). 1 H NMR(300 MHz,DMSO-d6)δ 8.02(d,J = 8.5 Hz,1H),7.79(d,J = 8.5 Hz,1H),4.95-4.91(m,1H),3.25(s,3H),1.37(d,J = 6.0 Hz,6H).LCMS(ESI,m / e)[M+1] + 294.

[0169] Example BB34: Synthesis of 2-bromo-4-(cyclopropylmethoxy)-6-methanesulfonylpyridine [ka] A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), CsCO (2.59 g, 7.94 mmol), and (bromomethyl)cyclopropane (0.80 g, 5.95 mmol) in DMF (10 mL) was stirred at 80 °C for 5 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (50 mL). The resulting solution was extracted with EA (30 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by preparative TLC (PE / EA = 5:1) to give the product (793 mg, 65%). 1H NMR(300 MHz,CDCl3)δ 7.54(s,1H),7.16(s,1H),3.94(d,J = 7.1 Hz,2H),3.23(s,3H),1.35-1.22(m,1H),0.77-0.65(m,2H),0.43-0.34(m,2H).LCMS(ESI)m / e[M+1] + 306.

[0170] Example BB35: Synthesis of 1-bromo-3-(cyclopropylmethoxy)-5-(methylsulfonyl)benzene [ka] Step 1: 1,3-Dibromo-5-(cyclopropylmethoxy)benzene [ka] A mixture of 3,5-dibromophenol (5.00 g, 19.85 mmol), DMF (50 mL), (bromomethyl)cyclopropane (8.04 g, 59.55 mmol), and K2CO3 (5.49 g, 39.72 mmol) was stirred at 80 °C for 2 h. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (100 mL). The resulting solution was extracted with EA (30 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-15%) to give the product (2.80 g, 46%). GCMS (ESI) m / e [M+1] + 304.

[0171] Step 2: (3-Bromo-5-(cyclopropylmethoxy)phenyl)(methyl)sulfane [ka] A mixture of 1,3-dibromo-5-(cyclopropylmethoxy)benzene (2.80 g, 9.15 mmol), 1,4-dioxane (20 mL), Pd2(dba)3 (418 mg, 0.46 mmol), Xantphos (529 mg, 0.915 mmol), and MeSNa (641 mg, 9.15 mmol) was stirred at 80 °C for 4 h. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by Combiflash (EA / PE = 0-15%) to give the product (2.0 g, 80%). LCMS (ESI) m / e [M+1] + 272.

[0172] Step 3: 1-Bromo-3-(cyclopropylmethoxy)-5-(methylsulfonyl)benzene [ka] A mixture of 1-bromo-3-(cyclopropylmethoxy)-5-(methylsulfanyl)benzene (2.00 g, 7.32 mmol), NaIO (6.26 g, 29.27 mmol), RuCl.HO (330 mg, 1.46 mmol) in THF (20 mL) and HO (20 mL) was stirred at 0 °C for 1 h. Upon completion of the reaction, EA (100 mL) was added, and the resulting mixture was washed with water (100 mL × 3). The mixture was dried over anhydrous NaSO and concentrated. The residue was purified by Combiflash (EA / PE = 0-20%) to give the product (1.07 g, 48%). 1 H NMR(300 MHz,DMSO-d6)δ 7.61(s,1H),7.52(s,1H),7.42(s,1H),3.96(d,J = 7.1 Hz,2H),3.28(s,3H),1.30-1.13(m,1H),0.63-0.53(m,2H),0.39-0.30(m,2H).

[0173] Example BB36: Synthesis of 2-bromo-4-cyclobutoxy-6-(methylsulfonyl)pyridine [ka] A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (700 mg, 2.78 mmol), bromocyclobutane (749 mg, 5.55 mmol), and K2CO3 (767 mg, 5.55 mmol) in DMF (7 mL) was stirred at 80 °C for 8 h. After cooling to room temperature, water was added, and the resulting mixture was extracted with EA (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (EA / PE = 1:3) to give the product (382 mg, 45%). 1 H NMR(300 MHz,DMSO-d6)δ 7.49(s,1H),7.41(s,1H),5.07-4.95(m,1H),3.28(s,3H),2.51-2.41(m,1H), 2.16-2.02(m,2H),1.83-1.80(m,1H),1.74-1.58(m,1H).LCMS(ESI)m / e[M+1] + 306.

[0174] Example BB37: Synthesis of 2-bromo-4-(cyclopentyloxy)-6-methanesulfonylpyridine [ka] To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol), PPh3 (780 mg, 2.97 mmol), and cyclopentanol (188 mg, 2.18 mmol) in THF (10 mL) was added dropwise DIAD (642 mg, 3.17 mmol) at 0 °C, and the resulting mixture was stirred at 50 °C overnight. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by preparative TLC (PE / EA = 5:1) to give the product (300 mg, 47%). 1H NMR(300 MHz,DMSO-d6)δ 7.53(s,1H),7.46(s,1H),5.14-5.10(m,1H),3.27(s,3H),2.04-1.89(m,3H),1.82-1.51(m,5H).LCMS(ESI)m / e[M+1] + 320.

[0175] Example BB38: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxolan-3-yloxy)pyridine [ka] To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (400 mg, 1.59 mmol) and 3-hydroxytetrahydrofuran (154 mg, 1.75 mmol) in THF, PPh3 (832 mg, 3.17 mmol) and DIAD (642 mg, 3.17 mmol) were added dropwise in small portions at 0 °C. The resulting mixture was stirred at room temperature overnight. Upon completion of the reaction, water was added, and the resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EA = 1:1) to give the product (250 mg, 47%). 1 H NMR(300 MHz,DMSO-d6)δ 7.60(s,1H),7.51(s,1H),5.38-5.34(m,1H),3.90-3.82(m,3H),3.82-3.72(m ,1H),3.28(s,3H),2.29-2.25(m,1H),2.00-1.95(m,1H).LCMS(ESI)m / e[M+1] + 322.

[0176] Example BB39: Synthesis of 2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine [ka] Step 1: 2,6-Dibromo-N-methoxy-N-methylisonicotinamide [ka] A mixture of 2,6-dibromoisonicotinic acid (9 g, 32.0 mmol) and CDI (5.7 g, 35.0 mmol) in DCM (100 mL) was stirred at 20 °C for 2 h, and N,O-dimethylhydroxylamine hydrochloride (3.4 g, 35.0 mmol) was added and stirred at 20 °C for 12 h. The mixture was diluted with HO (100 mL) and extracted with DCM (100 mL × 3). The combined organic layer was dried over NaSO and concentrated to give the product (7.3 g, 70%). 1 H NMR(400 MHz,CDCl3)δ 7.68(s,2H),3.58(s,3H),3.37(s,3H).MS(ESI)m / e[M+1] + 324.

[0177] Step 2: 1-(2,6-Dibromopyridin-4-yl)ethanone [ka] To a mixture of 2,6-dibromo-N-methoxy-N-methylisonicotinamide (4.0 g, 12.3 mmol) in THF (40 mL) was added MgBrCH (41 mL, 123 mmol, 3 M) dropwise at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was diluted with HO (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over NaSO and concentrated to give the product (3.2 g, 93%). 1 H NMR(400 MHz,CDCl3)δ 7.87(s,2H),2.61(s,3H).MS(ESI)m / e[M+1] + 278.

[0178] Step 3: 1-(2,6-Dibromopyridin-4-yl)ethanol [ka] To a solution of 1-(2,6-dibromopyridin-4-yl)ethanone (3.2 g, 11.5 mmol) in MeOH (30 mL) was added NaBH (434 mg, 11.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was diluted with H O (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over Na SO and concentrated to give the product (3.2 g, 99%). MS (ESI) m / e [M+1] + 282.

[0179] Step 4: 2,6-Dibromo-4-(1-methoxyethyl)pyridine [ka] To a solution of 1-(2,6-dibromopyridin-4-yl)ethanol (3.2 g, 11.4 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 592 mg, 14.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 20 min. MeI (4.9 g, 34.2 mmol) was added and stirred at 20 °C for 2 h. The mixture was diluted with saturated NH Cl (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried over Na SO and concentrated to give the crude product (3.2 g, crude), which was used directly. MS (ESI) m / e [M+1] + 294.

[0180] Step 5: 2-Bromo-4-(1-methoxyethyl)-6-(methylthio)pyridine [ka] To a solution of 2,6-dibromo-4-(1-methoxyethyl)pyridine (1.5 g, 5.1 mmol) in DMF (20 mL) was added NaSCH (392 mg, 5.6 mmol) at 20 °C. The mixture was stirred at 20 °C for 1 h. The mixture was diluted with brine (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over NaSO and concentrated to give the product (1.5 g, crude), which was used directly. MS (ESI) m / e [M+1] + 262.0.

[0181] Step 6: 2-Bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine [ka] A mixture of 2-bromo-4-(1-methoxyethyl)-6-(methylthio)pyridine (1.5 g, 5.1 mmol) and oxone (12.5 g, 20.4 mmol) in MeOH (16 mL) and HO (8 mL) was stirred at 20 °C for 12 h. The mixture was filtered, brine (20 mL) was added, and extracted with EA (20 mL × 3). The combined organic layers were dried over NaSO and concentrated. The crude was purified by column chromatography (PE / EA = 20:1-3:1) to give the product (1.1 g, 65%). 1 H NMR(400 MHz,CDCl3)δ 7.97(s,1H),7.70(s,1H),4.39-4.35(m,1H),3.33(s,3H),3.28(s,3H),1.45(d,J = 6.4 Hz,3H).MS(ESI)m / e[M+1] + 294.

[0182] Example BB40: Synthesis of 2-bromo-4-[(2S)-butan-2-yloxy]-6-methanesulfonylpyridine [ka] To a stirred solution of 2-bromo-6-methanesulfonylpyridin-4-ol (400 mg, 1.59 mmol), (S)-2-butanol (176 mg, 2.38 mmol), and PPh3 (624 mg, 2.38 mmol) in THF (10 mL) was added dropwise DIAD (513 mg, 2.54 mmol) under air atmosphere at 0 °C. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (PE / EA = 8:1) to give 2-bromo-4-[(2S)-butan-2-yloxy]-6-methanesulfonylpyridine (358 mg, 73% yield). 1 H NMR(400 MHz,DMSO-d6)δ 7.58(s,1H),7.48(s,1H),4.86-4.71(m,1H),3.27(s,3H),1.77-1.52(m,2H),1.27(d,J = 6.1 Hz,3H),0.91(t,J = 7.4 Hz,3H).LCMS(ESI)m / e[M+1] + 308.

[0183] Example BB41: Synthesis of 2-bromo-4-(difluoromethoxy)-6-methanesulfonylpyridine [ka] A mixture of KOH (1.11 g, 19.78 mmol), CHCN (5 mL), and HO (5 mL) was cooled to approximately −10° C. Over a period of 15 minutes, 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol) was added dropwise, followed by diethyl bromodifluoromethylphosphonate (1.06 g, 3.97 mmol). The mixture was allowed to warm to room temperature over 1 hour. The mixture was poured into water, extracted with EA (50 mL × 3), washed with brine, and dried over NaSO. The residue was purified by preparative TLC (EA / PE = 1:10) to give 2-bromo-4-(difluoromethoxy)-6-methanesulfonylpyridine (310 mg, 52% yield). 1H NMR(400 MHz,DMSO-d6)δ 7.94(t,J = 1.8 Hz,1H),7.88-7.50(m,2H),3.34(s,3H).LCMS(ESI)m / e[M+1] + 301.

[0184] Example BB42: Synthesis of 2-bromo-4-ethoxy-6-methanesulfonylpyridine [ka] A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (3.50 g, 13.88 mmol), CsCO (9.10 g, 27.84 mmol), and ethyl iodide (3.26 g, 20.90 mmol) in DMF (40 mL) was stirred at 80 °C for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (EA / PE = 20-25%) to give 2-bromo-4-ethoxy-6-methanesulfonylpyridine (3.05 g, 78% yield). 1H NMR(300 MHz,CDCl3)δ 7.55(d,J = 2.2 Hz,1H),7.17(d,J = 2.2 Hz,1H),4.19(m,2H),3.25(s,3H),1.49(t,J = 7.0 Hz,3H).LCMS(ESI)m / e[M+1] + 281.

[0185] Example BB43: Synthesis of [[(2R)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane [ka] Step 1: (2R)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol [ka] To a stirred solution of R-1,2-propanediol (5.00 g, 65.71 mmol) in Py (50 mL) was added TsCl (13.78 g, 72.28 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by Combiflash (EA / PE = 28-32%) to give (2R)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol (10.0 g, 66% yield). LCMS (ESI) m / e [M+1] + 230.

[0186] Step 2: (2R)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate [ka] To a stirred mixture of (2R)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol (10 g, 43.42 mmol), imidazole (8.87 g, 130.28 mmol) in DCM (100 mL) was added TBSCl (19.64 g, 130.28 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by Combiflash (EA / PE = 3-5%) to give the crude product (15.00 g, 100% yield). LCMS (ESI) m / e [M+1] + 344.

[0187] Step 3: tert-butyl([[(2R)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane [ka] A mixture of 3,5-dibromophenol (2.0 g, 7.94 mmol), (2R)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate (5.46 g, 15.85 mmol), and CsCO (5.17 g, 15.86 mmol) in DMF (20 mL) was stirred at 100 °C overnight. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EA (40 mL × 3). The combined organic layers were washed with brine (40 mL × 2) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (EA / PE = 3-5%) to give tert-butyl([[(2R)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (1.90 g, 56% yield).

[0188] Step 4: [[(2R)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl)dimethylsilane [ka] A mixture of tert-butyl([[(2R)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (1.00 g, 2.36 mmol), (methylsulfanyl)sodium (166 mg, 2.37 mmol), DIEA (0.82 mL, 4.71 mmol), Pd(dba) (108 mg, 0.12 mmol), and Xantphos (137 mg, 0.24 mmol) in dioxane (10 mL) was stirred at 70 °C for 4 h under a N atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EA (40 mL × 3). The combined organic layers were washed with brine (30 mL × 3) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA=20:1) to give [[(2R)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl)dimethylsilane (470 mg, 50% yield).

[0189] Step 5: [[(2R)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane [ka] To a stirred solution of [[(2R)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl)dimethylsilane (470 mg, 1.20 mmol) in THF (30 mL) was added RuCl3·HO (7.5 mg, 0.04 mmol) and NaIO4 (513.6 mg, 2.40 mmol) in HO (20 mL) at 0 °C, and the resulting solution was stirred at 0 °C for 1 h. The mixture was then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3) and dried over Na2SO4. After filtration, the filtrate was concentrated and purified by preparative TLC (PE / EA=10:1) to give [[(2R)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane (344.2 mg, 67% yield). 1 H NMR(400 MHz,CDCl3)δ 7.66(s,1H),7.38(s,1H),7.33(s,1H),4.23-4.15(m,1H),3.96-3.81(m,2H),3.08(s,3H),1.29-1.23(d,J = 8.0Hz,3H),0.91(s,9H),0.10(s,6H).LCMS(ESI)m / e[M+1] + 422.

[0190] Example BB44: Synthesis of 2-bromo-6-(ethanesulfonyl)-4-isopropoxypyridine [ka] Step 1: 2-Bromo-6-(ethylsulfanyl)pyridin-4-ol [ka] A stirred mixture of 2,6-dibromopyridin-4-ol (5.00 g, 19.77 mmol), EtSNa (1.66 g, 19.77 mmol), Pd(dba) (181 mg, 0.20 mmol), Xantphos (114.4 mg, 0.20 mmol), and DIEA (6.9 mL, 53.29 mmol) in dioxane (50 mL) was stirred at 80 °C for 3 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give crude 2-bromo-6-(ethylsulfanyl)pyridin-4-ol, which was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 234.

[0191] Step 2: 2-Bromo-6-(ethanesulfonyl)pyridin-4-ol [ka] To a stirred mixture of 2-bromo-6-(ethylsulfanyl)pyridin-4-ol (5.00 g, 21.36 mmol) in THF, an aqueous solution of RuCl3·H2O (133 mg, 0.64 mmol) was added over a short period of time, and NaIO4 (9.14 g, 42.72 mmol) was added in small portions to THF and water over 30 min at 0 °C. The resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (EA / PE = 28-32%) to give 2-bromo-6-(ethanesulfonyl)pyridin-4-ol (2.00 g, 35% yield). LCMS (ESI) m / e [M+1] + 266.

[0192] Step 3: 2-Bromo-6-(ethanesulfonyl)-4-isopropoxypyridine [ka] A solution of 2-bromo-6-(ethanesulfonyl)pyridin-4-ol (1.50 g, 5.64 mmol), CsCO (3.68 g, 11.27 mmol), and 2-iodopropane (1.44 g, 8.46 mmol) in dimethylformamide (10 mL) was stirred at 80 °C for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EA (40 mL × 3). The combined organic layers were washed with brine (30 mL × 2) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (EA / PE = 28-32%) to give 2-bromo-6-(ethanesulfonyl)-4-isopropoxypyridine (1.40 g, 78% yield). 1 H NMR(400 MHz,CDCl3)δ 7.53(s,1H),7.13(s,1H),4.75-4.70(m,1H),3.46-3.42(m,2H),1.41(d,J = 6.1 Hz,6H),1.35-1.32(m,3H).LCMS(ESI)m / e[M+1] + 307.

[0193] Example BB45: Synthesis of [[(2S)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane [ka] Step 1: (2S)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol [ka] To a stirred solution of (S)-1,2-propanediol (5.00 g, 65.71 mmol) in Py (50 mL) was added TsCl (13.78 g, 72.28 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 × 3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Combiflash (EA / PE = 28-32%) to give (2S)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol (10.00 g, 66% yield). LCMS (ESI) m / e [M+1] + 230.

[0194] Step 2: (2S)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate [ka] To a stirred mixture of (2S)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol (10.00 g, 43.42 mmol), imidazole (8.87 g, 130.28 mmol), and DCM (100 mL) was added TBSCl (19.64 g, 130.28 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated and purified by Combiflash (EA / PE = 3-5%) to give (2S)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate (15.00 g, 100% yield). LCMS (ESI) m / e [M+1] + 344.

[0195] Step 3: tert-butyl([[(2S)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane [ka] A mixture of 3,5-dibromophenol (2.0 g, 7.94 mmol), (2S)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate (5.46 g, 15.85 mmol), and CsCO (5.17 g, 15.86 mmol) in DMF (20 mL) was stirred at 100 °C overnight. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EA (40 mL × 3). The combined organic layers were washed with brine (40 mL × 2) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated and purified by Combiflash (EA / PE = 3-5%) to give tert-butyl([[(2S)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (1.90 g, 56% yield).

[0196] Step 4: [[(2S)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tertbutyl)dimethylsilane [ka] A mixture of tert-butyl([[(2S)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (2.00 g, 4.72 mmol), (methylsulfanyl)sodium (332.00 mg, 4.74 mmol), DIEA (1.64 mL, 3.48 mmol), Pd(dba) (216.00 mg, 0.24 mmol), and Xantphos (274.00 mg, 0.48 mmol) in dioxane (20 mL) was stirred at 75 °C for 4 h under a N atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous NaSO, and concentrated to give a residue, which was purified by preparative TLC (PE / EA = 20:1) to give [[(2S)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl)dimethylsilane (940 mg, 50% yield).

[0197] Step 5: [[(2S)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane [ka] To a stirred solution of [[(2S)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert-butyl)dimethylsilane (940 mg, 2.40 mmol) in THF (10 mL) was added a solution of RuCl3·HO (15 mg, 0.08 mmol) and NaIO4 (1.03 g, 4.80 mmol) in HO (10 mL) at 0 °C, and the resulting solution was stirred at 0 °C for 1 h. The resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous NaSO, concentrated, and purified by preparative TLC (PE / EA = 10:1) to give [[(2S)-1-(3-bromo-5-methanesulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane (646.4 mg, 63% yield). 1 H NMR(400 MHz,CDCl3)δ 7.58(m,1H),7.34(m,1H),7.31(m,1H),4.24-4.12(m,1H),3.89-3.72(m,2H),3.06(s,3H),1.29-1.23(d,J = 8.0 Hz,3H),0.91(s,9H),0.10(s,6H).LCMS(ESI)m / e[M+1] + 422.

[0198] Example BB46: Synthesis of 2-bromo-4-isobutoxy-6-(methylsulfonyl)pyridine [ka] A solution of 2-bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol), isobutyl bromide (815 mg, 5.95 mmol), and K2CO3 (548 mg, 3.97 mmol) in DMF (5 mL) was stirred at 80 °C for 2 h. The resulting mixture was extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE = 1:5) to give 2-bromo-4-isobutoxy-6-(methylsulfonyl)pyridine (547 mg, 89% yield). 1 H NMR(400 MHz,DMSO-d6)δ 7.61(s,1H),7.54(s,1H),4.02(d,J = 6.5 Hz,2H),3.29(s,3H),2.06-2.02(m,1H),0.98(d,J = 6.7 Hz,6H).LCMS(ESI)m / e[M+1] + 309.

[0199] Example BB48: Synthesis of 2-bromo-3-(difluoromethoxy)-6-(methylsulfonyl)pyridine [ka] Step 1: 2-Bromo-3-(difluoromethoxy)-6-iodopyridine [ka] A solution of 2-bromo-6-iodopyridin-3-ol (5.00 g, 16.67 mmol), sodium 2-chloro-2,2-difluoroacetate (5.08 g, 33.34 mmol), and CsCO (10.86 g, 33.34 mmol) in DMF (50 mL) was stirred at 80 °C for 4 h. The resulting mixture was extracted with EA (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the crude product, 2-bromo-3-(difluoromethoxy)-6-iodopyridine (5.00 g), which was used directly in the next step without further purification. LCMS (ESI) m / e [M] + 350.

[0200] Step 2: 2-Bromo-3-(difluoromethoxy)-6-(methylsulfanyl)pyridine [ka] To a solution of 2-bromo-3-(difluoromethoxy)-6-iodopyridine (2.00 g, 5.72 mmol) and CHClSNa (320 mg, 4.57 mmol) in dioxane (20 mL) was added Xantphos (331 mg, 0.57 mmol) and Pd(dba) (523 mg, 0.57 mmol). After stirring at 70 °C for 4 h under a nitrogen atmosphere, the resulting mixture was extracted with EA (200 mL × 3). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated to give the crude product, 2-bromo-3-(difluoromethoxy)-6-(methylsulfanyl)pyridine (2.0 g), which was used directly in the next step without further purification. LCMS (ESI) m / e [M] + 270.

[0201] Step 3: 2-Bromo-3-(difluoromethoxy)-6-methanesulfonylpyridine [ka] To a solution of 2-bromo-3-(difluoromethoxy)-6-(methylsulfanyl)pyridine (2.00 g, 7.41 mmol) in THF (20 mL) was added RuCl3·HO (50 mg, 0.22 mmol) at 0 °C. NaIO4 (6.34 g, 29.62 mmol) and HO (20 mL) were added, and the mixture was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was extracted with EA (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EA / PE = 1:3) to give 2-bromo-3-(difluoromethoxy)-6-methanesulfonylpyridine (556.8 mg, 25% yield). 1 H NMR(400 MHz,DMSO-d6)δ 8.17(d,J = 8.4 Hz,4H),8.08-8.01(m,1H),7.71-7.35(m 1H),3.32(s,3H).LCMS(ESI)m / e[M] + 301.

[0202] Example BB49: Synthesis of 5-bromo-7-methanesulfonyl-2H,3H-[1,4]dioxino[2,3-c]pyridine [ka] Step 1: 2-Bromo-6-iodo-3-methoxypyridine [ka] A mixture of 2-bromo-6-iodopyridin-3-ol (11.00 g, 36.68 mmol), CHI (10.41 g, 73.34 mmol), and KCO (10.14 g, 73.35 mmol) in DMF (165 mL) was stirred at room temperature for 1 h. The resulting solution was added to HO (200 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over anhydrous NaSO, and concentrated to give a residue that was purified by Combiflash (EA / PE = 0-6%) to give 2-bromo-6-iodo-3-methoxypyridine (11.00 g, 85% yield). LCMS (ESI) m / e [M+1] + 314.

[0203] Step 2: 2-Bromo-6-iodo-3-methoxypyridin-4-ol [ka] A 250 mL three-necked round-bottom flask, purged with nitrogen and maintained under an inert atmosphere, was charged with 2-bromo-6-iodo-3-methoxypyridine (5.00 g, 15.92 mmol) and THF (100 mL). To this was added LDA (2.0 M, 9.6 mL, 19.11 mmol) dropwise with stirring at −78 °C. The resulting solution was stirred at −78 °C for 1 h. To this mixture was added trimethyl borate (2.48 g, 23.86 mmol) dropwise with stirring at −78 °C. The resulting solution was stirred at −78 °C for 2 h. To this mixture was added H2O2 (0.15 mL) dropwise with stirring at −60 °C. The resulting solution was allowed to react at room temperature with stirring for an additional 1 h. The reaction was then quenched by the addition of Na2S2O3. The resulting solution was extracted with EA (50 mL x 3), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue that was purified by Combiflash (EA / PE = 0-36%) to give 2-bromo-6-iodo-3-methoxypyridin-4-ol (1.92 g, 32% yield). LCMS (ESI) m / e [M+1] + 330.

[0204] Step 3: 2-Bromo-6-iodopyridine-3,4-diol [ka] To a solution of 2-bromo-6-iodo-3-methoxypyridin-4-ol (1.92 g, 5.82 mmol) in DCM (35 mL) was added BBr3 (4.37 g, 17.45 mmol) dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 3 h. The reaction was then quenched by the addition of MeOH (5 mL). The resulting mixture was concentrated in vacuo and purified by Combiflash (EA / PE = 0-8%) to give 2-bromo-6-iodopyridine-3,4-diol (2.12 g, crude). LCMS (ESI) m / e [M+1] + 316.

[0205] Step 4: 5-Bromo-7-iodo-2H,3H-[1,4]dioxino[2,3-c]pyridine [ka] A mixture of 2-bromo-6-iodopyridine-3,4-diol (2.12 g, 6.71 mmol), 1,2-dibromoethane (1.89 g, 10.06 mmol), and K2CO3 (4.64 g, 33.55 mmol) in DMF (40 mL) was stirred at 90 °C for 2 h. The resulting solution was added to HO (100 mL), extracted with EA (50 mL × 3), dried over anhydrous Na2SO4, and concentrated to give 5-bromo-7-iodo-2H,3H-[1,4]dioxino[2,3-c]pyridine (1.26 g, 49% yield). LCMS (ESI) m / e [M+1] + 342.

[0206] Step 5: 5-Bromo-7-(methylsulfanyl)-2H,3H-[1,4]dioxino[2,3-c]pyridine [ka] A mixture of 5-bromo-7-iodo-2H,3H-[1,4]dioxino[2,3-c]pyridine (1.26 g, 3.68 mmol), (methylsulfanyl)sodium (0.23 g, 3.28 mmol), Pd2(dba)3 (0.17 g, 0.18 mmol), and Xantphos (0.21 g, 0.36 mmol) in dioxane (20 mL) was stirred at 75 °C for 3 h. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-5%) to give 5-bromo-7-(methylsulfanyl)-2H,3H-[1,4]dioxino[2,3-c]pyridine (492 mg, 45% yield). LCMS (ESI) m / e [M+1] + 262.

[0207] Step 6: 5-Bromo-7-methanesulfonyl-2H,3H-[1,4]dioxino[2,3-c]pyridine [ka] To a solution of 2-bromo-3-[(4-methoxyphenyl)methoxy]-6-(methylsulfanyl)pyridine (492.8 mg, 1.88 mmol) in THF (10 mL) was added RuCl3·HO (12.72 mg, 0.05 mmol) at 0 °C. A solution of NaIO4 (1206.4 mg, 5.64 mmol) in HO (10 mL) was added at 0 °C. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-25%) to give 5-bromo-7-methanesulfonyl-2H,3H-[1,4]dioxino[2,3-c]pyridine (207.0 mg, 33%). 1 H NMR(400 MHz,DMSO-d6)δ 7.56(s,1H),4.54-4.48(m,4H),3.23(s,3H).LCMS(ESI)m / e[M+1] + 294.

[0208] Example BB50: Synthesis of (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridine [ka] Step 1: (R)-2-Methoxypropyl 4-methylbenzenesulfonate [ka] To a mixture of NaH (60% in mineral oil, 1.2 g, 30 mmol) in DMF (20 mL) was added 4-(R)-2-methoxypropan-1-ol (1.8 g, 20 mmol) at 0-5°C. After 30 min, methylbenzenesulfonyl chloride (5.7 g, 30 mmol) was added to the mixture and stirred at room temperature for 16 h. The mixture was poured into water (50 mL) and extracted with EA (20 mL x 3). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give (R)-2-methoxypropyl 4-methylbenzenesulfonate (3.95 g, 82.3%). MS (ESI) m / e [M+1] + 245.

[0209] Step 2: (R)-2,6-Dibromo-4-(2-methoxypropoxy)pyridine [ka] A mixture of (R)-2-methoxypropyl 4-methylbenzenesulfonate (3.95 g, 16.2 mmol), 2,6-dibromopyridin-4-ol (3.37 g, 13.5 mmol), and K2CO3 (3.72 g, 27.0 mmol) in DMF (20 mL) was heated to 80 °C for 16 h. The mixture was poured into water (50 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give (R)-2,6-dibromo-4-(2-methoxypropoxy)pyridine (3.05 g, 71.3%). MS (ESI) m / e [M+1] + 325.

[0210] Step 3: (R)-2-Bromo-4-(2-methoxypropoxy)-6-(methylthio)pyridine [ka] A mixture of (R)-2,6-dibromo-4-(2-methoxypropoxy)pyridine (3.0 g, 9.23 mmol), sodium methyl mercaptan (20 wt%, 7.9 g, 27.7 mmol) and DMF (20 mL) was stirred at room temperature for 16 hours. The mixture was poured into water (50 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylthio)pyridine (2.4 g, 88.9%). MS (ESI) m / e [M+1] + 292.

[0211] Step 4: (R)-2-Bromo-4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridine [ka] A mixture of (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylthio)pyridine (2.4 g, 8.22 mmol), 3-chloroperbenzoic acid (2.12 g, 12.33 mmol) in DCM (30 mL) was stirred at room temperature for 16 h. The DCM was replaced with EA (30 mL), and the organic layer was then washed with a mixture of NaHCO (10 mL) and NaSO (10 mL), dried over NaSO, and concentrated to give the crude product, which was purified by column chromatography on silica gel using EA / PE (1 / 2) as the eluent to give (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridine (2.5 g, 93.6%). MS (ESI) m / e [M+1] + 324.

[0212] Example BB51: Synthesis of 6-bromo-3-methoxy-2-(methylsulfonyl)pyridine [ka] Step 1: 6-Bromo-3-methoxy-2-(methylthio)pyridine [ka] A 100 mL round-bottom flask was charged with 6-bromo-2-fluoro-3-methoxypyridine (1.00 g, 4.85 mmol), DMF (10 mL), and NaSCH3 (339.78 mg, 4.85 mmol). The resulting solution was stirred at room temperature for 1 hour. The resulting solution was diluted with EA (100 mL). The resulting mixture was washed with H2O (100 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by Combiflash (EA / PE = 0-15%) to give the product (0.90 g, 79% yield). LCMS (ESI) m / e [M+1] + 234.

[0213] Step 2: 6-Bromo-3-methoxy-2-(methylsulfonyl)pyridine [ka] A 100 mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere was charged with 6-bromo-3-methoxy-2-(methylsulfanyl)pyridine (1.00 g, 4.27 mmol), THF (10 mL), HO (10 mL), NaIO (3.65 g, 17.07 mmol), and RuCl.HO (192.59 mg, 0.85 mmol). The resulting solution was stirred at 0 °C for 1 h. The resulting solution was diluted with EA (100 mL). The resulting mixture was washed with HO (100 mL × 3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by Combiflash (EA / PE = 0-20%) to give the product (705.30 mg, 62% yield). 1 H NMR(400 MHz,CDCl3)δ 7.66(d,J = 8.7 Hz,1H),7.37(d,J = 8.7 Hz,1H),4.03(s,3H),3.35(s,3H).LCMS(ESI)m / e[M+1] + 266.

[0214] Example BB52: Synthesis of 2-bromo-6-(methylsulfonyl)-4-phenylpyridine [ka] Step 1: Synthesis of 2,6-dibromo-4-phenylpyridine [ka] A 250 mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere was charged with 2,6-dibromo-4-iodopyridine (5.20 g, 14.33 mmol), dioxane (30 mL), HO (10 mL), phenylboronic acid (1.75 g, 14.35 mmol), NaCO (3.04 g, 28.68 mmol), and Pd(PPh) (1656.31 mg, 1.43 mmol). The resulting solution was stirred at 90 °C for 2 h. The resulting solution was diluted with HCl (100 mL). The resulting mixture was washed with HO (100 mL × 3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by Combiflash (EA / PE = 0-15%) to give the product (0.77 g, 17% yield). LCMS (ESI) m / e [M+1] + 312.

[0215] Step 2: 2,6-Dibromo-4-phenylpyridine [ka] A 100 mL round-bottom flask was charged with 2,6-dibromo-4-phenylpyridine (770.00 mg, 2.460 mmol), DMF (10 mL), and NaSCH (172.21 mg, 2.46 mmol). The resulting solution was stirred at room temperature for 1 h. The resulting solution was diluted with EA (100 mL). The resulting mixture was washed with HO (100 mL × 3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by Combiflash (EA / PE = 0-10%) to give the product (0.43 g, 62% yield). LCMS (ESI) m / e [M+1] + 280.

[0216] Step 3: 2-Bromo-6-(methylsulfonyl)-4-phenylpyridine [ka] A 100 mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere was charged with 2-bromo-6-(methylsulfanyl)-4-phenylpyridine (430.00 mg, 1.54 mmol), THF (10 mL), HO (10 mL), NaIO (1313.06 mg, 6.14 mmol), and RuCl.HO (69.20 mg, 0.31 mmol). The resulting solution was stirred at 0 °C for 1 h. The resulting solution was diluted with EA (50 mL). The resulting mixture was washed with HO (50 mL × 3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by Combiflash (EA / PE = 0-25%) to give the product (386.50 mg, 80% yield). 1H NMR(400 MHz,DMSO-d6)δ 8.37(d,J = 1.5 Hz,1H),8.29(d,J = 1.5 Hz,1H),8.01-7.92(m,2H),7.63-7.54(m,3H),3.37(s,3H).LCMS(ESI)m / e[M+1] + 312.

[0217] Example BB53: Synthesis of 2-bromo-4-methyl-6-(methylsulfonyl)pyridine [ka] Step 1: 2-Bromo-4-methyl-6-(methylthio)pyridine [ka] A 250 mL round-bottom flask was charged with 2,6-dibromo-4-methylpyridine (4.00 g, 15.62 mmol), DMF (50 mL), and NaSCH (0.98 g, 14.00 mmol). The resulting solution was stirred at 25 °C for 3 h. The resulting solution was diluted with HO (100 mL) and extracted with 3 × 80 mL of EA (100 mL × 3). The organic layers were combined and concentrated. The residue was purified by Combiflash (EA / PE = 0-20%) to give the product (3.3 g, 87% yield). LCMS (ESI, m / z) [M+1]+ 218.

[0218] Step 2: 2-Bromo-4-methyl-6-(methylsulfonyl)pyridine [ka] A 250 mL round-bottom flask was charged with 2-bromo-4-methyl-6-(methylsulfanyl)pyridine (3.30 g, 13.61 mmol), THF (30 mL), and HO (10 mL). To this was added a solution of NaIO (11.65 g, 0.05 mmol) in HO (10 mL) in small portions at 0 °C. To this mixture was added a solution of RuCl (0.31 g, 1.37 mmol) in HO (10 mL) in small portions at 0 °C. The resulting solution was stirred at 25 °C for 1 h. The resulting solution was diluted with HO and extracted with EA (100 mL × 3). The organic layers were combined and concentrated. The residue was purified by Combiflash (EA / PE = 0-30%) to give the product (2.45 g, 65% yield). 1 H NMR(300 MHz,DMSO-d6)δ 7.97(t,J = 0.9 Hz,1H),7.92(t,J = 1.1 Hz,1H),3.30(s,3H),2.47(s,3H).LCMS(ESI,m / z):[M+H] 250.

[0219] Example BB54: Synthesis of 2-bromo-6-methanesulfonyl-4-phenoxypyridine [ka] Step 1: 2,6-Dibromo-4-phenoxypyridine [ka] A 250 mL round-bottom flask was charged with 2,6-dibromo-4-chloropyridine (4.80 g, 17.69 mmol), DMF (75 mL), phenol (1.50 g, 15.93 mmol), and CsCO (11.53 g, 35.38 mmol). The resulting solution was stirred in an oil bath at 90 °C for 2 h. The resulting solution was extracted with EA (50 mL × 3) and concentrated. The residue was purified by preparative MPLC (column: C18 spherical 20-35 μm, 100A, 330 g, phase: A - H2O (0.05% TFA), B - acetonitrile, B%: 60%-70% over 40 min) to give the product (0.96 g, 14% yield). LCMS (ESI) m / e [M+1] + 330.

[0220] Step 2: 2-Bromo-6-(methylsulfanyl)-4-phenoxypyridine [ka] A 50 mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere was charged with 2,6-dibromo-4-phenoxypyridine (0.96 g, 2.91 mmol), dioxane (15 mL), (methylsulfanyl)sodium (0.18 g, 2.56 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), and XantPhos (0.17 g, 0.29 mmol). The resulting solution was stirred in an oil bath at 75 °C for 3 h. The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-1%) to give the product (0.82 g, 85%). LCMS (ESI) m / e [M+1] + 296.

[0221] Step 3: 2-Bromo-6-methanesulfonyl-4-phenoxypyridine [ka] A 25 mL round-bottom flask was charged with 2-bromo-6-(methylsulfanyl)-4-phenoxypyridine (0.82 g, 2.76 mmol) and THF (7 mL). To this was added dropwise a solution of NaIO (1.78 g, 8.32 mmol) and RuCl (0.020 g, 0.080 mmol) in HO (7 mL) with stirring at 0 °C. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-11%) to give the product (488.80 mg, 48% yield). 1 H NMR(300 MHz,DMSO-d6)δ 7.60-7.51(m,3H),7.43-7.36(m,2H),7.34-7.27(m,2H),3.28(s,3H).LCMS(ESI)m / e[M+1] + 328.

[0222] Example BB55: Synthesis of 2-chloro-6-methanesulfonyl-4-(trifluoromethyl)pyridine [ka] Step 1: 2-chloro-6-(methylsulfanyl)-4-(trifluoromethyl)pyridine [ka] A 250 mL round-bottom flask was charged with 2,6-dichloro-4-(trifluoromethyl)pyridine (6.00 g, 27.78 mmol), DMF (90.00 mL), and (methylsulfanyl)sodium (1.75 g, 24.97 mmol). The resulting solution was stirred at room temperature for 1 h. The resulting solution was extracted with EA (3 × 50 mL) and concentrated. The residue was purified by Combiflash to give the product (2.56 g, 36% yield). GCMS (ESI) m / e [M] 227.

[0223] Step 2: 2-Chloro-6-methanesulfonyl-4-(trifluoromethyl)pyridine [ka] A 100 mL three-necked round-bottom flask was charged with 2-chloro-6-(methylsulfanyl)-4-(trifluoromethyl)pyridine (2.56 g, 11.24 mmol) and THF (20 mL). To this was added dropwise a solution of NaIO (7.22 g, 33.75 mmol) and RuCl (0.08 g, 0.337 mmol) in HO (20 mL) with stirring at 0 °C. The resulting solution was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EA / PE = 0-11%) to give the product (1.08 g, 33% yield). 1 H NMR(300 MHz,DMSO-d6)δ 8.49-8.46(m,1H),8.35-8.30(m,1H),3.38(s,3H).LCMS(ESI)m / e[M+1] + 260.

[0224] Example BB56: Synthesis of 6-bromo-3-methyl-2-(methylsulfonyl)pyridine [ka] Step 1: 6-Bromo-2-fluoro-3-methylpyridine [ka] A 500 mL three-necked round-bottom flask purged with nitrogen and maintained under an inert atmosphere was charged with 2-bromo-6-fluoropyridine (10.00 g, 56.82 mmol) and THF (200 mL). To this was added LDA (7.91 g, 73.87 mmol) dropwise over 15 minutes with stirring at −78°C. The resulting solution was stirred at −78°C for 3 hours in a liquid nitrogen bath. To this was added methyl iodide (8.87 g, 62.50 mmol) dropwise over 5 minutes with stirring at −78°C. The resulting solution was allowed to react at room temperature for an additional hour with stirring. The reaction was then quenched by the addition of aqueous NH4Cl (150 mL). The resulting solution was extracted with EA (100 mL × 3). The resulting mixture was washed with HO. The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (PE / EA=0-10%) to give the product (4.4 g, 40% yield). LCMS (ESI) m / e [M+1] + 190.

[0225] Step 2: 6-Bromo-3-methyl-2-(methylthio)pyridine [ka] A 100 mL round-bottom flask was charged with 6-bromo-2-fluoro-3-methylpyridine (3.40 g, 17.89 mmol), DMF (40 mL), and NaSCH (1.00 g, 14.31 mmol). The resulting solution was stirred at room temperature for 1.5 hours. Then, NH Cl solution (50 mL) was added to quench the reaction. The resulting solution was extracted with EA (50 mL x 3). The resulting mixture was washed with H O. The resulting mixture was concentrated under vacuum. The residue was purified by Combiflash (PE / EA = 0-1%) to give the product (2.9 g, 74% yield). LCMS (ESI) m / e [M+1] + 218.

[0226] Step 3: 6-Bromo-3-methyl-2-(methylsulfonyl)pyridine [ka] A 250 mL round-bottom flask was charged with 6-bromo-3-methyl-2-(methylsulfanyl)pyridine (2.90 g, 13.29 mmol) and THF (30 mL). To this was added NaIO (8.53 g, 39.88 mmol), HO (30 mL), and RuCl (82.57 mg, 0.40 mmol) in small portions over 5 min at 0 °C. The resulting solution was stirred at room temperature for 1 h. The resulting solution was extracted with EA (50 mL). The resulting mixture was washed with HO (25 mL × 2). The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (PE / EA = 0-13%) to give the product (2.48 g, 75% yield). 1 H NMR(400 MHz,DMSO-d6)δ 7.93-7.89(m,2H),3.38(s,3H),2.57(s,3H).LCMS(ESI)m / e[M+1] + 250.

[0227] Example BB57: Synthesis of 2-bromo-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridine [ka] Step 1: Synthesis of 2,6-dibromo-4-iodopyridine [ka] In a flame-dried, nitrogen-flushed, three-necked Schlenk tube equipped with a rubber septum and a magnetic stir bar, 2,6-dibromopyridine (5.0 g, 21.11 mmol) was dissolved in dry THF (20 mL). The mixture was cooled to -30 °C. 2,2,6,6-Tetramethylpiperidinylmagnesium chloride-lithium chloride complex (32 mL, 31.70 mmol, 1 M THF solution) was then added dropwise via syringe and stirred at that temperature for an additional 30 min. I2 (5.9 g, 23.24 mmol) was then quickly added to the mixture at -30 °C under nitrogen gas protection and stirred at the same temperature for 30 min. The reaction mixture was quenched by the addition of saturated NH4Cl (30 mL), followed by extraction with EtOAc, drying over anhydrous Na2SO4, and concentration under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 10, v / v) to give the product (3.0 g, 39% yield). LCMS (ESI) m / e [M+1] + = 362.

[0228] Step 2: Synthesis of 2,6-dibromo-4-(3,6-dihydro-2H-pyran-4-yl)pyridine [ka] To a stirred solution of 2,6-dibromo-4-iodopyridine (2.0 g, 5.51 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 5.71 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was added Pd(dppf)Cl (403 mg, 0.55 mmol) and KCO (1.5 g, 10.85 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and then dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 12, v / v) to give the product (1.2 g, 68% yield). LCMS (ESI) m / e [M+1] + = 318.

[0229] Step 3: Synthesis of 2,6-dibromo-4-(tetrahydro-2H-pyran-4-yl)pyridine [ka] To a solution of 2,6-dibromo-4-(3,6-dihydro-2H-pyran-4-yl)pyridine (1.0 g, 3.13 mmol) in EtOAc (30 mL) was added 5% Rh / C (200 mg, 5 wt%). The mixture was stirred under a hydrogen atmosphere at room temperature overnight. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give the product (1.0 g, 100% yield). LCMS (ESI) m / e [M+1] + = 320.

[0230] Step 4: Synthesis of 2-bromo-6-(methylthio)-4-(tetrahydro-2H-pyran-4-yl)pyridine [ka] A solution of 2,6-dibromo-4-(tetrahydro-2H-pyran-4-yl)pyridine (1.0 g, 3.11 mmol) and sodium thiomethoxide (195 mg, 2.79 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 4, v / v) to give the product (550 mg, 61% yield). LCMS (ESI) m / e [M+1] + = 288.

[0231] Step 5: Synthesis of 2-bromo-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridine [ka] To a stirred solution of 2-bromo-6-(methylthio)-4-(tetrahydro-2H-pyran-4-yl)pyridine (550 mg, 1.91 mmol) in water (5 mL) and THF (5 mL) was added dropwise a solution of RuCl3.HO (12 mg, 0.05 mmol) in water (2 mL) at 0 °C. To the above mixture was added dropwise a solution of NaIO4 (1.5 g, 7.01 mmol) in water (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for an additional 30 min. The resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:PE = 1:5) to give the product (361 mg, 59% yield). 1 H NMR(300 MHz,DMSO-d6)δ 7.97(s,1H),7.95(s,1H),3.97-3.94(m,2H),3.44-3.39(m,2H),3.33(s,3H),3.08-3.00(m,1H),1.78-1.69(m,4H).LCMS(ESI)m / e[M+1] + = 320.

[0232] Example BB58: Synthesis of 2-bromo-3,4-dimethoxy-6-(methylsulfonyl)pyridine [ka] Step 1: 2-Bromo-6-iodo-3,4-dimethoxypyridine [ka] A 250 mL round-bottom flask was charged with 2-bromo-6-iodo-3-methoxypyridin-4-ol (2.95 g, 8.94 mmol), DMF (90 mL), and K2CO3 (2.47 g, 17.88 mmol). To this was added CHI (2.54 g, 17.88 mmol) over 5 minutes at 0 °C. The resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched by adding aqueous NH4Cl (40 mL). The resulting solution was extracted with EtOAc (40 mL × 2), and the combined organic layers were washed with H2O and brine. The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (PE / EtOAc = 0-11%) to give the product (2.6 g, 84.5% yield). LCMS (ESI) m / e [M+1] + 344.

[0233] Step 2: 2-Bromo-3,4-dimethoxy-6-(methylthio)pyridine [ka] A 100 mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere was charged with 2-bromo-6-iodo-3,4-dimethoxypyridine (2.60 g, 7.56 mmol), Pd(dba) (346.1 mg, 0.38 mmol), Xant-phos (437.4 mg, 0.76 mmol), and dioxane (60 mL). To this was added CHClSNa (529.6 mg, 7.56 mmol). The resulting solution was stirred overnight at 75° C. in an oil bath. The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (PE / EtOAc = 0-6%) to give the product (1.64 g, 82%). LCMS (ESI) m / e [M+1] + 264.

[0234] Step 3: 2-Bromo-3,4-dimethoxy-6-(methylsulfonyl)pyridine [ka] A 100 mL round-bottom flask was charged with 2-bromo-3,4-dimethoxy-6-(methylsulfanyl)pyridine (1.60 g, 6.06 mmol), HO (35 mL), and THF (35 mL). To this was added RuCl (126 mg, 0.61 mmol) over 2 min at 0 °C. To this was added NaIO (3.89 g, 18.17 mmol) over 2 min at 0 °C, and the resulting solution was stirred at room temperature for 1 RT. The reaction was then quenched by the addition of aqueous NH Cl (50 mL). The resulting solution was extracted with EtOAc (80 mL), and the combined organic layers were washed with brine. The resulting mixture was concentrated in vacuo, and the residue was purified by Combiflash (PE / EtOAc = 0-18%) to give the product (354.5 mg, 19.8%). 1 H NMR(400 MHz,DMSO-d6)δ 7.72(s,1H),4.06(s,3H),3.88(s,3H),3.28(s,3H).LCMS(ESI)m / e[M+1] + 296.

[0235] Example BB59: Synthesis of 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine [ka] Step 1: 2,6-Dibromo-4-(methoxy-d3)pyridine [ka] A mixture of 2,6-dibromopyridin-4-ol (2.4 g, 9.5 mmol), CD3I (1.4 g, 9.5 mmol), and K2CO3 (3.9 g, 28.5 mmol) in DMF (30 mL) was stirred at 25 °C for 2 h. Upon completion of the reaction, HO (200 mL) was added, and the resulting solution was extracted with EA (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the crude product (2.56 g, crude). MS (ESI) m / e [M+1] + 269.

[0236] Step 2: 2-Bromo-4-(methoxy-d3)-6-(methylthio)pyridine [ka] To a solution of 2,6-dibromo-4-(methoxy-d3)pyridine (2.56 g, 9.5 mmol) in DMF (30 mL) was added NaSMe (731 mg, 10.4 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was poured into H2O (200 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product (2.4 g, crude). MS (ESI) m / e [M+1] + 237.

[0237] Step 3: 2-Bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine [ka] To a solution of 2-bromo-4-(methoxy-d3)-6-(methylthio)pyridine (2.4 g, 10.1 mmol) in MeOH (40 mL) / HO (20 mL) was added Oxone (12.4 g, 20.1 mmol) at 25 °C. The mixture was stirred at room temperature for 2 h. Upon completion of the reaction, the solid was filtered off and the filtrate was concentrated. The crude product was purified by silica gel column chromatography eluting with (PE / EtOAc 100:1-20:1) to give the product (1.3 g, 47% yield). 1 H NMR(400 MHz,CDCl3)δ 7.57(s,1 H),7.18(s,1 H),3.25(s,3 H).MS(ESI)m / e[M+1] + 269.

[0238] Example BB60: Synthesis of (R and S)-2-chloro-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine [ka] Step 1. Synthesis of 1-(2,6-dichloropyridin-4-yl)ethan-1-ol [ka] To a stirred solution of 2,6-dichloro-4-iodopyridine (10.00 g, 36.51 mmol) in THF (100 mL) was added dropwise a solution of n-BuLi in n-hexane (21.9 mL, 2.5 M, 54.77 mmol) under a N2 atmosphere at -78 °C. The resulting mixture was stirred at -78 °C for 1 h. To the above mixture, acetaldehyde (4.83 g, 0.11 mmol) was added dropwise over 15 min at -78 °C. The resulting mixture was stirred at -78 °C for an additional 1 h. The reaction was quenched with saturated aqueous NH4Cl at -78 °C. The resulting mixture was extracted with EtOAc (2 × 300 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (5.50 g, 78% yield) was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 191.99.

[0239] Step 2. Synthesis of 2,6-dichloro-4-(1-methoxyethyl)pyridine [ka] To a stirred solution of 1-(2,6-dichloropyridin-4-yl)ethanol (5.50 g, 28.64 mmol) and CHI (6.10 g, 42.98 mmol) in THF (100 mL) was added NaH (1.37 g, 60% in mineral oil, 57.28 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature under a N atmosphere for 2 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product (5 g, crude) was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 206.

[0240] Step 3. Synthesis of 2-chloro-4-(1-methoxyethyl)-6-(methylthio)pyridine [ka] To a stirred solution of 2,6-dichloro-4-(1-methoxyethyl)pyridine (5.00 g, 24.26 mmol) in DMF (50 mL) was added MeSNa (2.55 g, 36.43 mmol) in small portions at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The resulting mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (7 g, crude) was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 218.

[0241] Step 4. Synthesis of 2-chloro-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine [ka] To a stirred solution of 2-chloro-4-(1-methoxyethyl)-6-(methylsulfanyl)pyridine (7.00 g, 32.15 mmol) and RuCl3.HO (0.22 g, 0.97 mmol) in THF (70 mL) and HO (70 mL) was added NaIO4 (13.75 g, 64.29 mmol) in small portions at 0 °C, and the resulting mixture was stirred at room temperature for 10 h. The resulting mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (PE / EtOAc = 0-20%) to give the product (5 g, 62%). LCMS (ESI) m / e [M+1] + 250.

[0242] Step 5. Synthesis of (R and S)-2-chloro-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine [ka] Racemic 2-chloro-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine (3 g) was separated by chiral HPLC using the following conditions (Column: CHIRAL ART Cellulose-SB, 5 x 25 cm, 5 um, Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: EtOH, Flow Rate: 95 mL / min, Gradient: 20% B-20% B over 15 min, 220 nm, Retention Time 1: 8.55 min, Retention Time 2: 9.50 min), and the earlier peak was collected and concentrated to give one pure isomer (1.32 g, 44% yield). For the earlier peak (retention time: 8.55 min): 1 H NMR(400 MHz,CDCl3)δ 7.96(dd,J = 1.3 Hz,1H),7.56(dd,J = 1.3 Hz,1H),4.43-4.38(m,1H),3.35(s,3H),3.29(s,3H),1.47(d,J = 6.6 Hz,3H).LCMS(ESI)m / e[M+1]+ = 249.85. The later peak was collected and concentrated to give the product (1.22 g, 41% yield). For the later peak (retention time: 9.50 min): 1 H NMR(400 MHz,CDCl3)δ 7.96(dd,J = 1.2,Hz,1H),7.56(dd,J = 1.3 Hz,1H),4.46-4.36(m,1H),3.35(s,3H),3.29(s,3H),1.47(d,J = 6.5 Hz,3H).LCMS(ESI)m / e[M+1] + 250.

[0243] Example BB61: Synthesis of (S)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methylmorpholine [ka] Step 1: Synthesis of (S)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine [ka] A 250 mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere was charged with 2,6-dichloro-4-iodopyridine (5.00 g, 18.25 mmol), dioxane (100 mL), (3S)-3-methylmorpholine (1.85 g, 18.29 mmol), Pd(dba) CHCl (1.89 g, 1.82 mmol), XantPhos (2.11 g, 3.64 mmol), and CsCO (17.84 g, 54.75 mmol). The resulting solution was stirred in an oil bath at 110 °C for 3 h. After cooling to room temperature, the reaction was concentrated. The residue was purified by Combiflash (EtOAc / PE = 0-15%) to give the product (1.20 g, 24%). LCMS (ESI, m / z): [M+H] + 247.

[0244] Step 2: Synthesis of (S)-4-(2-chloro-6-(methylthio)pyridin-4-yl)-3-methylmorpholine [ka] A 100 mL round-bottom flask was charged with (3S)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine (1.90 g, 7.68 mmol), DMF (30 mL), and CHClSNa (1.08 g, 15.42 mmol). The resulting solution was stirred at 25 °C for 5 h. The resulting solution was diluted with HO (50 mL) and extracted with EtOAc (3 × 30 mL). The organic layers were combined and concentrated. The residue was purified by Combiflash (EtOAc / PE = 0-10%) to give the product (1.40 g, 63%). LCMS (ESI, m / z): [M+H] + 259.

[0245] Step 3: Synthesis of (S)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methylmorpholine [ka] A 100 mL round-bottom flask was charged with (3S)-4-[2-chloro-6-(methylsulfanyl)pyridin-4-yl]-3-methylmorpholine (1.40 g, 5.41 mmol), THF (20 mL), HO (20 mL), and NaIO (4.63 g, 21.64 mmol). To this mixture, RuCl·HO (0.12 g, 0.53 mmol) was added in small portions at 0 °C. The resulting solution was stirred at 25 °C for 3 h. The resulting solution was diluted with HO (50 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined and concentrated. The residue was purified by Combiflash (EtOAc / PE = 0-45%) to give the product (1.30 g, 79%). 1 H NMR(300 MHz,DMSO-d6)δ 7.31(d,J = 2.3 Hz,1H),7.11(d,J = 2.3 Hz,1H),4.17(d,J = 7.2 Hz,1H),4.02-3.90(m,1H),3.81-3.58(m,3H),3.58-3.45(m,1H),3.24-3.15(m,4 H),1.18(d,J = 6.7 Hz,3H).LCMS(ESI,m / z):[M+H]+ 291.

[0246] Example BB62: Synthesis of (R)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methylmorpholine [ka] Step 1: Synthesis of (R)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine [ka] A 250 mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere was charged with 2,6-dichloro-4-iodopyridine (2.50 g, 9.13 mmol), dioxane (50 mL), (3R)-3-methylmorpholine (0.97 g, 9.13 mmol), Pd(dba) CHCl (0.97 g, 0.91 mmol), XantPhos (1.06 g, 1.82 mmol), and CsCO (8.92 g, 27.38 mmol). The resulting solution was stirred in an oil bath at 110 °C for 3 h. After cooling to room temperature, the reaction was concentrated, and the residue was purified by Combiflash (0-15% EtOAc / PE) to give the product (1.9 g, 84%). LCMS (ESI, m / z): [M+H] + 247.

[0247] Step 2: Synthesis of (R)-4-(2-chloro-6-(methylthio)pyridin-4-yl)-3-methylmorpholine [ka] A 100 mL round-bottom flask was charged with (3R)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine (1.90 g, 7.68 mmol), DMF (30 mL), and CHClSNa (1.08 g, 15.42 mmol). The resulting solution was stirred at 25 °C for 5 h. The resulting solution was diluted with HO (50 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined and concentrated. The residue was purified by Combiflash (EtOAc / PE = 0-10%) to give the product (1.70 g, 86%). LCMS (ESI, m / z): [M+H] + 259.

[0248] Step 3: Synthesis of (R)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methylmorpholine [ka] A 100 mL round-bottom flask was charged with (3R)-4-[2-chloro-6-(methylsulfanyl)pyridin-4-yl]-3-methylmorpholine (1.70 g, 6.59 mmol), THF (20 mL), HO (20 mL), and NaIO (5.64 g, 26.36 mmol). To this mixture, RuCl·HO (0.17 g, 0.66 mmol) was added in small portions at 0 °C. The resulting solution was stirred at 25 °C for 3 h. The resulting solution was diluted with HO (50 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined and concentrated. The residue was purified by Combiflash (EtOAc / PE = 0-45%) to give the product (1.20 g, 63%). 1 H NMR(300 MHz,DMSO-d6)δ 7.30(d,J = 2.3 Hz,1H),7.12(d,J = 2.3 Hz,1H),4.16(d,J = 7.2 Hz,1H),4.05-3.93(m,1H),3.82-3.56(m,3H),3.57-3.45(m,1H),3.23-3.15(m,4H),1.19(d,J = 6.7 Hz,3H).LCMS(ESI,m / z):[M+H] + 291.

[0249] Example BB63: Synthesis of 2-chloro-6-methanesulfonyl-4-(3-methoxyazetidin-1-yl)pyridine [ka] Step 1: Synthesis of 2,6-dichloro-4-(3-methoxyazetidin-1-yl)pyridine [ka] To a stirred mixture of 2,6-dichloro-4-iodopyridine (3.0 g, 10.95 mmol), 3-methoxyazetidine (1.15 g, 13.14 mmol), Xantphos (633.80 mg, 1.09 mmol), and CsCO (7.14 g, 21.91 mmol) in 1,4-dioxane (30 mL) was added Pd(dba) (501.53 mg, 0.55 mmol) at room temperature. The resulting mixture was stirred at 100 °C under a N atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (2 × 50 mL), and the combined organic layers were dried over anhydrous NaSO. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (20% EtOAc / PE) to give the product (1.2 g, 47% yield). LCMS(ESI)m / e[M+1] + = 233.

[0250] Step 2: Synthesis of 2-chloro-4-(3-methoxyazetidin-1-yl)-6-(methylsulfanyl)pyridine [ka] To a stirred solution of 2,6-dichloro-4-(3-methoxyazetidin-1-yl)pyridine (1.2 g, 5.15 mmol) in DMF (10 mL) was added CHClSNa (900.94 mg, 12.87 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 h. Upon completion of the reaction, water was added and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (2×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the crude product (1.2 g), which was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + = 245.

[0251] Step 3: Synthesis of 2-chloro-6-methanesulfonyl-4-(3-methoxyazetidin-1-yl)pyridine [ka] To a stirred solution of 2-chloro-4-(3-methoxyazetidin-1-yl)-6-(methylsulfanyl)pyridine (1.2 g, 4.90 mmol) and RuCl3.HO (33.16 mg, 0.15 mmol) in THF (10 mL) and HO (10 mL) was added NaIO4 (2.1 g, 9.81 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (EtOAc / PE = 50%) to give the product (806.4 mg, 59% yield). 1 H NMR (300 MHz, chloroform-d) δ 6.96 (s, 1H), 6.35 (s, 1H), 4.48-4.37 (m, 1H), 4.30-4.20 (m, 2H), 3.99-3.90 (m, 2H), 3.38 (s, 3H), 3.21 (s, 3H). LCMS (ESI) m / e [M+1] + = 277.

[0252] Example BB64: Synthesis of 2-chloro-6-methanesulfonyl-4-(4-methoxypiperidin-1-yl)pyridine [ka] Step 1: Synthesis of 2,6-dichloro-4-(4-methoxypiperidin-1-yl)pyridine [ka] To a stirred mixture of 2,6-dichloro-4-iodopyridine (3.0 g, 10.95 mmol), 4-methoxypiperidine (1.51 g, 13.14 mmol), Xantphos (633.80 mg, 1.09 mmol), and CsCO (7.14 g, 21.91 mmol) in 1,4-dioxane (30 mL) was added Pd(dba) (501.53 mg, 0.55 mmol) at room temperature. The resulting mixture was stirred at 100 °C under a N atmosphere for 3 h. After cooling to room temperature, the resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (25% EtOAc / PE) to give the product (1.3 g, 45% yield). LCMS(ESI)m / e[M+1] + = 261.

[0253] Step 2: Synthesis of 2-chloro-4-(4-methoxypiperidin-1-yl)-6-(methylsulfanyl)pyridine [ka] To a stirred solution of 2,6-dichloro-4-(4-methoxypiperidin-1-yl)pyridine (1.3 g, 4.98 mmol) in DMF (10 mL) was added CHClSNa (522.69 mg, 7.47 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. Water was added, and the resulting mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (2×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give the crude product, which was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + = 273.

[0254] Step 3: Synthesis of 2-chloro-6-methanesulfonyl-4-(4-methoxypiperidin-1-yl)pyridine [ka] To a stirred solution of 2-chloro-4-(4-methoxypiperidin-1-yl)-6-(methylsulfanyl)pyridine (1.48 g, 5.42 mmol) and RuCl3.HO (36.69 mg, 0.16 mmol) in THF (15 mL) and HO (15 mL) was added NaIO4 (2.32 g, 10.85 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Upon completion of the reaction, the resulting mixture was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (EtOAc / PE = 50%) to give the product (613 mg, 37% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.36 (s, 1H), 6.75 (s, 1H), 3.70-3.62 (m, 2H), 3.59-3.50 (m, 1H), 3.40 (s, 3H), 3.40-3.31 (m, 2H), 3.22 (s, 3H), 1.98-1.88 (m, 2H), 1.84-1.69 (m, 2H). LCMS (ESI) m / e [M+1] + = 305.

[0255] Example BB65: Synthesis of 2-chloro-4-(1,4-dioxan-2-yl)-6-methanesulfonylpyridine, (R or S)-2-chloro-4-(1,4-dioxan-2-yl)-6-methanesulfonylpyridine [ka] Step 1: Synthesis of 2,6-dichloro-4-ethenylpyridine [ka] A 1000 mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere was charged with 2,6-dichloro-4-iodopyridine (20.00 g, 73.02 mmol), dioxane (200 mL), HO (100 mL), 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.50 g, 87.65 mmol), Pd(dppf)Cl (5.34 g, 7.30 mmol), and CsF (33.28 g, 219.07 mmol). The resulting solution was stirred at 90 °C for 2 h. The resulting solution was extracted with EtOAc (200 mL × 3). The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EtOAc / PE = 0.1%) to give the product (10.90 g, 86%). LCMS(ESI)m / e[M+1] + = 174.

[0256] Step 2: Synthesis of 1-(2,6-dichloropyridin-4-yl)ethane-1,2-diol [ka] A 500 mL round-bottom flask was charged with 2,6-dichloro-4-ethenylpyridine (10.90 g, 62.63 mmol), acetone (110 mL), HO (55 mL), NMO (8.07 g, 68.90 mmol), and OsO (7.95 mL, 1 g / mL, 313.20 mmol). The resulting solution was stirred at room temperature for 4 h. The reaction was then quenched by the addition of Florisil (500 mg). The resulting solution was extracted with EtOAc (3 × 100 mL). The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EtOAc / PE = 32%) to give the product (3.20 g, 24.56%). LCMS (ESI) m / e [M+1] + = 208.

[0257] Step 3: Synthesis of 2,6-dichloro-4-(1,4-dioxan-2-yl)pyridine [ka] A 1000 mL round-bottom flask was charged with 1-(2,6-dichloropyridin-4-yl)ethane-1,2-diol (3.00 g, 14.42 mmol), ethylene dichloride (250 mL), and TBAB (1.29 g, 4.00 mmol). To this was added NaOH (1 M aqueous solution, 50 mL) dropwise with stirring at 0 °C. The resulting solution was stirred in an oil bath at 35 °C for 48 hours. The resulting solution was extracted with EtOAc (3 × 150 mL). The resulting mixture was concentrated under vacuum. The residue was purified by Combiflash (EtOAc / PE = 7.90%) to give the product (1.45 g, 43%). LCMS (ESI) m / e [M+1] + = 234.

[0258] Step 4: Synthesis of 2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfanyl)pyridine [ka] A mixture of 2,6-dichloro-4-(1,4-dioxan-2-yl)pyridine (1.45 g, 6.19 mmol), DMF (17 mL), and (methylsulfanyl)sodium (0.52 g, 7.42 mmol) was stirred at room temperature overnight. Water was added, and the resulting solution was extracted with EtOAc (3 x 50 mL). The resulting mixture was concentrated in vacuo. The residue was purified by Combiflash (EtOAc / PE = 0.6% - 5.3%) to give the product (1.48 g, 97%). LCMS (ESI) m / e [M+1] + = 246.

[0259] Step 5: Synthesis of 2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridine and (R or S)-2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridine [ka] A 100 mL three-necked round-bottom flask was charged with 2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfanyl)pyridine (1.48 g, 6.02 mmol), THF (12 mL), and HO (12 mL). To this was added NaIO (3.86 g, 18.06 mmol) in small portions with stirring at 0 °C. To this was added RuCl·HO (0.20 g, 0.90 mmol) with stirring at 0 °C. The resulting solution was stirred at room temperature for 1 h. The resulting solution was extracted with EtOAc (3 × 50 mL), and the combined organic layers were concentrated in vacuo. The residue was purified by Combiflash (EtOAc / PE = 15-22%) to give the racemic product (1.10 g). The racemic product was purified by preparative SFC under the following conditions (column: CHIRALPAK AD-3, 3.0 × 50 mm, 3 μm, mobile phase B: MeOH (0.1% DEA), flow rate: 2 mL / min, gradient: isocratic 10% B, wavelength: 220 nm) to give the product.

[0260] First peak (434.90 mg, 26.00%, retention time 1:0.959 min): 1H NMR(300 MHz,DMSO-d6)δ 8.06(s,1H),7.90(s,1H),4.86-4.83(m,1H),4.15-3.92(m,2H),3.87-3.73(m,2H),3.61-3.59(m,1H),3.33(s,4H).LCMS(ESI)m / e[M+1] + = 278. Second peak (413.3 mg, 24.71%, retention time 2: 1.605 min): 1 H NMR(300 MHz,DMSO-d6)δ 8.05(s,1H),7.89(s,1H),4.85-4.82(m,J = 9.9 Hz,1H),4.14-3.92(m,2H),3.86-3.73(m,2H),3.60-3.57(m,1H),3.33-3.25(m,4H).LCMS(ESI)m / e[M+1] + = 278.

[0261] Example BB66: Synthesis of 1-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4-methylpiperidin-4-ol [ka] Step 1: 1-(2,6-dibromopyridin-4-yl)-4-methylpiperidin-4-ol [ka] To a solution of 2,6-dibromo-4-nitropyridine (2.0 g, 7.1 mmol) in DMSO (30 mL) was added KCO (2.0 g, 14.2 mmol) and 4-methylpiperidin-4-ol (899 mg, 7.8 mmol) under N at 0 °C. The mixture was stirred under N at 25 °C for 2 h. The mixture was poured into water (20 mL) and extracted with EtOAc (30 mL, 20 mL). The combined organic phase was washed with brine (50 mL, 30 mL), dried over NaSO, filtered, and concentrated to give a residue that was purified by column chromatography (SiO, PE / EA = 100 / 1 - 0 / 1). The product compound 1-(2,6-dibromopyridin-4-yl)-4-methylpiperidin-4-ol was obtained as a gray solid (1.4 g, 56% yield). LCMS(ESI)m / e[M+1] + = 350.8.

[0262] Step 2: 1-(2-bromo-6-(methylthio)pyridin-4-yl)-4-methylpiperidin-4-ol [ka] To a solution of 1-(2,6-dibromopyridin-4-yl)-4-methylpiperidin-4-ol (1.4 g, 4.0 mmol) in DMF (20 mL) was added sodium methanethiolate (336 mg, 4.8 mmol) under N at 0 °C. The reaction mixture was stirred under N at 25 °C for 3 hours. The mixture was poured into water (10 mL) and extracted with EtOAc (30 mL, 20 mL). The combined organic phase was washed with brine (30 mL, 20 mL), dried over Na SO , filtered, and concentrated to give a residue. The crude product was purified by column chromatography (SiO , PE:EA=100 / 1-0 / 1). The compound 1-(2-bromo-6-(methylthio)pyridin-4-yl)-4-methylpiperidin-4-ol (1.4 g, 95% yield) was obtained as a pale yellow solid. LCMS(ESI)m / e[M+1] + = 319.

[0263] Step 3: 1-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4-methylpiperidin-4-ol [ka] To a solution of 1-(2-bromo-6-(methylthio)pyridin-4-yl)-4-methylpiperidin-4-ol (1.1 g, 8.7 mmol) in HO / MeOH (1 / 1, 30 mL) was added Oxone (4.3 g, 6.9 mmol) under N at 25 °C. The reaction mixture was stirred under N at 25 °C for 5 h. The mixture was filtered to give a filtrate, which was poured into aqueous NaSO (20 mL) and extracted with EtOAc (30 mL, 20 mL). The combined organic phases were washed with brine (10 mL), dried over NaSO, filtered, and concentrated to give a residue. The crude was purified by column chromatography (SiO, PE:EA = 100 / 1 - 0 / 1). The compound 1-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4-methylpiperidin-4-ol (412 mg, 34% yield) was obtained as a white solid. 1 H NMR(DMSO)δ 7.30-7.31(d,J = 2.4,1H)7.21-7.22(d,J = 2.0,1H)4.48(s,1H)3.5-3.7(m,2H)3.31-3.34(m,2H)3.21(s,3H)1.51-1.52(m,4H)1.14(s,3H).LCMS(ESI)m / e[M+1] + = 349.

[0264] Example BB67: Synthesis of 2-chloro-4-((trans)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine and 2-chloro-4-((cis)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine [ka] Step 1: Synthesis of 3-hydroxycyclobutane-1-carbonitrile [ka] Under a nitrogen atmosphere, a solution of 3-oxocyclobutane-1-carbonitrile (5 g, 52.57 mmol) in MeOH was treated with NaBH (2.98 g, 78.86 mmol) at room temperature for 2 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0265] Step 2: Synthesis of 3-(benzyloxy)cyclobutane-1-carbonitrile [ka] To a solution of 3-hydroxycyclobutane-1-carbonitrile (3.90 g, 40.15 mmol) in DMF (40 mL) was added NaH (2.01 g, 52.20 mmol, 60 wt%) at 0 °C. The mixture was stirred for 15 min. BnBr (8.24 g, 48.18 mmol) was added, and the mixture was allowed to warm to room temperature and stirred at room temperature for 2 h. The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (3 × 40 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (EtOAc / PE = 0-20%) to give the product (7.01 g, 93% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.43-7.34 (m, 2H), 7.34 (m, 3H), 4.45 (s, 2H), 4.01 (m, 1H), 2.74-2.63 (m, 2H), 2.67-2.56 (m, 1H), 2.49-2.38 (m, 1H), 2.38 (m, 1H).

[0266] Step 3: Synthesis of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carbonitrile [ka] To a stirred mixture of 2,4,6-trichloropyridine (3 g, 16.44 mmol) and 3-(benzyloxy)cyclobutane-1-carbonitrile (3.08 g, 16.44 mmol) in THF (60 mL) was added LiHMDS (23.02 mL, 23.02 mmol, 1 M THF solution) dropwise in small portions at −10° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was quenched with water / ice at 0° C., and the resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with water (3×60 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (EtOAc / PE=0-20%) to give the product (4.5 g, 82% yield). LCMS (ESI) m / e [M+1] + = 333.

[0267] Step 4: Synthesis of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carboxylic acid [ka] A solution of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carbonitrile (4.50 g, 13.50 mmol) in HO (50 mL) was treated with KOH (2.27 g, 40.51 mmol) at 105 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + = 352.

[0268] Step 5: Synthesis of 4-[3-(benzyloxy)cyclobutyl]-2,6-dichloropyridine [ka] A solution of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carboxylic acid (4.50 g, 12.77 mmol) in pyridine (40 mL) was treated with Py-HCl (1.47 g, 12.77 mmol) at 90 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (EtOAc / PE = 0-40%) to give the product (2.2 g, 55% yield). LCMS (ESI) m / e [M+1] + = 308.

[0269] Step 6: Synthesis of 3-(2,6-dichloropyridin-4-yl)cyclobutan-1-ol [ka] A solution of 4-[3-(benzyloxy)cyclobutyl]-2,6-dichloropyridine (2.20 g, 7.13 mmol) in HCl (12 N) (20 mL) was stirred at 50° C. for 2 hours. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (PE / EtOAc=50%) to give the product (880 mg, 56% yield). LCMS (ESI) m / e [M+1] + = 218.

[0270] Step 7: Synthesis of 2,6-dichloro-4-(3-methoxycyclobutyl)pyridine [ka] To a solution of 3-(2,6-dichloropyridin-4-yl)cyclobutan-1-ol (830 mg, 3.80 mmol) in DMF was added NaH (182 mg, 4.56 mmol, 60 wt%) at 0 °C. The mixture was stirred at this temperature for 15 min, after which CHI (810 mg, 5.70 mmol) was added and the mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc = 5:1) to give the product (520 mg, 58% yield). LCMS (ESI) m / e [M+1] + = 232.

[0271] Step 8: Synthesis of 2-chloro-4-(3-methoxycyclobutyl)-6-(methylsulfanyl)pyridine [ka] A mixture of 2,6-dichloro-4-(3-methoxycyclobutyl)pyridine (520 mg, 2.24 mmol) and (methylsulfanyl)sodium (235 mg, 3.36 mmol) in DMF (6 mL) was stirred at room temperature for 2 hours. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + = 244.

[0272] Step 9: Synthesis of 2-chloro-6-methanesulfonyl-4-(3-methoxycyclobutyl)pyridine, 2-chloro-4-((trans)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine, 2-chloro-4-((cis)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine [ka] Under a nitrogen atmosphere, a solution of 2-chloro-4-(3-methoxycyclobutyl)-6-(methylsulfanyl)pyridine (520 mg, 2.13 mmol) in THF (10 mL) was treated with NaIO (912.61 mg, 4.26 mmol) at 0 °C for 2 h, followed by the dropwise addition of RuCl.HO (24.05 mg, 0.10 mmol) in HO (5 mL) in small portions at 0 °C. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (3 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc = 3:1) to give the product (268 mg, 45% yield). 1 H NMR(400 MHz,DMSO-d6)δ 7.92-7.81(s,1H),7.77(s,1H),3.88(tt,J = 7.7,6.6 Hz,1H),3.30(s,3H),3.34-3.20(m,1H),3.17(s,3H),2.70(m,2H),1.98(m,2H).LCMS(ESI)m / e[M+1] + = 276.

[0273] The racemic compound was separated by ACHIRAL-SFC (column: DAICEL DCpak P4VP, 3 × 25 cm, 5 μm, mobile phase A: CO, mobile phase B: IPA (0.5% 2M NH-MeOH), flow rate: 60 mL / min, gradient: isocratic 15% B, column temperature: 35 °C, back pressure: 100 bar, wavelength: 254 nm) to give the trans product (179 mg, retention time 1:4.78 min). 1 H NMR(300 MHz,DMSO-d6)δ 7.94-7.88(m,1H),7.84(s,1H),4.12-3.98(m,1H),3.76(p,J = 7.9 Hz,1H),3.31(s,3H),3.19(s,3H),2.51-2.33(m,4H).LCMS(ESI)m / e[M+1] + = 276.

[0274] Cis product (1.31 g, retention time 2:5.28 min): 1H NMR(300 MHz,DMSO-d6)δ 7.91-7.86(m,1H),7.86-7.74(m,1H),3.97-3.81(m,1H),3.31(s,3H),3.32-3 .20(m,1H),3.18(s,3H),2.71(m,2H),2.08-1.90(m,2H).LCMS(ESI)m / e[M+1] + = 276.

[0275] Example A1: Synthesis of N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide [ka] Step 1: 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine [ka] A mixture of 5-bromo-4-chloropyridin-2-amine (1.0 g, 4.8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.3 g, 5.3 mmol), KOAc (1.4 g, 14.5 mmol), and Pd(dppf)Cl-CHCl (197 mg, 0.2 mmol) in 1,4-dioxane (20 mL) was stirred at 115 °C for 6 h under N. After cooling to room temperature, the mixture was diluted with HO (30 mL), and the resulting solution was extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EA = 1:1 to 0:1) to give 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.5 g, crude). MS (ESI) m / e [M+1] + 173.

[0276] Step 2: 4-chloro-5-(pyridazin-3-yl)pyridin-2-amine [ka] A mixture of 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (478 mg, 1.9 mmol), 3-bromopyridazine (100 mg, 0.6 mmol), NaCO (133 mg, 1.3 mmol), and Pd(dppf)Cl (44 mg, 0.06 mmol) in CHCN (10 mL) and HO (2 mL) was stirred at 120 °C for 10 min in a microwave reactor. After cooling to room temperature, the mixture was diluted with HO (20 mL), and the resulting solution was extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EA=1:1-0:1) to give 4-chloro-5-(pyridazin-3-yl)pyridin-2-amine (51 mg, 39.4%). MS (ESI) m / e [M+1] + 207.

[0277] Step 3: N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide [ka] To a solution of N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide (40 mg, 0.2 mmol) in pyridine (2 mL) was added acetyl chloride (17 mg, 0.2 mmol) dropwise at 0° C., and the mixture was then stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated and the residue was diluted with water (5 mL). The mixture was then extracted with EA (10 mL×3) and citric acid (10 mL), dried over anhydrous NaSO, and concentrated in vacuo to give N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide (45 mg, 93%). (ESI) m / e [M+1] + 249.

[0278] Step 4: N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide [ka] A mixture of N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide (20.0 mg, 0.08 mmol), 3-(methylsulfonyl)aniline (27.0 mg, 0.16 mmol), CsCO (78 mg, 0.24 mmol), Xantphos (5 mg, 8 μmol), and Pd(dba) (7 mg, 8 μmol) in 1,4-dioxane (2 mL) was stirred at 110 °C for 12 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with HO (20 mL), and the resulting solution was extracted with EA (30 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The crude product was purified by preparative HPLC (Column: Phenomenex Gemini-NX 150 × 30 mm × 5 um, Phase: A - HO (10 mM NHHCO), B - ACN, B%: 15%-35% over 20 min) to give N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide (1.8 mg, 6%). 1 H NMR(400 MHz,MeOD-d4)δ 9.32(d,J = 4.4 Hz,1H),8.59(s,1H),8.36(d,J = 8.8 Hz,1H),8.05(s,1H),8.03-7.96(m,2H),7.86-7.78(m,2H),6.70(s,1H),3.20(s,3H),2.24(s,3H).MS(ESI)m / e[M+1] + 384.

[0279] Example A2: Synthesis of N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolan-2-yl)pyridin-2-yl]acetamide [ka] Step 1: 5-Bromo-2-chloro-N-(3-methanesulfonylphenyl)pyridin-4-amine [ka] A mixture of 5-bromo-2-chloro-4-iodopyridine (3.00 g, 9.42 mmol), CsCO (6.14 g, 18.848 mmol), Xantphos (1.09 g, 1.88 mmol), 3-methanesulfonylaniline (1.77 g, 10.37 mmol), and Pd(dba) (0.86 g, 0.942 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 100 °C under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with HO (20 mL), and the resulting solution was extracted with EA (80 mL × 3). The resulting mixture was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The resulting mixture was concentrated in vacuo and the residue was purified by Combiflash (EA / PE=0-15%) to give 5-bromo-2-chloro-N-(3-methanesulfonylphenyl)pyridin-4-amine (1.6 g, 46.95% yield). LCMS (ESI) m / e [M+1] + 362.

[0280] Step 2: 5-Bromo-N 2 -(4-Methoxybenzyl)-N 4 -(3-(methylsulfonyl)phenyl)pyridine-2,4-diamine [ka] A 20 mL sealed tube was charged with 5-bromo-2-chloro-N-(3-methanesulfonylphenyl)pyridin-4-amine (1.5 g, 4.148 mmol) and PMBNH (5 mL). The resulting solution was stirred at 135 °C overnight. After cooling to room temperature, the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX, phase: A - H O (0.05% TFA), B - acetonitrile, B%: 40%-60% over 20 min) to give 5-bromo-N-(4-methoxybenzyl)-N-(3-(methylsulfonyl)phenyl)pyridine-2,4-diamine (600 mg, 31%). LCMS (ESI) m / e [M+1] + 462.

[0281] Step 3: 5-(furan-2-yl)-N 4 -(3-methanesulfonylphenyl)-N 2 -[(4-methoxyphenyl)methyl]pyridine-2,4-diamine [ka] A mixture of 5-bromo-N-(3-methanesulfonylphenyl)-N-[(4-methoxyphenyl)methyl]pyridine-2,4-diamine (420 mg, 0.91 mmol), KCO (251 mg, 1.82 mmol), furan-2-ylboronic acid (152 mg, 1.36 mmol), and Pd(PPh) (105 mg, 0.091 mmol) in 1,4-dioxane (4.00 mL) and HO (0.80 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with HO (20 mL), and the resulting solution was extracted with EA (80 mL × 3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. The resulting mixture was concentrated in vacuo and the residue was purified by preparative TLC (MeOH / DCM=1:15) to give 5-(furan-2-yl)-N 4 -(3-methanesulfonylphenyl)-N 2 -[(4-Methoxyphenyl)methyl]pyridine-2,4-diamine was obtained (270 mg, 66%). LCMS (ESI) m / e [M+1] + 450.

[0282] Step 4:N 2 -(4-Methoxybenzyl)-N4-(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine [ka] A 20 mL pressure tank reactor was charged with 5-(furan-2-yl)-N-(3-methanesulfonylphenyl)-N-[(4-methoxyphenyl)methyl]pyridine-2,4-diamine (270 mg, 0.60 mmol), i-PrOH (5 mL), hydrochloric acid (12 M, 0.05 mL), and Pd(OH) / C (10%, 168 mg), and the resulting solution was stirred overnight at 65° C. under a hydrogen atmosphere (10 atm). After cooling to room temperature, the mixture was diluted with HO (20 mL), and the resulting solution was extracted with EA (50 mL×3). The reaction mixture was cooled to room temperature in a water bath. The resulting solution was extracted with EA (50 mL×3), and the organic layers were combined. The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. The resulting mixture was concentrated in vacuo, and the residue was purified by preparative TLC (MeOH / DCM=1:12) to give N 2 -(4-Methoxybenzyl)-N 4 -(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine was obtained (80 mg, 29%). LCMS (ESI) m / e [M+1] + 454.

[0283] Step 5:N 4 -(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine [ka] N 4 -(3-methanesulfonylphenyl)-N 2 A mixture of -[(4-methoxyphenyl)methyl]-5-(oxolan-2-yl)pyridine-2,4-diamine (80 mg) and TFA (2 mL) was stirred at 70° C. for 1 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX, phase: A - HO (0.05% TFA), B - acetonitrile, B%: 13%-20% over 20 min) to give N 4-(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine was obtained (50 mg, 85%). LCMS (ESI) m / e [M+1] + 334.

[0284] Step 6: N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolan-2-yl)pyridin-2-yl]acetamide [ka] A mixture of N4-(3-methanesulfonylphenyl)-5-(oxolan-2-yl)-1,6-dihydropyridine-2,4-diamine (50 mg, 0.15 mmol), pyridine (1 mL), and acetic anhydride (12 mg, 0.12 mmol) was stirred at 80 °C for 1 h. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL × 3), and the combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX, phase: A - HO (0.1% FA), B - acetonitrile, B%: 35%-55% over 8 min) to give N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolan-2-yl)pyridin-2-yl]acetamide (1.8 mg, 3%). 1 H NMR(400 MHz,DMSO-d6)δ 10.34(s,1H),8.20(d,J = 6.7 Hz,1H),8.11(s,1H),8.00(s,1H),7.73(s,1H),7.60(d,J = 8.9 Hz,1H),7.58-7.50(m,2H),5.08-5.03(m,1H),4.10-4.05(m,1H),3.82-3.78(m,1H),3.35(s, 3H),2.38-2.34(m,1H),2.03(s,3H),2.00-1.95(m,2H),1.78-1.72(m,1H).MS(ES,m / z):[M+H] + 376.

[0285] Example A3: Synthesis of N-(5-(1H-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide [ka] Step 1: 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole [ka] To a solution of 5-iodo-1H-imidazole (2 g, 10.3 mmol) in THF (15 mL) was added NaH (60% in mineral oil, 454 mg, 11.3 mmol) in small portions at 0° C. The resulting mixture was stirred at 0° C. for 30 min. Then, a solution of (2-(chloromethoxy)ethyl)trimethylsilane (1.72 g, 10.8 mmol) in THF (5 mL) was added dropwise with stirring at 0° C. The reaction was allowed to warm to room temperature with stirring for 1 h. The reaction was quenched with saturated NH4Cl at 0° C. and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give a residue, which was purified on a silica gel column with EA / DCM (1:1) to give a mixture of 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (2.66 g, 79.6%). MS (ESI) m / e [M+1] + 325.

[0286] Step 2: 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-amine and 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-amine [ka] A mixture of 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-amine and 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-amine (966 mg, 4.98 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (1.39 g, 5.48 mmol), Pd(dppf)Cl (182 mg, 0.25 mmol), and KCO (1.37 g, 9.96 mmol) in 1,4-dioxane (18 mL) and HO (3 mL) was charged with nitrogen, heated to 90 °C, and stirred for 1 h. The reaction mixture was cooled to room temperature, diluted with EA, washed with brine, dried and concentrated. The residue was applied to a silica gel column with EA / PE (1:2) to give the product (862 mg, 89.2%). MS (ESI) m / e [M+1] + 325.

[0287] Step 3: N-(2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine and N-(2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine [ka] A mixture of 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-amine and 2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-amine (412 mg, 1.27 mmol), 2-bromo-6-(methylsulfonyl)pyridine (358 mg, 1.5 mmol), Pd2dba3 (58 mg, 0.06 mmol), BINAP (118 mg, 0.19 mmol), and Cs2CO3 (829 mg, 2.5 mmol) in 1,4-dioxane (10 mL) was heated to 130 °C and stirred at this temperature for 3 h under a nitrogen atmosphere. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was subjected to preparative TLC with DCM / MeOH (30:1) to give the product (139 mg, 22.9%). MS (ESI) m / e [M+1] + 480.

[0288] Step 4: N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-2-yl)acetamide and N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide [ka] A mixture of N-(2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine and N-(2-chloro-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine (139 mg, 0.29 mmol), acetamide (51 mg, 0.87 mmol), Pd2dba3 (26.6 mg, 0.03 mmol), Xantphos (50 mg, 0.09 mmol), and Cs2CO3 (189 mg, 0.58 mmol) in 1,4-dioxane (4 mL) was heated at 130 °C for 3 h under a nitrogen atmosphere. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was applied to a silica gel column with DCM / MeOH (25:1) to give the product (94 mg, 64.5%). MS (ESI) m / e [M+1] + 502.

[0289] Step 5: N-(5-(1H-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide [ka] A solution of N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridin-2-yl)acetamide and N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyridin-2-yl)acetamide (94 mg, 0.19 mmol) in TFA (5 mL) was heated to 50 °C and stirred for 1 h. Then, TFA was removed in vacuo and the residue was treated with NH3MeOH solution (4 mL, 7 M). The solvent was removed in vacuo and the residue was purified by CH3CN / water to C 18Application to the column gave N-(5-(1H-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide (31.04 mg, 43.9%). 1 H NMR(400 MHz,DMSO-d6)δ 12.71(s,1H),12.67(s,1H),10.38(s,1H),9.21(s,1H),8.63(s,1H),8.04-7.93(m,2H),7.88(s,1H),7.54(d,J = 8.2 Hz,1H),7.23(d,J = 8.2 Hz,1H),3.49(s,3H),2.10(s,3H).MS(ESI)m / e[M+1] + 373.

[0290] Example A25: Synthesis of N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide [ka] A mixture of N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide (50 mg, 0.19 mmol), 2-bromo-4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridine (71 mg, 0.23 mmol), Pd(dba) (17 mg, 0.019 mmol), BINAP (12 mg, 0.019 mmol), and CsCO (186 mg, 0.57 mmol) in dioxane (5 mL) was stirred at 120 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (MeOH / DCM = 0-10%) to give the product (0.84 mg, 22%). 1H NMR(400 MHz,DMSO-d6)δ 11.39(s,1H),10.58(s,1H),8.96(s,1H),8.65(s,1H),8.25(d,J = 8.0 Hz,1H),7.41(d,J = 8.0 Hz,1H),7.10(s,1H),6.82(s,1H),4.11(s,3H),4.06-4.02(m,2H),3.37(s,3H),2.1 2(s,3H),1.26-1.24(m,1H),0.61-0.60(m,2H),0.38-0.37(m,2H).MS(ESI)m / e[M+1] + 485.

[0291] Example A26: Synthesis of N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide [ka] A mixture of N-(4-amino-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide (50 mg, 0.19 mmol), 2-bromo-4-isopropoxy-6-(methylsulfonyl)pyridine (67 mg, 0.23 mmol), Pd(dba) (17 mg, 0.019 mmol), BINAP (12 mg, 0.019 mmol), and CsCO (186 mg, 0.57 mmol) in dioxane (5 mL) was stirred at 120 °C for 16 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (MeOH / DCM = 0-10%) to give the product (4.20 mg, 4%). 1H NMR(400 MHz,DMSO-d6)δ 11.25(s,1H),10.52(s,1H),8.91(s,1H),8.59(s,1H),8.19(d,J = 8.0 Hz,1H),7.36(d,J = 8.0 Hz,1H),7.02(s,1H),6.74(s,1H),4.95-4.66(m,1H),4.07(s,3H),3.32(s,3H),2.07(s,3H),1.28(d,J = 4.0 Hz,6H).MS(ESI)m / e[M+1] + 473.

[0292] The following examples were prepared in a similar manner to the product of Example A3. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9]

[0293] Example B1: Synthesis of N-(4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] Step 1: tert-Butyl (5-bromo-2-chloropyridin-4-yl)carbamate [ka] To a mixture of 5-bromo-2-chloropyridin-4-amine (30 g, 144.6 mmol), DMAP (1.8 g, 14.4 mmol), and TEA (43.9 g, 434.0 mmol) in DCM (300 mL) was added BocO (38.0 g, 173.0 mmol) dropwise at room temperature, and the resulting mixture was stirred at this temperature for 12 hours. Upon completion of the reaction, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (PE / EA=20:1-5:1) to give tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (40.0 g, 90.2% yield). 1 H NMR(400 MHz,CDCl3)δ 8.35(s,1H),8.25(s,1H),7.19(s,1H),1.56(s,9H).MS(ESI)m / e[M+1] + 307.

[0294] Step 2: tert-Butyl (6'-chloro-[2,3'-bipyridin]-4'-yl)carbamate [ka] A mixture of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (5.0 g, 16.3 mmol), 2-bromopyridine (2.8 g, 17.9 mmol), Pd(PPh)Cl (1.1 g, 1.6 mmol), Pd(PPh) (1.9 g, 1.6 mmol), and SnMe (8.0 g, 24.0 mmol) in dioxane (50 mL) was stirred at 110 °C for 12 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with KF-HO (50 mL) and extracted with EA (50 mL × 3). The combined organic layer was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=20:1-10:1) to give tert-butyl (6'-chloro-[2,3'-bipyridin]-4'-yl)carbamate (880 mg, 18.0%). MS (ESI) m / e [M+1] + 306.

[0295] Step 3: tert-Butyl (6'-acetamido-[2,3'-bipyridin]-4'-yl)carbamate [ka] A mixture of tert-butyl (6'-chloro-[2,3'-bipyridin]-4'-yl)carbamate (2.0 g, 6.5 mmol), acetamide (773 mg, 13.1 mmol), CsCO (6.3 g, 19.5 mmol), Xant-Phos (753 mg, 1.3 mmol), and Pd(dba) (595 mg, 0.65 mmol) in dioxane (20 mL) was stirred at 110 °C for 12 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL × 3), and the combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (PE / EA=3:1-1:1) to give tert-butyl (6'-acetamido-[2,3'-bipyridin]-4'-yl)carbamate (1.3 g, 61.0%). 1H NMR(400 MHz,DMSO-d6)δ 12.02(s,1H),10.50(s,1H),8.98(s,1H),8.73(s,1H),8.68-8.63(m,1H),8.10-8.05(m ,1H),7.98(m,1H),7.45-7.40(m,1H),2.11(s,3H),1.50-1.47(m,9H).MS(ESI)m / e[M+1] + 329.

[0296] Step 4: N-(4'-amino-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of tert-butyl (6'-acetamido-[2,3'-bipyridin]-4'-yl)carbamate (4.0 g, 12.2 mmol) in TFA (20 mL) and DCM (20 mL) was stirred at room temperature for 3 hours. Upon completion of the reaction, the solvent was removed in vacuo, and the residue was diluted with water. NaHCO3 (40 mL) was added to adjust the pH to 9, and the resulting solution was extracted with EA (40 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give N-(4'-amino-[2,3'-bipyridin]-6'-yl)acetamide (2.7 g, 97.1%). 1 H NMR(400 MHz,DMSO-d6)δ 10.35(s,1H),8.60(d,J = 4.9 Hz,1H),8.42(s,1H),7.90-7.86(m,2H),7.38(s,1H),6.88(s,2H),7.33-7.28(m,1H),2.09(s,3H).MS(ESI)m / e[M+1] + 229.

[0297] Step 5: N-(4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-[2,3'-bipyridin]-6'-yl)acetamide (120 mg, 0.53 mmol), 1-bromo-3-(methylsulfonyl)benzene (120 mg, 0.5 mmol), Pd2dba3 (80 mg, 0.09 mmol), Xant-Phos (60 mg, 0.1 mmol), and Cs2CO3 (300 mg, 0.92 mmol) in dioxane (6 mL) was placed in a sealed tube and stirred at 130 °C for 3 h under N2. The reaction mixture was filtered, and the solid was washed with EA (10 mL). The filtrate was concentrated, and the residue was purified by preparative TLC (DCM / MeOH = 20:1) to give N-(4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide (24 mg, 12%). 1 H NMR(400 MHz,DMSO-d6)δ 11.52(s,1H),10.50(s,1H),8.74-8.66(m,2H),8.18(s,1H),8.07(d,J = 8.2 Hz,1H),7.99-7.90(m,1H),7.83(s,1H),7.67-7.57(m,3H),7.45-7.37(m,1H),3.29(s,3H),2.07(s,3H).MS(ESI)m / e[M+1] + 383.

[0298] The following examples were prepared in a similar manner to the product of Example B1. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14]

[0299] Example C1: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] Step 1: (cis)-4-(6-bromopyridin-3-yl)-2,6-dimethylmorpholine [ka] A mixture of 2-bromo-5-iodopyridine (20 g, 70.4 mmol), (cis)-2,6-dimethylmorpholine (8.9 g, 77.5 mmol, 1.1 equiv.), Pd2(dba)3 (3.22 g, 3.52 mmol, 0.05 equiv.), Xant-Phos (2 g, 3.52 mmol, 0.05 equiv.), and t-BuONa (13.5 g, 140.8 mmol, 2 equiv.) in toluene (300 mL) was stirred at 80 °C under N2 for 2 h. The reaction mixture was cooled and filtered, the filtrate was concentrated, and the residue was purified by column chromatography (PE:EA = 20:1-10:1) to give the product as a brown solid (16 g, 84%). MS (ESI) m / e [M+1] + =271.

[0300] Step 2: 6'-chloro-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridine]-4'-amine [ka] To a solution of cis-4-(6-bromopyridin-3-yl)-2,6-dimethylmorpholine (13.6 g, 50.4 mmol) in dioxane / HO (400 mL / 100 mL), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (15.4, 60.4 mmol), Pd(dppf)Cl (3.7 g, 5.04 mmol), and KCO (10.4 g, 75.6 mmol) were added, and the resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (500 mL). The resulting solution was extracted with EA (500 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by Combiflash (MeOH / DCM=0-5%) to give 6'-chloro-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridine]-4'-amine (18 g, crude). MS(ESI) m / e [M+1] + 319.

[0301] Step 3: N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] To a solution of 6'-chloro-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridine]-4'-amine (18 g, 56.6 mmol) in 1,4-dioxane (250 mL), acetamide (16.7 g, 283 mmol), Pd2(dba)3 (5.2 g, 5.7 mmol), XantPhos (6.6 g, 11.4 mmol), and Cs2CO3 (37.2 g, 114 mmol) were added, and the resulting mixture was stirred at 130 °C for 4 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL × 3), and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by Combiflash (MeOH / DCM = 0-7%) to give N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (12.54 g, 65% yield). MS(ESI) m / e [M+1] + 342.

[0302] Step 4: N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (50 mg, 0.17 mmol), 2-bromo-4-methyl-6-(methylsulfonyl)pyridine (52 mg, 0.21 mmol), Pd2dba3 (16 mg, 0.017 mmol), BINAP (11 mg, 0.017 mmol), and Cs2CO3 (111 mg, 0.34 mmol) in dioxane (10 mL) was stirred at 130 °C for 4 h. The mixture was filtered, and the filtrate was concentrated to give a residue, which was purified by preparative TLC (MeOH / DCM=1:20) to give N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide (38 mg, 51% yield). 1 H NMR(400 MHz,DMSO-d6)δ 13.13(s,1H),10.45(s,1H),9.23(s,1H),8.72(s,1H),8.51(s,1H),8.00(d,J = 8.7 Hz,1H),7.58(d,J = 8.7 Hz,1H),7.42(s,1H),7.20(s,1H),3.80-3.74(m,4H),3.46(s,3H),2.45-2.40(m,2H),2.35(s,3H),2.11(s,3H),1.20(d,J = 6.0 Hz,6H).MS(ESI)m / e[M+1] + 511.

[0303] Example C9: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (1.20 g, 3.52 mmol), 2-bromo-4-methoxy-6-(methylsulfonyl)pyridine (1.15 g, 4.22 mmol), Pd(dba) (320 mg, 0.35 mmol), BINAP (218 mg, 0.35 mmol), and CsCO (2.28 g, 7.04 mmol) in 1,4-dioxane (50 mL) was stirred at 130 °C for 4 h under a nitrogen atmosphere. The reaction mixture was filtered off, the filtrate was concentrated, and the residue was purified by Combiflash (MeOH / DCM=7:93) to give the crude product as a brown oil, which was then slurried with ACN (50 mL) at room temperature for 30 minutes, filtered to give the solid, and dried in a vacuum drying oven to give the product (1.3 g, 70% yield). 1 H NMR(400 MHz,DMSO-d6)δ 12.83(s,1H),10.46(s,1H),9.11(s,1H),8.69(s,1H),8.50(s,1H),7.96(d,J = 9.1 Hz,1H),7.57(d,J = 9.1 Hz,1H),7.11(s,1H),6.84(s,1H),3.97(s,3H),3.79-3.73(m,4H),3.44(s,3H),2.40(t,J = 11.0 Hz,2H),2.11(s,3H),1.19(d,J = 6.0 Hz,6H).MS(ESI)m / e[M+1] + 527.

[0304] Example C17: Synthesis of N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (2.1 g, 6.16 mmol), 2-bromo-4-(methoxy-d)-6-(methylsulfonyl)pyridine (2.0 g, 7.39 mmol), Pd(dba) (568 mg, 0.62 mmol), BINAP (386 mg, 0.62 mmol), and CsCO (4.02 g, 12.32 mmol) in 1,4-dioxane (75 mL) was stirred under N at 130 °C for 4 h. The solids were filtered off, the filtrate was concentrated, and the residue was purified by preparative TLC (MeOH / DCM = 1:20) to give the product (2.03 g, 62% yield). 1 H NMR(400 MHz,DMSO-d6)δ 12.82(s,1H),10.46(s,1H),9.11(s,1H),8.69(s,1H),8.50(s,1H),7.96(d,J = 9.1 Hz,1H),7.55(s,1H),7.11(s,1H),6.84(s,1H),3.79-3.76(m,4H),3.44(s,3H),2.43-2.37(m,2H),2.11(s,3H),1.19(d,J = 5.3 Hz,6H).MS(ESI)m / e[M+1] + 530.

[0305] Example C18: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (60 mg, 0.17 mmol), 2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine (62 mg, 0.21 mmol), Pd2dba3 (16 mg, 0.02 mmol), BINAP (11 mg, 0.02 mmol), and Cs2CO3 (111 mg, 0.34 mmol) in 1,4-dioxane (10 mL) was stirred at 130 °C for 4 h under a nitrogen atmosphere. The solids were filtered off, the filtrate was concentrated, and the residue was purified by preparative TLC (MeOH / DCM = 1:20) to give the product as a yellow solid (40.56 mg, 42% yield). 1 H NMR(400 MHz,DMSO-d6)δ 12.99(s,1H),10.46(s,1H),9.21(s,1H),8.71(s,1H),8.49(s,1H),7.98(d,J = 9.0 Hz,1H),7.57(d,J = 9.2 Hz,1H),7.48(s,1H),7.25(s,1H),4.50-4.49(m,1H),3.77-3.74(m,4H),3.48(s,3H),3.23(s,3H),2.41(t,J = 11.1 Hz,2H),2.11(s,3H),1.39(d,J = 6.5 Hz,3H),1.20(d,J = 6.0 Hz, 6H).MS(ESI) m / e[M+1] + =555.

[0306] Example C19: Synthesis of N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-((R or S)-1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-((cis)-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (50 mg, 0.147 mmol), (R or S)-2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine (44 mg, 0.176 mmol) (the earlier peak from Example BB60, Step 5), Pd(dba) (13 mg, 0.0147 mmol), BINAP (18 mg, 0.0294 mmol), and CsCO (72 mg, 0.221 mmol) in 1,4-dioxane (6 mL) was stirred at 130 °C under a nitrogen atmosphere for 4 hours. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=20:1) to give the product (33 mg, 40%). 1 H NMR(400 MHz,DMSO-d6)δ 13.01(s,1H),10.49(s,1H),9.21(s,1H),8.71(s,1H),8.50(s,1H),7.99(d,J = 8.9 Hz,1H),7.58(d,J = 8.9 Hz,1H),7.49(s,1H),7.26(s,1H),4.53-4.43(m,1H),3.84-3.70(m,4H),3.49(s,3H),3.23(s,3H),2.41(t,J = 10.9 Hz,2H),2.12(s,3H),1.39(d,J = 5.9 Hz,3H),1.20(d,J = 5.4 Hz, 6H).MS(ESI) m / e[M+1] + 555.

[0307] Example C20: Synthesis of N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-((R or S)-1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A solution of N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (60 mg, 0.18 mmol), (S or R)-2-bromo-4-(1-methoxyethyl)-6-(methylsulfonyl)pyridine (Peak Example BB60, later from Step 5) (62 mg, 0.21 mmol), Pd(dba) (33 mg, 0.036 mmol), Xantphos (41.7 mg, 0.072 mmol), and CsCO (117.4 mg, 0.36 mmol) in dioxane (3 mL) was stirred at 130 °C under a nitrogen atmosphere for 4 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=15:1) to give the product (35.83 mg, 35.89%). 1 H NMR(400 MHz,DMSO-d6)δ 13.00(s,1H),10.47(s,1H),9.22(s,1H),8.71(s,1H),8.50(s,1H),7.99(d,J = 9.0 Hz,1H),7.58(d,J = 9.0 Hz,1H),7.48(s,1H),7.26(s,1H),4.53-4.45(m,1H),3.84-3.67(m,4H),3.49(s,3H),3.23(s,3H),2.41(t,J = 11.1 Hz,2H),2.11(s,3H),1.39(d,J = 6.3 Hz,3H),1.20(d,J = 6.0 Hz, 6H).MS(ESI) m / e[M+1] + 555.

[0308] Example C21: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (60 mg, 0.17 mmol), 2-bromo-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridine (66 mg, 0.21 mmol), Pd(dba) (16 mg, 0.02 mmol), BINAP (11 mg, 0.02 mmol), and CsCO (111 mg, 0.34 mmol) in 1,4-dioxane (10 mL) was stirred under N at 130 °C for 4 h. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative TLC (MeOH / DCM = 1:20) to give the product (47.27 mg, 46% yield). 1 H NMR(400 MHz,DMSO-d6)12.97(s,1H),10.46(s,1H),9.20(s,1H),8.70(s,1H),8.52(s,1H),7.98(d,J = 8.7 Hz,1H),7.57(d,J = 8.7 Hz,1H),7.46(s,1H),7.21(s,1H),3.98(d,J = 10.2 Hz,2H),3.83-3.70(m,4H),3.47-3.42(m,5H),3.02-2.95(m,1H),2.41(t,J = 11.0 Hz,2H),2.11(s,3H),1.76-1.74(m,4H),1.20(d,J = 6.1 Hz, 6H).MS(ESI) m / e[M+1] + 581.

[0309] Example C22: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)pyrazin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (60 mg, 0.17 mmol), 2-bromo-6-(methylsulfonyl)pyrazine (49 mg, 0.21 mmol), Pd(dba) (16 mg, 0.02 mmol), BINAP (11 mg, 0.02 mmol), and CsCO (111 mg, 0.34 mmol) in 1,4-dioxane (10 mL) was stirred at 130 °C for 4 h under a N atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative TLC (MeOH / DCM = 1:20) to give the product (27.37 mg, 31% yield). 1 H NMR(400 MHz,DMSO-d6)δ 14.00(s,1H),10.50(s,1H),9.29(s,1H),8.78-8.75(m,2H),8.55-8.50(m ,2H),8.00(s,1H),7.55(s,1H),3.75-3.69(m,4H),3.53(s,3H),2.37(t,J = 11.0 Hz,2H),2.08(s,3H),1.15(d,J = 6.1 Hz,6H).MS(ESI)m / e[M+1] + 498.

[0310] Example C23: Synthesis of compound N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-((S)-3-methylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (50 mg, 0.15 mmol), (S)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methyl-morpholine (47 mg, 0.16 mmol), Pd2dba3 (13.4 mg, 0.02 mmol), BINAP (18.3 mg, 0.03 mmol), and Cs2CO3 (72 mg, 0.22 mmol) were added to 1,4-dioxane (10 mL). The resulting mixture was degassed with nitrogen and stirred at 130 °C for 2 hours. After cooling to room temperature, the solid was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the product (63.39 mg, yield: 72.7%). 1 H NMR(400 MHz,DMSO-d6)δ 12.28(s,1H),10.41(s,1H),9.00(s,1H),8.62(s,1H),8.46(s,1H),7.93(d,J = 8.5 Hz,1H),7.55(d,J = 8.5 Hz,1H),7.05(s,1H),6.53(s,1H),4.15-4.12(m,1H),3.97(d,J = 12.0 Hz,1H),3.88-3.57(m,7H),3.52(t,J = 11.6 Hz,1H),3.38(s,3H),3.17(t,J = 11.6 Hz,1H),2.39(t,J = 11.0 Hz,2H),2.10(s,3H),1.27-1.07(m,9H).MS(ESI)m / e[M+1] + 596.

[0311] Example C24: Synthesis of compound N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-((R)-3-methylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (50 mg, 0.15 mmol), (R)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methyl-morpholine (47 mg, 0.16 mmol), Pd2dba3 (13.4 mg, 0.02 mmol), BINAP (18.3 mg, 0.03 mmol), and Cs2CO3 (72 mg, 0.22 mmol) were added to 1,4-dioxane (10 mL). The resulting mixture was degassed with nitrogen and stirred at 130 °C for 2 hours. After cooling to room temperature, the solid was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the product (53.8 mg, yield: 61.7%). 1 H NMR(400 MHz,DMSO-d6)δ 12.27(s,1H),10.40(s,1H),8.99(s,1H),8.62(s,1H),8.46(s,1H),7.92(d,J = 8.6 Hz,1H),7.55(d,J = 8.6 Hz,1H),7.04(s,1H),6.52(s,1H),4.15-4.12(m,1H),3.96(d,J = 10.4 Hz,1H),3.78-3.71(m,5H),3.67-3.59(m,2H),3.52(t,J = 11.4 Hz,1H),3.37(s,3H),3.16(t,J = 11.4 Hz,1H),2.39(t,J = 11.1 Hz,2H),2.09(s,3H),1.24-1.08(m,9H).MS(ESI)m / e[M+1] + 596.

[0312] The following examples were prepared in a similar manner to the product of Example C1. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6]

[0313] Example D1: Synthesis of N-(5-(2-methoxyethoxy)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] Step 1: 2-Bromo-5-(2-methoxyethoxy)pyridine [ka] To a solution of 6-bromopyridin-3-ol (5 g, 28.7 mmol) in THF (50 mL), NaH (60% in mineral oil, 1.7 g, 43.1 mmol) was added in one portion at 0 °C. The resulting mixture was stirred at this temperature for 15 min. Then, 1-bromo-2-methoxyethane (8 g, 57.5 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was poured into HO (200 mL), and the resulting mixture was extracted with EA (40 mL × 3). The combined organic layers were dried over NaSO and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA = 20:1-5:1) to give 2-bromo-5-(2-methoxyethoxy)pyridine (4.8 g, 72%). MS (ESI) m / e [M+1] + 232.

[0314] Step 2: tert-butyl (6'-chloro-5-(2-methoxyethoxy)-[2,3'-bipyridin]-4'-yl)carbamate [ka] A mixture of 2-bromo-5-(2-methoxyethoxy)pyridine (2.5 g, 10.7 mmol), tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (3.6 g, 11.8 mmol), SnMe (5.2 g, 16.1 mmol), Pd(PPh) (1.2 g, 1.08 mmol), and Pd(PPh)Cl (756.1 mg, 1.1 mmol) in 1,4-dioxane (30 mL) was stirred at 110 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (40 mL × 3), and the combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (PE / EA=50:1-0:1) to give tert-butyl (6′-chloro-5-(2-methoxyethoxy)-[2,3′-bipyridin]-4′-yl)carbamate (1.2 g, 29%). 1 H NMR(400 MHz,CDCl3)δ 11.43(s,1H),8.40(s,1H),8.31-8.25(m,2H),7.57(d,J = 8.8 Hz,1H),7.33-7.27(m,1H),4.19-4.12(m,2H),3.77-3.60(m,2H),3.36(s,3H),1.42(s,9H).MS(ESI)m / e[M+1] + 380.

[0315] Step 3: tert-Butyl (6'-acetamido-5-(2-methoxyethoxy)-[2,3'-bipyridin]-4'-yl)carbamate [ka] To a solution of tert-butyl (6'-chloro-5-(2-methoxyethoxy)-[2,3'-bipyridin]-4'-yl)carbamate (0.8 g, 2.1 mmol) in 1,4-dioxane (10 mL), acetamide (149 mg, 2.5 mmol), CsCO (1.3 g, 4.2 mmol), XantPhos (243 mg, 0.42 mmol), and Pd(dba) (192.86 mg, 0.21 mmol) were added, and the resulting mixture was stirred at 110 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo, and the residue was diluted with water (10 mL). The resulting solution was extracted with EA (10 mL × 3), and the combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (PE / EA=50:1-0:1) to give tert-butyl (6'-acetamido-5-(2-methoxyethoxy)-[2,3'-bipyridin]-4'-yl)carbamate (0.5 g, 58%). MS(ESI) m / e[M+1] + 403.

[0316] Step 4: N-(4'-amino-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide [ka] To a mixture of tert-butyl (6'-acetamido-5-(2-methoxyethoxy)-[2,3'-bipyridin]-4'-yl)carbamate (0.5 g, 1.2 mmol) in DCM (8 mL) was added TFA (2 mL), and the resulting solution was stirred at room temperature for 3 hours. Upon completion of the reaction, the solvent was removed in vacuo, the residue was diluted with water, and then aqueous NaHCO3 (50%) was added to adjust the pH value to 10. The resulting mixture was extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give N-(4'-amino-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide (275 mg, 73%). 1H NMR(400 MHz,DMSO-d6)δ 10.09(s,1 H),8.37-8.29(m,2 H),7.82(d,J = 9.0 Hz,1 H),7.50-7.45(m,2H),7.44-7.34(m,2H),4.25-4.18(m,2 H),3.70-3.65(m,2 H),3.31(s,3 H),2.06(s,3 H).MS(ESI)m / e[M+1] + 303.

[0317] Step 5: N-(5-(2-methoxyethoxy)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A solution of N-(4'-amino-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide (50 mg, 0.17 mmol), 2-bromo-6-(methylsulfonyl)pyridine (60 mg, 0.26 mmol), Pd(dba) (16 mg, 0.017 mmol), BINAP (10 mg, 0.017 mmol), and CsCO (110 mg, 0.34 mmol) in dioxane (10 mL) was placed in a sealed tube and stirred at 120 °C for 2 h. The solution was concentrated and purified by preparative TLC to give N-(5-(2-methoxyethoxy)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide (10 mg). 1 H NMR(400 MHz,DMSO-d6)δ 12.66(s,1H),10.50(s,1H),9.19(s,1H),8.70(s,1H),8.55-8.51(m,1H),8.05-7.95(m,2H),7.62-7.59(m,1H),7.54-7.52 (m,1H),7.38-7.35(m,1H),4.27-4.25(m,2H),3.71-3.68(m,2H),3.45(s,3H),3.31(s,3H),2.10(s,3H).MS(ESI)m / e[M+1] + 458.

[0318] The following examples were prepared in a similar manner to the product of Example D1. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0319] Example E1: Synthesis of N-(5-(methoxymethyl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] Step 1: 2-Bromo-5-(methoxymethyl)pyridine [ka] A solution of 2-bromo-5-(bromomethyl)pyridine (10 g, 39.85 mmol), NaOMe (9.6 mL, 51.8 mmol) in MeOH (150 mL) was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was extracted between EA and HO. The organic layer was dried over NaSO. The organic layer was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EA=5:1) to give the desired product, 2-bromo-5-(methoxymethyl)pyridine (7.8 g, 96.9% yield). MS (ESI) m / e [M+1] + 202.

[0320] Step 2: tert-Butyl (6'-chloro-5-(methoxymethyl)-[2,3'-bipyridin]-4'-yl)carbamate [ka] A mixture of 2-bromo-5-(methoxymethyl)pyridine (3 g, 14.84 mmol), SnMe (5.4 g, 16.48 mmol), and Pd(PPh) (1.9 g, 1.65 mmol) in dioxane (50 mL) was stirred at 100 °C overnight under N. The mixture was cooled to room temperature, and then a solution of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (4.8 g, 15.6 mmol) and Pd(PPh)Cl (1.2 g, 1.75 mmol) in dioxane (40 mL) was added under N. The mixture was stirred at 100 °C for 10 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with KF-HO (50 mL) and extracted with EA (100 mL × 2). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=10:1-5:1) to give tert-butyl (6'-chloro-5-(methoxymethyl)-[2,3'-bipyridin]-4'-yl)carbamate (930 mg, 17.9%). MS (ESI) m / e [M+1] + 250.

[0321] Step 3: N-(4'-amino-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide TFA salt [ka] To a solution of tert-butyl (6'-chloro-5-(methoxymethyl)-[2,3'-bipyridin]-4'-yl)carbamate (580 mg, 1.56 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 5 hours. The solvent was removed and the crude was used in the next step without further purification (400 mg, TFA salt). MS (ESI) m / e [M+1] + 273.

[0322] Step 4: N-(5-(methoxymethyl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A solution of N-(4'-amino-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide TFA salt (100 mg, 0.27 mmol), 1-bromo-3-(methylsulfonyl)benzene (174 mg, 0.74 mmol), CsCO (479.8 mg, 1.47 mmol), Xant-phos Pd G (70.2 mg, 0.074 mmol), and Xant-phos (85.2 mg, 0.15 mmol) in dioxane (3 mL) was stirred at 130 °C overnight under N. The mixture was filtered, and the filtrate was concentrated to give a crude residue, which was purified by preparative TLC (MeOH / DCM=1:10) to give N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide (45.9 mg, 39.9% yield). 1 H NMR(400 MHz,DMSO-d6)δ 11.48(s,1H),10.50(s,1H),8.68(d,J = 7.9 Hz,2H),8.19(s,1H),8.06(d,J = 8.4 Hz,1H),7.89(d,J = 8.4 Hz,1H),7.83(s,1H),7.64(s,2H),7.62-7.58(m,1H),4.51(s,2H),3.28(s,3H),2.07(s,3H).MS(ESI)m / e[M+1] + 427.

[0323] The following examples were prepared in a similar manner to the product of Example E1. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0324] Example F1: Synthesis of N-(4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide (100 mg, 0.34 mmol), 2-bromo-4-methyl-6-(methylsulfonyl)pyridine (100 mg, 0.4 mmol), Pd2dba3 (27 mg, 0.03 mmol), BINAP (18 mg, 0.03 mmol), and Cs2CO3 (208 mg, 0.64 mmol) in dioxane (6 mL) was placed in a sealed tube and stirred at 130 °C for 4 h under N2. The reaction mixture was filtered, and the solid was washed with EA (10 mL). The filtrate was concentrated, and the residue was purified by preparative TLC (DCM / MeOH=20:1) to give N-(4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide (37 mg, 23%). 1 H NMR(400 MHz,DMSO-d6)δ 12.42(s,1H),10.61(s,1H),9.26(s,1H),9.20(s,1H),8.84(s,1H),8.32-8.30(m,2H ),7.44(s,1H),7.31(s,1H),3.44(s,3H),2.41(s,3H),2.11(s,3H).MS(ESI)m / e[M+1] + 466.

[0325] Example F17: Synthesis of N-(5-fluoro-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide (800 mg, 3.25 mmol), 2-bromo-4-methyl-6-(methylsulfonyl)pyridine (976 mg, 3.9 mmol), Pd(dba) (297 mg, 0.325 mmol), BINAP (405 mg, 0.65 mmol), and CsCO (1.59 g, 4.875 mmol) in 1,4-dioxane (14 mL) was stirred at 130 °C for 3 h under a N atmosphere. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 100:1) to give the product (600 mg, 44%). 1 H NMR(400 MHz,DMSO-d6)δ 12.06(s,1H),10.53(s,1H),9.20(s,1H),8.80(s,1H),8.71(s,1H),8.16(d,J = 7.3 Hz,1H),7.95(d,J = 7.3 Hz,1H),7.44(s,1H),7.23(s,1H),3.44(s,3H),2.41(s,3H),2.12(s,3H).MS(ESI)m / e[M+1] + 416.

[0326] Example F22: Synthesis of N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] Step 1: 6'-chloro-5-fluoro-[2,3'-bipyridine]-4'-amine [ka] A mixture of 2-bromo-5-fluoropyridine (1.6 g, 9.09 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (2.54 g, 10 mmol), Pd(dppf)Cl (664 mg, 0.909 mmol), and KCO (1.88 g, 13.64 mmol) in 1,4-dioxane (50 mL) and HO (5 mL) was stirred at 100 °C for 2 h. The reaction was cooled to room temperature, diluted with EA, washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography (EA / PE = 1:3) to give the product (1.9 g). MS (ESI) m / e [M+1] + 224.

[0327] Step 2: N-(4'-amino-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of 6'-chloro-5-fluoro-[2,3'-bipyridine]-4'-amine (1.4 g, 6.25 mmol), acetamide (2.21 g, 37.5 mmol), Pd2(dba)3 (572 mg, 0.625 mmol), Xantphos (724 mg, 1.25 mmol), and Cs2CO3 (4.08 g, 12.5 mmol) in 1,4-dioxane (20 mL) was degassed with nitrogen and heated to 130 °C in a sealed tube with stirring overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM / MeOH = 50:1) to give the product (1.4 g, crude). MS (ESI) m / e [M+1] + 247.

[0328] Step 3: N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide (1.5 g, 6.07 mmol), 2-bromo-4-methoxy-6-(methylsulfonyl)pyridine (1.78 g, 6.68 mmol), Pd2(dba)3 (555 mg, 0.607 mmol), BINAP (765 mg, 1.214 mmol), and Cs2CO3 (3.96 g, 12.14 mmol) in 1,4-dioxane (30 mL) was degassed with nitrogen and heated to 130 °C with stirring in a sealed tube for 3 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column eluting with DCM / MeOH (100:1) to give the desired product as a pale yellow solid. It was then washed with MeCN (10 mL) to give the product (27 mg, 30%). 1 H NMR(400 MHz,DMSO-d6)δ 11.82(s,1H),10.54(s,1H),9.10(s,1H),8.81(s,1H),8.68(s,1H),8.20-8.06(m,1H),7.95-7 .90(m,1H),7.11(s,1H),6.90(s,1H),3.95(s,3H),3.42(s,3H),2.12(s,3H).MS(ESI)m / e[M+1] + 432.

[0329] Example F23: Synthesis of N-(4'-((3,4-dimethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide (40 mg, 0.163 mmol), 2-bromo-3,4-dimethoxy-6-(methylsulfonyl)pyridine (53 mg, 0.179 mmol), Pd2(dba)3 (15 mg, 0.0163 mmol), BINAP (20 mg, 0.0326 mmol), and Cs2CO3 (106 mg, 0.326 mmol) in 1,4-dioxane (6 mL) was degassed with nitrogen and heated to 130 °C with stirring in a sealed tube for 4 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was subjected to preparative TLC (DCM / MeOH = 20:1) to give the product (40 mg, 30%). 1 H NMR(400 MHz,DMSO-d6)δ 12.64(s,1H),10.53(s,1H),9.40(s,1H),8.82(s,1H),8.75(s,1H),8.21(d,J = 4.8 Hz,1H),7.99(d,J = 6.4 Hz,1H),7.38(s,1H),4.02(s,3H),3.97(s,3H),3.50(s,3H),2.13(s,3H).MS(ESI)m / e[M+1] + 462.

[0330] Example F24: Synthesis of N-(5-fluoro-4'-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide (40 mg, 0.163 mmol), 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine (48 mg, 0.179 mmol), Pd2(dba)3 (15 mg, 0.0163 mmol), BINAP (20 mg, 0.0326 mmol), and Cs2CO3 (132 mg, 0.326 mmol) in 1,4-dioxane (6 mL) was degassed with nitrogen and heated to 130 °C with stirring in a sealed tube for 3 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was subjected to preparative TLC (DCM / MeOH = 20:1) to give the product (30 mg, 30%). 1 H NMR(400 MHz,DMSO-d6)δ 11.81(s,1H),10.54(s,1H),9.10(s,1H),8.81(s,1H),8.68(s,1H),8.13(d,J = 7.5 Hz,1H),7.94(d,J = 7.5 Hz,1H),7.11(s,1H),6.89(s,1H),3.42(s,3H),2.12(s,3H).MS(ESI)m / e[M+1] + 435.

[0331] Example F25: Synthesis of N-(4'-((4-cyclopropyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide (50 mg, 0.203 mmol), 2-chloro-4-cyclopropyl-6-(methylsulfonyl)pyridine (57 mg, 0.244 mmol), Pd2(dba)3 (19 mg, 0.0203 mmol), BINAP (25 mg, 0.0406 mmol), and Cs2CO3 (132 mg, 0.406 mmol) in 1,4-dioxane (6 mL) was degassed with nitrogen and heated to 130 °C with stirring in a sealed tube for 4 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was subjected to preparative TLC (DCM / MeOH = 20:1) to give the product (23 mg, 25%). 1 H NMR(400 MHz,DMSO-d6)δ 11.84(s,1H),10.49(s,1H),9.06(s,1H),8.77(s,1H),8.64(s,1H),8.10-8.08(m,1H),7.95-7.90(m,1H),7.22(s,1H) ),7.02(s,1H),3.37(s,3H),2.07(s,4H),1.96-1.94(m,1H),1.12-1.05(m,2H),0.95-0.88(m,2H).MS(ESI)m / e[M+1] + 442.

[0332] The following examples were prepared in a similar manner to the product of Example F1. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11]

[0333] Example G1: Synthesis of N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] Step 1: 2-(2-chloroethoxy)acetyl chloride [ka] A mixture of 2-(2-chloroethoxy)acetic acid (1.0 g, 7.2 mmol) and DMF (0.1 mL) in SOCl (20 mL) was heated at 70° C. for 3 h. After cooling to room temperature, the solvent was removed in vacuo to give 2-(2-chloroethoxy)acetyl chloride (1.1 g, crude).

[0334] Step 2: N-(6-bromopyridin-3-yl)-2-(2-chloroethoxy)acetamide [ka] To a mixture of 2-(2-chloroethoxy)acetyl chloride (1.1 g, 7.0 mmol) in THF (20 mL) was added 6-bromopyridin-3-amine (1.2 g, 7.0 mmol) and EtN (2.1 g, 21.0 mmol), and the resulting mixture was stirred at room temperature for 12 hours. Upon completion of the reaction, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (PE / EA=2:1-1:1) to give N-(6-bromopyridin-3-yl)-2-(2-chloroethoxy)acetamide (1.5 g, 72.8%). 1 H NMR(400MHz,CDCl3)δ 8.59(s,1 H),8.48(s,1 H),8.11(d,J = 8.4 Hz,1 H),7.47(d,J = 8.4 Hz,1 H),4.18(s,2 H),3.94-3.89(m,2 H),3.80-3.76(m,2 H).MS(ESI)m / e[M+1] + 293.

[0335] Step 3: 4-(6-bromopyridin-3-yl)morpholin-3-one [ka] To a solution of N-(6-bromopyridin-3-yl)-2-(2-chloroethoxy)acetamide (1.5 g, 5.1 mmol) in DMF (20 mL) was added NaH (60% in mineral oil, 307 mg, 7.7 mmol) dropwise at 0 °C, and the mixture was then stirred at room temperature for 2 h. Upon completion of the reaction, water was added, and the resulting mixture was extracted with EA (50 mL × 3). The combined organic layers were concentrated in vacuo to give 4-(6-bromopyridin-3-yl)morpholin-3-one (1.1 g, 84.6%). 1 H NMR(400 MHz,CDCl3)δ 8.35-8.30(m,1 H),7.61(s,1 H),7.49-7.42(m,1 H),4.28(s,2 H),4.02-3.97(m,1 H),4.02-3.97(m,1 H),3.76-3.71(m,1 H),3.76-3.71(m,1 H).MS(ESI)m / e[M+1] + 412.

[0336] Step 4: 4-(6'-amino-4'-chloro-[2,3'-bipyridin]-5-yl)morpholin-3-one [ka] A mixture of 4-(6-bromopyridin-3-yl)morpholin-3-one (200 mg, 673.4 μmol), 4-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (340 mg, 1.4 mmol), Pd(dppf)Cl (49 mg, 67.3 μmol), and NaCO (142 mg, 1.4 mmol) in ACN (10 mL) / HO (2 mL) was heated under a nitrogen atmosphere by microwave irradiation at 120 °C for 20 min. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography (EA / MeOH=100:1-30:1) to give 4-(6'-amino-4'-chloro-[2,3'-bipyridin]-5-yl)morpholin-3-one (120 mg, 58.5%). MS(ESI) m / e[M+1] + 305.

[0337] Step 5: N-(4'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] To a mixture of 4-(6'-amino-4'-chloro-[2,3'-bipyridin]-5-yl)morpholin-3-one (340 mg, 1.1 mmol) in pyridine (10 mL) was added AcCl (105 mg, 1.3 mmol) dropwise at 0 °C, and the mixture was then stirred at room temperature for 12 hours. Upon completion of the reaction, water (0.2 mL) was added and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (EA / MeOH = 100:1-30:1) to give N-(4'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (150 mg, 39%). 1H NMR(400MHz,DMSO-d6)δ 10.97(s,1 H),8.88(s,1 H),8.61(s,1 H),8.37(s,1 H),8.08(d,J = 8.4 Hz,1 H),7.89(d,J = 8.4 Hz,1 H),4.34(s,2 H),4.13-4.05(m,2 H),3.97-3.89(m,2 H),2.21(s,3 H).MS(ESI)m / e[M+1] + 347.

[0338] Step 6: N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (150 mg, 432 µmol), 3-(methylsulfonyl)aniline (147 mg, 865 µmol), Pd2(dba)3 (39 mg, 43 µmol), Xant-Phos (25 mg, 43 µmol), and Cs2CO3 (421 mg, 1.3 mmol) in dioxane (5 mL) was heated at 110 °C for 12 h under a nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by neutral preparative HPLC (Column: Phenomenex Gemini-NX 150 × 30 mm × 5 um, Phase: A - HO (10 mM NHHCO), B - ACN, B%: 10%-40% over 20 min) to give N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (5.6 mg, 2.7%). 1H NMR(400MHz,DMSO-d6)δ 11.31(s,1 H),10.52(s,1 H),8.84(s,1 H),8.71(s,1 H),8.20(s,1 H),8.13(d,J = 8.0 Hz,1 H),8.05(d,J = 8.0 Hz,1 H),7.84(s,1 H),7.69-7.64(m,2 H),7.63-7.58(m,1 H),4.29(s,2 H),4.08-4.01(m,2 H),3.91-3.84(m,2 H),3.30(s,3 H),2.09(s,3 H).MS(ESI)m / e[M+1] + 482.

[0339] Example G2: Synthesis of N-(4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] Step 1: tert-butyl (6'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridin]-4'-yl)carbamate [ka] A mixture of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (3.0 g, 9.8 mmol), 4-(6-bromopyridin-3-yl)morpholin-3-one (2.9 g, 9.8 mmol), Pd(PPh3)2Cl2 (688 mg, 977 µmol), Pd(PPh3)4 (1.1 g, 977 µmol), and Sn2Me6 (4.8 g, 14.7 mmol) in 1,4-dioxane (30 mL) was heated at 100 °C for 12 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was quenched with 10% KF solution (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=1:1-1:2) to give tert-butyl (6′-chloro-5-(3-oxomorpholino)-[2,3′-bipyridin]-4′-yl)carbamate (1.1 g, 28%). 1 H NMR(400MHz,DMSO-d6)δ 11.96(s,1 H),8.87(s,1 H),8.86-8.83(m,1 H),8.28(s,1 H),8.24-8.18(m,1 H),8.17-8.10(m,1 H),4.29(s,2 H),4.08-3.99(m,2 H),3.93-3.86(m,2 H),1.50(s,9 H).MS(ESI)m / e[M+1] + 405.

[0340] Step 2: tert-Butyl (6'-acetamido-5-(3-oxomorpholino)-[2,3'-bipyridin]-4'-yl)carbamate [ka] A mixture of tert-butyl (6'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridin]-4'-yl)carbamate (500 mg, 1.2 mmol), acetamide (146 mg, 2.5 mmol), Pd(dba) (113 mg, 123 µmol), Xantphos (72 mg, 124 µmol), and CsCO (808 mg, 2.5 mmol) in 1,4-dioxane (10 mL) was heated at 110 °C for 12 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (EA / MeOH=100:1-30:1) to give tert-butyl (6'-acetamido-5-(3-oxomorpholino)-[2,3'-bipyridin]-4'-yl)carbamate (300 mg, 57%). MS (ESI) m / e [M+1] + 428.

[0341] Step 3: N-(4'-amino-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of tert-butyl (6'-acetamido-5-(3-oxomorpholino)-[2,3'-bipyridin]-4'-yl)carbamate (300 mg, 703 µmol) in HCl / EA (20 mL, v:v = 1:9) was stirred at room temperature for 2 hours. Upon completion of the reaction, the solvent was removed in vacuo, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 µm, liquid phase: [A - 10 mM NH4HCO3HO solution, B - ACN], B%: 5%-45% over 8 min) to give N-(4'-amino-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (98 mg, 43%). 1H NMR(400MHz,DMSO-d6)δ 10.11(s,1 H),8.63(s,1 H),8.41(s,1 H),7.96-7.86(m,2 H),7.55-7.45(m,3 H),4.22(s,2 H),3.99-3.95(m,2 H),3.82-3.78(m,2 H),2.03(s,3 H).MS(ESI)m / e[M+1] + 328.

[0342] Step 4: N-(4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4',5-diamino-[2,3'-bipyridin]-6'-yl)acetamide (98 mg, 0.40 mmol), 2-bromo-6-(methylsulfonyl)pyridine (96 mg, 0.41 mmol), Pd(dba) (18 mg, 0.02 mmol), BINAP (23 mg, 0.04 mmol), and KPO (174 mg, 0.82 mmol) in 1,4-dioxane (10 mL) was heated to 100 °C under a nitrogen atmosphere for 4 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (MeOH / DCM=1 / 15) to give N-(4′-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3′-bipyridin]-6′-yl)acetamide (15 mg, 7.6%). 1 H NMR(400 MHz,DMSO-d6)δ 12.70(s,1H),10.56(s,1H),9.20(s,1H),8.93-8.83(m,1H),8.79(s,1H),8.17(d,J = 8.4 Hz,1H),8.06(d,J = 8.4 Hz,1H),8.02-7.95(m,1H),7.54(s,1H),7.45-7.41(m,1H),4.27(s,2H),4.05 -4.00(m,2H),3.90-3.82(m,2H),3.45(s,3H),2.11(s,3H).MS(ESI)m / e[M+1]+ 483.

[0343] The following examples were prepared in a similar manner to the product of Example G2. [Table 8-1] [Table 8-2]

[0344] Example H1: Synthesis of N-(5-(2-hydroxypropan-2-yl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] Step 1: tert-Butyl (6'-chloro-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)carbamate [ka] A mixture of tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (650 mg, 2.1 mmol), 2-(6-bromopyridin-3-yl)propan-2-ol (525 mg, 2.4 mmol), SnMe (1.0 g, 3.1 mmol), Pd(PPh) (244.2 mg, 211.3 mmol), and Pd(PPh)Cl in 1,4-dioxane (10 mL) was heated to 105 °C under a nitrogen atmosphere for 12 h. After cooling to room temperature, the mixture was washed with KF (5 mL) and filtered. The organic layer was concentrated under vacuum, and the residue was purified by silica gel column chromatography (PE / EA=10:1) to give tert-butyl (6′-chloro-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-4′-yl)carbamate (0.4 g, 52%). 1H NMR(400 MHz,CDCl3)δ 11.93(s,1 H),8.82(s,1 H),8.59(s,1 H),8.45(s,1 H),7.97(d,J = 8.4 Hz,1 H),7.74(d,J = 8.4 Hz,1 H)1.68(s,6 H),1.56(s,9 H).MS(ESI)m / e[M+1] + 364.

[0345] Step 2: tert-Butyl (6'-acetamido-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)carbamate [ka] A mixture of tert-butyl (6'-chloro-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)carbamate (0.3 g, 824 µmol), acetamide (97 mg, 1.6 mmol), CsCO (841 mg, 2.4 mmol), Xantphos (95 mg, 165 µmol), and Pd(dba) (151 mg, 165 µmol) in 1,4-dioxane (50 mL) was gradually heated to 90 °C and stirred at this temperature for 12 h under a nitrogen atmosphere. After cooling to room temperature, the solution was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EA=1 / 1-0 / 1) to give tert-butyl (6'-acetamido-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)carbamate (0.22 g, 69%). 1 H NMR(400 MHz,CDCl3)δ 11.81(s,1 H),9.15(s,1 H),8.79(s,1 H),8.50(s,1 H),7.94(d,J = 8.4 Hz,2 H),7.72-7.68(m,1 H),2.23(s,3 H),1.67(s,6 H),1.66-1.69(m,1 H),1.56(s,9 H).MS(ESI)m / e[M+1] + 387.

[0346] Step 3: N-(4'-amino-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of tert-butyl (6'-acetamido-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-4'-yl)carbamate (150 mg, 388 umol) in TFA (1 mL) and DCM (2 mL) was stirred under a nitrogen atmosphere at 15°C for 2 hours. Upon completion of the reaction, the solvent was removed in vacuo to give N-(4'-amino-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide (0.1 g, crude), which was used directly in the next step without further purification. MS (ESI) m / e [M+1] + 287.

[0347] Step 4: N-(5-(2-hydroxypropan-2-yl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide (0.1 g, 349 µmol), 1-bromo-3-(methylsulfonyl)benzene (246 mg, 1.1 mmol), Cs2CO3 (358 mg, 1.1 mmol), Xantphos (20 mg, 35 µmol), and Pd2(dba)3 (35 mg, 35 µmol) in 1,4-dioxane (5 mL) was gradually heated to 110 °C and stirred at this temperature for 12 h under a nitrogen atmosphere. After cooling to room temperature, the solution was filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150 × 30 mm × 5 um, phase: A - HO (10 mM NH4HCO3), B - ACN, B%: 10%-40% over 20 min) to give N-(5-(2-hydroxypropan-2-yl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide (11 mg, 7.1%). 1 H NMR(400 MHz,DMSO-d6)δ 11.66(s,1 H),10.47(s,1 H),8.81(s,1 H),8.69(s,1 H),8.18(s,1 H),8.00(s,2 H),7.82(s,1 H),7.66-7.62(m,2 H),7.60-7.55(m,1 H),5.29(s,1 H),3.28(s,3 H),2.07(s,3 H),1.50(s,6 H).MS(ESI)m / e[M+1] + 441.

[0348] Example H2: Synthesis of N-(5-(2-hydroxypropan-2-yl)-4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide [ka] A mixture of N-(4'-amino-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide (400 mg, 1.40 mmol), 2-bromo-4-isopropoxy-6-(methylsulfonyl)pyridine (492 mg, 1.68 mmol), Pd2(dba)3 (128 mg, 0.14 mmol), BINAP (88 mg, 0.14 mmol), and Cs2CO3 (1.368 g, 4.20 mmol) in dioxane (20 mL) was stirred at 130 °C for 4 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Combiflash (MeOH / DCM = 0-10%) to giv...

Claims

1. A compound of formula (IA), 【Chemistry 2】 During the ceremony, X is N or CH; L １ is a direct bond, —O— or —O—(CR ａ R ｂ ) ｑ -, where q is a number from 1 to 7; R ａ and R ｂ are independently hydrogen, R １ But, -C １－６ Alkyl, —C ３－６ cycloalkyl, or —NR ｍ R ｎ and R ２ , R ３ , and R ４ are each independently hydrogen, halogen, or —C １－６ Alkyl, —C ３－８ cycloalkyl, heterocyclyl, aryl, heteroaryl, -oxo-, -CN, or -ORe; Here, -C １－６ Alkyl, —C ３－８ cycloalkyl, heterocyclyl, aryl, or heteroaryl are each unsubstituted or substituted with cyano, oxo, halogen, or C １－６ alkyl, hydroxy-substituted -C １－６ Alkyl, -OR ｈ , —C(O)NR ｍ R ｎ , -NH ２ , N.H. ２ C substituted with １－６ Alkyl, or C １－６ -C substituted with alkoxy １－６ independently substituted with at least one substituent selected from alkyl; In the formula, R ｈ is hydrogen, alkyl, hydroxy-C １－６ alkyl, or heterocyclyl; R ｅ is hydrogen, -C １－６ Alkyl, —C １－６ Alkoxy, -C ２－６ Alkenyl, -C ２－６ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where -C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ each alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with halogen, hydroxy, cyano, or —C １－６ Alkoxy; unsubstituted or substituted with halogen, hydroxy, or C １－６ -C substituted with alkoxy ３－６ cycloalkyl; or heterocyclyl; R ５ is hydrogen, Cy １ is a 5- to 14-membered heteroaryl, or a 5- to 14-membered heterocyclyl, each of which is unsubstituted or contains at least one substituent R ｉ is replaced by R ｉ are independently halogen, cyano, -C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C ３－８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —NO ２ , -OR ｊ , -SO ２ R ｊ , -COR ｊ , -CO ２ R ｋ , -CONR ｊ R ｋ , -C(=NR ｊ ) NR ｋ R ｌ , -NR ｊ R ｋ , -NR ｊ COR ｋ , -NR ｊ CONR ｋ R ｌ , -NR ｊ CO ２ R ｋ , -NR ｊ SONR ｋ R ｌ , -NR ｊ SO ２ NR ｋ R ｌ , or -NR ｊ SO ２ R ｋ and Here, the -C １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ Alkynyl, —C ３－８ Each of cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with halogen, OR ｍ , C(O)R ｍ , -NR ｍ R ｎ , -C １－６ Alkyl, C １－６ Alkoxy-, C １－６ Alkoxy-C １－６ alkyl- or oxo-substituted; R ｊ , R ｋ , R ｌ , R ｍ , R ｎ are each independently hydrogen, —C １－６ Alkyl, C １－６ -C substituted with alkoxy １－６ Alkyl, —C ２－６ Alkenyl, -C ２－６ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R １ and R ２ ), or (R ２ and R ３ ), or (R ３ and R ４ ), taken together with the atom to which they are attached, form a fused ring system, said fused ring system containing 0 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur as ring member(s), and is unsubstituted or selected from halogen, —C １－６ Alkyl, —C １－６ Alkoxy, -haloC １－６ Alkyl, -haloC １－６ Alkoxy, or -C ３－６ is independently substituted with cycloalkyl; either said alkyl or said alkoxy is non-enriched or deuterium-enriched; The compound, or a stereoisomer or a pharmaceutically acceptable salt thereof.

2. R １ But, -C １－３ Alkyl, —NRmRn, or —C ３－６ 2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, which is cycloalkyl.

3. R ２ and R ４ are each independently hydrogen, halogen, or —C １－６ Alkyl, or -C １－６ 2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, which is alkoxy.

4. R ３ but, - hydrogen or -cyano or - is halogen, -unsubstituted or halogen, 3- to 6-membered heterocyclyl, or -OR ｈ -C substituted with at least one substituent independently selected from １－４ alkyl, A 3- to 6-membered heterocyclyl contains one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s) and is unsubstituted or substituted with cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ and wherein the substituted group is substituted with at least one substituent independently selected from: １－６ Alkyl or -C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ substituted with at least one substituent independently selected from alkoxy; R ｈ is hydrogen, alkyl, or heterocyclyl; １－４ Is it alkyl? -unsubstituted or cyano, -oxo, halogen, -NR ｍ R ｎ , hydroxy, -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ -C substituted with at least one substituent independently selected from ３－６ cycloalkyl, where —C １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ substituted with at least one substituent independently selected from alkoxy; ３－６ is cycloalkyl, or -unsubstituted or cyano, -oxo-, halogen, hydroxy, C １－６ Alkyl, alkoxy, -NRR ｍ R ｎ , or —C(O)NR ｍ R ｎ and a heterocyclyl containing one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s), substituted with at least one substituent independently selected from: １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ said heterocyclyl substituted with at least one substituent independently selected from alkoxy; --OR ｅ wherein R ｅ But, -C １－６ Alkyl, —C ３－６ cycloalkyl, 3- to 6-membered heterocyclyl, or aryl; i)-C １－６ Alkyl is unsubstituted or substituted with cyano; -oxo-; halogen; hydroxy; -NR ｍ R ｎ ;-C １－６ Alkoxy-; unsubstituted or cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－６ Alkyl, C １－６ Alkoxy, or —C(O)NR ｍ R ｎ -C substituted with ３－６ Cycloalkyl; unsubstituted or substituted with cyano, halogen, hydroxy, C １－６ Alkyl or C １－６ substituted by a 4- to 6-membered heterocyclyl substituted by alkoxy; ii) -C ３－６ The cycloalkyl or 3- to 6-membered heterocyclyl is unsubstituted or is selected from the group consisting of cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , C １－６ Alkyl, C １－６ Alkoxy, or —C(O)NR ｍ R ｎ is substituted with -C １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ substituted with at least one substituent independently selected from alkoxy; ｅ Or --C ５－１０ is aryl, or -unsubstituted or cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ Heteroaryl containing one oxygen (O), nitrogen (N), or sulfur (S) heteroatom as a ring member, substituted with at least one substitution independently selected from: １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ said heteroaryl being substituted with at least one substituent independently selected from alkoxy; In the formula, R ｍ and R ｎ are independently hydrogen or C １－３ alkyl, 4. The compound of any one of claims 1 to 3, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein either said alkyl or said alkoxy is non-enriched or deuterium-enriched.

5. R ３ but, - hydrogen or -cyano or - is halogen, -unsubstituted or halogen, 3- to 6-membered heterocyclyl, or -OR ｈ -C substituted with at least one substituent independently selected from １－４ alkyl, The 3- to 6-membered heterocyclyl contains one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s), and is unsubstituted or substituted with cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ and wherein the substituted group is substituted with at least one substituent independently selected from: １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ substituted with at least one substituent independently selected from alkoxy; R ｈ is hydrogen, alkyl, or heterocyclyl; １－４ Is it alkyl? -unsubstituted or cyano, -oxo, halogen, -NR ｍ R ｎ , hydroxy, -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ -C substituted with at least one substituent independently selected from ３－６ cycloalkyl, where —C １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ substituted with at least one substituent independently selected from alkoxy; ３－６ is cycloalkyl, or -unsubstituted or cyano, -oxo, halogen, hydroxy, -C １－６ Alkyl, alkoxy, -NR ｍ R ｎ or —C(O)NR ｍ R ｎ heterocyclyl substituted with at least one substituent independently selected from: １－６ Alkyl or -C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ said heterocyclyl substituted with at least one substituent independently selected from alkoxy; --OR ｅ wherein R ｅ But, -C １－６ Alkyl, —C ３－６ cycloalkyl, 3- to 6-membered heterocyclyl, or aryl; i)-C １－６ Alkyl is unsubstituted or substituted with cyano; -oxo-; halogen; hydroxy; -NR ｍ R ｎ ;-C １－６ Alkoxy-; unsubstituted or cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－６ Alkyl, C １－６ Alkoxy, or —C(O)NR ｍ R ｎ -C substituted with ３－６ Cycloalkyl; unsubstituted or substituted with cyano, halogen, hydroxy, -C １－６ Alkyl or -C １－６ substituted by a 4- to 6-membered heterocyclyl substituted by alkoxy; ii) -C ３－６ The cycloalkyl or 3- to 6-membered heterocyclyl is unsubstituted or is substituted with cyano, -oxo, halogen, hydroxy, NR ｍ R ｎ , C １－６ Alkyl, C １－６ Alkoxy, or —C(O)NR ｍ R ｎ is substituted with -C １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ substituted with at least one substituent independently selected from alkoxy; ｅ Or --C ５－１０ is aryl, or -unsubstituted or cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ heteroaryl substituted with at least one substituent independently selected from: １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ said heteroaryl being substituted with at least one substituent independently selected from alkoxy; In the formula, R ｍ and R ｎ are independently hydrogen or C １－３ 5. The compound of claim 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

6. R ３ but, - hydrogen, cyano or halogen, -unsubstituted or halogen, 3- to 6-membered heterocyclyl, or -OR ｈ -C substituted with at least one substituent independently selected from １－４ alkyl, The 3- to 6-membered heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, thiazolidinyl, or azetidinyl, each of which is unsubstituted or substituted with cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ and wherein the substituted group is substituted with at least one substituent independently selected from: １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ alkoxy; and R ｈ But hydrogen, C １－６ alkyl, or 3- to 6-membered heterocyclyl; １－４ Is it alkyl? -unsubstituted or cyano, -oxo, halogen, NR ｍ R ｎ , hydroxy, -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ , hydroxy, or C １－６ -C substituted with at least one substituent independently selected from alkoxy ３－６ cycloalkyl, where —C １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ substituted with at least one substituent independently selected from alkoxy; ３－６ is cycloalkyl, or heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, and is unsubstituted or substituted with cyano, -oxo, halogen, hydroxy, C １－６ Alkyl, alkoxy, -NRR ｍ R ｎ or —C(O)NR ｍ R ｎ and wherein the substituted group is substituted with at least one substituent independently selected from: １－６ Alkyl or -C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or -C １－６ substituted with at least one substituent independently selected from alkoxy; --OR ｅ wherein R ｅ But, -C １－６ Alkyl, —C ３－６ cycloalkyl, 4-6 membered monocyclic saturated heterocyclyl containing one oxygen heteroatom as a ring member, or C ６－１０ is aryl, i)-C １－６ Alkyl is unsubstituted or substituted with deuterium; cyano; -oxo-; halogen; hydroxy; -NR ｍ R ｎ ;-C １－６ Alkoxy-; unsubstituted or cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ -C substituted with ３－６ Cycloalkyl; unsubstituted or substituted with cyano, halogen, hydroxy, -C １－６ Alkyl or -C １－６ substituted by a 4- to 6-membered heterocyclyl substituted by alkoxy; ii) -C ３－６ The cycloalkyl or 3- to 6-membered heterocyclyl is unsubstituted or is substituted with cyano, -oxo, halogen, hydroxy, NR ｍ R ｎ , C １－６ Alkyl, C １－６ Alkoxy, or —C(O)NR ｍ R ｎ is substituted with -C １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ substituted with at least one substituent independently selected from alkoxy; ｅ Or --C ６－１０ is aryl, or - a 5-6 membered heteroaryl selected from pyridinyl, pyridazinyl, pyrazinyl, thiazolyl, or isoxazolyl, each of which is unsubstituted or substituted with cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ and wherein the substituted group is substituted with at least one substituent independently selected from: １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or C １－６ said 5- to 6-membered heteroaryl being substituted with at least one substituent independently selected from alkoxy; In the formula, R ｍ and R ｎ are independently hydrogen or —C １－３ 5. The compound of claim 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

7. R ３ but, - hydrogen, cyano or halogen, -unsubstituted -C 1-4 alkyl or unsubstituted or cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , or -C １－３ substituted with at least one substituent independently selected from alkyl, halogen, hydroxy, C １－３ -C substituted with at least one substituent independently selected from alkoxy, thiazolidin-3-yl １－４ Is it alkyl? -unsubstituted or cyano, -oxo, halogen, -NR ｍ R ｎ , hydroxy, -C １－６ Alkyl, or -C １－６ -C substituted with at least one substituent independently selected from alkoxy ３－６ cycloalkyl, where —C １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or -C １－３ substituted with at least one substituent independently selected from alkoxy; ３－６ is cycloalkyl, or heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, and is unsubstituted or substituted with cyano, -oxo, halogen, hydroxy, C １－６ Alkyl, alkoxy, -NR ｍ R ｎ or —C(O)NR ｍ R ｎ and wherein the substituted group is substituted with at least one substituent independently selected from: １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or -C １－６ substituted with at least one substituent independently selected from alkoxy; --OR ｅ wherein R ｅ But, -C １－６ Alkyl, —C ３－６ cycloalkyl, 4-6 membered monocyclic saturated heterocyclyl containing one oxygen heteroatom as a ring member, or C ６－１０ is aryl, i)-C １－６ Alkyl is unsubstituted or substituted with cyano; -oxo-; halogen; hydroxy; -NR ｍ R ｎ ;-C １－６ Alkoxy-; unsubstituted or cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ -C substituted with ３－６ Cycloalkyl; unsubstituted or substituted with cyano, halogen, hydroxy, -C １－６ Alkyl or -C １－６ substituted by a 4- to 6-membered heterocyclyl substituted by an alkoxy; ii) -C ３－６ The cycloalkyl or 3- to 6-membered heterocyclyl is unsubstituted or is selected from the group consisting of cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ is substituted with -C １－６ Alkyl or -C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or -C １－６ substituted with at least one substituent independently selected from alkoxy; ｅ Or --C ６－１０ is aryl, or - a 5-6 membered heteroaryl selected from pyridinyl, pyridazinyl, pyrazinyl, thiazolyl, or isoxazolyl, each of which is unsubstituted or substituted with cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－６ Alkyl, —C １－６ Alkoxy, or —C(O)NR ｍ R ｎ and wherein the substituted group is substituted with at least one substituent independently selected from: １－６ Alkyl or -C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or -C １－６ said 5- to 6-membered heteroaryl being substituted with at least one substituent independently selected from alkoxy; In the formula, R ｍ and R ｎ are independently hydrogen or —C １－３ 5. The compound of claim 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

8. R ３ but, - hydrogen, cyano or halogen, -methyl, ethyl, propyl, or butyl, each of which is unsubstituted or substituted with at least one substituent independently selected from halogen, hydroxy, methoxy, ethoxy, propoxy, or 2,4-dioxothiazolidin-3-yl; or -cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is unsubstituted or substituted with at least one substituent independently selected from cyano, -oxo, halogen, -NR ｍ R ｎ , hydroxy, -C １－３ Alkyl, or -C １－３ substituted with at least one substituent independently selected from alkoxy, wherein １－３ Alkyl or C １－３ The alkoxy may be unsubstituted or may be substituted with cyano, halogen, hydroxy, -NH ２ , -C １－３ Alkyl, or -C １－３ said cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl substituted with at least one substituent independently selected from alkoxy; -heterocyclyl is morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-1-yl, and wherein the aryl group is selected from the group consisting of 3-azabicyclo[3.1.0]hexan-2-yl, 4-azabicyclo[3.1.0]hexan-3-yl, 5-azabicyclo[3.1.0]hexan-2-yl, 5-azabicyclo[3.1.0]hexan-3-yl, 6-azabicyclo[3.1.0]hexan-3-yl, 7-azabicyclo[3.1.0]hexan-2-yl, 8-azabicyclo[3.1.0]hexan-3-yl, 9-azabicyclo[3.1.0]hexan-2-yl, 10-azabicyclo[3.1.0]hexan-3-yl, 11-azabicyclo[3.1.0]hexan-2-yl, 12-azabicyclo[3.1.0]hexan-2-yl, 13-azabicyclo[3.1.0]hexan-3-yl, 14-azabicyclo[3.1.0]hexan-2-yl, 15-azabicyclo[3.1.0]hexan-3-yl, 16-azabicyclo[3.1.0]hexan-2-yl, 17-azabicyclo[3.1.0]hexan-2-yl, 18-azabicyclo[3.1.0]hexan-3-yl, 19-azabicyclo[3.1.0]hexan-2-yl, 20-azabicyclo[3.1.0]hexan-2-yl, 21-azabicyclo[3.1.0]hexan-3-yl, 22-azabicyclo[3.1.0]hexan-2-yl, 23-azabicyclo[3.1.0]hexan-2-yl, 24-azabicyclo[3.1.0]hexan-3-yl, 25-azabicyclo[3.1.0]hexan-2-yl, 2 １－６ Alkyl, —C １－６ Alkoxy, —NR ｍ R ｎ or —C(O)NR ｍ R ｎ and wherein the substituted group is substituted with at least one substituent independently selected from: １－６ Alkyl or C １－６ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－６ Alkyl, or -C １－６ substituted with at least one substituent independently selected from alkoxy; --OR ｅ wherein R ｅ but, i) methyl, ethyl, propyl (isopropyl), butyl, pentyl, or hexyl, each of which is unsubstituted or substituted with deuterium; cyano; -oxo-; halogen; hydroxy; -NR ｍ R ｎ ;-C １－３ Alkoxy-; unsubstituted or cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－３ Alkyl, —C １－３ Alkoxy, or —C(O)NR ｍ R ｎ -C substituted with ３－６ cycloalkyl; or unsubstituted or substituted with cyano, halogen, hydroxy, -C １－３ Alkyl or -C １－３ substituted by a 4- to 6-membered heterocyclyl substituted by alkoxy; ii) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,4-dioxan-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, azetidin-1-yl, azetidin-2-yl, or azetidin-3-yl, each of which is unsubstituted or substituted with cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－３ Alkyl, —C １－３ Alkoxy, or —C(O)NR ｍ R ｎ is substituted with -C １－３ Alkyl or -C １－３ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－３ Alkyl, or -C １－３ substituted with at least one substituent independently selected from alkoxy; ｅ Or --C ６－１０ is aryl, or -5-6 membered heteroaryl selected from pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-1-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-1-yl, pyrazin-2-yl, thiazol-2-yl, thiazol-3-yl, thiazol-4-yl, isoxazol-2-yl, isoxazol-3-yl, or isoxazol-4-yl, each of which is unsubstituted or selected from cyano, -oxo, halogen, hydroxy, -NR ｍ R ｎ , -C １－３ Alkyl, —C １－３ Alkoxy, or —C(O)NR ｍ R ｎ and wherein the substituted group is substituted with at least one substituent independently selected from: １－３ Alkyl or -C １－３ Alkoxy is cyano, halogen, hydroxy, -NH ２ , -C １－３ Alkyl, or C １－３ said 5- to 6-membered heteroaryl being substituted with at least one substituent independently selected from alkoxy; In the formula, R ｍ and R ｎ are independently hydrogen or —C １－３ 5. The compound of claim 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

9. R ３ but, -hydrogen, -methyl, 1-methoxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, or (2,4-dioxothiazolidin-3-yl)methyl, -isopropoxy, methoxy-d3, methoxy, ethoxy, difluoromethoxy, 2-methoxyethoxy, 2-methoxy-2-methylpropoxy, 2-hydroxy-2-methylpropoxy, cyclopropylmethoxy, (1,4-dioxan-2-yl)methoxy, cyclobutoxy, (4-hydroxycyclohexyl)oxy, (cis-4-hydroxycyclohexyl)oxy, (trans-4-hydroxycyclohexyl)oxy, (4-methoxycyclohexyl)oxy, (cis-4-methoxycyclohexyl)oxy, (trans-4-methoxycyclohexyl)oxy, (3-methyloxetan-3-yl)methoxy, 2-methyl-2-morpholinopropoxy, -Cyano, -3-methoxycyclobutyl, (trans)-3-methoxycyclobutyl, (cis)-3-methoxycyclobutyl, 2,2-dichlorocyclopropyl, or 1-cyanocyclopropyl, -morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, 3(S)-methyl-morpholino, 3,3-dimethylmorpholino, -tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, (R)-tetrahydro-2H-pyran-3-yl, (S)-tetrahydro-2H-pyran-3-yl, 2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl, -3-methoxypyrrolidin-1-yl, 3(R)-methoxypyrrolidin-1-yl, 3(S)-methoxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, 3-(2-hydroxyethoxy)pyrrolidin-1-yl, 3-(trifluoromethoxy)pyrrolidin-1-yl, 3(R)-(trifluoromethoxy)pyrrolidin-1-yl, 3(S)-(trifluoromethoxy)pyrrolidin-1-yl, 2-(aminocarbonyl)pyrrolidin-1-yl, 2(R)-(aminocarbonyl)pyrrolidin-1-yl, 2(S)-(aminocarbonyl)pyrrolidin-1-yl, 3-(methoxymethyl)pyrrolidin-1-yl, 3(R)-(methoxymethyl)pyrrolidin-1-yl, 3(S)-(methoxymethyl)pyrrolidin-1-yl pyrolidin-1-yl, 3-cyano-4-hydroxypyrrolidin-1-yl, cis-3-cyano-4-hydroxypyrrolidin-1-yl, trans-3-cyano-4-hydroxypyrrolidin-1-yl, 3-cyano-4-methoxypyrrolidin-1-yl, cis-3-cyano-4-methoxypyrrolidin-1-yl, trans-3-cyano-4-methoxypyrrolidin-1-yl, 2-(methoxymethyl)pyrrolidin-1-yl, 2(R)-(methoxymethyl)pyrrolidin-1-yl, 2(S)-(methoxymethyl)pyrrolidin-1-yl, 3-methylpyrrolidin-1-yl, 3(R)-methylpyrrolidin-1-yl, 3(S)-methylpyrrolidin-1-yl, pyrrolidin-1-yl, 3-(cyanomethoxy)pyrrolidin-1-yl, -5-azaspiro[2.4]heptan-5-yl, -tetrahydrofuran-3-yl, -3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl, -1,4-dioxan-2-yl, -4-aminotetrahydro-2H-pyran-4-yl, 4-(aminomethyl)tetrahydro-2H-pyran-4-yl, -4-methoxypiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl, 1-(2,2,2-trifluoroethyl)piperidin-4-yl, 3-methoxypiperidin-1-yl, 3(R)-methoxypiperidin-1-yl, 3(S)-methoxypiperidin-1-yl, 3-ethoxypiperidin-1-yl, 3(R)-ethoxypiperidin-1-yl, 3(S)-ethoxypiperidin-1-yl, -3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, (3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 4-methylpyridin-3-yl, 5-methylpyridazin-4-yl, 5-methoxypyridazin-4-yl, 3,5-dimethylisoxazol-4-yl, 4-methoxypyridin-3-yl, 4-(2-hydroxypropan-2-yl)pyridin-3 5. The compound of claim 4, wherein the compound is 4-(1-hydroxyethyl)pyridin-3-yl, 4-(1-methoxyethyl)pyridin-3-yl, pyridin-2-yl, or thiazol-4-yl, or a stereoisomer or a pharmaceutically acceptable salt thereof.

10. (R １ and R ２ ), or (R ２ and R ３ ), or (R ３ and R ４ ), taken together with the atom to which they are attached, form a fused 5-7 membered ring system, said fused ring system containing 0-2 oxygen heteroatoms as ring member(s) and being unsubstituted or containing halogen, —C １－６ Alkyl, —C １－６ Alkoxy, -haloC １－６ Alkyl, -haloC １－６ Alkoxy, or -C ３－６ 10. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, independently substituted with cycloalkyl.

11. R １ and R ２ together with the atoms to which they are bonded, 【Chemistry 3】 or R ２ and R ３ together with the atoms to which they are attached form a fused ring system 【Chemistry 4】 and R ３ and R ４ together with the atoms to which they are bonded, 【Chemistry 5】 and each fused ring system is unsubstituted or is selected from the group consisting of halogen, -C １－６ Alkyl, -C １－６ Alkoxy, -haloC １－６ Alkyl, -haloC １－６ Alkoxy, or -C ３－６ 10. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, independently substituted with cycloalkyl.

12. 12. The compound of any one of claims 1 to 11, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond.

13. Cy １ but, a. a 5-7 membered monocyclic heterocyclyl or heteroaryl containing 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen, or sulfur as ring member(s); or b. a 7-14 membered bicyclic or tricyclic heterocyclyl or heteroaryl having 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur as ring member(s); Each of these is either unsubstituted or contains at least one substituent R ｉ 12. The compound of any one of claims 1 to 11, or a stereoisomer or pharmaceutically acceptable salt thereof, substituted with:

14. Cy １ but, a. the 5-7 membered monocyclic heteroaryl containing 1, 2, 3, or 4 heteroatom(s) selected from oxygen (O), nitrogen (N), or sulfur (S) as ring member(s), wherein the monocyclic heteroaryl is unsubstituted; or i. halogens, ii. cyano, iii. Unsubstituted or substituted with halogen, hydroxy, -C １－６ Alkoxy, —C(O)R ｍ , or -NR ｍ R ｎ -C substituted with １－６ Alkyl, iv. Unsubstituted or halogen, C １－６ Alkyl-, -C １－６ -C substituted with alkoxy １－６ heterocyclyl substituted with alkyl or oxo; v. Unsubstituted or substituted with halogen, -oxo, -C １－６ Alkyl, C １－６ Alkoxy- or -C １－６ -C substituted with alkoxy １－６ Alkyl-substituted —C ３－６ cycloalkyl, or vi. -OR ｊ wherein R ｊ But, -C １－６ Alkyl, -C １－６ -C substituted with alkoxy １－６ alkyl, or heterocyclyl; ｊ , vii. oxo, the 5- to 7-membered monocyclic heteroaryl substituted by one or two substituents selected from b. The aforementioned 7-14 membered bicyclic or tricyclic heteroaryl containing, as ring member(s), 1, 2, or 3 heteroatom(s) selected from oxygen, nitrogen, or sulfur, each of which is unsubstituted or substituted with halogen, —C １－６ Alkyl, —NH ２ , or -C(O)R ｍ wherein R ｍ But C １－６ 14. The compound of claim 13, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein said 7-14 membered bicyclic or tricyclic heteroaryl is alkyl, and wherein any of said alkyls is non-enriched or deuterium-enriched.

15. Cy １ is a 7- to 14-membered bicyclic heteroaryl in which R is a pyridinyl, pyrazolyl, thienyl, or thiazolyl ring fused to a 5- or 6-membered heterocyclyl ring, said 5- or 6-membered heterocyclyl ring containing one or two heteroatoms selected from oxygen or nitrogen as ring member(s), said 5- or 6-membered heterocyclyl ring being unsubstituted or containing one or two C １－６ 14. The compound of claim 13, or a stereoisomer or pharmaceutically acceptable salt thereof, which is substituted with alkyl or oxo, wherein either said alkyl or said alkoxy is non-enriched or deuterium-enriched.

16. Cy １ but, a. 【Chemistry 6】 b. 【Chemistry 7】 c. 【Chemistry 8】 d. 【Chemistry 9】 e. 【Chemistry 10】 f. 【Chemistry 11】 g. 【Chemistry 12】 h. 【Chemistry 13】 14. The compound of claim 13, wherein:

17. The compound is N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide, N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolan-2-yl)pyridin-2-yl]acetamide, N-(5-(1H-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(5-methylpyrazin-2-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)acetamide, N-(5-(2,6-dimethylpyrimidin-4-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(furan-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-1,2,4-triazol-3-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((3-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide, N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1H-pyrazol-1-yl)pyridin-2-yl)acetamide, N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(2-morpholino-2-oxoethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(6-cyano-4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-cyano-4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(1H-imidazol-1-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-cyclobutyl-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2-aminopropan-2-yl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(1H-imidazol-4-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1H-imidazol-4-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1H-imidazol-4-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide, N-(5-(6-methoxypyridazin-3-yl)-4-((6-(methylsulfonyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(6-isopropoxypyridazin-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(6-isopropoxypyridazin-3-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(6-isopropoxypyridazin-3-yl)-4-(4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-ylamino)pyridin-2-yl)acetamide, N-(4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-[3,3′-bipyridin]-6-yl)acetamide, N-(4'-((6-sulfamoylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-(methoxymethyl)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-(2-hydroxypropan-2-yl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-(2-hydroxypropan-2-yl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-morpholino-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,2-dimethylmorpholino)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-chloro-5-(2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-(methoxymethyl)morpholino)-[2,3'-bipyridin]-6'-yl)acetamide, (S)—N-(4′-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((tetrahydrofuran-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)acetamide, N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((tetrahydrofuran-3-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-((tetrahydrofuran-3-yl)oxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,5-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((cis)-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-((cis)-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((trans)-2,6-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(cis-2,6-dimethylmorpholino)-4'-((7-(methylsulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-5-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-((R)-2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-((R)-sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((cis)-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-((cis)-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-((R or S)-1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-((R or S)-1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(cis-2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(cis-2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)pyrazin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-((S)-3-methylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-((R)-3-methylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-(3-methoxyazetidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-methoxyethoxy)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-methoxyethoxy)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-methoxyethoxy)-4'-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-methoxyethoxy)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide, (R)—N-(5-(2-methoxyethoxy)-4′-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide, N-(5-(2-methoxyethoxy)-4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(methoxymethyl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(methoxymethyl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, (R)—N-(5-(methoxymethyl)-4′-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide, N-(4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-((1r,3r)-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(methoxymethyl)-4'-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-methyl-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-((trans)-3-hydroxycyclobutoxy)-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamidecarboxamide, N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-fluoro-4'-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-fluoro-4'-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-fluoro-4'-((3-((trans)-3-hydroxycyclobutoxy)-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-fluoro-4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-fluoro-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-fluoro-4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide, (S)—N-(4′-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3′-bipyridin]-6′-yl)acetamide, N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3,4-dimethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-fluoro-4'-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-cyclopropyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(trans)-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)-4-(oxetan-3-ylmethoxy)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-(methoxymethyl)-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-(3-hydroxypyrrolidin-1-yl)-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-(methylsulfonyl)-5-(trifluoromethoxy)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-methyl-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-cyclopropoxy-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((3-(difluoromethyl)-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)-4-(oxetan-3-yloxy)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(cis-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((4-(3-methoxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-cyclobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((5-fluoro-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((2-methyl-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4'-((6-(ethylsulfonyl)-4-isopropoxypyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((7-(methylsulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-5-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, (R)—N-(5-(2-hydroxypropan-2-yl)-4′-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3′-bipyridin]-6′-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((4-isobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, (S)—N-(4′-((4-(sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide, (R)—N-(4′-((4-(sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropan-2-yl)-[2,3′-bipyridin]-6′-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4'-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-sulfamoylpyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((6-(ethylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-methyl-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)-5-(trifluoromethoxy)phenyl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (R)—N-(4-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-((trans)-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-((cis)-3-hydroxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(3-methoxycyclobutoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(cyanomethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(oxetan-3-yloxy)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((3-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(oxetan-3-ylmethoxy)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((6-(cyclopropylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((6-(isopropylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-fluoro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-(difluoromethyl)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((3-(methoxymethyl)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-cyclopropoxy-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-((trans)-3-hydroxycyclobutoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-phenylpyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-phenoxypyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-chloro-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(difluoromethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-cyclobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(cyclopentyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-((tetrahydrofuran-3-yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(4-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(2,3-dihydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((5-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((5-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((6-(ethylsulfonyl)-4-isopropoxypyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((5-fluoro-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (S)—N-(4-((3-(2-hydroxypropoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (R)—N-(4-((3-(2-hydroxypropoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(difluoromethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-isobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (S)—N-(4-((4-(sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((3-(difluoromethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-(difluoromethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((7-(methylsulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-5-yl)amino)pyridin-2-yl)acetamide, (R)—N-(4-((4-(sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-cyclopropyl-1H-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-methoxy-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-methyl-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(methoxymethyl)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(cyclopentyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-ethyl-1H-pyrazol-3-yl)-4-((3-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-isopropyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-isopropyl-1H-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-isopropyl-1H-pyrazol-3-yl)-4-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-isopropyl-1H-pyrazol-3-yl)-4-((3-methoxy-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(4-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-isopropyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (R)—N-(4-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (S)—N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (R)—N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, (R)—N-(4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide, N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-([1,3]dioxolo[4,5-b]pyridin-5-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-7-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(imidazo[1,2-b]pyridazin-6-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(4-acetyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(benzo[b]thiophen-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(6,7-dihydro-4H-thieno[3,2-c]pyran-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-([1,3]dioxolo[4,5-b]pyridin-5-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-([1,3]dioxolo[4,5-b]pyridin-5-yl)-4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-([1,3]dioxolo[4,5-b]pyridin-5-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyridin-2-yl)acetamide, N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-((1,4-dioxan-2-yl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)pyrazin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]ylidin-6-yl)-4-((4-(2-hydroxypropan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((5-fluoro-4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-morpholinopyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-morpholinopyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((3,4-dimethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methyl-morpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methyl-morpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-pyridin-2-yl)acetamide, N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-methoxyethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(4-aminotetrahydro-2H-pyran-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((4-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxyazetidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R / S)—N-(4-((4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, (S / R)—N-(4-((4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(4-methoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((cis)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((trans)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(4-hydroxy-4-methylpiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-hydroxy-3-methylazetidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-hydroxy-3-methylpyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(6-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-5-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridazin-3-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-(2-hydroxyethoxy)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-(2-hydroxyethoxy)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)-3-oxo-3,4-dihydropyrazin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-ethoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-ethoxypiperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(3-(trifluoromethoxy)pyrrolidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(3-(trifluoromethoxy)pyrrolidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)-1-(2-((2-acetamido-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-yl)amino)-6-(methylsulfonyl)pyridin-4-yl)pyrrolidine-2-carboxamide, (R)-1-(2-((2-acetamido-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-4-yl)amino)-6-(methylsulfonyl)pyridin-4-yl)pyrrolidine-2-carboxamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-(methoxymethyl)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-(methoxymethyl)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((5-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((5-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(5-methylpyridazin-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(5-methoxypyridazin-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(cis-3-cyano-4-hydroxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((4-(trans-3-cyano-4-hydroxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((4-(cis-3-cyano-4-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((4-(trans-3-cyano-4-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-(methoxymethyl)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-(methoxymethyl)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((3-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((3-(3-methoxypyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, cis-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((cis-4-hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((trans-4-hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((cis-4-methoxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((trans-4-methoxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(5-azaspiro[2.4]heptan-5-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((3-methyloxetan-3-yl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3,5-dimethylisoxazol-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-((2,4-dioxothiazolidin-3-yl)methyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methoxy-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide, (R)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylpyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (S)—N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylpyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(pyrrolidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-hydroxypropan-2-yl)-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(3-azabicyclo[3.1.0]hexan-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, (S)—N-(4-((4-(3-(cyanomethoxy)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((6-cyano-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((2-cyano-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3-methylpyrazin-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, (R)—N-(4-((4-(2,2-dichlorocyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, (S)—N-(4-((4-(2,2-dichlorocyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((4-(5-cyanopyridazin-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((4-cyano-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(5-fluoropyridazin-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-fluoro-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6'-(methylsulfonyl)-[2,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(thiazol-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(1-cyanocyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((4-((3R)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((4-((3S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-methyl-2-morpholinopropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-methoxy-2-methylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(2-hydroxy-2-methylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(3,3-dimethylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-isopropyl-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-hydroxyethyl)-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(1-methoxyethyl)-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((7-(methylsulfonyl)-2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-5-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(difluoromethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(4-((4-cyclobutoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide, N-(5-(2,2-bis(methyl-d3)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-bis(methyl-d3)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(4,4-dimethyl-4,5-dihydrothiazol-2-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1,3a,4,6,7,7a-hexahydropyrano[4,3-c]pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(5-([1,3]dioxolo[4,5-c]pyridin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-([1,3]dioxolo[4,5-c]pyridin-4-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(benzo[d][1,3]dioxol-4-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(imidazo[1,2-a]pyrimidin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1,4-dihydrochromeno[4,3-c]pyrazol-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(imidazo[2',1':2,3]thiazolo[5,4-b]pyridin-7-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-7-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4'-((4,4-dioxido-2,3-dihydro-[1,4]oxathiino[3,2-b]pyridin-6-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(4-((4,4-dioxido-2,3-dihydro-[1,4]oxathiino[3,2-b]pyridin-6-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(imidazo[1,2-b]pyridazin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((7-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-5-yl)amino)pyridin-2-yl)acetamide, N-(4-((5,5-dioxido-3,4-dihydro-2H-[1,4]oxathiepino[3,2-b]pyridin-7-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-hydroxypropan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(1-hydroxycyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-hydroxy-2-methylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(3-hydroxy-2,2-dimethylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(imidazo[1,5-b]pyridazin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(3-hydroxytetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((4-(1-methyl-1H-pyrazol-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-((1-hydroxycyclopropyl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(4-((4-((1-methoxycyclopropyl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-morpholinopyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(benzo[d]thiazol-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((1,1-dioxide-3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-7-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((7-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-5-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)imidazo[1,2-a]pyrazin-8-yl)amino)pyridin-2-yl)acetamide, N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((5-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-(2-hydroxypropan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(tetrahydrofuran-3-yl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-(1-hydroxycyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-(2-hydroxy-2-methylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-(3-hydroxy-2,2-dimethylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-(3-methoxytetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-(3-hydroxytetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-(1-methyl-1H-pyrazol-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-((1-hydroxycyclopropyl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((4-((1-methoxycyclopropyl)methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-morpholinopyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((5,5-dioxide-3,4-dihydro-2H-[1,4]oxathiepino[3,2-b]pyridin-7-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((1,1-dioxide-3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-7-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((7-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-5-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-[1,3]dioxolo[4,5-c]pyridin-4-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)imidazo[1,2-a]pyrazin-8-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((5-(methylsulfonyl)-3,4-dihydro-2H-pyrano[3,2-c]pyridin-7-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(benzo[d][1,3]dioxol-4-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(benzo[d]isoxazol-3-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(benzo[d]isothiazol-3-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(benzo[b]thiophen-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(imidazo[1,2-a]pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1,4-dihydrochromeno[4,3-c]pyrazol-6-yl)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(imidazo[2',1':2,3]thiazolo[5,4-b]pyridin-7-yl)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-7-yl)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-oxo-1,6-dihydropyridazin-3-yl)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-oxopyridazin-1(6H)-yl)pyridin-2-yl)acetamide, N-(5-(6-((2S,6R)-2,6-dimethylmorpholino)pyridazin-3-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxo-8,9-dihydropyrano[4,3,2-de]phthalazin-2(3H)-yl)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(7-methyl-3-oxo-8,9-dihydro-3H-pyrido[4,3,2-de]phthalazin-2(7H)-yl)pyridin-2-yl)acetamide, N-(4'-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-oxoisoindolin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(5′H,7′H-spiro[cyclopropane-1,6′-pyrazolo[5,1-b][1,3]oxazine]-2′-yl)pyridin-2-yl)acetamide, N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyridin-2-yloxy)pyridin-2-yl)acetamide, N-(5-(1H-imidazol-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(4-(2-hydroxypropan-2-yl)furan-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(furan-2-yl)-4-((4-(3-methoxytetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(1H-benzo[d]imidazol-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(3-fluoro-5-(2-hydroxypropan-2-yl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(3-fluoro-5-(2-hydroxypropan-2-yl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2-hydroxypropan-2-yl)-4-methyl-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-((tetrahydrofuran-3-yl)methoxy)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide, N-(5-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-methoxy-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide, N-(5-(6,7-dihydro-4H-furo[3,2-c]pyran-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(5-methyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(cyclopropylmethoxy)-4-((4-(1-methyl-1H-pyrazol-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-((1-hydroxycyclopropyl)methoxy)-4-((4-(1-methyl-1H-pyrazol-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(benzo[d]oxazol-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(5-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide, N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrazin-2-yl)pyridin-2-yl)acetamide, N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-c]pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-c]pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-2-yl)pyridin-2-yl)acetamide, N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)acetamide, N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(pyrazolo[1,5-a]pyrimidin-5-yl)pyridin-2-yl)acetamide, or 17. The compound according to any one of claims 1 to 16, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from N-(5-(2,2-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)-4-((6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide.

18. 18. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 17, or stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable excipient.

19. 18. A composition for treating a disease, the composition comprising a compound according to any one of claims 1 to 17, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the disease is an inflammatory disease or an autoimmune disease.

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