Tyk-2 inhibitors

Abstract

Disclosed herein is a compound of Formula (I) for inhibiting TYK2 and treating diseases associated with undesirable tyk-2 activity (tyk-2 associated diseases), a method of treating an inflammatory disease or an autoimmune disease using the compound disclosed herein, and a pharmaceutical composition comprising the compound.

Description

TECHNICAL FIELD

[0001] Disclosed herein is a compound of Formula (I) for use in inhibiting TYK2 and treating diseases associated with undesirable tyk-2 activity (tyk-2 associated diseases), a method of using the compounds disclosed herein to treat an inflammatory disease or an autoimmune disease, and a pharmaceutical composition comprising the compound. BACKGROUND

[0002] The Janus kinase family includes JAK1, JAK2, JAK3, and Tyrosine Kinase 2 (Tyk2), and are non-receptor tyrosine kinases that bind to the intracellular domains of cell surface cytokine receptors. In response to stimulation of these receptors, Janus kinases phosphorylate signal transducer and activator 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 shown to play a critical role in the signaling cascade downstream of IL-12, IL-23, and type I interferon receptors in both 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-Murphy, 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 immunity”, Immunity, 25: 745-755 (2006)). Tyk2 mediates receptor-induced phosphorylation of STAT family members, a signal that is essential for dimerization of STAT proteins and STAT-dependent transcription of proinflammatory genes.Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis, and multiple sclerosis, demonstrating the importance of Tyk2-mediated signaling in autoimmunity 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 known small molecule JAK inhibitors that have entered the development stage are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein, also known as the JH1 or "Janus Homology 1" domain, which in turn hinders the catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and the resulting pathway signal transduction (Bryan, M. et al., "Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances", J. Med. Chem. 2018, 61, 9030-9058).It is well known that 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 that inhibition of JAK2 can lead to side effects such as anemia, neutropenia, and increased risk of infection and dyslipidemia (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, C.A 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 (WO 2014074661 Al, WO 2018183649 Al, WO 2018183656 Al, and WO 2019232138 Al) is the first TYK2-JH2 inhibitor, and multiple clinical trials are currently ongoing for psoriasis, ulcerative colitis (UC), lupus, and systemic lupus erythematosus. Another TYK2-JH2 inhibitor that is entering clinical trials is ABBV-712 (see, e.g., WO 2019178079 Al, WO 2019178079 A9, JP 6557436 Bl, and US 2019276450 Al), and ABBV-712 is in clinical trials for psoriasis. SUMMARY

[0005] The present disclosure provides a series of compounds that inhibit the pseudokinase (JH2) domain of TYK2. These compounds show picomolar to nanomolar biochemical activity in a TYK2-JH2 binding assay, and also show nanomolar activity in cellular assays. At the same time, these compounds show excellent selectivity against JAK1 in biochemical assays, and against JAK2 in cellular assays.

[0006] In the present disclosure, the compounds bind to the pseudokinase (JH2) domain of TYK2 and inhibit its function through an allosteric mechanism. At the same time, these compounds greatly improve selectivity over other JAK family members (JAK1, JAK2, and JAK3).

[0007] In a first aspect, disclosed herein are compounds of Formula (I)

[0008]

[0009] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0010] X is N or CH;

[0011] Y is N, NR 3 or CR 3 ;

[0012] 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-(CR a Rb ) 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)2NR b -、-NR a S(O)NR b -、-C(O)NR a SO2-、-C(O)NR a SO- or -C (=NR) a )NR b - where q is a number from 1 to 7, and,

[0013] R a and R b It is hydrogen and -C independently. 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0014] R 1 It is -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, aryl, or -NRc R d ;

[0015] R 2 , R 3 , and R 4 each independently is 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 ,

[0016] wherein each -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently and optionally substituted with at least one substituent selected from:

[0017] i) cyano, -oxo-, halogen, -NR m R n , -OR h , -C(O)NR m R n ;

[0018] ii) heterocyclyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R nSubstituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 1-6 Alkyl or -C(O)NR m R; or

[0019] iii) C that is optionally substituted with at least one substituent 1-6 Alkyl group, wherein the substituent is independently selected from cyano, halogen, hydroxyl, -NH2 or C 1-6 Alkoxy;

[0020] Where R h It is hydrogen, hydroxyl group, -NH2, -C 1-6 Alkyl groups, C groups substituted with hydroxyl groups 1-6 Alkyl or heterocyclic groups,

[0021] R e R f and R g Each is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be independently substituted by one to three substituents selected from the following: cyano, -oxo-, halogen, hydroxyl, -NR. m R n -C 1-6 Alkyl, -C 1-6 Alkyl group, optionally surrounded by halogen, hydroxyl group or -C 1-6 Alkoxy-substituted -C 3-6 Cycloalkyl, -C(O)NR m R n , or heterocyclic group;

[0022] R 5 Is it hydrogen or C? 1-6 alkyl;

[0023] Cy 1 It is a 6- to 12-membered aryl group, or a 5- to 14-membered heteroaryl group, or a 5- to 14-membered heterocyclic group, each optionally substituent R. i replace,

[0024] R i Independently, it is halogen, cyano, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 3-8cycloalkyl, 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 , wherein each of the -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, -OR m , -C(O)R m , -NR m R n , -C 1-6 alkyl, C 1-6 alkoxy-, C 1-6 alkyl substituted with -C 1-6 alkoxy, or -oxo-;

[0025] 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;

[0026] or (R 1 and R 2 ) or (R 2and R 3 ), or (R 3 ) and R 4 ) together with the atom to which they are attached form a fused ring system comprising 0-4 heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as one or more ring members and optionally and independently substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, C 1-6 alkyl substituted with halogen, C 1-6 alkoxy substituted with halogen, or -C 3-6 cycloalkyl;

[0027] any of said alkyl or alkoxy groups is optionally enriched in deuterium.

[0028] In some embodiments, disclosed herein are compounds of Formula (I-A)

[0029]

[0030] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0031] X is N or CH;

[0032] 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-(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)2NR b -、-NR a S(O)NR b -、-C(O)NR a SO2-、-C(O)NR a SO- or -C (=NR) a )NR b - where q is a number from 1 to 7, and,

[0033] R a and R b It is hydrogen and -C independently. 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0034] R 1 It is -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, aryl, or -NR m R n ;

[0035] R 2 R 3 and R 4 Each of these elements is independently hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 3-8 Cycloalkyl, heterocyclic, 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 Rf -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 -NR e SO2R f ,

[0036] wherein -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl is each independently and optionally substituted with at least one substituent chosen from cyano, oxo, halogen, C 1-6 alkyl optionally substituted with halogen, C 1-6 alkyl substituted with -OR h , -C(O)NR m R n , -NH2, -C 1-6 alkyl substituted with -NH2, or -C 1-6 alkyl substituted with -OC 1-6 alkyl; wherein R h is hydrogen, C 1-6 alkyl, or heterocyclyl,

[0037] 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, wherein each of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally and independently substituted with one to three substituents chosen from halogen, hydroxyl, cyano, or C 1-6 alkoxy; C 1-6 alkyl optionally substituted with halogen, hydroxyl, or C 3-6 cycloalkyl, or heterocyclyl;

[0038] R 5 is hydrogen or C 1-6 alkyl;

[0039] Cy 1 is 6- to 12-membered aryl or 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl, each of which is optionally substituted with at least one substituent R i , and wherein each R

[0040] R i is 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 , wherein each of said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally 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;

[0041] Rj , R k , R l , R m , R n each independently is hydrogen, -C 1-6 alkyl, -C 1-6 alkyl substituted with C 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0042] or (R 1 and R 2 ) or (R 2 and R 3 ) or (R 3 and R 4 ), together with the atoms to which they are attached, form a fused ring system comprising 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur as a ring member(s) and optionally and independently substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -haloC 1-6 alkoxy, or -C 3-6 cycloalkyl;

[0043] any of said alkyl or alkoxy groups are optionally enriched in deuterium.

[0044] 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.

[0045] In some embodiments, R 1 is -C 1-3 alkyl, -NR c R d , or -C 3-6 cycloalkyl, preferably -NH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclopentyl.

[0046] In some embodiments, R 2 and R 4 are each independently hydrogen, halogen, -C 1-6 alkyl, or -C 1-6 alkoxy, preferably hydrogen, fluorine, methyl, methoxy, ethoxy, or isopropoxy.

[0047] In some embodiments, R 3 is

[0048] -hydrogen;

[0049] - cyano;

[0050] - halogen;

[0051] - C 1-4 alkyl, optionally substituted with at least one substituent independently selected from halogen, 3- to 6-membered heterocyclyl, or -OR h wherein

[0052] 3- to 6-membered heterocyclyl comprising one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (O) as ring member(s), which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , C 1-6 alkyl, -C 1-6 alkoxy, or -C(O)NR m R n wherein -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl, or C 1-6 alkoxy; and

[0053] R h is hydrogen, alkyl, or heterocyclyl;

[0054] - C 3-6 cycloalkyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, -NR m R n , hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, or -C(O)NR m R n wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl, or C 1-6 alkoxy;

[0055] - heterocyclyl comprising one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s), which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo-, halogen, hydroxyl, C 1-6 alkyl, alkoxy, -NRR m R n , or -C(O)NR m R nand wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy;

[0056] -C e wherein R e is -C 1-6 alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, or aryl, wherein i) -C 1-6 alkyl is optionally substituted with cyano, -oxo-, halo, hydroxyl, -NR m R n , -C 1-6 alkyl-, -C m alkoxy-, optionally substituted with cyano, -oxo, halo, hydroxyl, -NR n R 1-6 , -C 1-6 alkyl, C m alkoxy or -C(O)NR n R 3-6 substituted -C 1-6 cycloalkyl, optionally substituted with cyano, halo, hydroxyl, C 1-6 alkyl or C 3-6 alkoxy; and,

[0057] ii) -C m R n , C 1-6 alkyl, C 1-6 alkoxy or -C(O)NR m R n substituted, wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy;

[0058] -C 5-10 aryl; or

[0059] -heteroaryl comprising one oxygen (O), nitrogen (N) or sulfur (S) heteroatom as a ring member, which heteroaryl is optionally substituted with at least one substituent independently selected from cyano, -oxo-, halo, hydroxyl, -NR m R n , -C 1-6 alkyl, -C1-6 alkyl or C m R n wherein -C 1-6 alkyl or C 1-6 alkyl or C 1-6 alkyl or C 1-6 alkyl or C

[0060] and wherein R m and R n are independently selected from hydrogen or C 1-3 alkyl;

[0061] any of said alkyl or alkoxy groups is optionally enriched in deuterium.

[0062] In some embodiments, R 3 is

[0063] hydrogen;

[0064] cyano;

[0065] halogen;

[0066] -C 1-4 alkyl optionally substituted by at least one substituent independently selected from halogen, 3- to 6-membered heterocyclyl or -OR h wherein

[0067] said 3- to 6-membered heterocyclyl comprises one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (O) as one or more ring members, which heterocyclyl is optionally substituted by at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , C 1-6 alkyl, -C 1-6 alkyl or C m alkyl or C n wherein -C 1-6 alkyl or C 1-6 alkyl or C 1-6 alkyl or C 1-6 alkyl or C

[0068] R h is hydrogen, alkyl or heterocyclyl (preferably, 3- to 6-membered heterocyclyl, e.g., tetrahydrofuranyl, thiazolidinyl);

[0069] -C 3-6Cycloalkyl group, optionally substituted independently by at least one of the following substituents: cyano, -oxo, halogen, -NR. m R n hydroxyl group, -C 1-6 Alkyl, -C 1-6 Alkyl or -C(O)NR m R n , where -C 1-6 Alkyl or C 1-6 The alkoxy group is independently substituted by at least one of the following substituents: cyano, halogen, hydroxyl, -NH2, -C 1-6 Alkyl or C 1-6 Alkoxy;

[0070] - Heterocyclic groups, preferably 4- to 6-membered monocyclic saturated heterocyclic groups, saturated monospirocyclic heterocyclic groups, saturated bicyclic fused heterocyclic groups, or saturated bridged heterocyclic groups, comprising one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as one or more ring members; more preferably morpholino, tetrahydrofurano, tetrahydropyrano, pyrrolidinyl, 1,4-dioxane, piperidinyl, or aziridine, optionally having at least one independently selected from cyano, -oxo, halogen, hydroxyl, -C 1-6 Alkyl, alkoxy, -NR m R n 、or -C(O)NR m R n The substituents are substituted, and where -C 1-6 Alkyl or -C 1-6 The alkoxy group is independently selected from at least one cyano, halogen, hydroxyl, -NH2, -C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups;

[0071] --OR e , where R e It is -C 1-6 Alkyl, -C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic groups (preferably 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen heteroatom as a ring member), or aryl, wherein

[0072] i)-C 1-6 Alkyl groups may optionally be substituted with: cyano, -oxo-, halogen, hydroxyl, -NR m R n -C 1-6 Alkyl group, optionally replaced by cyano, -oxo, halogen, hydroxyl, or -NR m R n -C 1-6 Alkyl, C 1-6 Alkyl or -C(O)NRm R n substituted -C 3-6 cycloalkyl, optionally substituted with cyano, halo, hydroxyl, -C 1-6 alkyl or -C 1-6 alkoxy; and,

[0073] ii) -C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl, optionally substituted with cyano, -oxo, halo, hydroxyl, NR m R n , C 1-6 alkyl, C 1-6 alkoxy or -C(O)NR m R n substituted, wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy;

[0074] -C 5-10 aryl; or

[0075] -heteroaryl, preferably a 5- to 6-membered heteroaryl comprising one oxygen (O), nitrogen (N) or sulfur (S) heteroatom as a ring member, which heteroaryl is optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, hydroxyl, NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy;

[0076] and wherein R m and R n are independently selected from hydrogen or C 1-3 alkyl.

[0077] In some embodiments, R 3 is

[0078] -hydrogen, cyano, halo;

[0079] -C 1-4alkyl, -C(O)NR h wherein the 3- to 6-membered heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, thiazolidinyl, or azetidinyl, each optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, hydroxyl, -NR m R n , C 1-6 alkyl, -C 1-6 alkyl, -C m alkyl, -C(O)NR n R 1-6 wherein -C 1-6 alkyl or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl, and R h is hydrogen, C 1-6 alkyl, or 3- to 6-membered heterocyclyl (e.g., tetrahydrofuranyl or thiazolidinyl);

[0080] -C 3-6 cycloalkyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, NR m R n , hydroxyl, -C 1-6 alkyl, -C 1-6 alkyl, -C(O)NR m R n , hydroxyl, or C 1-6 alkyl, wherein -C 1-6 alkyl or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl, and R 1-6 is hydrogen, C 1-6 alkyl, or 3- to 6-membered heterocyclyl (e.g., tetrahydrofuranyl or thiazolidinyl);

[0081] -heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, the heterocyclyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, hydroxyl, C 1-6 alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n , and wherein -C 1-6 alkyl or -C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C1-6 alkyl or -C 1-6 substituted by a substituent of alkoxy;

[0082] -OR e wherein R e is -C 1-6 alkyl, -C 3-6 cycloalkyl, 4- to 6-membered monocyclic saturated heterocyclyl comprising one oxygen atom as a ring member, or C 6-10 aryl, wherein

[0083] i) -C 1-6 alkyl is optionally substituted by cyano, -oxo, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl-, -C m alkoxy-, optionally substituted by cyano, -oxo, halogen, hydroxyl, -NR n R 1-6 , -C 1-6 alkyl, -C m alkoxy or -C(O)NR n R 3-6 substituted -C 1-6 cycloalkyl, optionally substituted by cyano, halogen, hydroxyl, -C 1-6 alkyl or -C 3-6 alkoxy; and,

[0084] ii) -C m cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted by cyano, -oxo, halogen, hydroxyl, NR n R 1-6 , C 1-6 alkyl, C m alkoxy or -C(O)NR n R 1-6 substituted, wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted by at least one substituent independently selected from the group consisting of cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 6-10 alkoxy;

[0085] -C m aryl; or

[0086] -5- to 6-membered heteroaryl selected from the group consisting of pyridyl, pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each of which is optionally substituted by at least one substituent independently selected from the group consisting of cyano, -oxo, halogen, hydroxyl, -NR n R 1-6 , -C 1-6alkyl or C m R n wherein -C 1-6 alkyl or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C m and R n are independently selected from hydrogen or -C 1-3 alkyl.

[0087] In some embodiments, R 3 is

[0088] -hydrogen, cyano, halo;

[0089] -C 1-4 alkyl optionally substituted with at least one substituent independently selected from halo, hydroxyl, C 1-3 alkyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, hydroxyl, -NR m R n , or -C 1-3 alkyl;

[0090] -C 3-6 cycloalkyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, -NR m R n , hydroxyl, C 1-6 alkyl, or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-3 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C

[0091] -heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, hydroxyl, C 1-6 alkyl, alkoxy, -NR m R n , or -C(O)NR m R n alkyl or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C1-6 substituted by a substituent selected from halo, hydroxy, -NR

[0092] --OR e wherein R e is -C 1-6 alkyl, -C 3-6 cycloalkyl, 4- to 6-membered monocyclic saturated heterocyclyl comprising one oxygen atom as a ring member, or C 6-10 aryl, wherein

[0093] i) -C 1-6 alkyl optionally substituted by cyano, -oxo, halo, hydroxy, -NR m R n , -C 1-6 alkoxy-, optionally substituted by cyano, -oxo, halo, hydroxy, -NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n substituted -C 3-6 cycloalkyl, optionally substituted by cyano, halo, hydroxy, -C 1-6 alkyl or -C 1-6 alkoxy; and,

[0094] ii) -C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl optionally substituted by cyano, -oxo, halo, hydroxy, -NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n substituted, wherein -C 1-6 alkyl or -C 1-6 alkoxy is substituted by at least one substituent independently selected from cyano, halo, hydroxy, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy;

[0095] --C 6-10 aryl; or

[0096] -5- to 6-membered heteroaryl selected from pyridyl, pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each of which is optionally substituted by at least one substituent independently selected from cyano, -oxo, halo, hydroxy, -NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NRm R n , -C 1-6 alkyl or -C 1-6 alkoxy is optionally substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy is optionally substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C m alkyl or -C n alkoxy is optionally substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-3 alkyl.

[0097] In some embodiments, R 3 is

[0098] - hydrogen, cyano, halo;

[0099] - methyl, ethyl, propyl or butyl, each optionally substituted with at least one substituent independently selected from halo, hydroxyl, methoxy, ethoxy, propoxy, or 2,4-dioxothiazolidin-3-yl;

[0100] - cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, -NR m R n , hydroxyl, -C 1-3 alkyl, or -C 1-3 alkoxy is optionally substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-3 alkyl or -C 1-3 alkoxy is optionally substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C

[0101] - 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]heptan-3-yl, 3-azabicyclo[3.1.0]hexan-3-yl or 2-azabicyclo[3.1.0]hexan-2-yl, each optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -NR m R n , or -C(O)NR m R nThe substituents are substituted, and where -C 1-6 Alkyl or C 1-6 The alkoxy group is independently selected from at least one cyano, halogen, hydroxyl, -NH2, -C 1-6 Alkyl or -C 1-6 Substitution of alkoxy groups;

[0102] --OR e , where R e yes

[0103] i) Methyl, ethyl, propyl (isopropyl), butyl, pentyl, or hexyl, each optionally substituted with: deuterium, cyano, -oxo-, halogen, hydroxyl, -NR m R n -C 1-3 Alkyl group, optionally replaced by cyano, -oxo, halogen, hydroxyl, or -NR m R n -C 1-3 Alkyl, -C 1-3 Alkyl or -C(O)NR m R n Replacement -C 3-6 Cycloalkyl, or optionally dilated by cyano, halogen, hydroxyl, -C 1-3 Alkyl or -C 1-3 Alkoxy-substituted 4- to 6-membered heterocyclic groups; or

[0104] 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, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, 1,4-dioxane-2-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, aziridine-1-yl, aziridine-2-yl, or aziridine-3-yl, each optionally prefixed with a cyano, -oxo, halogen, hydroxyl, or -NR group. m R n -C 1-3 Alkyl, -C 1-3 Alkyl or -C(O)NR m R n Replace, where -C 1-3 Alkyl or -C 1-3 The alkoxy group is independently selected from at least one cyano, halogen, hydroxyl, -NH2, -C 1-3 Alkyl or -C 1-3 Substitution of alkoxy groups;

[0105] --C 6-10 Aryl; or

[0106] -5- to 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 optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , -C 1-3 alkyl, -C 1-3 alkoxy, or -C(O)NR m R n , wherein the -C 1-3 alkyl or -C 1-3 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-3 alkyl, or C 1-3 alkoxy;

[0107] and wherein R m and R n are independently selected from hydrogen or -C 1-3 alkyl.

[0108] In some embodiments, R 3 is

[0109] -hydrogen;

[0110] -methyl, 1-methoxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, or (2,4-dioxothiazolidin-3-yl)methyl;

[0111] - 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;

[0112] -cyano

[0113] -3-methoxycyclobutyl, (trans)-3-methoxycyclobutyl, (cis)-3-methoxycyclobutyl, 2,2-dichlorocyclopropyl, or 1-cyanocyclopropyl;

[0114] - morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, 3(S)-methyl-morpholino, 3,3-dimethylmorpholino;

[0115] - 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;

[0116] - 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, 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;

[0117] - 5-azaspiro[2.4]heptan-5-yl;

[0118] - tetrahydrofuran-3-yl;

[0119] - 3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl;

[0120] - 1,4-dioxan-2-yl;

[0121] - 4-aminotetrahydro-2H-pyran-4-yl, 4-(aminomethyl)tetrahydro-2H-pyran-4-yl,

[0122] - 4-methoxy-piperidin-1-yl, 4-hydroxy-4-methyl-piperidin-1-yl, 1-(2,2,2- trifluoroethyl)piperidin-4-yl, 3-methoxy-piperidin-1-yl, 3(R)-methoxy-piperidin-1-yl, 3(S)-methoxy-piperidin-1-yl, 3-ethoxy-piperidin-1-yl, 3(R)-ethoxy-piperidin-1-yl, 3(S)-ethoxy-piperidin-1-yl;

[0123] - 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.

[0124] In some embodiments, (R 1 and R 2 ) or (R 2 and R 3 ) or (R 3 and R 4 ), together with the atoms to which they are attached, form a fused 5- to 7-membered ring system comprising 0-2 oxygen heteroatoms as one or more ring members and optionally and independently substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -haloC 1-6 alkoxy, or -C 3-6 cycloalkyl.

[0125] In some embodiments, R 1 and R 2 , together with the atoms to which they are attached, form a fused ring system selected from In some embodiments, R 2 and R 3 , together with the atoms to which they are attached, form a fused ring system In some embodiments, R 3 and R 4 , together with the atoms to which they are attached, form a fused ring system selected from A fused ring system; and wherein each fused ring system is optionally and independently affected by a halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 alkoxy or -C 3-6 Cycloalkyl substitution.

[0126] In some embodiments, Cy 1 yes

[0127] - A 5- to 7-membered monocyclic heterocyclic group or heteroaryl group, wherein the heterocyclic group or heteroaryl group comprises one, two, three, or four heteroatoms selected from oxygen, nitrogen, or sulfur as one or more ring members, or

[0128] - A 7- to 14-membered bicyclic or tricyclic heterocyclic group or heteroaryl group, wherein the heterocyclic group or heteroaryl group has one, two, or three heteroatoms selected from oxygen, nitrogen, or sulfur as one or more ring members.

[0129] Each of them is optionally substituent R i replace.

[0130] In some embodiments, Cy 1 yes

[0131] - The 5- to 7-membered monocyclic heteroaryl group comprises one, two, three, or four heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as one or more ring members, preferably pyrazolyl, triazolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, pyridinyl, pyridazinyl, or pyrimidinyl, wherein the monocyclic heteroaryl group is optionally substituted by one or two substituents selected from the following:

[0132] i. Halogens;

[0133] ii. Cyano group;

[0134] iii.-C 1-6 Alkyl groups, optionally surrounded by halogens, hydroxyl groups, or -C 1-6 Alkoxy, -C(O)R m (Preferably, R) m (Is it morpholino) or -NR m R n replace;

[0135] iv. Heterocyclic group, optionally coated with halogen, C 1-6 Alkyl-, β-C 1-6 Alkoxy-substituted -C 1-6alkyl, or oxo; preferably, the heterocyclyl group is selected from tetrahydrofuranyl (preferably, tetrahydrofuran-3-yl), morpholinyl (preferably, morpholino), 2-oxa-5- azabicyclo[2.2.1]heptyl (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 with methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-butyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, or oxo;

[0136] v.-C 3-6 cycloalkyl, optionally substituted with halogen, -oxo, -C 1-6 alkyl, C 1-6 alkoxy-, or -C 1-6 alkyl, optionally substituted with -C 1-6 alkyl; or

[0137] vi.-OR j wherein R j is -C 1-6 alkyl, -C 1-6 alkyl, -C 1-6 alkyl, or heterocyclyl;

[0138] vii. oxo;

[0139] - the 7- to 14-membered bicyclic or tricyclic heteroaryl group comprising 1, 2, or 3 heteroatoms as ring member(s), preferably is benzoimidazolyl, 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-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 optionally substituted with halo, -C(O)R 1-6 alkyl, -NH2, or -C(O)R m wherein R m is C 1-6 alkyl.

[0140] In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl group which is a pyridinyl ring, pyrazolyl ring, thiophenyl ring, or thiazolyl ring fused to a 5- or 6-membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring comprises one or two heteroatoms selected from oxygen or nitrogen as ring member(s) and the 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C 1-6 alkyl or oxo, preferably two C 1-6alkyl, more preferably, two methyl groups, most preferably two methyl groups on the same carbon atom. In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridyl ring fused to a 5- or 6- membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring comprises one or two heteroatoms selected from oxygen (O) or nitrogen (N) as one or more ring members and the 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C 1-6 alkyl or oxo, preferably, two C 1-6 alkyl, more preferably, two methyl groups, most preferably two methyl groups on the same carbon atom. In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridyl ring fused to a 5- or 6- membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring comprises two oxygen atoms as one or more ring members and the 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C 1-6 alkyl, preferably, two C 1-6 alkyl, more preferably, two methyl groups, most preferably two methyl groups on the same carbon atom. In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl that is a pyridyl ring fused to a 1,4- dioxane ring, wherein the 1,4-dioxane ring is optionally substituted with one or two C 1-6 alkyl, preferably, two C 1-6 alkyl, more preferably, two methyl groups, most preferably two methyl groups on the same carbon atom; any of the alkyl or alkoxy groups are optionally enriched in deuterium. In some preferred embodiments, Cy 1 is preferably

[0141] In some embodiments, Cy 1 is

[0142]

[0143]

[0144]

[0145] In one embodiment, disclosed herein is a compound of Formula (I-B):

[0146]

[0147] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0148] X is N or CH;

[0149] 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-(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)2NR 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, and;

[0150] R a and R b are independently hydrogen, -C 1-6 alkyl, -C2-6 alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl;

[0151] R 1 It is -C 1-6 Alkyl, -halogenated C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkoxy, -C 3-6 cycloalkyl, aryl, or -NR c R d ;

[0152] R 2 R 3 and R 4 Each of these elements is independently hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 3-8 Cycloalkyl, heterocyclic (preferably morpholino-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 ,

[0153] Where -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 3-8 Each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is independently and optionally substituted by at least one substituent selected from the following: halogen, hydroxyl-C1-6 Alkyl (preferably hydroxymethyl), -OR h or C 1-6 Alkoxy-C 1-6 alkyl-;

[0154] Where R h It is a hydrogen, alkyl, or heterocyclic group.

[0155] R e R f and R g Each is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be independently substituted by one to three substituents selected from the following: halogen, hydroxyl, cyano, -C 1-6 Alkyl group; optionally coated with halogen, hydroxyl group or C 1-6 Alkoxy-substituted -C 3-6 cycloalkyl; R 5 Is it hydrogen or C? 1-6 alkyl;

[0156] Cy 1 It is a 6- to 12-membered aryl group, or a 5- to 14-membered heteroaryl group, or a 5- to 14-membered heterocyclic group, each optionally substituent R. i replace,

[0157] R i Independently, it is halogen, cyano, -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 3-8 Cycloalkyl, heterocyclic, 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 CONRk R l -NR j CO2R k -NR j SONR k R l -NR j SO2NR k R l , or -NR j SO2R k ,

[0158] Wherein -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 3-8 Each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is optionally halogenated, 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;

[0159] R j R k R l R m R n Each is independently hydrogen, -C 1-6 Alkyl, C 1-6 Alkoxy-C 1-6 Alkyl-, -C 2-6 alkenyl, -C 2-6 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0160] Or (R) 1 and R 2 ) or (R 2 and R 3 ) or (R 3 and R 4 Together with the atoms to which they are attached, they form a fused ring system comprising 0-4 heteroatoms selected from oxygen, nitrogen, or sulfur as one or more ring members and optionally and independently influenced by halogens, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 alkoxy or -C 3-6 Cycloalkyl substitution;

[0161] Any of the alkyl or alkoxy groups can optionally be enriched in deuterium.

[0162] In some embodiments, disclosed herein are compounds of Formula (I-C)

[0163]

[0164] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0165] X is N or CH;

[0166] L 1 is a direct bond;

[0167] R 1 is -C 1-6 alkyl or -haloC 1-6 alkyl;

[0168] R 2 and R 4 each independently are hydrogen, halogen, -C 1-6 alkyl or -C 1-6 alkoxy;

[0169] R 3 independently are 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,

[0170] Where -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -C 3-8 Each of the cycloalkyl, heterocyclic, aryl, or heteroaryl groups is independently and optionally substituted by at least one substituent selected from the following:

[0171] i) Cyano, oxo, halogen, -NH2, -OR h -C(O)NR m R n ;

[0172] ii) A heterocyclic group optionally substituted with at least one substituent, which is independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n Substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 1-6 Alkyl or -C(O)NR m R; or

[0173] iii)C 1-6 Alkyl groups may optionally be substituted with: halogens, -C substituted with hydroxyl groups (preferably hydroxymethyl, hydroxyethyl). 1-6 Alkyl group, -C replaced by -NH2 1-6 Alkyl, -NH2 or C 1-6 Alkoxy-substituted -C 1-6 alkyl;

[0174] Where R h It is hydrogen, hydroxyl, alkyl group substituted with hydroxyl, or heterocyclic group.

[0175] R e R f and R g Each is independently hydrogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 2-6 alkenyl, -C 2-6 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 Each of the alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl groups may optionally be independently substituted by one to three substituents selected from the following: halogen, hydroxyl, cyano, -oxo-, -NR. m R n -C 1-6 Alkyl, -C 1-6 Alkyl group; optionally coated with halogen, hydroxyl group, or C1-6 alkoxy-substituted -C 3-6 cycloalkyl, -C(O)NR m R n , or heterocyclyl;

[0176] R 5 is hydrogen or C 1-6 alkyl;

[0177] Cy 1 is a 7- to 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 members, which is optionally substituted with at least one substituent R i substituted,

[0178] R i independently is 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 ,

[0179] wherein each of said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally 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-substituted C 1-6 Alkyl or oxo-substituted;

[0180] R j R k R l R m R n Each is independently hydrogen, -C 1-6 Alkyl, C 1-6 Alkoxy-substituted -C 1-6 Alkyl, -C 2-6 alkenyl, -C 2-6 Alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl;

[0181] Or (R) 1 and R 2 ) or (R 2 and R 3 ) or (R 3 and R 4 These atoms, together with the atoms to which they are attached, form a fused ring system comprising 0-4 heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as one or more ring members and optionally and independently influenced by halogens, -C 1-6 Alkyl, -C 1-6 Alkoxy, -halogenated C 1-6 Alkyl, -halogenated C 1-6 alkoxy or -C 3-6 Cycloalkyl substitution;

[0182] Either of the alkyl or alkoxy groups is optionally enriched with deuterium.

[0183] In some embodiments, R 1 It is -C 1-3 Alkyl, preferably methyl, ethyl, propyl, or isopropyl.

[0184] In some embodiments, R 2 and R 4 Each is independently hydrogen, halogen, -C 1-3 Alkyl, or -C 1-3 Alkoxy, preferably hydrogen, fluorine, methyl, methoxy, ethoxy or isopropoxy.

[0185] In some embodiments, R 3 yes

[0186] -hydrogen;

[0187] -cyano;

[0188] -halogen;

[0189] --C 1-4 alkyl optionally substituted with at least one substituent independently selected from halogen, 3- to 6-membered heterocyclyl, or -OR h wherein

[0190] 3- to 6-membered heterocyclyl comprising one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (O) as one or more ring members, the heterocyclyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , C 1-6 alkyl, -C 1-6 alkoxy, or -C(O)NR m R n wherein -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl, or C 1-6 alkoxy; and

[0191] R h is hydrogen, alkyl, or heterocyclyl;

[0192] --C 3-6 cycloalkyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, -NR m R n , hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, or -C(O)NR m R n wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl, or C 1-6 alkoxy;

[0193] -heterocyclyl comprising one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as one or more ring members, the heterocyclyl optionally substituted with at least one substituent independently selected from cyano, -oxo-, halogen, hydroxyl, C 1-6 alkyl, alkoxy, -NRR m R n , or -C(O)NRm R n , and wherein -C 1-6 alkyl or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkyl;

[0194] -C e , wherein R e is -C 1-6 alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, or aryl, wherein

[0195] i) -C 1-6 alkyl optionally substituted with cyano, -oxo-, halo, hydroxyl, -NR m R n , -C 1-6 alkyl-, optionally substituted with cyano, -oxo-, halo, hydroxyl, -NR m R n , -C 1-6 alkyl, C 1-6 alkyl, or -C(O)NR m R n substituted -C 3-6 cycloalkyl, optionally substituted with cyano, halo, hydroxyl, C 1-6 alkyl, or C 1-6 alkyl; and,

[0196] ii) -C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl optionally substituted with cyano, -oxo-, halo, hydroxyl, -NR m R n , C 1-6 alkyl, C 1-6 alkyl, or -C(O)NR m R n substituted, wherein -C 1-6 alkyl or C 1-6 alkyl is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkyl;

[0197] -C 5-10 aryl; or

[0198] -heteroaryl comprising one oxygen (O), nitrogen (N), or sulfur (S) heteroatom as a ring member, optionally substituted with at least one substituent independently selected from cyano, -oxo-, halo, hydroxyl, -NRm R n , -C 1-6 alkyl, -C 1-6 alkoxy, or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy;

[0199] and wherein R m and R n are independently selected from hydrogen or C 1-3 alkyl;

[0200] any of said alkyl or alkoxy groups is optionally enriched in deuterium.

[0201] In some preferred embodiments, R 3 is a heterocyclyl comprising one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as one or more ring members, which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo-, halogen, hydroxyl, C 1-6 alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n , and wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy.

[0202] In some embodiments, R 3 is

[0203] -hydrogen;

[0204] -cyano;

[0205] -halogen;

[0206] -C 1-4 alkyl, which is optionally substituted with at least one substituent independently selected from halogen, 3- to 6-membered heterocyclyl, or -OR h , wherein

[0207] The 3- to 6-membered heterocyclyl comprises one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (O) as one or more ring members, which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy; and,

[0208] R h is hydrogen, alkyl or heterocyclyl (preferably, 3- to 6-membered heterocyclyl, e.g., tetrahydrofuranyl, thiazolidinyl);

[0209] -C 3-6 cycloalkyl, which is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, -NR m R n , hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy;

[0210] -heterocyclyl, preferably 4- to 6-membered monocyclic saturated heterocyclyl, saturated monospire heterocyclyl, saturated bicyclic fused heterocyclyl, or saturated bridged heterocyclyl, which comprises one or two heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as one or more ring members; more preferably morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or azetidinyl, which is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -C 1-6 alkyl, alkoxy, -NR m R n , or -C(O)NR m R n , wherein -C 1-6 alkyl or -C 1-6alkyl, -C 1-6 alkyl, -C 1-6 alkyl, -C

[0211] -OR e wherein R e is -C 1-6 alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl (preferably, 4- to 6-membered monocyclic saturated heterocyclyl comprising one oxygen atom as a ring member), or aryl, wherein

[0212] i) -C 1-6 alkyl optionally substituted with cyano, -oxo-, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl-, optionally substituted with cyano, -oxo-, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl, C 1-6 alkyl-, or -C(O)NR m R n substituted -C 3-6 cycloalkyl, optionally substituted with cyano, halogen, hydroxyl, -C 1-6 alkyl-, or -C 1-6 alkyl-; and,

[0213] ii) -C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl optionally substituted with cyano, -oxo-, halogen, hydroxyl, NR m R n , C 1-6 alkyl, C 1-6 alkyl-, or -C(O)NR m R n substituted -C 1-6 alkyl or C 1-6 alkyl-; and, 1-6 alkyl-; and, 1-6 alkyl-;

[0214] -C 5-10 aryl; or

[0215] -heteroaryl, preferably 5- to 6-membered heteroaryl comprising one oxygen (O), nitrogen (N) or sulfur (S) heteroatom as a ring member, optionally substituted with at least one substituent independently selected from cyano, -oxo-, halogen, hydroxyl, -NR m Rn -C 1-6 Alkyl, -C 1-6 Alkyl or -C(O)NR m R n , where -C 1-6 Alkyl or C 1-6 The alkoxy group is independently substituted by at least one of the following substituents: cyano, halogen, hydroxyl, -NH2, -C 1-6 Alkyl or C 1-6 Alkoxy;

[0216] And R m and R n Independently selected from hydrogen or C 1-3 alkyl.

[0217] In some preferred embodiments, R 3 It is a heterocyclic group, preferably a 4- to 6-membered monocyclic saturated heterocyclic group, a saturated monospirocyclic heterocyclic group, a saturated bicyclic fused heterocyclic group, or a saturated bridged heterocyclic group, which contains one or two heteroatoms selected from oxygen (O), nitrogen (N), or sulfur (S) as one or more ring members; more preferably it is morpholino, tetrahydrofurano, tetrahydropyrano, pyrrolidinyl, 1,4-dioxyl, piperidinyl, or azircyclic butyl, which optionally has at least one independently selected from cyano, -oxo, halogen, hydroxyl, -C 1-6 Alkyl, alkoxy, -NR m R n 、or -C(O)NR m R n The substituents are substituted, and where -C 1-6 Alkyl or -C 1-6 The alkoxy group is independently selected from at least one cyano, halogen, hydroxyl, -NH2, -C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups.

[0218] In some embodiments, R 3 yes

[0219] - Hydrogen, cyano, halogen;

[0220] --C 1-4 Alkyl group, optionally substituted independently with at least one of the following substituents: halogen, 3- to 6-membered heterocyclic group or -OR h ,in

[0221] The 3- to 6-membered heterocyclic groups are selected from morpholino, tetrahydrofurano, tetrahydropyrano, pyrrolidinyl, 1,4-dioxane, piperidinyl, thiazolyl, or azacyclic butyl, each optionally being independently substituted by at least one of the following substituents: cyano, -oxo, halogen, hydroxyl, -NR.m R n , C 1-6 alkyl, -C 1-6 alkoxy, or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy, and R h is hydrogen, C 1-6 alkyl, or 3- to 6-membered heterocyclyl (e.g., tetrahydrofuranyl or thiazolidinyl);

[0222] -C 3-6 cycloalkyl optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, NR m R n , hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, or -C(O)NR m R n , hydroxyl, or C 1-6 alkoxy, wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy;

[0223] -heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, hydroxyl, C 1-6 alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n , and wherein -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy;

[0224] -OR e , wherein R e is -C 1-6 alkyl, -C 3-6cycloalkyl, 4- to 6-membered monocyclic saturated heterocyclyl comprising one oxygen atom as a ring member, or C 6-10 aryl, wherein

[0225] i) -C 1-6 alkyl optionally substituted with cyano, -oxo-, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl, -C m alkoxy-, optionally substituted with cyano, -oxo, halogen, hydroxyl, -NR n R 1-6 , -C 1-6 alkyl, -C m alkoxy or -C(O)NR n R 3-6 substituted with cycloalkyl, optionally substituted with cyano, halogen, hydroxyl, -C 1-6 alkyl or -C 1-6 alkoxy; and,

[0226] ii) -C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl optionally substituted with cyano, -oxo, halogen, hydroxyl, NR m R n , C 1-6 alkyl, C 1-6 alkoxy or -C(O)NR m R n substituted, wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy;

[0227] -C 6-10 aryl; or

[0228] -5- to 6-membered heteroaryl selected from pyridyl, pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each of which is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m and R n are independently selected from hydrogen or -C 1-3 alkyl.

[0229] In some preferred embodiments, R 3 is a heterocyclyl selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, C 1-6 alkyl, alkoxy, -NRR m R n , or -C(O)NR m R n , and wherein -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy.

[0230] In some embodiments, R 3 is

[0231] -hydrogen, cyano, halogen;

[0232] -C 1-4 alkyl, which is optionally substituted with at least one substituent independently selected from halogen, hydroxyl, C 1-3 alkoxy, which is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , or -C 1-3 alkyl;

[0233] -C 3-6 cycloalkyl, which is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, -NR m R n , hydroxyl, C 1-6 alkyl, or C 1-6 alkoxy, wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or -C 1-3 alkoxy;

[0234] - The heterocyclic group is selected from morpholino, tetrahydrofurano, tetrahydropyrano, pyrrolidinyl, 1,4-dioxane, piperidinyl, or aziridine, and the heterocyclic group is optionally selected from at least one of the following groups independently: cyano, oxo, halogen, hydroxyl, C. 1-6 Alkyl, alkoxy, -NR m R n 、or -C(O)NR m R n The substituents are substituted, and where -C 1-6 Alkyl or C 1-6 The alkoxy group is independently selected from at least one cyano, halogen, hydroxyl, -NH2, -C 1-6 Alkyl or -C 1-6 Substitution of alkoxy groups;

[0235] --OR e , where R e It is -C 1-6 Alkyl, -C 3-6 Cycloalkyl groups, 4- to 6-membered monocyclic saturated heterocyclic groups containing one oxygen heteroatom as a ring member, or C 6-10 Aryl, of which

[0236] i)-C 1-6 Alkyl groups may optionally be substituted with: cyano, -oxo-, halogen, hydroxyl, -NR m R n -C 1-6 Alkyl group, optionally replaced by cyano, -oxo, halogen, hydroxyl, or -NR m R n -C 1-6 Alkyl, -C 1-6 Alkyl or -C(O)NR m R n Replacement -C 3-6 Cycloalkyl, optionally prefixed with cyano, halogen, hydroxyl, -C 1-6 Alkyl or -C 1-6 Alkoxy-substituted 4- to 6-membered heterocyclic groups; and

[0237] ii)-C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic groups are optionally replaced by cyano, -oxo, halogen, hydroxyl, or -NR groups. m R n -C 1-6 Alkyl, -C 1-6 Alkyl or -C(O)NR m R n Replace, where -C 1-6 Alkyl or -C 1-6 The alkoxy group is independently substituted by at least one of the following substituents: cyano, halogen, hydroxyl, -NH2, -C1-6 alkyl or -C 1-6 alkoxy;

[0238] -C 6-10 aryl; or

[0239] -5- to 6-membered heteroaryl selected from pyridyl, pyridazinyl, pyrazinyl, thiazolyl, or isoxazolyl, each of which is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy, or -C(O)NR m R n , wherein -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy; and wherein R m and R n are independently selected from hydrogen or -C 1-3 alkyl.

[0240] In some preferred embodiments, R 3 is heterocyclyl selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, or azetidinyl, which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, C 1-6 alkyl, alkoxy, -NR m R n , or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy

[0241] In some embodiments, R 3 is

[0242] -hydrogen, cyano, halogen;

[0243] -methyl, ethyl, propyl, or butyl, each of which is optionally substituted with at least one substituent independently selected from halogen, hydroxyl, methoxy, ethoxy, propoxy, or 2,4-dioxothiazolidin-3-yl;

[0244] - cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally 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 alkoxy, wherein -C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with at least one substituent independently selected from cyano, halogen, hydroxy, -NH2, -C 1-3 alkyl or -C 1-3 alkoxy;

[0245] - 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]heptan-3-yl, 3-azabicyclo[3.1.0]hexan-3-yl or 2-azabicyclo[3.1.0]hexan-2-yl, each optionally substituted with at least one substituent independently 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 , wherein -C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with at least one substituent independently selected from cyano, halogen, hydroxy, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy;

[0246] -OR e , wherein R e is

[0247] i) methyl, ethyl, propyl (iso-propyl), butyl, pentyl or hexyl, each optionally substituted with deuterium, cyano, -oxo-, halogen, hydroxy, -NR m R n , -C 1-3 alkoxy-, optionally substituted with cyano, -oxo, halogen, hydroxy, -NR m R n , -C 1-3 alkyl, -C 1-3 alkoxy;alkyl, -C(O)NR m R n substituted -C 3-6 cycloalkyl, or optionally substituted with cyano, halo, hydroxyl, -C 1-3 alkyl or -C 1-3 alkoxy; or

[0248] 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 optionally substituted with cyano, -oxo, halo, hydroxyl, -NR m R n , -C 1-3 alkyl, -C 1-3 alkoxy or -C(O)NR m R n substituted, wherein -C 1-3 alkyl or -C 1-3 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-3 alkyl or -C 1-3 alkoxy;

[0249] -C 6-10 aryl; or

[0250] -5- to 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 optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, hydroxyl, -NR m R n , -C 1-3 alkyl, -C 1-3 alkoxy or -C(O)NR m R n substituted, wherein -C 1-3 alkyl or -C 1-3 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-3 alkyl or C 1-3substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C1-6alkyl, or -C1-6alkoxy;

[0251] and wherein R m and R n are independently selected from hydrogen or -C1-6alkyl. 1-3 alkyl.

[0252] In some preferred embodiments, R 3 is heterocyclyl 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]heptan-3-yl, 3-azabicyclo[3.1.0]hexan-3-yl, or 2-azabicyclo[3.1.0]hexan-2-yl, each optionally substituted with at least one substituent independently selected from cyano, -oxo, halo, hydroxyl, -C1-6alkyl, -C1-6alkoxy, -NR 1-6 alkyl, -C 1-6 alkoxy, -NR m R n , or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-6 alkyl, or -C 1-6 alkoxy

[0253] In some embodiments, R 3 is

[0254] -hydrogen;

[0255] -methyl, 1-methoxyethyl, 2-hydroxypropan-2-yl, 1-methoxyethyl, or (2,4-dioxothiazolidin-3-yl)methyl;

[0256] - 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;

[0257] - cyano

[0258] - 3-methoxycyclobutyl, (trans)-3-methoxycyclobutyl, (cis)-3-methoxycyclobutyl, 2,2-dichlorocyclopropyl, or 1-cyanocyclopropyl;

[0259] - morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, 3(S)-methyl-morpholino;

[0260] - 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-dimethylmorpholino;

[0261] - 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, 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;

[0262] - 5-azaspiro[2.4]heptan-5-yl;

[0263] - tetrahydrofuran-3-yl;

[0264] - 3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl;

[0265] - 1,4-dioxan-2-yl;

[0266] - 4-aminotetrahydro-2H-pyran-4-yl, 4-(aminomethyl)tetrahydro-2H-pyran-4-yl,

[0267] - 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;

[0268] - 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;

[0269] - 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.

[0270] In some preferred embodiments, R 3 is

[0271] - morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, 3(S)-methyl-morpholino;

[0272] - 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;

[0273] - 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, 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;

[0274] - 5-azaspiro[2.4]heptan-5-yl;

[0275] - tetrahydrofuran-3-yl;

[0276] - 3-methoxyazetidin-1-yl, 3-hydroxy-3-methylazetidin-1-yl;

[0277] - 1,4-dioxan-2-yl;

[0278] - 4-aminotetrahydro-2H-pyran-4-yl, 4-(aminomethyl)tetrahydro-2H-pyran-4-yl,

[0279] - 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;

[0280] -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.

[0281] In some further preferred embodiments, R 3 is morpholino, 3-methyl-morpholino, 3(R)-methyl-morpholino, or 3(S)-methyl-morpholino.

[0282] In some embodiments, (R 1 and R 2 ) or (R 2 and R 3 ) or (R 3 and R 4 ), together with the atoms to which they are attached, form a fused 5- to 7-membered ring system comprising 0-2 oxygen heteroatoms as one or more ring members and optionally and independently substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -haloC 1-6 alkoxy, or -C 3-6 cycloalkyl.

[0283] In some embodiments, R 1 and R 2 , together with the atoms to which they are attached, form a fused ring system selected from ; or R 2 and R 3 , together with the atoms to which they are attached, form a fused ring system R 3 and R 4 , together with the atoms to which they are attached, form a fused ring system selected from ; and wherein each fused ring system is optionally and independently substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -haloC 1-6 alkoxy, or -C 3-6 cycloalkyl.

[0284] In some embodiments, Cy 1 is

[0285] - the 7- to 14-membered bicyclic or tricyclic heteroaryl group comprising 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur as one or more ring members, preferably is a 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-pyrano[4,3-d]thiazolyl, [1,3]dioxolino[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 optionally substituted with halo, -C(O)R 1-6 alkyl, -NH2, or -C(O)R m wherein R m is C 1-6 alkyl; each of said alkyl groups is optionally enriched with deuterium.

[0286] In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl group which is a pyridinyl ring, pyrazolyl ring, thiophenyl ring, or thiazolyl ring fused to a 5- or 6-membered heterocyclyl ring comprising one or two heteroatoms selected from oxygen or nitrogen as one or more ring members and the 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C 1-6 alkyl groups or oxo, preferably two C 1-6alkyl, more preferably, two methyl groups, most preferably two methyl groups on the same carbon atom. In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl which is a pyridyl ring fused to a 5- or 6- membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring comprises one or two heteroatoms selected from oxygen or nitrogen as one or more ring members and the 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C 1-6 alkyl or oxo, preferably, two C 1-6 alkyl, more preferably, two methyl groups, most preferably two methyl groups on the same carbon atom. In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl which is a pyridyl ring fused to a 5- or 6- membered heterocyclyl ring, wherein the 5- or 6-membered heterocyclyl ring comprises two oxygen atoms as one or more ring members and the 5- or 6-membered heterocyclyl ring is optionally substituted with one or two C 1-6 alkyl, preferably, two C 1-6 alkyl, more preferably, two methyl groups, most preferably two methyl groups on the same carbon atom. In some embodiments, Cy 1 is a 7- to 14-membered bicyclic heteroaryl which is a pyridyl ring fused to a 1,4- dioxane ring, wherein the 1,4-dioxane ring is optionally substituted with one or two C 1-6 alkyl, preferably, two C 1-6 alkyl, more preferably, two methyl groups, most preferably two methyl groups on the same carbon atom. In some preferred embodiments, Cy 1 is preferably,

[0287] In some embodiments, Cy 1 is

[0288]

[0289]

[0290] In some embodiments, the compound is selected from the example compounds in the Examples.

[0291] In a second aspect, disclosed herein is a pharmaceutical composition comprising one or more compounds of the disclosure, or a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0292] In a third aspect, the present disclosure provides a method for treating a disease associated with unwanted TYK2 activity (TYK2-related disease), the method comprising administering to a subject in need of such treatment a therapeutically effective amount of the compound of the present disclosure or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0293] In one embodiment, the disease is an inflammatory disease or an autoimmune disease. Detailed Implementation

[0294] Definitions

[0295] The following terms have indicative meanings throughout the specification:

[0296] As used herein, including the appended claims, unless the context clearly indicates otherwise, the singular forms of such words as “a,” “an,” and “the” include their respective plural references.

[0297] Unless the context clearly indicates otherwise, the term “or” means the term “and / or” and is used interchangeably with the term “and / or”.

[0298] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms (e.g., 1 to 12, further, for example, 1 to 10, even further, for example, 1 to 8, or 1 to 6, or 1 to 4). Alkyl groups containing 1 to 6 carbon atoms (i.e., C64) are also considered alkyl groups. 1-6 Examples of alkyl groups 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 sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2- The alkyl group may be enriched with deuterium, for example, -CD3, -CD2CD3, etc.

[0299] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0300] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, and iodine). Examples of haloalkyl groups include halogenated C-type alkyl groups.1-8 alkyl, haloC 1-6 alkyl or haloC 1-4 alkyl, but is not limited to -CF3, -CH2Cl, -CH2CF3, -CCl2, CF3, and the like.

[0301] The term“alkyloxy” or“alkoxy” refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom. Examples of alkyloxy (e.g., C1-6alkyloxy) include, but are not limited to: methyloxy, ethyloxy, isopropyloxy, propyloxy, n-butyloxy, t-butyloxy, pentyloxy, and hexyloxy, and the like. 1-6 alkyloxy or C 1-4 alkyloxy) include, but are not limited to: methyloxy, ethyloxy, isopropyloxy, propyloxy, n-butyloxy, t-butyloxy, pentyloxy, and hexyloxy, and the like.

[0302] The term“alkyloxy-alkyl-” refers to an alkyl group as defined above further substituted with an alkyloxy group as defined above. Examples of alkyloxy-alkyl-, e.g., C1-6alkyloxy-C1-6alkyl-, include, but are not limited to: methyloxy-methyl, ethyloxy-methyl, ethyloxy-ethyl, isopropyloxy-methyl, or propyloxy-methyl, and the like. 1-8 alkyloxy-C 1-8 alkyl- or C 1-6 alkyloxy-C 1-6 Examples of alkyloxy-C1-6alkyl- include, but are not limited to: methyloxy-methyl, ethyloxy-methyl, ethyloxy-ethyl, isopropyloxy-methyl, or propyloxy-methyl, and the like.

[0303] The term“amino” refers to -NH2. The term“alkylamino” refers to -NH(alkyl). The term“dialkylamino” refers to -N(alkyl)2.

[0304] The term“alkenyl” herein refers to a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C=C double bond and from 2 to 18 (e.g., from 2 to 8, further e.g., from 2 to 6) carbon atoms. Examples of alkenyl groups (e.g., C2-6alkenyl) 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, butan-1,3-dienyl, 2-methylbutan-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexan-1,3-dienyl groups.

[0305] The term“alkynyl” herein refers to a hydrocarbon group selected from linear and branched hydrocarbon groups comprising at least one C≡C triple bond and from 2 to 18 (e.g., from 2 to 8, further e.g., from 2 to 6) carbon atoms. Examples of alkynyl groups (e.g., C2-6alkynyl) include, but are not limited to: ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0306] The term“cycloalkyl” refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups (including fused, bridged, or spiro cycloalkyl groups).

[0307] For example, a cycloalkyl group can comprise from 3 to 12, for example from 3 to 10, further for example 3 to 8, further for example 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, a cycloalkyl group can be selected from monocyclic groups comprising from 3 to 12, for example from 3 to 10, further for example 3 to 8, 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 cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups (e.g. C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, the cycloalkyl group is a monocyclic group comprising 3 to 6 carbon atoms (abbreviated as C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, the cycloalkyl group is a monocyclic group comprising 3 to 6 carbon atoms (abbreviated as C

[0308] The term “cycloalkenyl” refers to a non-aromatic cycloalkyl group having a single ring or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds of from 3 to 10 carbon atoms. In one embodiment, the cycloalkenyl group is a cyclopentenyl or cyclohexenyl, preferably cyclohexenyl.

[0309] The term “cycloalkynyl” refers to a non-aromatic cycloalkyl group having a single ring or multiple rings and having at least one triple bond of from 5 to 10 carbon atoms.

[0310] The term “deuterated” is used herein to modify a chemical structure or organic group (group or radical) in which one or more carbon-bonded hydrogens are replaced by one or more deuterium, e.g., “deuterated alkyl,” “deuterated cycloalkyl,” “deuterated heterocycloalkyl,” “deuterated-aryl,” “deuterated morpholino,” and the like. For example, the term “deuterated alkyl” as defined above refers to an alkyl group as defined herein in which at least one carbon-bonded hydrogen atom is replaced by deuterium. In a deuterated alkyl group, at least one carbon atom is bonded to deuterium; and a carbon atom can be bonded to up to more than one deuterium; more than one carbon atom in an alkyl group can also be bonded to deuterium.

[0311] The term "aryl," alone or in combination with other terms, refers to a group selected from:

[0312] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0313] - bicyclic ring systems (e.g., 7- to 12-membered bicyclic ring systems), wherein at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0314] - tricyclic ring systems (e.g., 10- to 15-membered tricyclic ring systems), wherein at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0315] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, a 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, anthryl, phenanthryl, 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.

[0316] The term "heteroaryl" herein refers to a group selected from:

[0317] - 5-, 6-, or 7-membered aromatic monocyclic rings comprising at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, in some embodiments, from 1 to 2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), wherein the remaining ring atoms are carbon;

[0318] - 7- to 12-membered bicyclic rings comprising at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0319] - 11- to 14-membered tricyclic rings comprising at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0320] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocyclic ring does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. A nitrogen atom in one or more rings of a heteroaryl group can be oxidized to form an N-oxide.

[0321] The term "optionally oxidized sulfur" as used herein means S, SO, or SO2.

[0322] The terms "aromatic heterocyclic ring" and "heteroaryl" are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic heterocyclic ring has 5, 6, 7, 8, 9, or 10 ring members, wherein 1, 2, 3, or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocyclic ring is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocyclic 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, a monocyclic or bicyclic aromatic heterocyclic ring is an 8- to 10-membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0323] Examples of heteroaryl groups, or monocyclic or bicyclic aromatic heterocycles, include, but are not limited to: (numbering from the attachment position designated as 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), tetrazolyl, thienyl (e.g., thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furanyl or furanyl, benzofuranyl, benzoimidazolyl, 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-2,4-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, fluoropyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0324] Additionally, "heteroaryl" further fused with "heterocyclyl" is defined as "heteroaryl".

[0325] "Heterocyclyl", "heterocycle", or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclyl groups (which contain one or more heteroatoms as ring members selected from nitrogen, oxygen, or optionally oxidized sulfur, wherein the remaining ring members are carbon), including monocyclic, fused, bridged, and spiro rings, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclyl groups.

[0326] The term "monocyclic heterocyclyl" refers to monocyclic groups in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated.

[0327] Exemplary monocyclic 4- to 9-membered heterocyclyl groups include, but are not limited to: (numbering starting with the attachment position designated as 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, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocin-1-yl, azocin-2-yl, azocin-3-yl, azocin-4-yl, azocin-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-thiacyclobutane, 1,3-thiacyclobutane, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxasulfuranyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepin-1-yl, azepin-2-yl, azepin-3-yl, azepin-4-yl, oxepinyl, thiepinyl, 1,4-oxasulfuranyl, 1,4-dioxanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, and 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydropyryl, 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. diazepinyl thiazepinyl dihydrothienyl, dihydropyranyl, 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.

[0328] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group having a ring connected through a common carbon atom (referred to as the spiro atom), which contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the spiroheterocyclyl group can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl is 6- to 14-membered, and more preferably 7- to 12-membered. Depending on the number of common spiro atoms, the spiroheterocyclyl is classified as a mono-, bi-, or polyspiroheterocyclyl, and preferably refers to a monosprioheterocyclyl or a bispiroheterocyclyl, and more preferably a 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 monosprioheterocyclyl.

[0329] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of atoms (a carbon and carbon atom, or a carbon and nitrogen atom) with another ring, which contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the fused heterocyclic group can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, the fused heterocyclic group is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, the fused heterocyclic group is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic group, preferably refers to a bicyclic or tricyclic fused heterocyclic group, and more preferably a 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused heterocyclic group. 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]dioxin.

[0330] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocycloalkyl group in which each two rings in the system share two noncontiguous atoms, which contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the remaining ring members are carbon. One or more rings of the bridged heterocyclyl group can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, the bridged heterocyclyl is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, the bridged heterocyclyl is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and preferably refers to a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, and more preferably a bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocycles 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.

[0331] The compounds disclosed herein can contain asymmetric centers and therefore can exist in enantiomeric forms. "Enantiomers" refer to two stereoisomers of a compound which are mirror images of one another and are not superimposable. When a compound disclosed herein has two or more chiral centers, it can additionally exist as diastereomers. Enantiomers and diastereomers are within the broader class of stereoisomers. All possible stereoisomers are intended, for example, substantially pure resolved enantiomers, racemic mixtures, and mixtures of diastereomers. All stereoisomers of a compound of this disclosure, and / or pharmaceutically acceptable salts thereof, are intended to be within the scope of this disclosure. Unless otherwise specified, a reference to a particular enantiomer includes all possible enantiomers.

[0332] As used herein, the term "substantially pure" means that the target stereoisomer contains no more than 35% by weight, for example, no more than 30%, further for example, no more than 25%, even further for example, no more than 20% of any one or more other stereoisomers. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% by weight, for example, no more than 5%, for example, no more than 1% of any one or more other stereoisomers.

[0333] When a compound disclosed herein contains an olefinic double bond, unless otherwise specified, such double bond is intended to include both the E and the Z geometry.

[0334] When a compound disclosed herein contains a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can form in the cis and trans. The cis formation means that both substituents are on the same side of the carbon at the 2 substituent positions, while the trans indicates that they are on opposite sides.

[0335] It can be advantageous to isolate the reaction products from one another and / or from the starting materials. The desired product of each step or series of steps is isolated and / or purified (hereinafter referred to as isolated) to the desired homogeneity by conventional techniques, by one of ordinary skill in the art. Typically, such isolation will involve multiphase extraction, crystallization from a solvent or a mixture of solvents, distillation, sublimation, or chromatography. Chromatography can involve many methods including, for example: reverse and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatographic methods and apparatus; small scale analytical; simulated moving bed (“SMB”) and preparative thin or thick layer chromatography, and small scale thin and flash chromatography. The skilled artisan will apply the technique most likely to achieve the desired isolation.

[0336] "Diastereomers" refer to stereoisomers that have two or more chiral centers but are not mirror images of each other. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical differences by methods well known from the art, for example, by chromatography or fractional crystallization. The racemic mixtures of enantiomers can be separated on the basis of their difference in optical rotation by adapting the methods described by Jacques, Jacques and Collet, "Enantiomers, Racemates, and Resolutions," in Wilen, Stanley, Ed., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994, pp. 287-342.

[0337] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained, for example, by using optically active resolvants to form diastereomeric mixtures of enantiomers [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 the chiral compounds of the present application can be separated using any appropriate method, including: (1) formation of a salt with an active enantiomer and separation by fractional crystallization of the salt; (2) formation of a diastereomeric pair with an active enantiomer and separation by fractional crystallization of the diastereomeric pair; (3) direct separation of the racemic mixture by chromatography using a chiral stationary phase; and (4) resolution of the racemic mixture using a compound that forms a diastereomeric pair with the active enantiomer. See: Wainer, Irving W., ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0338] The term "pharmaceutically acceptable salt" means those salts which 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, and the like, and 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 separately, by reacting the free base group with a suitable organic acid, or by reacting the acidic group with a suitable base.

[0339] Additionally, if the compounds disclosed herein are obtained as acid addition salts, the free bases can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, addition salts (e.g., pharmaceutically acceptable addition salts) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those of skill in the art will recognize a variety of synthetic methodologies that can be used to prepare nontoxic pharmaceutically acceptable addition salts without undue experimentation.

[0340] As defined herein, "pharmaceutically acceptable salts thereof" includes at least one salt of a compound of Formula (I), and a salt of a stereoisomer of a compound of Formula (I), e.g., an enantiomer, and / or a diastereomer.

[0341] The terms "administration" and "administering" as applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contacting the animal, human, subject, cell, tissue, organ, or biological fluid with an exogenous drug, therapeutic agent, diagnostic agent, or composition. Treatment of a cell encompasses contacting of a reagent with a cell and contacting of a reagent with a fluid, wherein the fluid is in contact with a cell. The terms "administration" and "treatment" also mean in vitro and ex vivo treatment of a cell, e.g., by a reagent, diagnostic agent, binding compound, or another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), most preferably a human.

[0342] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) which is sufficient to affect treatment, as measured by improvement in the disease, disorder, or at least one clinical symptom of the disease or disorder, when administered to a subject. The "therapeutically effective amount" can vary with the compound, the disease, the disorder, and / or the 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 to be treated, and / or the body weight of the subject to be treated. An appropriate amount in any given instance will be readily 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 disclosed herein, and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, effective to treat a disease or disorder in a subject as defined above. In the case of combination therapy, "therapeutically effective amount" refers to the total amount of the combination that is effective to treat the disease, disorder, or condition.

[0343] The pharmaceutical composition comprising the compound disclosed herein can be administered orally, inhaled, rectally, parenterally, or topically to a subject in need thereof. For oral administration, the pharmaceutical composition can be a conventional solid formulation, such as a tablet, powder, granule, capsule, etc.; a liquid formulation, such as an aqueous or oil suspension; or other liquid formulation, such as a syrup, solution, suspension, etc.; for parenteral administration, the pharmaceutical composition can be a solution, aqueous solution, oil suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from a tablet, a coated tablet, a capsule, a suppository, a nasal spray, or an injection, more preferably a tablet or a capsule. The pharmaceutical composition can be a single unit administration with a precise dose. In addition, the pharmaceutical composition can further comprise other active ingredients.

[0344] All formulations of the pharmaceutical composition disclosed herein can be produced by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients, and then manufactured into a desired formulation. The "pharmaceutically acceptable excipient" refers to a conventional pharmaceutical carrier suitable for the desired pharmaceutical formulation, such as: diluents, vehicles (e.g., water, various organic solvents, etc.), fillers (e.g., starch, sucrose, etc.), binders (e.g., cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP)); wetting agents, such as glycerol; disintegrants, such as agar, calcium carbonate, and sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants, such as cetyl alcohol; absorption carriers, such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition further comprises other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, aromatic compounds, sweeteners, and dyes.

[0345] The term "disease" refers to any illness, malaise, sickness, symptom, or indication, and can be used interchangeably with the terms "disorder" or "condition."

[0346] Throughout this specification and the annexed claims, the term "comprising", as well as variations such as "comprise" and "comprises", is intended to designate the presence of the subsequent characteristics, but not the exclusion of one or more other characteristics or the addition thereof, unless the context otherwise requires. The term "comprising" can be replaced by the term "containing" or "including" when used herein, or sometimes by "having".

[0347] Throughout this specification and the annexed claims, the term "Cn-m" indicates a range including the endpoints, wherein n and m are integers, and indicates the number of carbons. Examples include C1-8, C1-6, and the like.

[0348] Unless specifically defined otherwise in this document, all other technical and scientific terms used in the present application have the meaning commonly understood by one of ordinary skill in the art to which this application belongs.

[0349] Examples

[0350] The following examples are intended to be purely exemplary, and should not be considered to be limiting in any way. Although efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) used in these examples, some experimental errors and deviations should be accounted for. Unless indicated otherwise, temperatures are in degrees Celsius. Reagents were purchased from commercial vendors such as Sigma-Aldrich, Alfa Aesar, or TCI, and were used without further purification unless otherwise noted.

[0351] Unless otherwise indicated, the reactions described below were performed under a positive pressure of nitrogen or argon or in anhydrous solvents using a dry tube; the reaction flasks were equipped with a rubber septum for the introduction of substrates and reagents through a syringe; and the glassware was oven-dried and / or heated-dried.

[0352] Unless otherwise indicated, the reactions described below were performed under a positive pressure of nitrogen or argon or in anhydrous solvents using a dry tube; the reaction flasks were equipped with a rubber septum for the introduction of substrates and reagents through a syringe; and the glassware was oven-dried and / or heated-dried.

[0353] Column chromatography purification was performed on a Biotage system (manufacturer: Dyax Corporation) with a silica gel column or on a silica SepPak cartridge (Waters), or on a Teledyne Isco Combiflash purification system using pre-packed silica gel columns, unless otherwise stated.

[0354] Varian instrument operating at 400 MHz was used 1 H NMR spectra. CDCl3, CD2Cl2, CD3OD, D2O, d6-DMSO, d6-acetone or (CD3)2CO were used as solvents and tetramethylsilane (0.00 ppm) or residual solvents (CDCl3: 7.25 ppm; CD3OD: 3.31 ppm; D2O: 4.79 ppm; d6-DMSO: 2.50 ppm; d6-acetone: 2.05; (CD3)2CO: 2.05) as reference standards were obtained 1 H-NMR spectra. When multiplicity of peaks is reported, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), sx (sextet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). If coupling constants are given, they are reported in Hertz (Hz). Compound names, except reagents, were generated by ChemDraw version 12.0.

[0355] Abbreviations:

[0356] AcOH acetic acid

[0357] Aq aqueous

[0358] Brine saturated aqueous sodium chloride solution

[0359] Bn benzyl

[0360] BnBr benzyl bromide

[0361] (Boc)2O di-tert-butyl dicarbonate

[0362] DMF N,N-dimethylformamide

[0363] Dppf 1,1”-bis(diphenylphosphino)ferrocene

[0364] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0365] DIEA or DIPEA N-ethyl-N-isopropylpropan-2-amine

[0366] DMAP 4-N,N-dimethylaminopyridine

[0367] DMSO dimethyl sulfoxide

[0368] EtOAc or EA EA

[0369] EtOH ethanol

[0370] Et20 or ether diethyl ether

[0371] Et3N triethylamine

[0372] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0373] HPLC high performance liquid chromatography

[0374] IPA 2-propanol

[0375] i-PrOH isopropanol

[0376] ms or MS mass spectrum

[0377] NaHMDS sodium hexamethyldisilazane

[0378] PE petroleum ether

[0379] PPA polyphosphoric acid

[0380] p-TSA p-toluenesulfonic acid

[0381] Rt retention time

[0382] Rt or rt room temperature

[0383] TBAF tetrabutylammonium fluoride

[0384] TBSCl tert-butyldimethylsilyl chloride

[0385] TFA trifluoroacetic acid

[0386] THF tetrahydrofuran

[0387] TLC thin layer chromatography

[0388] Example BB1 : Synthesis of 2-bromo-4-(methoxymethyl)-6-(methylsulfonyl)pyridine

[0389]

[0390] Step 1 : 2,6-dibromo-4-(bromomethyl)pyridine

[0391]

[0392] A mixture of 2,6-dibromo-4-methylpyridine (10.0 g, 39.85 mmol), CCI 4 A mixture of 2,6-dibromo-4-methylpyridine (10.0 g, 39.85 mmol), CCI + 328.

[0393] Step 2: 2,6-dibromo-4-(methoxymethyl)pyridine

[0394]

[0395] A mixture of 2,6-dibromo-4-methylpyridine (10.0 g, 39.85 mmol), CCI + 280.

[0396] Step 3: 2-bromo-4-(methoxymethyl)-6-(methylsulfanyl)pyridine

[0397]

[0398] A mixture of 2,6-dibromo-4-methylpyridine (10.0 g, 39.85 mmol), CCI+ 248.

[0399] Step 4: 2-Bromo-6-methanesulfonyl-4-(methoxymethyl)pyridine

[0400]

[0401] A mixture of 2-bromo-4-(methoxymethyl)-6-(methylsulfanyl)pyridine (1.40 g, 5.64 mmol), THF (10 mL), H2O (10.00 mL), NaIO4(2.41 g, 11.26 mmol), and RuCl3.H2O (127.19 mg, 0.56 mmol) was stirred at 0 °C for 1 h. After the reaction was completed, EA (100 mL) was added and the resulting mixture was washed with H2O (200 mL x 3). The organic layer was dried over anhydrous Na2SO4, concentrated and purified by combi-flash (EA / PE = 0-30%) to give 2-bromo-6-methanesulfonyl-4-(methoxymethyl)pyridine (1.10 g, 69%). 1 H NMR (300 MHz, CDC13) 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.

[0402] Example BB2: Synthesis of 2-bromo-4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]-6- methanesulfonylpyridine

[0403]

[0404] Step 1: 2-bromo-6-(methylthio)pyridin-4-ol

[0405]

[0406] 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), NaSCH3(2.93 g, 39.54 mmol) and Pd2(dba)3(0.18 g, 0.20 mmol) in 1,4-dioxane (200 mL) was stirred at 75 °C under nitrogen atmosphere overnight. After cooling to room temperature, water was added and the resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum and the crude 2-bromo-6-(methylthio)pyridin-4-ol was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 220.

[0407] Step 2: 2-bromo-6-methanesulfonylpyridin-4-ol

[0408]

[0409] To a stirred solution of 2-bromo-6-(methylsulfanyl)pyridin-4-ol (6.00 g, 27.26 mmol) in H2O (100 mL) / THF (100 mL) was added dropwise RuCl3.H2O (0.18 g, 0.82 mmol) in water (30 mL) at 0 °C, followed by continuous dropwise addition of NaIO4(11.66 g, 0.055 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for another 30 min. After the reaction was completed, the resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. 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.

[0410] Step 3: 2-bromo-4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]-6-methanesulfonylpyridine

[0411]

[0412] 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 x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. 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.

[0413] Example BB3: Synthesis of 2-bromo-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-6- (methylsulfonyl)pyridine

[0414]

[0415] A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (200 mg, 0.79 mmol), Cs2CO3(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. After cooling to room temperature, water was added and the resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. 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.

[0416] Example BB4: Synthesis of 2-bromo-4-(2-((tert-butyldimethylsilyl)oxy)propoxy)-6- (methylsulfonyl)pyridine

[0417]

[0418] Step 1: 1-((2-bromo-6-(methylsulfonyl)pyridin-4-yl)oxy)propan-2-ol

[0419]

[0420] A mixture of 2-bromo-6-methylsulfonylpyridin-4-ol (500 mg, 1.98 mmol), 2- propanol-1-bromide (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 x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to give the crude 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] 367.0. + 310.

[0421] Step 2: 2-bromo-4-(2-((tert-butyldimethylsilyl)oxy)propoxy)-6-(methylsulfonyl)pyridine

[0422]

[0423] A solution of 1-[(2-bromo-6-methylsulfonylpyridin-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 RT for 12 h. After the reaction was completed, 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- methylsulfonylpyridine (635 mg, 77%). 1H 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.

[0424] Example BB5: Synthesis of 2-[(2-bromo-6-methanesulfonylpyridin-4-yl)oxy]acetonitrile

[0425]

[0426] 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 K2CO3 (548 mg, 3.97 mmol) in portions at room temperature, then the resulting mixture was stirred at 80 °C overnight. After cooling to room temperature, water was added and the resulting mixture was extracted with EA (40 mL x 3). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, 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.

[0427] Example BB6: Synthesis of 2-bromo-4-isopropoxy-6-methanesulfonylpyridine

[0428]

[0429] 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 portions at room temperature. After cooling to room temperature, water was added and the resulting mixture was extracted with EA (40 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (PE / EA = 3: 1) to give the product (570 mg, 82%).1 H 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.

[0430] Example BB7: Synthesis of 2-bromo-6-methanesulfonyl-4-[(trans)-3-[(tert- butyldimethylsilyl)oxy]cyclobutoxy]pyridine

[0431]

[0432] 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 x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. 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.

[0433] Example BB8: Synthesis of 2-bromo-6-methanesulfonylpyridine-4-carbonitrile

[0434]

[0435] Step 1: 2-bromo-6-(methylsulfanyl)pyridine-4-carbonitrile

[0436]

[0437] A mixture of 2,6-dibromopyridine-4-carbonitrile (4.00 g, 15.27 mmol), DMF (40 mL) and CH3SNa (1.28 g, 18.33 mmol) was stirred at rt overnight. After completion of the reaction, water was added and the resulting solution was extracted with EA (60 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2S04. The solids were filtered off and the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-5%) to give the product (1.50 g, 43%). GCMS (ESI) [M] 228.

[0438] Step 2: 2-Bromo-6-methanesulfonylpyridine-4-carbonitrile

[0439]

[0440] To a solution of 2-bromo-6-(methylsulfanyl)pyridine-4-carbonitrile (1.50 g, 6.55 mmol) in THF (15 mL) was added NaI04(2.80 g, 13.10 mmol) in H20 (20 mL) portion wise at 0 °C, followed by RuCI3.H20 (147.60 mg, 0.655 mmol) in H20 (10 mL) portion wise at 0 °C. The resulting solution was stirred at RT for 2 h. After completion of the reaction, the resulting solution was extracted with EA (60 mL x 3) and the combined organic layers were washed with brine and dried over anhydrous Na2S04. The solids were filtered off and the resulting mixture was concentrated under vacuum 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) d 8.65 (s, 1H), 8.55 (s, 1H), 3.40 (s, 3H); GC-MS (ESI) [M] 260.

[0441] Example BB9: Synthesis of 2-bromo-6-methanesulfonyl-4-methoxypyridine

[0442]

[0443] 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 CH3I (4.20 g, 29.59 mmol) dropwise at 60 °C for 2 h. After cooling to rt, water was added and the resulting mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 25-35%) to give the product (4.00 g, 76%). 1 H NMR (300 MHz, CDC13) δ 7.56 (s, 1H), 7.18 (s, 1H), 3.95 (s, 3H), 3.24 (s, 3H). LCMS (ESI) m / e [M+1] + 266.

[0444] Example BB10: Synthesis of 6-bromo-4-methylpyridine-2-sulfonamide

[0445]

[0446] Step 1: 2-(benzylsulfanyl)-6-bromo-4-methylpyridine

[0447]

[0448] 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 Cs2CO3(5.19 g, 15.93 mmol) was stirred at RT for 2 h. After the reaction was completed, EA (100 mL) was added and the resulting mixture was washed with water (100 mL x 3). The mixture was then dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-25%) to give the product (2.30 g, 98%). LCMS (ESI) m / e [M+1] + 294.

[0449] Step 2: 6-bromo-4-methylpyridine-2-sulfonyl chloride

[0450]

[0451] A mixture of 2-(benzylsulfanyl)-6-bromo-4-methylpyridine (2.30 g, 7.82 mmol), AcOH (36 mL), H2O (4 mL), and NCS (3.65 g, 27.33 mmol) was stirred at RT for 1 h. After the reaction was complete, EA (100 mL) was added and the resulting mixture was washed with water (100 mL x 3). The mixture was dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-25%) to give the product (2.00 g, 94%).

[0452] Step 3: 4-methylpyridine-2-sulfonamide

[0453]

[0454] To a solution of 6-bromo-4-methylpyridine-2-sulfonic acid chloride (2.00 g, 7.39 mmol) in THF (20 mL) was added ammonium (10 mL, 33% wt) dropwise at 0 °C and stirred at RT for 1 h. After the reaction was complete, EA (100 mL) was added and the resulting mixture was washed with water (100 mL x 3). The mixture was dried over anhydrous Na2SO4and concentrated. The residue was purified by combi-flash (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.

[0455] Example BB11: Synthesis of 6-bromo-4-(2-methoxyethoxy)pyridine-2-sulfonamide

[0456]

[0457] Step 1: 2,6-dibromo-4-(2-methoxyethoxy)pyridine

[0458]

[0459] A mixture of 2,6-dibromopyridine-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 RT, water was added and the resulting mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum 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.

[0460] Step 2: 6-Bromo-4-(2-methoxyethoxy)pyridine-2-sulfonyl chloride

[0461]

[0462] 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 RT for 1 h under nitrogen atmosphere. SO2Cl2(1.2 mL) in hexane (3 mL) was added dropwise at 0 °C and the resulting mixture was stirred at rt for 1 h under nitrogen atmosphere. After completion of the reaction, the reaction was quenched with cold water. The resulting mixture was concentrated under vacuum to give the crude product 6-bromo-4-(2-methoxyethoxy)pyridine-2-sulfonyl chloride (2.0 g). This was used directly in the next step without purification.

[0463] Step 3: 6-Bromo-4-(2-methoxyethoxy)pyridine-2-sulfonamide

[0464]

[0465] 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 RT for 1 h. After completion of the reaction, the solvent was removed under vacuum and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX; phase: A-H2O; B-acetonitrile, B%: 15%-25% over 15 min) to give the product (128 mg, 81%). 1H 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.

[0466] Example BB12: Synthesis of 2-bromo-4-(difluoromethyl)-6-(methylsulfonyl)pyridine

[0467]

[0468] Step 1: (2,6-dibromopyridin-4-yl)methanol

[0469]

[0470] 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 in THF) dropwise and the resulting mixture was stirred at RT for 48 h. After the reaction was complete, water was added slowly 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.

[0471] Step 2: 2,6-dibromoisonicotinaldehyde

[0472]

[0473] 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 RT for 12 h. After the reaction was complete, water was added and the resulting mixture was extracted with DCM (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (DCM / PE = 1:1) to give the product (900 mg, 60%).

[0474] Step 3: 2,6-dibromo-4-(difluoromethyl)pyridine

[0475]

[0476] 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 rt. The resulting mixture was stirred at rt for another 1 h. After the reaction was completed, EtOH was added and the resulting mixture was concentrated under vacuum. The crude product was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 286.

[0477] Step 4: 2-bromo-4-(difluoromethyl)-6-(methylthio)pyridine

[0478]

[0479] 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 rt for 2 h. After the reaction was completed, 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 under vacuum. The crude product was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 254.

[0480] Step 5: 2-bromo-4-(difluoromethyl)-6-(methylsulfonyl)pyridine

[0481]

[0482] To a stirred solution of 2-bromo-4-(difluoromethyl)-6-(methylsulfanyl)pyridine (450 mg, 1.77 mmol) in H2O (5 mL) and THF (5 mL) was added RuCl3.H2O (12 mg, 0.053 mmol) in water (2 mL) dropwise at 0 °C. To the above mixture was added NaIO4(1515 mg, 7.08 mmol) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for another 30 min. After the reaction was completed, the resulting mixture was extracted with EA (3 x 100 mL) and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. 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) d 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.

[0483] Example BB13: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxetan-3- ylmethoxy)pyridine

[0484]

[0485] 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 RT, water was added and the resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (hexanes / 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.

[0486] Example BB14: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxetan-3- yloxy)pyridine

[0487]

[0488] 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 RT, water was added and the resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (hexanes / EA = 5:1) to give the product (899 mg, 89%). 1H 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.

[0489] Example BB15: Synthesis of 2-bromo-6-methanesulfonyl-4- (oxetan-3-ylmethoxy)pyridine

[0490]

[0491] 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 RT, water was added and the resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by preparative TLC (hexanes / 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.

[0492] Example BB16: Synthesis of 2-bromo-6-methanesulfonyl-3-methoxy pyridine

[0493]

[0494] Step 1: 2-bromo-3-methoxy-6-(methylsulfanyl)pyridine

[0495]

[0496] A mixture of 2-bromo-6-iodo-3-methoxypyridine (4.00 g, 12.74 mmol), (methylsulfanyl)sodium (0.80 g, 11.41 mmol), Pd2(dba)3(0.58 g, 0.63 mmol), Xantphos (0.74 g, 1.27 mmol) in dioxane (64 mL) was stirred at 75 °C for 3 h under nitrogen atmosphere. After cooling to rt, water was added and the resulting mixture was extracted with EA (200 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum and purified by combi-flash (EA / PE = 0-4%) to give the product (1.72 g, 52%). LCMS (ESI, m / e) [M+1] + 234.

[0497] Step 2: 2-bromo-6-methanesulfonyl-3-methoxypyridine

[0498]

[0499] To a mixture of 2-bromo-3-methoxy-6-(methylsulfanyl)pyridine (1.72 g, 7.34 mmol) in THF (15 mL) was added dropwise NaIO4(4.73 g, 22.14 mmol) and RuCl3(0.05 g, 0.22 mmol) in H2O (15 mL) at 0 °C. The resulting solution was stirred at RT for 1 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (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.

[0500] Example BB17: Synthesis of 1-bromo-3-methanesulfonyl-5-(2-methoxyethoxy)benzene

[0501]

[0502] Step 1: 1,3-dibromo-5-(2-methoxyethoxy)benzene

[0503]

[0504] A mixture of 3,5-dibromo-phenol (11.00 g, 43.66 mmol), 2-bromoethyl methyl ether (15.17 g, 109.14 mmol) and Cs2CO3(28.46 g, 87.33 mmol) in DMF (165 mL) was stirred at 80 °C for 4 h. After cooling to RT, water was added, then extracted with EA (500 mL x 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 and the crude product was used directly in the next step without further purification. LCMS (ESI, m / e) [M+1] + 311.

[0505] Step 2: 1-Bromo-3-(2-methoxyethoxy)-5-(methylsulfanyl)benzene

[0506]

[0507] A mixture of 1,3-dibromo-5-(2-methoxyethoxy)benzene (15.00 g, 48.39 mmol), sodium (methylsulfanyl) (2.71 g, 38.67 mmol), Pd2(dba)3(2.22 g, 2.42 mmol), Xantphos (2.80 g, 4.83 mmol) in dioxane (150 mL) was stirred at 75 °C overnight. After cooling to RT, the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-1%) to give the product (5.71 g, 38%). LCMS (ESI, m / e) [M+1] + 277.

[0508] Step 3: 1-Bromo-3-methylsulfonyl-5-(2-methoxyethoxy)benzene

[0509]

[0510] To a mixture of 1-bromo-3-(2-methoxyethoxy)-5-(methylsulfanyl)benzene (5.71 g, 20.60 mmol) in THF (60 mL) and H2O (30 mL) was added portionwise a solution of NaIO4(13.22 g, 61.81 mmol) in H2O (15 mL) at 0 °C. Then to the mixture was added portionwise a solution of RuCl3(0.14 g, 0.62 mmol) in H2O (15 mL) at 0 °C. The resulting solution was stirred at RT for 1 h. After the reaction was completed, the resulting solution was extracted with EA (50 mL x 3). The solvent was removed under vacuum and the residue was purified by combi-flash (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.

[0511] Example BB18: Synthesis of [2-(3-bromo-5-methylsulfonylphenoxy)ethoxy](tert- butyl)dimethylsilane

[0512]

[0513] Step 1: tert-Butyl [2-(3,5-dibromophenoxy)ethoxy]dimethylsilane

[0514]

[0515] A mixture of 3,5-dibromophenol (5.00 g, 19.85 mmol), (2-bromoethoxy)(tert- butyl)dimethylsilane (7.12 g, 29.77 mmol), Cs2CO3(12.93 g, 39.69 mmol) in DMF (50 mL) was stirred at 80 °C for 2 h. After cooling to RT, water was added and the resulting mixture was extracted with EA (80 mL x 3). The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-20%) to give the product (5.00 g, 61%).

[0516] Step 2: [2-[3-bromo-5-(methylsulfanyl)phenoxy]ethoxy](tert-butyl)dimethylsilane

[0517]

[0518] A mixture of tert-butyl [2-(3,5-dibromophenoxy)ethoxy]dimethylsilane (5.00 g, 12.19 mmol), sodium (methylsulfanyl) (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 under nitrogen atmosphere overnight. After cooling to RT, water was added and the resulting mixture was extracted with EA (120 mL x 3). The combined organic layers were washed with brine (50 mL x 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-10%) to give the product (2.80 g, 60%). LCMS (ESI, m / e) [M+1] + 377.

[0519] Step 3: [2-(3-Bromo-5-methylsulfonylphenoxy)ethoxy](tert-butyl)dimethylsilane

[0520]

[0521] 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) at 0 °C was added RuCl3.H2O (50 mg, 0.22 mmol) and NaIO4(3.17 g, 14.84 mmol) in H2O (20 mL) and the resulting solution was stirred at this temperature for 2 h. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by combi-flash (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.

[0522] Example BB19: Synthesis of 1-bromo-3-isopropoxy-5-(methylsulfonyl)benzene

[0523] Step 1: 1,3-Dibromo-5-isopropoxybenzene

[0524]

[0525] A mixture of 3,5-dibromo phenol (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 RT, EA (200 mL) was added and the resulting mixture was washed with H2O (200 mL x 3). The mixture was dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-15%) to give the product (7.6 g, 65%).

[0526] Step 2: 1 -Bromo-3-isopropoxy-5-(methylsulfanyl)benzene

[0527]

[0528] A mixture of 1,3-dibromo-5-isopropoxybenzene (7.60 g, 25.85 mmol), dioxane (100 mL), Pd2(dba)3(1.18 g, 1.29 mmol), Xantphos (1.50 g, 2.59 mmol), MeSNa (1.81 g, 25.85 mmol) was stirred at 75 °C for 3 h. After cooling to RT, EA (200 mL) was added and the resulting mixture was washed with H2O (200 mL x 3). The mixture was dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-15%) to give the product (7.1 g, crude). GCMS (ESI) m / e [M+l] 260.

[0529] Step 3: 1 -Bromo-3-isopropoxy-5-(methylsulfonyl)benzene

[0530]

[0531] A mixture of 1 -bromo-3-isopropoxy-5-(methylsulfanyl)benzene (7.10 g, 27.18 mmol), THF (60 mL), H2O (60 mL), NaIO4(23.26 g, 108.75 mmol) and RuCl3.H2O (1.23 g, 5.46 mmol) was stirred at 0 °C for 1 h. After completion of the reaction, the resulting solution was diluted with EA (200 mL). The resulting mixture was washed with H2O (100 mL x 3). The mixture was dried over anhydrous Na2SO4and concentrated. The residue was purified by combi-flash (EA / PE = 0-25%) to give the product (4.25 g, 53%). 1H NMR (300MHz, CDCl3) δ7.63 (s, 1H), 7.37 (s, 1H), 7.30 (s, 1H), 4.62 (q, J = 6.1Hz, 1H), 3.08 (s, 3H), 1.38 (d, J = 6.0Hz, 6H). GCMS(ESI)m / e[M]292.

[0532] Example BB20: Synthesis of 1-bromo-3-methoxy-5-(methylsulfonyl)benzene

[0533]

[0534] Step 1: (3-bromo-5-methoxyphenyl)(methyl)thion

[0535]

[0536] Under a nitrogen atmosphere, a mixture of 1,3-dibromo-5-methoxybenzene (9.00 g, 33.16 mmol), dioxane (100 mL), NaSCH3 (3.19 g, 33.19 mmol), Pd2(dba)3 (1.52 g, 1.66 mmol), and Xantphos (1.92 g, 3.31 mmol) was stirred overnight at 75 °C. After cooling to RT, the solvent was removed under vacuum, and the residue was purified by combi-flash (EA / PE = 0–10%) to give the product (3.2 g, 39%). GCMS (ESI) m / e [M] 232.

[0537] Step 2: 1-Bromo-3-methoxy-5-(methylsulfonyl)benzene

[0538]

[0539] At 0 °C, NaIO4 (10.81 g, 50.54 mmol) was added in portions to a mixture of 1-bromo-3-methoxy-5-(methylthioalkyl)benzene (3.10 g, 12.63 mmol) and THF (30 mL) / H2O (30 mL), followed by the addition of RuCl3 (0.14 g, 0.62 mmol) in portions to H2O (15 mL) at 0 °C. The resulting solution was stirred at RT for 1 h. The resulting solution was diluted with H2O (50 mL), extracted with EA (30 mL x 3), the organic layer was concentrated and purified by combi-flash (EA / PE = 0-30%) to give the product (3.22 g, 91%). 1H 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.

[0540] Example BB21 : Synthesis of 1-bromo-3-methyl-5-(methylsulfonyl)benzene

[0541]

[0542] Step 1 : (3-bromo-5-methylphenyl)(methyl)sulfane

[0543]

[0544] A mixture of 1,3-dibromo-5-methylbenzene (11.00 g, 43.13 mmol), dioxane (150 mL), NaSCH3(3.02 g, 43.14 mmol), Pd2(dba)3(1.97 g, 2.15 mmol) and Xantphos (2.50 g, 4.32 mmol) was stirred at 75 °C overnight under a nitrogen atmosphere. After cooling to RT, the solvent was removed under vacuum and the residue was purified by combi-flash (EA / PE = 0-8%) to give the product (4.40 g, 42%). GCMS (ESI) m / e [M] 216

[0545] Step 2: 1-bromo-3-methyl-5-(methylsulfonyl)benzene

[0546]

[0547] To a mixture of 1-bromo-3-methyl-5-(methylsulfanyl)benzene (4.30 g, 17.82 mmol) and THF (20 mL) was added NaIO4(15.25 g, 71.29 mmol) in H2O (10 mL) portionwise at 0 °C, then RuCl3(0.20 g, 0.89 mmol) in H2O (10 mL) was added portionwise consecutively at 0 °C. The resulting solution was stirred at RT for 1 h. After completion of the reaction, the resulting solution was diluted with 50 mL of H2O, extracted with 3 x 30 mL of EA and the organic layers were combined and concentrated. The residue was purified by combi-flash (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.

[0548] Example BB22: Synthesis of 1-bromo-3-methylsulfonyl-5- (methoxymethyl)benzene

[0549]

[0550] Step 1: 1,3-dibromo-5-(methoxymethyl)benzene

[0551]

[0552] A mixture of 1,3-dibromo-5-(bromomethyl)benzene (7.00 g, 21.28 mmol), MeONa (5.75 g, 106.40 mmol) in MeOH (70 mL) was stirred at 70 °C for 1 h. After cooling to rt, the solvent was removed under vacuum and the residue was diluted with water. The resulting solution was extracted with EA (100 mL x 3) and the combined organic layers were washed with brine. The organic layer was dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-5%) to give the product (5.00 g, 84%). GCMS (ESI) m / e [M] 280.

[0553] Step 2: 1-bromo-3-(methoxymethyl)-5-(methylsulfanyl)benzene

[0554]

[0555] A mixture of 1,3-dibromo-5-(methoxymethyl)benzene (5.00 g, 17.86 mmol), DMF (50 mL) and CH3SNa (1.50 g, 21.43 mmol) was stirred at rt overnight. After the reaction was complete, water (20 mL) was added and the resulting solution was extracted with EA (100 mL x 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 under vacuum. The residue was purified by combi-flash (EA / PE = 0-2%) to give the product (3.50 g, 79%). GCMS (ESI) m / e [M] 246.

[0556] Step 3: 1-bromo-3-methylsulfonyl-5-(methoxymethyl)benzene

[0557]

[0558] A mixture of 1-bromo-3-(methoxymethyl)-5-(methylsulfanyl)benzene (3.50 g, 14.16 mmol), RuCl3.H2O (319.26 mg, 1.416 mmol) and NaIO4(6.06 g, 28.32 mmol) in THF (35 mL) and H2O (35 mL) was stirred at RT for 2 h. After completion of the reaction, the resulting solution was extracted with EA (100 mL x 3) and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum and the residue was purified by combi-flash (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.

[0559] Example BB23: Synthesis of 1-bromo-3-(difluoromethyl)-5-methylsulfonylbenzene

[0560]

[0561] Step 1: 1-bromo-3-(difluoromethyl)-5-(methylsulfanyl)benzene

[0562]

[0563] A mixture of 1-bromo-3-(methoxymethyl)-5-(methylsulfanyl)benzene (3.50 g, 14.16 mmol), RuCl3.H2O (319.26 mg, 1.416 mmol) and NaIO4(6.06 g, 28.32 mmol) in THF (35 mL) and H2O (35 mL) was stirred at RT for 2 h. After completion of the reaction, the resulting solution was extracted with EA (100 mL x 3) and the combined organic layers were washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum and the residue was purified by combi-flash (EA / PE = 0-10%) to give the product (2.21 g, 56%).

[0564] Step 2: 1-bromo-3-(difluoromethyl)-5-methylsulfonylbenzene

[0565]

[0566] To a stirred solution of 1-bromo-3-(difluoromethyl)-5-(methylsulfanyl)benzene (2.60 g, 10.27 mmol) in THF (40 ml) and H20 (40 mL) was added RuCl3.H20 (69.48 mg, 0.31 mmol) and NaI04(4.39 g, 20.55 mmol) portion wise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. After completion of the reaction, the resulting mixture was filtered off and the filtrate was concentrated under vacuum. The residue was purified by combi-flash (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).

[0567] Example BB24: Synthesis of 3-bromo-5-methanesulfonylbenzonitrile

[0568]

[0569] Step 1: 3-bromo-5-(methylsulfanyl)benzonitrile

[0570]

[0571] A mixture of 3,5-dibromobenzonitrile (10.00 g, 38.32 mmol), dioxane (160 mL), sodium (methylsulfanyl) (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 in an oil bath at 75 °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 (100 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA / PE = 0-9%) to give the product (8.52 g, 88%). LCMS (ESI, m / e) [M+1] + 228.

[0572] Step 2: 3-bromo-5-methanesulfonylbenzonitrile

[0573]

[0574] To a mixture of 3-bromo-5-(methylsulfanyl)benzonitrile (8.52 g, 37.35 mmol) and THF (75 mL) was added dropwise NaI04(23.97 g, 112.06 mmol) in H20 (35 mL) and RuCI3(0.25 g, 1.12 mmol) in H20 (35 mL) at 0 °C with stirring. The resulting solution was stirred at RT for 1 h. After completion of the reaction, the resulting solution was extracted with EA (100 mL x 3) and then concentrated under vacuum. The residue was purified by combi-flash (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.

[0575] Example BB25: Synthesis of 1-bromo-3-methylsulfonyl-5- (trifluoromethoxy)benzene

[0576]

[0577] Step 1: 1-bromo-3-(methylsulfanyl)-5-(trifluoromethoxy)benzene

[0578]

[0579] A mixture of 1,3-dibromo-5-(trifluoromethoxy)benzene (5.00 g, 15.63 mmol), 1,4-dioxane (50 mL), CH3SNa (984.67 mg, 14.07 mmol), Pd2(dba)3(715.62 mg, 0.78 mmol) and XantPhos (904.37 mg, 1.56 mmol) was stirred at 75 °C for 2 h under 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 layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuum and the residue was purified by combi-flash (EA / PE = 0-5%) to give the product (3.00 g, 67%). GCMS (ESI) m / e [M] 286.

[0580] Step 2: 1-bromo-3-methylsulfonyl-5-(trifluoromethoxy)benzene

[0581]

[0582] A mixture of 1-bromo-3-(methylsulfanyl)-5-(trifluoromethoxy)benzene (3.00 g, 10.45 mmol), RuCl3.H2O (235.58 mg, 1.05 mmol), NaIO4(6.71 g, 31.35 mmol), H2O (30 mL) in THF (30 mL) was stirred at RT for 2 h. After the reaction was completed, the resulting solution was extracted with EA (100 mL x 3) and the organic layers were combined. The resulting mixture was washed with brine and dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum and the residue was purified by combi-flash (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.

[0583] Example BB26: Synthesis of 2-bromo-4-[(2R)-2-[(tert-butyldimethylsilyl)oxy]propoxy]-6- methanesulfonylpyridine

[0584]

[0585] 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 Cs2CO3(2.59 g, 7.90 mmol) in DMF (10 mL) was stirred at 100 °C overnight. 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 x 3) and the combined organic layers were washed with brine, 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%). 1 H 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.

[0586] Example BB27: Synthesis of 7-bromo-2H,3H-[1,4]dioxino[2,3-c]pyridine

[0587]

[0588] Step 1: 2-[(6-bromo-4-iodopyridin-3-yl)oxy]ethanol

[0589]

[0590] To a mixture of 2-bromo-5-fluoro-4-iodopyridine (11.00 g, 36.43 mmol) in NMP (135 mL) was added dropwise ethylene glycol (10.81 g, 174.16 mmol) and t-BuOK (4.50 g, 40.08 mmol) in NMP (30 mL) 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 x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA / PE = 0-41%) to give the product (12.00 g, 86%). LCMS (ESI, m / e) [M+1] + 344.

[0591] Step 2: 7-bromo-2H,3H-[1,4]dioxino[2,3-c]pyridine

[0592]

[0593] 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 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 x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (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.

[0594] Example BB29: Synthesis of 2-bromo-4-chloro-6-(methylsulfonyl)pyridine

[0595]

[0596] Step 1: 2-bromo-6-(methylthio)pyridin-4-amine

[0597]

[0598] A mixture of 2,6-dibromopyridin-4-amine (5.00 g, 19.85 mmol), Cs2CO3(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 rt, water was added and the resulting mixture was extracted with EA (500 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum and the residue was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] 251.0. + 219.

[0599] Step 2: 2-bromo-6-(methylsulfonyl)pyridin-4-amine

[0600]

[0601] To a solution of 2-bromo-6-(methylsulfanyl)pyridin-4-amine (2.50 g, 11.41 mmol) in THF (25 mL) was added RuCl3.H2O (77.17 mg, 0.34 mmol), NaIO4(9.76 g, 45.64 mmol) and H2O (25 mL) at 0 °C and the resulting mixture was stirred at rt for 1 h. After the reaction was completed, the resulting mixture was extracted with EA (300 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 1:1) to give the product (1.02 g, 35%). LCMS (ESI) m / e [M+1] 279.0. + 251.

[0602] Step 3: 2-bromo-4-chloro-6-(methylsulfonyl)pyridine

[0603]

[0604] To a solution of 2-bromo-6-methanesulfonylpyridin-4-amine (800 mg, 3.18 mmol) in HC1 (12 M, 14.4 mL) was added NaNCte (1.10 g, 15.93 mmol) at 0 °C and the mixture was stirred at this temperature for 1 hour. After the reaction was completed, the resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under vacuum. 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.

[0605] Example BB30: Synthesis of l-bromo-3-fluoro-5-methanesulfonylbenzene

[0606]

[0607] Step 1: l-bromo-3-fluoro-5-(methylsulfanyl)benzene

[0608]

[0609] A mixture of l-bromo-3,5-difluorobenzene (5.00 g, 25.91 mmol), sodium (methylsulfanyl) (1.82 g, 25.91 mmol) in DMF (50 mL) was stirred at RT for 2 hours. After the reaction was completed, water was added and the resulting solution was extracted with EA (100 mL x 3) and the organic layers were combined. The resulting mixture was washed with brine and dried over anhydrous Na2S04. The solids were filtered off and the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-2%) to give the product (4.80 g, 84%). GCMS (ESI) m / e [M] 220.

[0610] Step 2: l-bromo-3-fluoro-5-methanesulfonylbenzene

[0611]

[0612] To a mixture of 1-bromo-3-fluoro-5-(methylsulfanyl)benzene (4.80 g, 21.71 mmol) and THF (50 mL) / H2O (50 mL) was added RuCl3.H2O (489 mg, 2.17 mmol) and NaIO4(13.93 g, 65.13 mmol) in portions at 0 °C. The resulting solution was stirred at RT for 2 h. After completion of the reaction, water was added and the resulting solution was extracted with EA (100 mL x 3) and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA / PE = 0-15%) to give the product (4.60 g, 80%). 1 H NMR (300 MHz, CDC13) δ 7.91 (s, 1H), 7.60-7.50 (m, 2H), 3.13 (s, 3H). GCMS (ESI) m / e [M] 252.

[0613] Example BB31 : Synthesis of 1-bromo-3-chloro-5-(methylsulfonyl)benzene

[0614]

[0615] Step 1: 1-bromo-3-chloro-5-(methylsulfanyl)benzene

[0616]

[0617] 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 RT for 1 h. After completion of the reaction, the resulting solution was diluted with EA (200 mL) and the resulting mixture was washed with H2O (200 mL x 3). The mixture was dried over anhydrous Na2SO4and concentrated. The residue was purified by combi-flash (EA / PE = 0-15%) to give the product (7.6 g, 87%). GCMS (ESI) m / e [M] 236.

[0618] Step 2: 1-bromo-3-chloro-5-methylsulfonylbenzene

[0619]

[0620] A mixture of 1-bromo-3-chloro-5-(methylsulfanyl)benzene (7.60 g, 31.99 mmol), THF (60 mL), H2O (60 mL), NaIO4(27.37 g, 127.96 mmol), and RuCl3.H2O (1.44 g, 6.39 mmol) was stirred at 0 °C for 1 h. After the reaction was completed, the resulting solution was diluted with EA (200 mL) and the resulting mixture was washed with H2O (200 mL x 3). The mixture was dried over anhydrous Na2SO4and concentrated. The residue was purified by combi-flash (EA / PE = 0-30%) to give the product (1.13 g, 13%). 1 H NMR (400 MHz, CDC13) δ 7.91 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 3.02 (s, 3H). GCMS (ESI) m / e [M] 268.

[0621] Example BB32: Synthesis of 1-bromo-3-cyclopropoxy-5-methylsulfonylbenzene

[0622]

[0623] Step 1: 1,3-dibromo-5-cyclopropoxybenzene

[0624]

[0625] A mixture of 3,5-dibromophenol (5.00 g, 19.85 mmol), cyclopropyl trifluoro-λ4-borane potassium (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 H2O (15 mL) was stirred at 70 °C overnight. After cooling to room temperature, water was added and the resulting solution was extracted with EA (200 mL x 3), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4. The solids were filtered off and the resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-5%) to give the product (1.00 g, 17%). GCMS (ESI) m / e [M] 290.

[0626] Step 2: 1-bromo-3-cyclopropoxy-5-(methylsulfanyl)benzene

[0627]

[0628] A mixture of 1,3-dibromo-5-cyclopropoxybenzene (1.00 g, 3.43 mmol), 1,4-dioxane (10 mL), CH3SNa (191.8 mg, 2.74 mmol), Xantphos (396.35 mg, 0.69 mmol) and Pd2(dba)3(313.6 mg, 0.34 mmol) was stirred at 75 °C under nitrogen for 2 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was diluted with 40 mL of water. The resulting solution was extracted with EA (60 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA / PE = 0-5%) to give the product (300 mg, 34%). GCMS (ESI) m / e [M] 258.

[0629] Step 3: 1 -Bromo-3-cyclopropoxy-5-methanesulfonylbenzene

[0630]

[0631] To a mixture of 1 -bromo-3-cyclopropoxy-5-(methylsulfanyl)benzene (300 mg, 1.16 mmol) in THF (5 mL) / H2O (5 mL) was added RuCI3.H2O (26 mg, 0.12 mmol) at 0 °C. Then NaIO4(742.79 mg, 3.47 mmol) was added in several batches at 0 °C. The resulting solution was stirred at RT for 2 h. After completion of the reaction, water was added and the resulting solution was extracted with EA (30 mL x 3) and the organic layers were combined. The resulting mixture was washed with brine, dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum and the residue was purified by preparative TLC (EA / PE = 1 :2) to give the product (165 mg, 49%). 1 H NMR (300 MHz, CDCI3) d 7.69 (s, 1 H), 7.55 (s, 1 H), 7.49 (s, 1 H), 3.85-3.81 (m, 1 H), 3.09 (s, 3H), 0.94-0.76 (m, 4H). GCMS (ESI) m / e [M] 290.

[0632] Example BB33: Synthesis of 2-bromo-3-isopropoxy-6-methanesulfonylpyridine

[0633]

[0634] Step 1 : 2-bromo-6-iodo-3-isopropoxy-pyridine

[0635]

[0636] 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 Cs2CO3(21.73 g, 66.69 mmol) was stirred at 80 °C for 3 h. After cooling to RT, water was added and the resulting solution was extracted with EA (100 mL x 3). The resulting mixture was concentrated under vacuum to give the product (11.08 g, 87%). LCMS (ESI, m / e) [M+1] + 342.

[0637] Step 2: 2-bromo-3-isopropoxy-6-(methylsulfanyl)pyridine

[0638]

[0639] A mixture of 2-bromo-6-iodo-3-isopropoxy-pyridine (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), Xantphos (1.87 g, 3.24 mmol) was stirred at 75 °C under nitrogen atmosphere for 3 h. After cooling to RT, the solvent was removed in vacuum and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuum and the residue was purified by combi-flash (EA / PE = 10:1) to give the product (8.00 g, 84%). LCMS (ESI, m / e) [M+1] + 262.

[0640] Step 3: 2-bromo-3-isopropoxy-6-methylsulfonylpyridine

[0641]

[0642] 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 NaIO4(12.24 g, 57.22 mmol) and RuCl3(0.13 g, 0.57 mmol) in H2O (30 mL) at 0 °C and the resulting solution was stirred at RT for 1 h. After completion of the reaction, the resulting solution was extracted with EA (30 mL x 3) and the combined organic layers were concentrated under vacuum. The residue was purified by combi-flash (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.

[0643] Example BB34: Synthesis of 2-bromo-4-(cyclopropylmethoxy)-6- methanesulfonylpyridine

[0644]

[0645] A mixture of 2-bromo-6-methanesulfonylpyridin-4-ol (1.00 g, 3.97 mmol), Cs2CO3(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 nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo and the residue was diluted with 50 mL of water. The resulting solution was extracted with EA (30 mL x 3) and the combined organic layers were washed with brine, 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%). 1 H 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.

[0646] Example BB35: Synthesis of l-bromo-3-(cyclopropylmethoxy)-5- (methylsulfonyl)benzene

[0647]

[0648] Step 1: l,3-dibromo-5-(cyclopropylmethoxy)benzene

[0649]

[0650] A mixture of 3,5-dibromo-phenol (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 x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA / PE = 0-15%) to give the product (2.80 g, 46%). GCMS (ESI) m / e [M+1] 323.0, 325.0. + 304.

[0651] Step 2: (3-bromo-5-(cyclopropylmethoxy)phenyl)(methyl)sulfane

[0652]

[0653] 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 x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (EA / PE = 0-15%) to give the product (2.0 g, 80%). LCMS (ESI) m / e [M+1] 257.0, 259.0. + 272.

[0654] Step 3: 1-bromo-3-(cyclopropylmethoxy)-5-(methylsulfonyl)benzene

[0655]

[0656] A mixture of 1-bromo-3-(cyclopropylmethoxy)-5-(methylsulfanyl)benzene (2.00 g, 7.32 mmol), NaI04(6.26 g, 29.27 mmol), RuCI3.H20 (330 mg, 1.46 mmol) in THF (20 mL) and H20 (20 mL) was stirred at 0 °C for 1 h. After the reaction was completed, EA (100 mL) was added and the resulting mixture was washed with water (100 mL x 3). The mixture was dried over anhydrous Na2S04and concentrated. The residue was purified by combi-flash (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).

[0657] Example BB36: Synthesis of 2-bromo-4-cyclobutoxy-6-(methylsulfonyl)pyridine

[0658]

[0659] A solution of 2-bromo-6-methylsulfonylpyridin-4-ol (700 mg, 2.78 mmol), bromocyclobutane (749 mg, 5.55 mmol) and K2C03(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 x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under vacuum. 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.

[0660] Example BB37: Synthesis of 2-bromo-4-(cyclopentyloxy)-6-methylsulfonylpyridine

[0661]

[0662] 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 DIAD (642 mg, 3.17 mmol) dropwise at 0 °C and the resulting mixture was stirred at 50 °C overnight. After cooling to RT, the solvent was removed in vacuo and the residue was diluted with water (20 mL). The resulting solution was extracted with EA (30 mL x 3) and the combined organic layers were washed with brine, dried over anhydrous Na2S04. 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%). 1 H 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+l] + 320.

[0663] Example BB38: Synthesis of 2-bromo-6-methanesulfonyl-4-(oxolan-3-yloxy)pyridine

[0664]

[0665] 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 was added PPh3 (832 mg, 3.17 mmol) and DIAD (642 mg, 3.17 mmol) dropwise in portions at 0 °C. The resulting mixture was stirred at RT overnight. After completion of the reaction, water was added and the resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2S04, concentrated under vacuum. 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+l]+ 322.

[0666] Example BB39: Synthesis of 2-bromo-4-(l-methoxyethyl)-6-(methylsulfonyl)pyridine

[0667]

[0668] Step 1: 2,6-Dibromo-N-methoxy-N-methylisonicotinamide

[0669]

[0670] 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, 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 H2O (100 mL) and extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4and 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+l] + 324.

[0671] Step 2: l-(2,6-Dibromopyridin-4-yl)ethanone

[0672]

[0673] To a mixture of 2,6-dibromo-N-methoxy-N-methylisonicotinamide (4.0 g, 12.3 mmol) in THF (40 mL) was added MgBrCH3(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 H2O (50 ml) and extracted with EA (50 mL x 3). The combined organic layers were dried over Na2SO4and 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+l] + 278.

[0674] Step 3: l-(2,6-Dibromopyridin-4-yl)ethanol

[0675]

[0676] To a solution of 1-(2,6-dibromopyridin-4-yl)ethanone (3.2 g, 11.5 mmol) in MeOH (30 mL) was added NaBH4(434 mg, 11.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The mixture was diluted with H2O (50 ml) and extracted with EA (50 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the product (3.2 g, 99%). MS (ESI) m / e [M+1] + 282.

[0677] Step 4: 2,6-dibromo-4-(l-methoxyethyl)pyridine

[0678]

[0679] 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. Mel (4.9 g, 34.2 mmol) was added and stirred at 20 °C for 2 h. The mixture was diluted with saturated NH4Cl (50 ml) and extracted with EA (50 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give the crude product (3.2 g, crude), which was used directly. MS (ESI) m / e [M+1] + 294.

[0680] Step 5: 2-bromo-4-(l-methoxyethyl)-6-(methylthio)pyridine

[0681]

[0682] To a solution of 2,6-dibromo-4-(l-methoxyethyl)pyridine (1.5 g, 5.1 mmol) in DMF (20 mL) was added NaSCH3(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 x 3). The combined organic layers were dried over Na2SO4and concentrated to give the product (1.5 g, crude), which was used directly. MS (ESI) m / e [M+1] + 262.0.

[0683] Step 6: 2-bromo-4-(l-methoxyethyl)-6-(methylsulfonyl)pyridine

[0684]

[0685] A mixture of 2-bromo-4-(l-methoxyethyl)-6-(methylthio)pyridine (1.5 g, 5.1 mmol) and oxone (12.5 g, 20.4 mmol) in MeOH (16 mL) and H2O (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 x 3). The combined organic layers were dried over Na2SO4 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, CDC13) 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+l] + 294.

[0686] Example BB40: Synthesis of 2-bromo-4-[(2S)-butan-2-yloxy]-6- methanesulfonylpyridine

[0687]

[0688] 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 DIAD (513 mg, 2.54 mmol) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred at 50 °C overnight. The resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL), 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+l] + 308.

[0689] Example BB41: Synthesis of 2-bromo-4-(difluoromethoxy)-6- methanesulfonylpyridine

[0690]

[0691] A mixture solution of KOH (1.11 g, 19.78 mmol), CH3CN (5 mL) and H2O (5 mL) was cooled to about -10 °C. 2-Bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol) was added dropwise over 15 min, followed by diethyl bromodifluoromethylphosphonate (1.06 g, 3.97 mmol). The mixture was allowed to warm to RT over 1 h. The mixture was poured into water and extracted with EA (50 mL x 3), washed with brine and dried over Na2SO4. The residue was purified by preparative TLC (EA / PE = 1:10) to give 2-bromo-4-(difluoromethoxy)-6-methanesulfonylpyridine (310 mg, 52% yield). 1 H 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.

[0692] Example BB42: Synthesis of 2-bromo-4-ethoxy-6-methanesulfonylpyridine

[0693]

[0694] A mixture solution of KOH (1.11 g, 19.78 mmol), CH3CN (5 mL) and H2O (5 mL) was cooled to about -10 °C. 2-Bromo-6-methanesulfonylpyridin-4-ol (500 mg, 1.98 mmol) was added dropwise over 15 min, followed by diethyl bromodifluoromethylphosphonate (1.06 g, 3.97 mmol). The mixture was allowed to warm to RT over 1 h. The mixture was poured into water and extracted with EA (50 mL x 3), washed with brine and dried over Na2SO4. The residue was purified by preparative TLC (EA / PE = 1:10) to give 2-bromo-4-(difluoromethoxy)-6-methanesulfonylpyridine (310 mg, 52% yield). + 281.

[0695] Example BB43: Synthesis of [[(2R)-1-(3-bromo-5-methylsulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane

[0696]

[0697] Step 1: (2R)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol

[0698]

[0699] 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) portion wise at 0 °C. The resulting mixture was stirred at RT overnight. The resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by combi-flash (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.

[0700] Step 2: (2R)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate

[0701]

[0702] 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) portion wise at 0 °C. The resulting mixture was stirred at RT for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by combi-flash (EA / PE = 3-5%) to give crude product (15.00 g, 100% yield). LCMS (ESI) m / e [M+1] + 344.

[0703] Step 3: tert-butyl([[(2R)-1-(3,5-dibromo-phenoxy)propan-2-yl]oxy])dimethylsilane

[0704]

[0705] A mixture of 3,5-dibromophenol (2.0 g, 7.94 mmol) and (2R)-2-[(tert- butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate (5.46 g, 15.85 mmol) and Cs2CO3(5.17 g, 15.86 mmol) in DMF (20 mL) was stirred at 100 °C overnight. The mixture was allowed to cool to RT. The resulting mixture was extracted with EA (40 mL x 3). The combined organic layers were washed with brine (40 mL x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EA / PE = 3-5%) to give tert-butyl([[(2R)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (1.90 g, 56% yield).

[0706] Step 4: [[(2R)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert- butyl)dimethylsilane

[0707]

[0708] A mixture of tert-butyl([[(2R)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (1.00 g, 2.36 mmol), sodium (methylsulfanyl) (166 mg, 2.37 mmol), DIEA (0.82 mL, 4.71 mmol), Pd2(dba)3(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 N2atmosphere. The mixture was allowed to cool to RT. The resulting mixture was extracted with EA (40 mL x 3). The combined organic layers were washed with brine (30 mL x 3) and dried over anhydrous Na2SO4. 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).

[0709] Step 5: [[(2R)-1-(3-bromo-5-methylsulfonylphenoxy)propan-2-yl]oxy](tert- butyl)dimethylsilane

[0710]

[0711] To a stirred solution of [(2R)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy}(tert- butyldimethylsilane (470 mg, 1.20 mmol) in THF (30 mL) at 0 °C was added RuCl3-H2O (7.5 mg, 0.04 mmol) and NaIO4(513.6 mg, 2.40 mmol) in H2O (20 mL) and the resulting solution was stirred at 0 °C for 1 h. The mixture was then extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 3), 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-methylsulfonylphenoxy)propan-2-yl]oxy}(tert- butyldimethylsilane (344.2 mg, 67% yield). 1 H NMR (400 MHz, CDC13) 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 = 8.0 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 6H). LCMS (ESI) m / e [M+1] + 422.

[0712] Example BB44: Synthesis of 2-bromo-6-(ethanesulfonyl)-4-isopropoxy-pyridine

[0713]

[0714] Step 1: 2-bromo-6-(ethylsulfanyl)pyridin-4-ol

[0715]

[0716] A stirred mixture of 2,6-dibromopyridin-4-ol (5.00 g, 19.77 mmol), EtSNa (1.66 g, 19.77 mmol), Pd2(dba)3(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 RT. The resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-bromo-6-(ethylsulfanyl)pyridin-4-ol as a crude product, which was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] + 234.

[0717] Step 2: 2-bromo-6-(ethanesulfonyl)pyridin-4-ol

[0718]

[0719] To a stirred mixture of 2-bromo-6-(ethylsulfanyl)pyridin-4-ol (5.00 g, 21.36 mmol) in THF was added RuCl3-H2O (133 mg, 0.64 mmol) in water for a few minutes and NaIO4(9.14 g, 42.72 mmol) was added portionwise to THF and water at 0 °C for 30 min. The resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (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.

[0720] Step 3: 2-bromo-6-(ethanesulfonyl)-4-isopropoxy-pyridine

[0721]

[0722] A stirred solution of 2-bromo-6-(ethanesulfonyl)pyridin-4-ol (1.50 g, 5.64 mmol), Cs2CO3(3.68 g, 11.27 mmol), and 2-iodopropane (1.44 g, 8.46 mmol) in dimethylformamide (10 mL) was allowed to stir at 80 °C for 1 h. The mixture was allowed to cool to rt. The resulting mixture was extracted with EA (40 mL x 3). The combined organic layers were washed with brine (30 mL x 2) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EA / PE = 28-32%) to give 2-bromo-6-(ethanesulfonyl)-4-isopropoxy-pyridine (1.40 g, 78% yield). 1 HNMR (400 MHz, CDC13) 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.

[0723] Example BB45: Synthesis of [[(2S)-1-(3-bromo-5-methylsulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane

[0724]

[0725] Step 1: (2S)-1-[(4-methylbenzenesulfonyl)oxy]propan-2-ol

[0726]

[0727] 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) portion wise at 0 °C. The resulting mixture was stirred at RT overnight. The resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 x 3 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by combi-flash (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.

[0728] Step 2: (2S)-2-[(tert-butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate

[0729]

[0730] 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) in DCM (100 mL) was added TBSCl (19.64 g, 130.28 mmol) in portions at 0 °C. The resulting mixture was stirred at RT for 1 h. The mixture was concentrated and purified by combi-flash (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] 395.2. + 344.

[0731] Step 3: tert-Butyl([[(2S)-1-(3,5-dibromo-phenoxy)propan-2-yl]oxy])dimethyl- silane

[0732]

[0733] A mixture of 3,5-dibromo-phenol (2.0 g, 7.94 mmol) and (2S)-2-[(tert- butyldimethylsilyl)oxy]propyl 4-methylbenzenesulfonate (5.46 g, 15.85 mmol) and Cs2CO3 (5.17 g, 15.86 mmol) in DMF (20 mL) was stirred at 100 °C overnight. The mixture was allowed to cool to RT. The resulting mixture was extracted with EA (40 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated and purified by combi-flash (EA / PE = 3-5%) to give tert-butyl([[(2S)-1-(3,5-dibromo-phenoxy)propan-2-yl]oxy])dimethyl- silane (1.90 g, 56% yield).

[0734] Step 4: [[(2S)-1-[3-bromo-5-(methylsulfanyl)phenoxy]propan-2-yl]oxy](tert- butyl)dimethylsilane

[0735]

[0736] A mixture of tert-butyl([[(2S)-1-(3,5-dibromophenoxy)propan-2-yl]oxy])dimethylsilane (2.00 g, 4.72 mmol), sodium(methylsulfanyl)ide (332.00 mg, 4.74 mmol), DIEA (1.64 mL, 3.48 mmol), Pd2(dba)3 (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 N2 atmosphere. The mixture was allowed to cool to RT. The resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4, concentrated to give a residue and purified by prep-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).

[0737] Step 5: [[(2S)-1-(3-bromo-5-methylsulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane

[0738]

[0739] 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 RuCl3·H2O (15 mg, 0.08 mmol) and NaIO4 (1.03 g, 4.80 mmol) in H2O (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 x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous Na2SO4, concentrated and purified by prep-TLC (PE / EA = 10:1) to give [[(2S)-1-(3-bromo-5-methylsulfonylphenoxy)propan-2-yl]oxy](tert-butyl)dimethylsilane (646.4 mg, 63% yield). 1 H NMR (400 MHz, CDCl3) d 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.

[0740] Example BB46: Synthesis of 2-bromo-4-isobutoxy-6-(methylsulfonyl)pyridine

[0741]

[0742] A solution of 2-bromo-6-methylsulfonylpyridin-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 x 3). The combined organic layers were washed with brine (100 mL x 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) d 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.

[0743] Example BB46: Synthesis of 2-bromo-4-isobutoxy-6-(methylsulfonyl)pyridine

[0744]

[0745] Step 1: 2-bromo-3-(difluoromethoxy)-6-iodopyridine

[0746]

[0747] 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 Cs2CO3(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 x 3). The combined organic layers were washed with brine (200 mL x 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give crude 2-bromo-3-(difluoromethoxy)-6-iodopyridine (5.00 g) and used directly in the next step without further purification. LCMS (ESI) m / e [M + 350.

[0748] Step 2: 2-bromo-3-(difluoromethoxy)-6-(methylsulfanyl)pyridine

[0749]

[0750] To a solution of 2-bromo-3-(difluoromethoxy)-6-iodopyridine (2.00 g, 5.72 mmol) and CH3SNa (320 mg, 4.57 mmol) in dioxane (20 mL) was added Xantphos (331 mg, 0.57 mmol) and Pd2(dba)3(523 mg, 0.57 mmol). After stirring at 70 °C for 4 h under nitrogen atmosphere, the resulting mixture was extracted with EA (200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to give the crude product 2-bromo-3-(difluoromethoxy)-6-(methylsulfanyl)pyridine (2.0 g) and it was used directly in the next step without further purification. LCMS (ESI) m / e [M+1] 285.0. + 270.

[0751] Step 3: 2-bromo-3-(difluoromethoxy)-6-methanesulfonylpyridine

[0752]

[0753] To a solution of 2-bromo-3-(difluoromethoxy)-6-(methylsulfanyl)pyridine (2.00 g, 7.41 mmol) in THF (20 mL) was added RuCl3-H2O (50 mg, 0.22 mmol) at 0 °C. NaIO4(6.34 g, 29.62 mmol) and H2O (20 mL) were added and the mixture was allowed to warm to RT and stirred for 1 h. The resulting mixture was extracted with EA (200 mL x 3). The combined organic layers were washed with brine (200 mL x 3), 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 HNMR (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+1] 285.0. + 301.

[0754] Example BB49: Synthesis of 5-bromo-7-methanesulfonyl-2H,3H-[1,4]dioxino[2,3- c]pyridine

[0755]

[0756] Step 1: 2-Bromo-6-iodo-3-methoxypyridine

[0757]

[0758] A mixture of 2-bromo-6-iodopyridin-3-ol (11.00 g, 36.68 mmol), CH3I (10.41 g, 73.34 mmol), and K2CO3 (10.14 g, 73.35 mmol) in DMF (165 mL) was stirred at RT for 1 h. The resulting solution was added to H2O (200 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over anhydrous Na2SO4, concentrated to give the residue, and purified by combi-flash (EA / PE = 0-6%) to give 2-bromo-6-iodo-3-methoxypyridine (11.00 g, 85% yield). LCMS(ESI) m / e[M+1] + 314.

[0759] Step 2: 2-Bromo-6-iodo-3-methoxypyridine-4-ol

[0760]

[0761] 2-Bromo-6-iodo-3-methoxypyridine (5.00 g, 15.92 mmol) and THF (100 mL) were placed in a 250 mL three-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere. Then, LDA (2.0 M, 9.6 mL, 19.11 mmol) was added dropwise with stirring at -78 °C. The resulting solution was stirred at -78 °C for 1 hour. Trimethyl borate (2.48 g, 23.86 mmol) was added dropwise with stirring at -78 °C. The resulting solution was stirred at -78 °C for 2 hours. H₂O₂ (0.15 mL) was added dropwise with stirring at -60 °C. The resulting solution was allowed to react again with stirring at RT for 1 hour. The reaction was then quenched by adding Na₂S₂O₃. The resulting solution was extracted with EA (50 mL x 3), dried over anhydrous Na₂SO₄, concentrated under reduced pressure to give the residue, and purified by combi-flash (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.

[0762] Step 3: 2-Bromo-6-iodopyridine-3,4-diol

[0763]

[0764] Subsequently, 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 rt for 3 h. The reaction was then quenched by the addition of MeOH (5 mL). The resulting mixture was concentrated under vacuum and purified by combi-flash (EA / PE = 0-8%) to give 2-bromo-6-iodopyridine-3,4-diol (2.12 g crude). LCMS (ESI) m / e [M+1] 323.0. + 316.

[0765] Step 4: 5-Bromo-7-iodo-2H,3H-[l,4]dioxino[2,3-c]pyridine

[0766]

[0767] 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), 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 H2O (100 mL) and extracted with EA (50 mL x 3), dried over anhydrous Na2SO4, concentrated to give 5-bromo-7-iodo-2H,3H- [l,4]dioxino[2,3-c]pyridine (1.26 g, 49% yield). LCMS (ESI) m / e [M+1] 323.0. + 342.

[0768] Step 5: 5-Bromo-7-(methylsulfanyl)-2H,3H-[l,4]dioxino[2,3-c]pyridine

[0769]

[0770] A mixture of 5-bromo-7-iodo-2H,3H-[l,4]dioxino[2,3-c]pyridine (1.26 g, 3.68 mmol), sodium (methylsulfanyl) (0.23 g, 3.28 mmol), Pd2(dba)3(0.17 g, 0.18 mmol), 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 under vacuum. The residue was purified by combi-flash (EA / PE = 0-5%) to give 5-bromo-7-(methylsulfanyl)-2H,3H-[l,4]dioxino[2,3-c]pyridine (492 mg, 45% yield). LCMS (ESI) m / e [M+l] + 262.

[0771] Step 6: 5-Bromo-7-methanesulfonyl-2H,3H-[l,4]dioxino[2,3-c]pyridine

[0772]

[0773] 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-H2O (12.72 mg, 0.05 mmol) at 0 °C. NaIO4(1206.4 mg, 5.64 mmol) in H2O (10 mL) was added at 0 °C. The resulting solution was stirred at RT for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-25%) to give 5-bromo-7-methanesulfonyl-2H,3H-[l,4]dioxino[2,3-c]pyridine (207.0 mg, 33%). 1 HNMR (400 MHz, DMSO-d6) δ 7.56 (s, 1H), 4.54-4.48 (m, 4H), 3.23 (s, 3H). LCMS (ESI) m / e [M+l] + 294.

[0774] Example BB50: Synthesis of (R)-2-bromo-4-(2-methoxypropoxy)-6- (methylsulfonyl)pyridine

[0775]

[0776] Step 1: (R)-2-methoxypropyl 4-methylbenzenesulfonate

[0777]

[0778] 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 RT 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 Na2SO4, concentrated under reduced pressure to give (R)-2-methoxypropyl 4-methylbenzenesulfonate (3.95 g, 82.3%). MS (ESI) m / e [M+1] + 245.

[0779] Step 2: (R)-2,6-dibromo-4-(2-methoxypropoxy)pyridine

[0780]

[0781] 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), 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 x 3). The combined organic layers were dried over Na2SO4, 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.

[0782] Step 3: (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylthio)pyridine

[0783]

[0784] A mixture of (R)-2,6-dibromo-4-(2-methoxypropoxy)pyridine (3.0 g, 9.23 mmol), sodium methyl mercaptan (wt: 20%, 7.9 g, 27.7 mmol) in DMF (20 mL) was stirred at RT 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 Na2SO4, 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.

[0785] Step 4: (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridine

[0786]

[0787] 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 RT for 16 h. The DCM was exchanged with EA (30 mL), then the organic layer was washed with a mixture solution of NaHCO3(10 mL) and Na2S2O3(10 mL), dried over Na2SO4, concentrated to give the crude product and purified by silica gel column chromatography using EA / PE (1 / 2) as eluent to give (R)-2-bromo-4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridine (2.5 g, 93.6%). MS (ESI) m / e [M+1] 366.0. + 324.

[0788] Example BB51 : Synthesis of 6-bromo-3-methoxy-2-(methylsulfonyl)pyridine

[0789]

[0790] Step 1 : 6-bromo-3-methoxy-2-(methylthio)pyridine

[0791]

[0792] Into a 100-mL round-bottom flask, was placed 6-bromo-2-fluoro-3-methoxypyridine (1.00 g, 4.85 mmol), DMF (10 mL), NaSCH3(339.78 mg, 4.85 mmol). The resulting solution was stirred at RT for 1 h. 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 combi-flash (EA / PE = 0-15%) to give the product (0.90 g, 79% yield). LCMS (ESI) m / e [M+1] 256.0. + 234.

[0793] Step 2: 6-bromo-3-methoxy-2-(methylsulfonyl)pyridine

[0794]

[0795] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-methoxy-2-(methylsulfanyl)pyridine (1.00 g, 4.27 mmol), THF (10 mL), H2O (10 mL), NaIO4(3.65 g, 17.07 mmol), RuCl3.H2O (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 H2O (100 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by combi-flash (EA / PE = 0-20%) to give the product (705.30 mg, 62% yield). 1 H NMR (400 MHz, CDC13) 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+l] + 266.

[0796] Example BB52: Synthesis of 2-bromo-6-(methylsulfonyl)-4-phenylpyridine

[0797]

[0798] Step 1: Synthesis of 2,6-dibromo-4-phenylpyridine

[0799]

[0800] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,6-dibromo-4-iodopyridine (5.20 g, 14.33 mmol), dioxane (30 mL), H2O (10 mL), phenylboronic acid (1.75 g, 14.35 mmol), Na2CO3(3.04 g, 28.68 mmol), Pd(PPh3)4(1656.31 mg, 1.43 mmol). The resulting solution was stirred at 90 °C for 2 h. The resulting solution was diluted with (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 combi-flash (EA / PE = 0-15%) to give the product (0.77 g, 17% yield). LCMS (ESI) m / e [M+l] + 312.

[0801] Step 2: 2,6-dibromo-4-phenylpyridine

[0802]

[0803] Into a 100 mL round-bottom flask, was placed 2,6-dibromo-4-phenylpyridine (770.00 mg, 2.460 mmol), DMF (10 mL), NaSCH3 (172.21 mg, 2.46 mmol). The resulting solution was stirred at rt for 1 h. 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 combi-flash (EA / PE = 0-10%) to give the product (0.43 g, 62% yield). LCMS (ESI) m / e [M+1] + 280.

[0804] Step 3: 2-bromo-6-(methylsulfonyl)-4-phenylpyridine

[0805]

[0806] Into a 100 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-6-(methylsulfanyl)-4-phenylpyridine (430.00 mg, 1.54 mmol), THF (10 mL), H2O (10 mL), NaIO4 (1313.06 mg, 6.14 mmol), RuCl3.H2O (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 H2O (50 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by combi-flash (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.

[0807] Example BB53: Synthesis of 2-bromo-4-methyl-6-(methylsulfonyl)pyridine

[0808]

[0809] Step 1: 2-bromo-4-methyl-6-(methylthio)pyridine

[0810]

[0811] Into a 250-mL round bottom flask, was placed 2,6-dibromo-4-methylpyridine (4.00 g, 15.62 mmol), DMF (50 mL), NaSCH3(0.98 g, 14.00 mmol). The resulting solution was stirred at 25 °C for 3 h. The resulting solution was diluted with H2O (100 mL), extracted with 3x80 mL of EA (100 mL x 3) and the organic layers combined and concentrated. The residue was purified by combi-flash (EA / PE = 0-20%) to give the product (3.3 g, 87% yield). LCMS (ESI, m / z) [M+1] + 218.

[0812] Step 2: 2-bromo-4-methyl-6-(methylsulfonyl)pyridine

[0813]

[0814] Into a 250-mL round bottom flask, was placed 2-bromo-4-methyl-6- (methylsulfanyl)pyridine (3.30 g, 13.61 mmol), THF (30 mL), H2O (10 mL). Then at 0 °C, NaIO4(11.65 g, 0.05 mmol) in H2O (10 mL) was added portion wise. To the mixture at 0 °C, RuCl3(0.31 g, 1.37 mmol) in H2O (10 mL) was added portion wise. The resulting solution was stirred at 25 °C for 1 h. The resulting solution was diluted with H2O, extracted with EA (100 mL x 3) and the organic layers combined and concentrated. The residue was purified by combi-flash (EA / PE = 0-30%) to give the product (2.45 g, 65% yield). 1 HNMR (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.

[0815] Example BB54: Synthesis of 2-bromo-6-methylsulfonyl-4-phenoxy pyridine

[0816]

[0817] Step 1: 2,6-dibromo-4-phenoxy pyridine

[0818]

[0819] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-6-(methylsulfanyl)-4-phenoxypyridine (0.82 g, 2.76 mmol), THF (7 mL). Subsequently, NaIO4(1.78 g, 8.32 mmol) and RuCl3(0.020 g, 0.080 mmol) in H2O (7 mL) were added dropwise at 0 °C with stirring. The resulting solution was stirred at RT for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-11%) to give the product (488.80 mg, 48% yield). LCMS (ESI) m / e [M+1] + 330.

[0820] Step 2: 2-bromo-6-(methylsulfanyl)-4-phenoxypyridine

[0821]

[0822] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-6-(methylsulfanyl)-4-phenoxypyridine (0.82 g, 2.76 mmol), THF (7 mL). Subsequently, NaIO4(1.78 g, 8.32 mmol) and RuCl3(0.020 g, 0.080 mmol) in H2O (7 mL) were added dropwise at 0 °C with stirring. The resulting solution was stirred at RT for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-11%) to give the product (488.80 mg, 48% yield). LCMS (ESI) m / e [M+1] + 296.

[0823] Step 3: 2-bromo-6-methylsulfonyl-4-phenoxypyridine

[0824]

[0825] Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-6-(methylsulfanyl)-4-phenoxypyridine (0.82 g, 2.76 mmol), THF (7 mL). Subsequently, NaIO4(1.78 g, 8.32 mmol) and RuCl3(0.020 g, 0.080 mmol) in H2O (7 mL) were added dropwise at 0 °C with stirring. The resulting solution was stirred at RT for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EA / PE = 0-11%) to give the product (488.80 mg, 48% yield). LCMS (ESI) m / e [M+1] 1H 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.

[0826] Example BB55: Synthesis of 2-chloro-6-methylsulfonyl-4- (trifluoromethyl)pyridine

[0827]

[0828] Step 1: 2-chloro-6-(methylsulfanyl)-4-(trifluoromethyl)pyridine

[0829]

[0830] Into a 250-mL round-bottom flask, was placed 2,6-dichloro-4- (trifluoromethyl)pyridine (6.00 g, 27.78 mmol), DMF (90.00 mL), sodium (methylsulfanyl) (1.75 g, 24.97 mmol). The resulting solution was stirred at RT for 1 h. The resulting solution was extracted with 3 x 50 mL of EA and concentrated. The residue was purified by combi-flash to give the product (2.56 g, 36% yield). GCMS (ESI) m / e [M] 227.

[0831] Step 2: 2-chloro-6-methylsulfonyl-4-(trifluoromethyl)pyridine

[0832]

[0833] Into a 100-mL three-necked round-bottom flask, was placed 2-chloro-6- (methylsulfanyl)-4-(trifluoromethyl)pyridine (2.56 g, 11.24 mmol), THF (20 mL). Subsequently, at 0 °C, with stirring, NaIO4(7.22 g, 33.75 mmol) and RuCl3(0.08 g, 0.337 mmol) in H2O (20 mL) were added dropwise. The resulting solution was stirred at RT for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (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.

[0834] Example BB56: Synthesis of 6-bromo-3-methyl-2-(methylsulfonyl)pyridine

[0835]

[0836] Step: 1: 6-bromo-2-fluoro-3-methylpyridine

[0837]

[0838] Into a 100-mL round-bottom flask, was placed 6-bromo-2-fluoro-3- methylpyridine (3.40 g, 17.89 mmol), DMF (40 mL), NaSCH3(1.00 g, 14.31 mmol). The resulting solution was stirred at RT for 1.5 h. The reaction was then quenched by the addition of aqueous NH4Cl (50 mL). The resulting solution was extracted with EA (50 mL x 3). The resulting mixture was washed with H2O. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (PE / EA = 0-1%) to give the product (2.9 g, 74% yield). LCMS (ESI) m / e [M+1] + 190.

[0839] Step: 2: 6-bromo-3-methyl-2-(methylthio)pyridine

[0840]

[0841] Into a 100-mL round-bottom flask, was placed 6-bromo-2-fluoro-3- methylpyridine (3.40 g, 17.89 mmol), DMF (40 mL), NaSCH3(1.00 g, 14.31 mmol). The resulting solution was stirred at RT for 1.5 h. The reaction was then quenched by the addition of aqueous NH4Cl (50 mL). The resulting solution was extracted with EA (50 mL x 3). The resulting mixture was washed with H2O. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (PE / EA = 0-1%) to give the product (2.9 g, 74% yield). LCMS (ESI) m / e [M+1] + 218.

[0842] Step: 3: 6-bromo-3-methyl-2-(methylsulfonyl)pyridine

[0843]

[0844] Into a 250-mL round-bottom flask, was placed 6-bromo-3-methyl-2- (methylsulfanyl)pyridine (2.90 g, 13.29 mmol), THF (30 mL). Subsequently, at 0 °C, NaIO4(8.53 g, 39.88 mmol), H2O (30 mL) and RuCl3(82.57 mg, 0.40 mmol) were added portionwise over 5 min. The resulting solution was stirred at RT for 1 h. The resulting solution was extracted with 50 mL of EA. The resulting mixture was washed with H2O (25 mL x 2). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (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.

[0845] Example BB57: Synthesis of 2-bromo-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4- yl)pyridine

[0846]

[0847] Step 1: Synthesis of 2,6-dibromo-4-iodopyridine

[0848]

[0849] In a flame-dried and 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. Then 2,2,6,6-tetramethylpiperidyl magnesium chloride lithium chloride complex (32 mL, 31.70 mmol, 1 M in THF) was added dropwise via syringe and stirred for another 30 min at this temperature. Then I2(5.9 g, 23.24 mmol) was added rapidly to the mixture at -30 °C under the protection of nitrogen and stirred for 30 min at the same temperature. The reaction mixture was quenched by adding 30 mL of saturated NH4Cl, then extracted with EtOAc, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted using EtOAc / PE (1 / 10, v / v)) to give the product (3.0 g, 39% yield). LCMS (ESI) m / e [M+1] + = 362.

[0850] Step 2: Synthesis of 2,6-dibromo-4-(3,6-dihydro-2H-pyran-4-yl)pyridine

[0851]

[0852] 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-l,3,2-dioxaborolane (1.2 g, 5.71 mmol) in 1,4-dioxane (40 mL) and water (8 mL) was added Pd(dppf)Cl2(403 mg, 0.55 mmol) and K2CO3(1.5 g, 10.85 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL) and then 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 / 12, v / v) to give the product (1.2 g, 68% yield). LCMS (ESI) m / e [M+l] + = 318.

[0853] Step 3: Synthesis of 2,6-dibromo-4-(tetrahydro-2H-pyran-4-yl)pyridine

[0854]

[0855] 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 at rt under hydrogen atmosphere overnight. The resulting mixture was filtered, 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+l] + = 320.

[0856] Step 4: Synthesis of 2-bromo-6-(methylthio)-4-(tetrahydro-2H-pyran-4-yl)pyridine

[0857]

[0858] 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.

[0859] Step 5: Synthesis of 2-bromo-6-(methylsulfonyl)-4-(tetrahydro-2H-pyran-4- yl)pyridine

[0860]

[0861] 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 RuCl3.H2O (12 mg, 0.05 mmol) in water (2 mL) at 0 °C. To the above mixture was added dropwise NaIO4(1.5 g, 7.01 mmol) in water (10 mL) at 0 °C. The resulting mixture was stirred for another 30 min at 0 °C. 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) d 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.

[0862] Example BB58: Synthesis of 2-bromo-3,4-dimethoxy-6-(methylsulfonyl)pyridine

[0863]

[0864] Step: 1: 2-bromo-6-iodo-3,4-dimethoxypyridine

[0865]

[0866] Into a 250-mL round bottom flask, was placed 2-bromo-6-iodo-3- methoxy-pyridin-4-ol (2.95 g, 8.94 mmol), DMF (90 mL) and K2CO3(2.47 g, 17.88 mmol). Then at 0 °C, CH3I (2.54 g, 17.88 mmol) was added over 5 min. The resulting solution was stirred at rt for 1 h. The reaction was quenched by the addition of 40 mL of NH4Cl (aq). The resulting solution was extracted with EtOAc (40 mL x 2) and the combined organic layers were washed with H2O and brine. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (PE / EtOAc = 0-11%) to give the product (2.6 g, 84.5% yield). LCMS (ESI) m / e [M+1] + 344.

[0867] Step: 2: 2-bromo-3,4-dimethoxy-6-(methylthio)pyridine

[0868]

[0869] Into a 100-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-bromo-6-iodo-3,4-dimethoxy-pyridine (2.60 g, 7.56 mmol), Pd2(dba)3(346.1 mg, 0.38 mmol), Xant-phos (437.4 mg, 0.76 mmol) and dioxane (60 mL). Then CH3SNa (529.6 mg, 7.56 mmol) was added. The resulting solution was stirred in an oil bath at 75 °C overnight. The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (PE / EtOAc = 0-6%) to give the product (1.64 g, 82%). LCMS (ESI) m / e [M+1] + 264.

[0870] Step: 3: 2-bromo-3,4-dimethoxy-6-(methylsulfonyl)pyridine

[0871]

[0872] Into a 100-mL round bottom flask, was placed 2-bromo-3,4-dimethoxy-6- (methylsulfanyl)pyridine (1.60 g, 6.06 mmol), H2O (35 mL), THF (35 mL). Then at 0 °C, RuCl3 (126 mg, 0.61 mmol) was added over 2 min. To this, NaIO4 (3.89 g, 18.17 mmol) was added over 2 min at 0 °C. The resulting solution was stirred at rt for 1 RT. The reaction was quenched by the addition of 50 mL of NH4Cl (aq). The resulting solution was extracted with EtOAc (80 mL) and the combined organic layers were washed with brine. The resulting mixture was concentrated under vacuum and the residue was purified by combi-flash (PE / EtOAc = 0-18%) to give the product (354.5 mg, 19.8%). 1 H NMR (400 MHz, DMSO-d6) d 7.72 (s, 1H), 4.06 (s, 3H), 3.88 (s, 3H), 3.28 (s, 3H). LCMS (ESI) m / e [M+1] + 296.

[0873] Example BB59: Synthesis of 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine

[0874]

[0875] Step 1: 2,6-dibromo-4-(methoxy-d3)pyridine

[0876]

[0877] A mixture of 2,6-dibromopyridin-4-ol (2.4 g, 9.5 mmol), CD3I (1.4 g, 9.5 mmol), K2CO3 (3.9 g, 28.5 mmol) in DMF (30 mL) was stirred at 25 °C for 2 h. After the reaction was completed, H2O (200 mL) was added and the resulting solution was extracted with EA (30 mL x 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.

[0878] Step 2: 2-bromo-4-(methoxy-d3)-6-(methylthio)pyridine

[0879]

[0880] 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 Na2SO4and concentrated to give the crude product (2.4 g, crude). MS (ESI) m / e [M+1] + 237.

[0881] Step 3: 2-bromo-4-(methoxy-d3)-6-(methylsulfonyl)pyridine

[0882]

[0883] To a solution of 2-bromo-4-(methoxy-d3)-6-(methylthio)pyridine (2.4 g, 10.1 mmol) in MeOH (40 ml) / H2O (20 ml) was added oxone (12.4 g, 20.1 mmol) at 25 °C. The mixture was stirred at RT for 2 h. After the reaction was completed, 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 to 20:1) to give the product (1.3 g, 47% yield). 1 H NMR (400 MHz, CDC13) δ 7.57 (s, 1H), 7.18 (s, 1H), 3.25 (s, 3H). MS (ESI) m / e [M+1] + 269.

[0884] Example BB60: Synthesis of (R and S)-2-chloro-4-(1-methoxyethyl)-6- (methylsulfonyl)pyridine

[0885]

[0886] Step 1. Synthesis of 1-(2,6-dichloropyridin-4-yl)ethan-1-ol

[0887]

[0888] To a stirred solution of 2,6-dichloro-4-iodopyridine (10.00 g, 36.51 mmol) in THF (100 mL) was added dropwise n-butyllithium (21.9 mL, 2.5 M, 54.77 mmol) in n-hexane at -78 °C under N2atmosphere. The resulting mixture was stirred at -78 °C for 1 h. To the above mixture was added dropwise acetaldehyde (4.83 g, 0.11 mmol) at -78 °C over 15 min. The resulting mixture was stirred at -78 °C for another 1 h. The reaction was quenched with saturated NH4Cl (aq.) at -78 °C. The resulting mixture was extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine (2 x 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.

[0889] Step 2. Synthesis of 2,6-dichloro-4-(l-methoxyethyl)pyridine

[0890]

[0891] To a stirred solution of l-(2,6-dichloropyridin-4-yl)ethanol (5.50 g, 28.64 mmol) and CH3I (6.10 g, 42.98 mmol) in THF (100 mL) was added NaH (1.37 g, 60% in mineral oil, 57.28 mmol) portion wise at 0 °C. The resulting mixture was stirred at rt for 2 h under N2atmosphere. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (1 x 200 mL) and dried over anhydrous Na2SO4. 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.

[0892] Step 3. Synthesis of 2-chloro-4-(l-methoxyethyl)-6-(methylthio)pyridine

[0893]

[0894] To a stirred solution of 2,6-dichloro-4-(l-methoxyethyl)pyridine (5.00 g, 24.26 mmol) in DMF (50 mL) was added MeSNa (2.55 g, 36.43 mmol) portion wise at 0 °C. The resulting mixture was stirred at rt for 3 h. The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The crude product (7 g, crude) was used directly for the next step without further purification. LCMS (ESI) m / e [M+l] 235.0. + 218.

[0895] Step 4. Synthesis of 2-chloro-4-(l-methoxyethyl)-6-(methylsulfonyl)pyridine

[0896]

[0897] To a stirred solution of 2-chloro-4-(l-methoxyethyl)-6-(methylsulfanyl)pyridine (7.00 g, 32.15 mmol) and RuCl3.H20 (0.22 g, 0.97 mmol) in THF (70 mL) and H20 (70 mL) was added NaI04(13.75 g, 64.29 mmol) portion wise at 0 °C and the resulting mixture was stirred at rt for 10 h. The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (PE / EtOAc = 0-20%) to give the product (5 g, 62%). LCMS (ESI) m / e [M+l] 275.0. + 250.

[0898] Step 5. Synthesis of (R and S)-2-chloro-4-(l-methoxyethyl)-6-(methylsulfonyl)pyridine

[0899]

[0900] Racemic 2-chloro-4-(l-methoxyethyl)-6-(methylsulfonyl)pyridine (3g) 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 to 20% B in 15 min; 220 nm; RT1 : 8.55 min; RT2: 9.50 min), the faster peak was collected and concentrated to give one pure isomer (1.32 g, 44% yield). For the faster peak (retention time: 8.55 min): 1 H NMR (400 MHz, CDC13) 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+l] + = 249.85. The slower peak was collected and concentrated to give the product (1.22 g, 41% yield). For the slower peak (retention time: 9.50 min): 1 H NMR (400 MHz, CDC13) 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+l] + 250.

[0901] Example BB61 : Synthesis of (S)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3- methylmorpholine

[0902]

[0903] Step 1 : Synthesis of (S)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine

[0904]

[0905] Into a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (3S)-4-(2,6-dichloropyridine-4-yl)-3-methylmorpholine (1.90 g, 7.68 mmol), DMF (30 mL) and CH3SNa (1.08 g, 15.42 mmol). The resulting solution was stirred at 25 °C for 5 h. The resulting solution was diluted with 50 mL of H2O, extracted with 3x30 mL of EtOAc and the organic layers combined and concentrated. The residue was purified by combi-flash (EtOAc / PE = 0-10%) to give the product (1.40 g, 63%). LCMS (ESI, m / z): [M+H] + 247.

[0906] Step 2: Synthesis of (S)-4-(2-chloro-6-(methylthio)pyridin-4-yl)-3-methylmorpholine

[0907]

[0908] Into a 100 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (3S)-4-(2,6-dichloropyridine-4-yl)-3-methylmorpholine (1.90 g, 7.68 mmol), DMF (30 mL) and CH3SNa (1.08 g, 15.42 mmol). The resulting solution was stirred at 25 °C for 5 h. The resulting solution was diluted with 50 mL of H2O, extracted with 3x30 mL of EtOAc and the organic layers combined and concentrated. The residue was purified by combi-flash (EtOAc / PE = 0-10%) to give the product (1.40 g, 63%). LCMS (ESI, m / z): [M+H] + 259.

[0909] Step 3: Synthesis of (S)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3-methylmorpholine

[0910]

[0911] Into a 100 mL round bottom flask, was placed (3S)-4-[2-chloro-6- (methylsulfanyl)pyridin-4-yl]-3-methylmorpholine (1.40 g, 5.41 mmol), THF (20 mL), H2O (20 mL), NaIO4(4.63 g, 21.64 mmol). To the mixture was added RuCl3-H2O (0.12 g, 0.53 mmol) in portions at 0 °C. The resulting solution was stirred at 25 °C for 3 h. The resulting solution was diluted with 50 mL of H2O, extracted with 3 x 30 mL of ethyl acetate and the organic layers combined and concentrated. The residue was purified by combi-flash (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, 4H), 1.18 (d, J = 6.7 Hz, 3H). LCMS (ESI, m / z): [M+H] + 291.

[0912] Example BB62: Synthesis of (R)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3- methylmorpholine

[0913]

[0914] Step 1: Synthesis of (R)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine

[0915]

[0916] Into a 250 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,6-dichloro-4-iodopyridine (2.50 g, 9.13 mmol), dioxane (50 mL), (3R)-3-methylmorpholine (0.97 g, 9.13 mmol), Pd2(dba)3-CHCl3(0.97 g, 0.91 mmol), XantPhos (1.06 g, 1.82 mmol), Cs2CO3(8.92 g, 27.38 mmol). The resulting solution was stirred at 110 °C in an oil bath for 3 h. After cooling to room temperature, the reaction was concentrated and the residue was purified by combi-flash (EtOAc / PE = 0-15%) to give the product (1.9 g, 84%). LCMS (ESI, m / z): [M+H] + 247.

[0917] Step 2: Synthesis of (R)-4-(2-chloro-6-(methylthio)pyridin-4-yl)-3- methylmorpholine

[0918]

[0919] Into a 100 mL round-bottom flask was placed (3R)-4-(2,6-dichloropyridin-4-yl)-3- methylmorpholine (1.90 g, 7.68 mmol), DMF (30 mL), CH3SNa (1.08 g, 15.42 mmol). The resulting solution was stirred at 25 °C for 5 h. The resulting solution was diluted with 50 mL of H2O, extracted with 3x30 mL of ethyl acetate and the organic layers combined and concentrated. The residue was purified by combi-flash (EtOAc / PE = 0-10%) to give the product (1.70 g, 86%). LCMS (ESI, m / z): [M+H] + 259.

[0920] Step 3: Synthesis of (R)-4-(2-chloro-6-(methylsulfonyl)pyridin-4-yl)-3- methylmorpholine

[0921]

[0922] Into a 100 mL round-bottom flask was placed (3R)-4-[2-chloro-6-(methylsulfanyl)pyridin-4- yl]-3-methylmorpholine (1.70 g, 6.59 mmol), THF (20 mL), H2O (20 mL), NaIO4(5.64 g, 26.36 mmol). To the mixture was added RuCl3·H2O (0.17 g, 0.66 mmol) portion wise at 0 °C. The resulting solution was stirred at 25 °C for 3 h. The resulting solution was diluted with 50 mL of H2O, extracted with 3x30 mL of ethyl acetate and the organic layers combined and concentrated. The residue was purified by combi-flash (EtOAc / PE = 0-45%) to give the product (1.20 g, 63%). 1 H NMR (300 MHz, DMSO-d6) d 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.

[0923] Example BB63: Synthesis of 2-chloro-6-methanesulfonyl-4-(3-methoxyazetidin-l- yl)pyridine

[0924]

[0925] Step 1: Synthesis of 2,6-dichloro-4-(3-methoxyazetidin-l-yl)pyridine

[0926]

[0927] 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 Cs2C03(7.14 g, 21.91 mmol) in 1,4-dioxane (30 mL) was added Pd2(dba)3(501.53 mg, 0.55 mmol) at rt. The resulting mixture was stirred at 100 °C for 2 h under N2atmosphere. The mixture was allowed to cool to rt. The resulting mixture was extracted with EtOAc (2 x 50 mL) and the combined organic layers were dried over anhydrous Na2S04. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc / PE = 20%) to give the product (1.2 g, 47% yield). LCMS (ESI) m / e [M+l] + = 233.

[0928] Step 2: Synthesis of 2-chloro-4-(3-methoxyazetidin-l-yl)-6- (methylsulfanyl)pyridine

[0929]

[0930] To a stirred solution of 2,6-dichloro-4-(3-methoxyazetidin-l-yl)pyridine (1.2 g, 5.15 mmol) in DMF (10 mL) was added CH3SNa (900.94 mg, 12.87 mmol) at 0 °C. The resulting mixture was stirred at rt for 2 h. After completion of the reaction, water was added and the resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure to give the crude product (1.2 g). This was used as such in the next step without further purification. LCMS (ESI) m / e [M+l] + = 245.

[0931] Step 3: Synthesis of 2-chloro-6-methanesulfonyl-4-(3-methoxyazacyclobutane-1-yl)pyridine

[0932]

[0933] At 0 °C, NaIO4 (2.1 g, 9.81 mmol) was added to a stirred solution of 2-chloro-4-(3-methoxyazacyclobutan-1-yl)-6-(methylthioalkyl)pyridine (1.2 g, 4.90 mmol) and RuCl3·H2O (33.16 mg, 0.15 mmol) in THF (10 mL) and H2O (10 mL). The mixture was stirred at rt for 1 hour. The resulting mixture was extracted with EtOAc (2 x 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 combi-flash (EtOAc / PE = 50%) to give the product (806.4 mg, 59% yield). 1 ¹H NMR (300MHz, 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.

[0934] Example BB64: Synthesis of 2-chloro-6-methanesulfonyl-4-(4-methoxypiperidin-1-yl)pyridine

[0935]

[0936] Step 1: Synthesis of 2,6-dichloro-4-(4-methoxypiperidin-1-yl)pyridine

[0937]

[0938] 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 Cs2CO3(7.14 g, 21.91 mmol) in 1,4-dioxane (30 mL) was added Pd2(dba)3(501.53 mg, 0.55 mmol) at rt. The resulting mixture was stirred at 100 °C for 3 h under N2atmosphere. After cooling to rt, the resulting mixture was extracted with EtOAc (2 x 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 combi-flash (EtOAc / PE = 25%) to give the product (1.3 g, 45% yield). LCMS (ESI) m / e [M+1]= 261. + = 261.

[0939] Step 2: Synthesis of 2-chloro-4-(4-methoxypiperidin-l-yl)-6- (methylsulfanyl)pyridine

[0940]

[0941] To a stirred solution of 2,6-dichloro-4-(4-methoxypiperidin-l-yl)pyridine (1.3 g, 4.98 mmol) in DMF (10 mL) was added CH3SNa (522.69 mg, 7.47 mmol) at 0 °C. The resulting mixture was stirred at rt for 2 h. Water was added and the resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product. It was used directly in the next step without further purification. LCMS (ESI) m / e [M+1]= 273. + = 273.

[0942] Step 3: Synthesis of 2-chloro-6-methylsulfonyl-4-(4-methoxypiperidin-l- yl)pyridine

[0943]

[0944] To a stirred solution of 2-chloro-4-(4-methoxy-piperidin-l-yl)-6- (methylsulfanyl)pyridine (1.48 g, 5.42 mmol) and RuCl3.H2O (36.69 mg, 0.16 mmol) in THF (15 mL) and H2O (15 mL) was added NaIO4(2.32 g, 10.85 mmol) at 0 °C. The resulting mixture was stirred at rt for 1 h. After completion of the reaction, the resulting mixture was extracted with EtOAc (2 x 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 combi-flash (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.

[0945] Example BB65: Synthesis of 2-chloro-4-(l,4-dioxan-2-yl)-6-methanesulfonylpyridine, R or S 2-chloro-4-(l,4-dioxan-2-yl)-6-methanesulfonylpyridine

[0946]

[0947] Step 1: Synthesis of 2,6-dichloro-4-vinylpyridine

[0948]

[0949] Into a 1000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,6-dichloro-4-iodopyridine (20.00 g, 73.02 mmol), dioxane (200 mL), H2O (100 mL), 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.50 g, 87.65 mmol), Pd(dppf)Cl2(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 x 3). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EtOAc / PE = 0.1%) to give the product (10.90 g, 86%). LCMS (ESI) m / e [M+1] + = 174.

[0950] Step 2: Synthesis of 1-(2,6-dichloropyridin-4-yl)ethan-1,2-diol

[0951]

[0952] Into a 500-mL round-bottom flask, was placed 2,6-dichloro-4-vinylpyridine (10.90 g, 62.63 mmol), acetone (110 mL), H2O (55 mL), NMO (8.07 g, 68.90 mmol) and OsO4(7.95 mL, 1 g / mL, 313.20 mmol). The resulting solution was stirred at rt for 4 h. The reaction was quenched by the addition of 500 mg of florisil. The resulting solution was extracted with EtOAc (3 x 100 mL). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EtOAc / PE = 32%) to give the product (3.20 g, 24.56%). LCMS (ESI) m / e [M+1] + = 208.

[0953] Step 3: Synthesis of 2,6-dichloro-4-(1,4-dioxan-2-yl)pyridine

[0954]

[0955] 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), dichloroethane (250 mL), and TBAB (1.29 g, 4.00 mmol). NaOH (1 M aqueous solution, 50 mL) was then added dropwise with stirring at 0 °C. The resulting solution was stirred in an oil bath at 35 °C for 48 h. The resulting solution was extracted with EtOAc (3 x 150 mL). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EtOAc / PE = 7.90%) to give the product (1.45 g, 43%). LCMS (ESI) m / e [M+1] + = 234.

[0956] Step 4: Synthesis of 2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfanyl)pyridine

[0957]

[0958] A mixture of 2,6-dichloro-4-(1,4-dioxan-2-yl)pyridine (1.45 g, 6.19 mmol), DMF (17 mL), and sodium (methylsulfanyl) (0.52 g, 7.42 mmol) was stirred at rt overnight. Water was added and the resulting solution was extracted with EtOAc (3 x 50 mL). The resulting mixture was concentrated under vacuum. The residue was purified by combi-flash (EtOAc / PE = 0.6-5.3%) to give the product (1.48 g, 97%). LCMS (ESI) m / e [M+1] + = 246.

[0959] Step 5: Synthesis of 2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridine or (R or S)-2-chloro-4-(1,4-dioxan-2-yl)-6-(methylsulfonyl)pyridine

[0960]

[0961] Into a 100-mL three necked round bottom flask was placed 2-chloro-4-(l,4-dioxan-2-yl)-6-(methylsulfanyl)pyridine (1.48 g, 6.02 mmol), THF (12 mL) and H20 (12 mL). Subsequently, NaI04(3.86 g, 18.06 mmol) was added portion wise with stirring at 0 °C. To this, RuCI3-H20 (0.20 g, 0.90 mmol) was added with stirring at 0 °C. The resulting solution was stirred at rt for 1 h. The resulting solution was extracted with EtOAc (3 x 50 mL) and the combined organic layer was concentrated under vacuum. The residue was purified by combi-flash (EtOAc / PE = 15-22%) to give the racemic product (1.10 g). The racemic product was purified by preparative SFC using the following conditions (column: CHIRALPAK AD-3, 3.0 x 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.

[0962] First peak (434.90 mg, 26.00%, RT1 : 0.959 min): 1 H 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.

[0963] Second peak (413.3 mg, 24.71%, RT2: 1.605 min): 1 H 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.

[0964] Example BB66: Synthesis of l-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4- methylpiperidin-4-ol

[0965]

[0966] Step 1: 1 -(2,6-dibromopyridin-4-yl)-4-methylpiperidin-4-ol

[0967]

[0968] To a solution of 2,6-dibromo-4-nitropyridine (2.0 g, 7.1 mmol) in DMSO (30 mL) was added K2CO3(2.0 g, 14.2 mmol) and 4-methylpiperidin-4-ol (899 mg, 7.8 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 2 h under N2. 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 Na2SO4, filtered and concentrated to give a residue, which was purified by column chromatography (SiO2, PE / EA = 100 / 1 to 0 / 1). Compound 1 -(2,6-dibromopyridin-4-yl)-4-methylpiperidin-4-ol was obtained as a grey solid to give the product (1.4 g, 56% yield). LCMS (ESI) m / e [M+1] + = 350.8.

[0969] Step 2: 1 -(2-bromo-6-(methylthio)pyridin-4-yl)-4-methylpiperidin-4-ol

[0970]

[0971] 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) at 0 °C under N2. The reaction mixture was stirred at 25 °C for 3 h under N2. 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 Na2SO4, filtered and concentrated to give a residue. The crude product was purified by column chromatography (SiO2, PE:EA = 100 / 1 to 0 / 1 ). Compound 1 -(2-bromo-6-(methylthio)pyridin-4-yl)-4-methylpiperidin-4-ol was obtained as a light yellow solid (1.4 g, 95% yield). LCMS (ESI) m / e [M+1] + = 319.

[0972] Step 3: 1 -(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4-methylpiperidin-4-ol

[0973]

[0974] To a solution of l-(2-bromo-6-(methylthio)pyridin-4-yl)-4-methylpiperidin-4-ol (1.1 g, 8.7 mmol) in H2O / MeOH (1 / 1, 30 mL) was added oxone (4.3 g, 6.9 mmol) under N2at 25 °C. The reaction mixture was stirred at 25 °C for 5 h under N2. The mixture was filtered to give the filtrate, the filtrate was poured into aqueous Na2SO3solution (20 mL) and extracted with EtOAc (30 mL, 20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give a residue. The crude product was purified by column chromatography (SiO2, PE:EA = 100 / 1 to 0 / 1). Compound l-(2-bromo-6-(methylsulfonyl)pyridin-4-yl)-4-methylpiperidin-4-ol was obtained as a white solid (412 mg, 34% yield). 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+l] + = 349.

[0975] Example BB67: Synthesis of 2-chloro-4-((trans)-3-methoxycyclobutyl)-6- (methylsulfonyl)pyridine and 2-chloro-4-((cis)-3-methoxycyclobutyl)-6- (methylsulfonyl)pyridine

[0976]

[0977] Step 1: Synthesis of 3-hydroxycyclobutane-1-carbonitrile

[0978]

[0979] Under nitrogen atmosphere, a solution of 3-oxocyclobutane-1-carbonitrile (5 g, 52.57 mmol) in MeOH was treated with NaBH4(2.98 g, 78.86 mmol) at rt for 2 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with water (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0980] Step 2: Synthesis of 3-(benzyloxy)cyclobutane-1-carbonitrile

[0981]

[0982] At 0 °C, NaH (2.01 g, 52.20 mmol, 60% wt) was added to a solution of 3-hydroxycyclobutane-1-carboxynitrile (3.90 g, 40.15 mmol) in DMF (40 mL). The mixture was stirred for 15 min. BnBr (8.24 g, 48.18 mmol) was added and the mixture was allowed to heat to rt and stirred at rt for 2 h. The resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (3 x 40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc / PE = 0-20%) to give the product (7.01 g, 93% yield). 1 ¹H NMR (400MHz, 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).

[0983] Step 3: Synthesis of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carboxylonitrile

[0984]

[0985] Under a nitrogen atmosphere at -10 °C, LiHMDS (23.02 mL, 23.02 mmol in THF) was added dropwise to a stirred mixture of 2,4,6-trichloropyridine (3 g, 16.44 mmol) and 3-(benzyloxy)cyclobutane-1-carboxynitrile (3.08 g, 16.44 mmol) in 60 mL of THF. The resulting mixture was stirred at rt for 2 h under a nitrogen atmosphere. The reaction was quenched with water / ice at 0 °C, and the resulting mixture was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with water (3 x 60 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (EtOAc / PE = 0-20%) to give the product (4.5 g, 82% yield). LCMS (ESI) m / e [M+1] + =333.

[0986] Step 4: Synthesis of 3-(benzyloxy)-1-(2,6-dichloropyridin-4-yl)cyclobutane-1-carboxylic acid

[0987]

[0988] A solution of 3-(benzyloxy)-l-(2,6-dichloropyridin-4-yl)cyclobutane-l- carbonitrile (4.50 g, 13.50 mmol) in H2O (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 for the next step without further purification. LCMS (ESI) m / e [M+l] + = 352.

[0989] Step 5: Synthesis of 4-[3-(benzyloxy)cyclobutyl]-2,6-dichloropyridine

[0990]

[0991] A solution of 3-(benzyloxy)-l-(2,6-dichloropyridin-4-yl)cyclobutane-l- carbonitrile (4.50 g, 13.50 mmol) in H2O (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 for the next step without further purification. LCMS (ESI) m / e [M+l] + = 308.

[0992] Step 6: Synthesis of 3-(2,6-dichloropyridin-4-yl)cyclobutanol

[0993]

[0994] 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 h. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 30 mL) and dried over anhydrous Na2S04. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by combi-flash (PE / EtOAc = 50%) to give the product (880 mg, 56% yield). LCMS (ESI) m / e [M+l] + = 218.

[0995] Step 7: Synthesis of 2,6-dichloro-4-(3-methoxycyclobutyl)pyridine

[0996]

[0997] 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 and then CH3I (810 mg, 5.70 mmol) was added and the mixture was allowed to warm to rt and stirred for 2 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 20 mL), dried over anhydrous Na2SO4. 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.

[0998] Step 8: Synthesis of 2-chloro-4-(3-methoxycyclobutyl)-6- (methylsulfanyl)pyridine

[0999]

[1000] A mixture of 2,6-dichloro-4-(3-methoxycyclobutyl)pyridine (520 mg, 2.24 mmol) and sodium (methylsulfanyl) (235 mg, 3.36 mmol) in DMF (6 mL) was stirred at rt for 2 h. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 20 mL), dried over anhydrous Na2SO4. 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.

[1001] Step 9: Synthesis of 2-chloro-6-methylsulfonyl-4-(3-methoxycyclobutyl)pyridine; 2-chloro-4-((trans)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine; 2-chloro-4-((cis)-3-methoxycyclobutyl)-6-(methylsulfonyl)pyridine

[1002]

[1003] A solution of 2-chloro-4-(3-methoxycyclobutyl)-6- (methylsulfanyl)pyridine (520 mg, 2.13 mmol) in THF (10 mL) was treated with NaI04(912.61 mg, 4.26 mmol) at 0 °C for 2 h, followed by dropwise portion wise addition of RuCI3.H20 (24.05 mg, 0.10 mmol) in H20 (5 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with water (3 x 30 mL) and dried over anhydrous Na2S04. 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+l] + = 276.

[1004] The racemic compound was separated by ACHIRAL-SFC (Column: DAICEL DCpak P4VP, 3x25 cm, 5 pm; Mobile Phase A: C02, Mobile Phase B: IPA (0.5% 2M NH3-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, RT1: 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+l] + = 276.

[1005] The cis product (1.31 g, RT2: 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.

[1006] Example A1 : Synthesis of N-(4-((3-(methylsulfonyl)phenyl)amino)-5- (pyridazin-3-yl)pyridin-2-yl)acetamide

[1007]

[1008] Step 1: 4-Chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine

[1009]

[1010] 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(l,3,2-dioxaborolane) (1.3 g, 5.3 mmol), KOAc (1.4 g, 14.5 mmol) and Pd(dppf)Cl2-CH2Cl2(197 mg, 0.2 mmol) in 1,4-dioxane (20 mL) was stirred at 115 °C for 6 h under N2. After cooling to room temperature, the mixture was diluted with H2O (30 mL) and the resulting solution was extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum. 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-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.5 g, crude). MS (ESI) m / e [M+1] + 173.

[1011] Step 2: 4-Chloro-5-(pyridazin-3-yl)pyridin-2-amine

[1012]

[1013] A mixture of 4-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (478 mg, 1.9 mmol), 3-bromopyridazine (100 mg, 0.6 mmol), Na2C03(133 mg, 1.3 mmol) and Pd(dppf)C12(44 mg, 0.06 mmol) in CH3CN (10 mL) and H20 (2 mL) was stirred in a microwave reactor at 120 °C for 10 min. After cooling to RT, the mixture was diluted with H20 (20 mL) and the resulting solution was extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na2S04and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EA = 1:1 to 0:1) to give 4-chloro-5-(pyridazin-3-yl)pyridin-2-amine (51 mg, 39.4%). MS (ESI) m / e [M+l] + 207.

[1014] Step 3: N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide

[1015]

[1016] 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. The mixture was then stirred at RT for 2 h. After the reaction was completed, the mixture was concentrated and the residue was diluted with water (5 mL), then the mixture was extracted with EA (10 mL x 3) and citric acid (10 mL), dried over anhydrous Na2S04, concentrated under vacuum to give N-(4-chloro-5-(pyridazin-3-yl)pyridin-2-yl)acetamide (45 mg, 93%). (ESI) m / e [M+l] + 249.

[1017] Step 4: N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide

[1018]

[1019] 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), Cs2CO3(78 mg, 0.24 mmol), Xantphos (5 mg, 8 μmol) and Pd2(dba)3(7 mg, 8 μmol) in 1,4-dioxane (2 mL) was stirred at 110 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and the resulting solution was extracted with EA (30 mL x 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 150x30 mm x 5um; Phase: A-H2O (10 mM NH4HCO3); B-ACN; B%: 15%-35% in 20 min) to give N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3- yl)pyridin-2-yl)acetamide (1.8 mg, 6%). 1 HNMR (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+l] + 384.

[1020] Example A2: Synthesis of N-[4-[(3-methanesulfonylphenyl)amino]-5- (oxolan-2-yl)pyridin-2-yl]acetamide

[1021]

[1022] Step 1: 5-Bromo-2-chloro-N-(3-methanesulfonylphenyl)pyridin-4-amine

[1023]

[1024] A mixture of 5-bromo-2-chloro-4-iodopyridine (3.00 g, 9.42 mmol), Cs2CO3(6.14 g, 18.848 mmol), Xantphos (1.09 g, 1.88 mmol), 3-methanesulfonylaniline (1.77 g, 10.37 mmol), Pd2(dba)3(0.86 g, 0.942 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C under nitrogen atmosphere overnight. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and the resulting solution was extracted with EA (80 mL x 3). The resulting mixture was washed with brine (10 mL), dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and the residue was purified by combi-flash (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.

[1025] Step 2: 5-bromo-N 2 -(4-methoxybenzyl)-N 4 -(3-(methylsulfonyl)phenyl)pyridine-2,4-diamine

[1026]

[1027] Into a 20-mL sealed tube was placed 5-bromo-2-chloro-N-(3- methanesulfonylphenyl)pyridin-4-amine (1.5 g, 4.148 mmol) and PMBNH2(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-H2O (0.05% TFA); B-acetonitrile, B%: 40%-60% in 20 min) to give 5-bromo-N2-(4-methoxybenzyl)-N4-(3- (methylsulfonyl)phenyl)pyridine-2,4-diamine (600 mg, 31%). LCMS (ESI) m / e [M+1] + 462.

[1028] Step 3: 5-(furan-2-yl)-N 4 -(3-methanesulfonylphenyl)-N 2 -[(4-methoxyphenyl)methyl]pyridine-2,4-diamine

[1029]

[1030] A mixture of 5-bromo-N4-(3-methanesulfonylphenyl)-N2-[(4- methoxyphenyl)methyl]pyridine-2,4-diamine (420 mg, 0.91 mmol), K2CO3 (251 mg, 1.82 mmol), furan-2-ylboronic acid (152 mg, 1.36 mmol) and Pd(PPh3)4 (105 mg, 0.091 mmol) in 1,4-dioxane (4.00 mL) and H2O (0.80 mL) was stirred at 100 °C under nitrogen atmosphere for 2 h. After cooling to rt, the mixture was diluted with H2O (20 mL) and the resulting solution was extracted with EA (80 mL x 3). The combined organic layers were washed with 100 mL of brine, dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and the residue was purified by preparative TLC (MeOH / DCM = 1:15) to give 5-(furan-2-yl)-N4-(3-methanesulfonylphenyl)-N2-[(4-methoxyphenyl)methyl]pyridine-2,4-diamine (270 mg, 66%) as a yellow solid. LCMS (ESI) m / e [M+1] 550.0. 4 -(3-methanesulfonylphenyl)-N 2 -[(4-methoxyphenyl)methyl]pyridine-2,4-diamine (270 mg, 66%) as a yellow solid. LCMS (ESI) m / e [M+1] 550.0. +

[1031] Step 4: N 2 -(4-methoxybenzyl)-N4-(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine

[1032]

[1033] To a 20-mL pressure tank reactor was placed 5-(furan-2-yl)-N4-(3- methanesulfonylphenyl)-N2-[(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)2 / C (10%, 168 mg), the resulting solution was stirred at 65 °C under hydrogen atmosphere (10 atm) overnight. After cooling to rt, the mixture was diluted with H2O (20 mL) and the resulting solution was extracted with EA (50 mL x 3). The reaction mixture was cooled to rt with a water bath. The resulting solution was extracted with EA (50 mL x 3) and the organic layers were combined. The combined organic layers were washed with 100 mL of brine, dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and the residue was purified by preparative TLC (MeOH / DCM = 1:12) to give N 2 -(4-methoxybenzyl)-N4-(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine 4 ​-(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine (80 mg, 29%). LCMS (ESI) m / e [M+1] 378.0. + 454.

[1034] Step 5: N 4 -(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine

[1035]

[1036] A mixture of N4-(3-methanesulfonylphenyl)-5-(oxolane-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 20 mL of water. The resulting solution was extracted with EA (30 mL x 3) and the combined organic layers were washed with 50 mL of brine, 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-H2O (0.1% FA); B-acetonitrile, B%: 35%-55% in 8 min) to give N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolane-2-yl)pyridin-2- yl]acetamide (1.8 mg, 3%). 4 -(3-methanesulfonylphenyl)-N 2 A mixture of N4-(3-methanesulfonylphenyl)-5-(oxolane-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 20 mL of water. The resulting solution was extracted with EA (30 mL x 3) and the combined organic layers were washed with 50 mL of brine, 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-H2O (0.1% FA); B-acetonitrile, B%: 35%-55% in 8 min) to give N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolane-2-yl)pyridin-2- yl]acetamide (1.8 mg, 3%). 4 -(3-(methylsulfonyl)phenyl)-5-(tetrahydrofuran-2-yl)pyridine-2,4-diamine (50 mg, 85%). LCMS (ESI) m / e [M+1] 378.0. + 334.

[1037] Step 6: N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolane-2-yl)pyridin-2- yl]acetamide

[1038]

[1039] A mixture of N4-(3-methanesulfonylphenyl)-5-(oxolane-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 20 mL of water. The resulting solution was extracted with EA (30 mL x 3) and the combined organic layers were washed with 50 mL of brine, 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-H2O (0.1% FA); B-acetonitrile, B%: 35%-55% in 8 min) to give N-[4-[(3-methanesulfonylphenyl)amino]-5-(oxolane-2-yl)pyridin-2- yl]acetamide (1.8 mg, 3%). 1H 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.

[1040] Example A3: Synthesis of N-(5-(lH-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide

[1041]

[1042] 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

[1043]

[1044] 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 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 at 0 °C with stirring. The reaction was warmed 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, concentrated to give a residue and purified by silica gel column using 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.

[1045] Step 2: 2-chloro-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)pyridin-4- amine and 2-chloro-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-5-yl)pyridin-4- amine

[1046]

[1047] A mixture of 2-chloro-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)pyridin-4- amine and 2-chloro-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-5-yl)pyridin-4- amine (966 mg, 4.98 mmol), 2-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-4- amine (1.39 g, 5.48 mmol), Pd(dppf)Cl2(182 mg, 0.25 mmol) and K2CO3(1.37 g, 9.96 mmol) in 1,4-dioxane (18 mL) and H2O (3 mL) was charged with nitrogen and heated to 90 °C with stirring for 1 h. The reaction was cooled to room temperature and diluted with EA, washed with brine, dried and concentrated. The residue was applied to a silica gel column (using EA / PE (1:2)) to give the product (862 mg, 89.2%). MS (ESI) m / e [M+l] + 325.

[1048] Step 3: N-(2-chloro-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)pyridin-4- yl)-6-(methylsulfonyl)pyridin-2-amine and N-(2-chloro-5-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-5-yl)pyridin-4-yl)-6- (methylsulfonyl)pyridin-2-amine

[1049]

[1050] A mixture of 2-chloro-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4- yl)pyridin-4-amine and 2-chloro-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-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. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was applied to a preparative TLC using DCM / MeOH (30: 1) to give the product (139 mg, 22.9%). MS (ESI) m / e [M+l] 538.0. + 480.

[1051] Step 4: N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)pyridin-2-yl)acetamide and N-(4-((6- (methylsulfonyl)pyridin-2-yl)amino)-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazol-5-yl)pyridin-2-yl)acetamide

[1052]

[1053] A mixture of N-(2-chloro-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-4- yl)pyridin-4-yl)-6-(methylsulfonyl)pyridin-2-amine and N-(2-chloro-5-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-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. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was applied to a silica gel column using DCM / MeOH (25: 1) to give the product (94 mg, 64.5%). MS (ESI) m / e [M+l] 538.0. + 502.

[1054] Step 5: N-(5-(lH-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide

[1055]

[1056] A solution of N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-4-yl)pyridin-2-yl)acetamide and N-(4-((6- (methylsulfonyl)pyridin-2-yl)amino)-5-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazol-5-yl)pyridin-2-yl)acetamide (94 mg, 0.19 mmol) in TFA (5 mL) was heated to 50 °C with stirring for 1 h. Then, the TFA was removed under vacuum and the residue was treated with NH3in MeOH (4 mL, 7 M). The solvent was removed under vacuum and the residue was applied to a C 18 column (using CH3CN / water) to give N-(5-(lH-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+l] + 373.

[1057] Example A25: Synthesis of N-(4-((4-(cyclopropylmethoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2- yl)acetamide

[1058]

[1059] 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), Pd2(dba)3(17 mg, 0.019 mmol), BINAP (12 mg, 0.019 mmol) and Cs2CO3(186 mg, 0.57 mmol) in dioxane (5 mL) was stirred at 120 °C for 16 hours 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 combi-flash (MeOH / DCM = 0-10%) to give the product (0.84 mg, 22%). 1 H 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), 2.12 (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.

[1060] Example A26: Synthesis of N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide

[1061]

[1062] 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), Pd2(dba)3(17 mg, 0.019 mmol), BINAP (12 mg, 0.019 mmol) and Cs2CO3(186 mg, 0.57 mmol) in dioxane (5 mL) was stirred at 120 °C for 16 hours 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 combi-flash (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+l] + 473.

[1063] In a similar manner to Product Example A3, the following examples were prepared:

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072] Example Bl : Synthesis of N-(4'-((3-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide

[1073]

[1074] Step 1 : tert-Butyl (5-bromo-2-chloropyridin-4-yl)carbamate

[1075]

[1076] To a mixture of 5-bromo-2-chloropyridin-4-amine (30 g, 144.6 mmol), DMAP (1.8 g, 14.4 mmol), TEA (43.9 g, 434.0 mmol) in DCM (300 mL) was added Boc20 (38.0 g, 173.0 mmol) dropwise at room temperature and the resulting mixture was stirred at this temperature for 12 h. After the reaction was completed, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE / EA = 20:1 to 5:1) to give tert-butyl (5-bromo-2-chloropyridin-4- yl)carbamate (40.0 g, 90.2% yield). 1 H NMR (400 MHz, CDC13) δ 8.35 (s, 1H), 8.25 (s, 1H), 7.19 (s, 1H), 1.56 (s, 9H). MS (ESI) m / e [M+l] + 307.

[1077] Step 2: tert-Butyl (6'-chloro-[2,3'-bipyridin]-4'-yl)carbamate

[1078]

[1079] 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(PPh3)2Cl2 (1.1 g, 1.6 mmol), Pd(PPh3)4 (1.9 g, 1.6 mmol) and Sn2Me6 (8.0 g, 24.0 mmol) in dioxane (50 mL) was stirred at 110 °C for 12 h. After cooling to room temperature, the mixture was diluted with KF-H2O (50 mL) and extracted with EA (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 20:1 to 10:1) to give tert-butyl (6'-chloro-[2,3'-bipyridin]-4'- yl)carbamate (880 mg, 18.0%). MS (ESI) m / e [M+l] + 306.

[1080] Step 3: tert-Butyl (6'-acetamido-[2,3'-bipyridin]-4'-yl)carbamate

[1081]

[1082] 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), Cs2CO3(6.3 g, 19.5 mmol), Xant-Phos (753 mg, 1.3 mmol) and Pd2(dba)3(595 mg, 0.65 mmol) in dioxane (20 mL) was stirred at 110 °C for 12 h under 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 x 3) and the combined organic layers were washed with 50 mL of brine, 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 to 1:1) to give tert-butyl (6'-acetamido-[2,3'-bipyridin]-4'- yl)carbamate (1.3 g, 61.0%). 1 H 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.

[1083] Step 4: N-(4'-amino-[2,3'-bipyridin]-6'-yl)acetamide

[1084]

[1085] 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 h. After 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 value to 9 and the resulting solution was extracted with EA (40 mL x 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated in vacuo to give N-(4'-amino-[2,3'-bipyridin]-6'-yl)acetamide (2.7 g, 97.1%). 1H 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+l] + 229.

[1086] Step 5: N-(4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1087]

[1088] 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 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+l] + 383.

[1089] The following examples were prepared in a similar manner to Product Example Bl:

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100] 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

[1101]

[1102] Step 1: (cis)-4-(6-bromopyridin-3-yl)-2,6-dimethylmorpholine

[1103]

[1104] In N 2 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 for 2 h. The reaction mixture was cooled, filtered and 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. +

[1105] Step 2: 6'-chloro-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-4'-amine

[1106]

[1107] ​To a solution of cis-4-(6-bromopyridin-3-yl)-2,6-dimethylmorpholine (13.6 g, 50.4 mmol) in dioxane / H2O (400 mL / 100 mL) was added 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (15.4, 60.4 mmol), Pd(dppf)Cl2(3.7 g, 5.04 mmol) and K2CO3(10.4 g, 75.6 mmol) and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. 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 x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (MeOH / DCM = 0-5%) to give 6'-chloro-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-4'-amine (18 g, crude). MS (ESI) m / e [M+1] 323.2. + 319.

[1108] Step 3: N-(4'-amino-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-6'-yl)acetamide

[1109]

[1110] To a solution of 6'-chloro-5-(cis-2,6-dimethylmorpholino)-[2,3'-bipyridin]-4'-amine (18 g, 56.6 mmol) in 1,4-dioxane (250 mL) was added 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) and the resulting mixture was stirred at 130 °C under nitrogen atmosphere 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 x 3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by combi-flash (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] 337.2. + 342.

[1111] Step 4: N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methoxy-6- (methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1112]

[1113] 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-methoxy-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 and purified by preparative TLC (MeOH / DCM = 1 :20) to afford N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methoxy-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+l] + 511.

[1114] 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

[1115]

[1116] 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), Pd2(dba)3 (320 mg, 0.35 mmol), BINAP (218 mg, 0.35 mmol) and Cs2CO3 (2.28 g, 7.04 mmol) in 1,4-dioxane (50 mL) was stirred at 130 °C under nitrogen atmosphere for 4 h. The reaction mixture was filtered off and the filtrate was concentrated, the residue was purified by combi-flash (MeOH / DCM = 7:93) to give crude product as brown oil, then slurry with ACN (50 mL) at RT for 30 min to give solid by filtration and dried in vacuum drying oven to give 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+l] + 527.

[1117] 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

[1118]

[1119] 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-d3)-6-(methylsulfonyl)pyridine (2.0 g, 7.39 mmol), Pd2(dba)3(568 mg, 0.62 mmol), BINAP (386 mg, 0.62 mmol), and Cs2CO3(4.02 g, 12.32 mmol) in 1,4-dioxane (75 mL) was stirred at 130 °C under N2for 4 h. The solids were filtered off and the filtrate was concentrated, 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+l] + 530.

[1120] 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

[1121]

[1122] 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 under N2for 4 h. The solids were filtered off and the filtrate was concentrated, the residue was purified by preparative TLC (MeOH / DCM = 1:20) to give the product as a yellow solid (40.56 mg, 42% yield). 1HNMR (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+l] + = 555.

[1123] 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

[1124]

[1125] 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) (faster peak in Example BB60, step 5), Pd2(dba)3(13 mg, 0.0147 mmol), BINAP (18 mg, 0.0294 mmol), and Cs2CO3(72 mg, 0.221 mmol) in 1,4-dioxane (6 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 under vacuum. The residue was purified using preparative TLC (DCM / MeOH = 20:1) to give the product (33 mg, 40%). 1H NMR (400 MHz, DMSO-c / 6) 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+l] + 555.

[1126] 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

[1127]

[1128] 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 (slower peak in Example BB60, step 5) (62 mg, 0.21 mmol), Pd2(dba)3(33 mg, 0.036 mmol), Xantphos (41.7 mg, 0.072 mmol), and Cs2CO3(117.4 mg, 0.36 mmol) in dioxane (3 mL) was stirred at 130 °C for 4 h under a nitrogen atmosphere. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was purified using preparative TLC (DCM / MeOH = 15: 1) to give the product (35.83 mg, 35.89%). 1H 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+l] + 555.

[1129] 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

[1130]

[1131] 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), Pd2(dba)3(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 under N2for 4 h. The reaction mixture was filtered off and the filtrate was concentrated, the residue was purified by preparative TLC (MeOH / DCM = 1:20) to give the product (47.27 mg, 46% yield). 1H 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.

[1132] Example C22: Synthesis of N-(5-(cis-2,6-dimethylmorpholino)-4'-((6- (methylsulfonyl)pyrazin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1133]

[1134] 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), Pd2(dba)3(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 N2atmosphere. The reaction mixture was filtered off and the filtrate was concentrated, 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.

[1135] 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.

[1136]

[1137] To a solution of 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) in 1,4-dioxane (10 mL) was added. The resulting mixture was degassed with nitrogen and stirred at 130 °C for 2 hours. After cooling to room temperature, the solid was filtered off. The filtrate was concentrated under vacuum. 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+l] + 596.

[1138] 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.

[1139]

[1140] To a solution of 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) in 1,4-dioxane (10 mL) was added. The resulting mixture was degassed with nitrogen and stirred at 130 °C for 2 hours. After cooling to room temperature, the solid was filtered off. The filtrate was concentrated under vacuum. The residue was purified using 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.

[1141] In a similar manner to Product Example Cl, the following examples were prepared:

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148] Example D1 : Synthesis of N-(5-(2-methoxyethoxy)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridin]-6'-yl)acetamide

[1149]

[1150] Step 1: 2-bromo-5-(2-methoxyethoxy)pyridine

[1151]

[1152] To a solution of 6-bromopyridin-3-ol (5 g, 28.7 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 1.7 g, 43.1 mmol) in one portion at 0 °C and 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 and the mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was poured into H2O (200 mL) and the resulting mixture was extracted with EA (40 mL x 3). The combined organic layers were dried over Na2SO4and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 20:1 to 5:1) to give 2-bromo-5-(2-methoxyethoxy)pyridine (4.8 g, 72%). MS (ESI) m / e [M+1] 231.0. + 232.

[1153] Step 2: tert-butyl (6'-chloro-5-(2-methoxyethoxy)-[2,3'-bipyridin]-4'- yl)carbamate

[1154]

[1155] 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), Sn2Me6 (5.2 g, 16.1 mmol), Pd(PPh3)4 (1.2 g, 1.08 mmol) and Pd(PPh3)2Cl2 (756.1 mg, 1.1 mmol) in 1,4-dioxane (30 mL) was stirred at 110 °C under nitrogen atmosphere for 16 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was diluted with 20 mL of water. The resulting solution was extracted with EA (40 mL x 3) and the combined organic layers were washed with brine (50 mL), 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 to 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, CDC13) 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+l] + 380.

[1156] Step 3: tert-Butyl (6'-acetamido-5-(2-methoxyethoxy)-[2,3'-bipyridin]-4'- yl)carbamate

[1157]

[1158] To a solution of tert-butyl (6'-chloro-5-(2-methoxyethoxy)-[2,3'-bipyridinyl]-4'- yl)carbamate (0.8 g, 2.1 mmol) in 1,4-dioxane (10 mL) was added acetamide (149 mg, 2.5 mmol), Cs2CO3(1.3 g, 4.2 mmol), XantPhos (243 mg, 0.42 mmol) and Pd2(dba)3(192.86 mg, 0.21 mmol), the resulting mixture was stirred at 110 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuum and the residue was diluted with 10 mL of water. The resulting solution was extracted with EA (10 mL x 3), and the combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate. The solvent was removed in vacuum and the residue was purified by silica gel column chromatography (PE / EA = 50:1 to 0:1) to give tert-butyl (6'-acetamido-5-(2-methoxyethoxy)-[2,3'-bipyridinyl]-4'- yl)carbamate (0.5 g, 58%). MS (ESI) m / e [M+1] + 403.

[1159] Step 4: N-(4'-amino-5-(2-methoxyethoxy)-[2,3'-bipyridinyl]-6'- yl)acetamide

[1160]

[1161] To a mixture of tert-butyl (6'-acetamido-5-(2-methoxyethoxy)-[2,3'-bipyridinyl]-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 h. After completion of the reaction, the solvent was removed in vacuum and the residue was diluted with water, then aqueous NaHCO3(50%) was added to adjust the pH value to 10. The resulting mixture was extracted with EA (10 mL x 3). The combined organic layers were dried over Na2SO4and concentrated to give N-(4'-amino-5-(2-methoxyethoxy)-[2,3'-bipyridinyl]-6'- yl)acetamide (275 mg, 73%). 1 HNMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.37-8.29 (m, 2H), 7.82 (d, J = 9.0 Hz, 1H), 7.50-7.45 (m, 2H), 7.44-7.34 (m, 2H), 4.25-4.18 (m, 2H), 3.70-3.65 (m, 2H), 3.31 (s, 3H), 2.06 (s, 3H). MS (ESI) m / e [M+1] + 303.

[1162] Step 5: N-(5-(2-methoxyethoxy)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide

[1163]

[1164] In a sealed tube, N-(4'-amino-5-(2-methoxyethoxy)-[2,3'-bipyridinyl]-6'- yl)acetamide (50 mg, 0.17 mmol), 2-bromo-6-(methylsulfonyl)pyridine (60 mg, 0.26 mmol), Pd2(dba)3(16 mg, 0.017 mmol), BINAP (10 mg, 0.017 mmol), Cs2CO3(110 mg, 0.34 mmol) in 10 ml dioxane was stirred at 120 °C for 2 hours, the solution was concentrated and purified by preparative TLC to give N-(5-(2-methoxyethoxy)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridinyl]-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+l] + 458.

[1165] The following examples were prepared in a similar manner to Product Example D1 :

[1166]

[1167]

[1168]

[1169]

[1170] Example El: Synthesis of N-(5-(Methoxymethyl)-4'-((3-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide

[1171]

[1172] Step 1: 2-bromo-5-(methoxymethyl)pyridine

[1173]

[1174] 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 RT overnight. The solvent was removed in vacuo and the residue was extracted between EA and H2O. The organic layer was dried over Na2SO4. 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] 207.0 + 202.

[1175] Step 2: tert-butyl (6'-chloro-5-(methoxymethyl)-[2,3'-bipyridin]-4'- yl)carbamate

[1176]

[1177] A mixture of 2-bromo-5-(methoxymethyl)pyridine (3 g, 14.84 mmol), Sn2Me6 (5.4 g, 16.48 mmol) and Pd(PPh3)4 (1.9 g, 1.65 mmol) in dioxane (50 mL) was stirred at 100 °C overnight. The mixture was cooled to RT and then tert-butyl (5-bromo-2-chloropyridin-4-yl)carbamate (4.8 g, 15.6 mmol) and Pd(PPh3)2Cl2 (1.2 g, 1.75 mmol) in dioxane (40 mL) were added under N2. The mixture was stirred at 100 °C for 10 h under nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with KF-H2O (50 mL) and extracted with EA (100 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 10:1 to 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] 339.0 + 250.

[1178] Step 3: N-(4'-amino-5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide TFA salt

[1179]

[1180] To a solution of tert-butyl (6'-chloro-5-(methoxymethyl)-[2,3'-bipyridinyl]-4'- yl)carbamate (580 mg, 1.56 mmol) in DCM (4 mL) was added TFA (2 mL). The mixture was stirred at RT for 5 h. 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.

[1181] Step 4: N-(5-(Methoxymethyl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'- bipyridinyl]-6'-yl)acetamide

[1182]

[1183] A solution of N-(4'-amino-5-(methoxymethyl)-[2,3'-bipyridinyl]-6'- yl)acetamide TFA salt (100 mg, 0.27 mmol), 1-bromo-3-(methylsulfonyl)benzene (174 mg, 0.74 mmol), Cs2CO3(479.8 mg, 1.47 mmol), Xant-phos Pd G3 (70.2 mg, 0.074 mmol), and Xant-phos (85.2 mg, 0.15 mmol) in dioxane (3 mL) was stirred at 130 °C under N2overnight. 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'-bipyridinyl]-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.

[1184] The following examples were prepared in a similar manner to Product Example El:

[1185]

[1186]

[1187]

[1188]

[1189] Example F1: Synthesis of N-(4'-((4-methyl-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide

[1190]

[1191] Under N2, in a sealed tube, a mixture of N-(4'-amino-5-(trifluoromethyl)-[2,3'-bipyridinyl]-6'-yl)acetamide (100 mg, 0.34 mmol), 2-bromo-4-methyl-6-(methanesulfonyl)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 stirred at 130 °C for 4 hours. The reaction mixture was filtered and the solids were 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-(methanesulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide (37 mg, 23%). 1 H NMR(400MHz,DMSO-d6)δ12.42(s,1H),10.61(s,1H),9.26(s,1H),9.20(s,1H),8.84(s,1 H),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.

[1192] Example F17: Synthesis of N-(5-fluoro-4'-((4-methyl-6-(methanesulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1193]

[1194] 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), Pd2(dba)3 (297 mg, 0.325 mmol), BINAP (405 mg, 0.65 mmol) and Cs2CO3 (1.59 g, 4.875 mmol) in 1,4-dioxane (14 mL) was stirred at 130 °C for 3 h under N2 atmosphere. The reaction was cooled to rt, filtered and the filtrate was concentrated under vacuum. 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.

[1195] Example F22: Synthesis of N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide

[1196]

[1197] Step 1: 6'-chloro-5-fluoro-[2,3'-bipyridin]-4'-amine

[1198]

[1199] 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)Cl2 (664 mg, 0.909 mmol) and K2CO3 (1.88 g, 13.64 mmol) in 1,4-dioxane (50 mL) and H2O (5 mL) was stirred at 100 °C for 2 h. The reaction was cooled to rt and 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.

[1200] Step 2: N-(4'-amino-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide

[1201]

[1202] A mixture of 6'-chloro-5-fluoro-[2,3'-bipyridin]-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 in a sealed tube and heated to 130 °C with stirring overnight. The reaction was cooled to room temperature and concentrated under vacuum. 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] 231.0. + 247.

[1203] Step 3: N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide

[1204]

[1205] 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 in a sealed tube and heated to 130 °C with stirring for 3 h. The reaction was cooled to room temperature, filtered and the filtrate concentrated under vacuum. The residue was purified by flash column on silica gel (eluted with DCM / MeOH (100:1) to give the desired product as a light yellow solid. It was then washed with 10 mL of MeCN to give the product (27 mg, 30%). 1H 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.

[1206] Example F23: Synthesis of N-(4'-((3,4-dimethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5- fluoro-[2,3'-bipyridinyl]-6'-yl)acetamide

[1207]

[1208] A mixture of N-(4'-amino-5-fluoro-[2,3'-bipyridinyl]-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 in a sealed tube and heated to 130 °C with stirring for 4 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was applied to preparative TLC using 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.

[1209] Example F24: Synthesis of N-(5-fluoro-4'-((4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide

[1210]

[1211] 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 in a sealed tube and heated to 130 °C with stirring for 3 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was applied 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+l] + 435.

[1212] Example F25: Synthesis of N-(4'-((4-cyclopropyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro-[2,3'-bipyridin]-6'-yl)acetamide

[1213]

[1214] 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 in a sealed tube and heated to 130 °C with stirring for 4 h. The reaction was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum. The residue was applied to preparative TLC using DCM / MeOH = 20:1 to give the product (23 mg, 25%). 1H 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.

[1215] In a similar manner to Product Example Fl, the following examples were prepared:

[1216]

[1217]

[1218]

[1219]

[1220]

[1221]

[1222]

[1223] Example Gl: Synthesis of N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-(3- oxomorpholino)-[2,3'-bipyridinyl]-6'-yl)acetamide

[1224]

[1225] Step 1: 2-(2-chloroethoxy)acetyl chloride

[1226]

[1227] A mixture of 2-(2-chloroethoxy)acetic acid (1.0 g, 7.2 mmol) and DMF (0.1 mL) in SOCl2(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).

[1228] Step 2: N-(6-bromopyridin-3-yl)-2-(2-chloroethoxy)acetamide

[1229]

[1230] 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 Et3N (2.1 g, 21.0 mmol) and the resulting mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (PE / EA = 2:1 to 1:1) to give N-(6-bromopyridin-3-yl)-2-(2-chloroethoxy)acetamide (1.5 g, 72.8%). 1 H NMR (400 MHz, CDC13) δ 8.59 (s, 1H), 8.48 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.18 (s, 2H), 3.94-3.89 (m, 2H), 3.80-3.76 (m, 2H). MS (ESI) m / e [M+l] + 293.

[1231] Step 3: 4-(6-bromopyridin-3-yl)morpholin-3-one

[1232]

[1233] 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) portionwise at 0 °C. The mixture was then stirred at room temperature for 2 hours. After the reaction was completed, water was added and the resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were concentrated under vacuum to give 4-(6-bromopyridin-3-yl)morpholin-3-one (1.1 g, 84.6%). 1 H NMR (400 MHz, CDC13) δ 8.59 (s, 1H), 8.48 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 4.18 (s, 2H), 3.94-3.89 (m, 2H), 3.80-3.76 (m, 2H). MS (ESI) m / e [M+l] + 412.

[1234] Step 4: 4-(6'-amino-4'-chloro-[2,3'-bipyridin]-5-yl)morpholin-3-one

[1235]

[1236] A mixture of 4-(6-bromopyridin-3-yl)morpholin-3-one (200 mg, 673.4 umol), 4-chloro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (340 mg, 1.4 mmol), Pd(dppf)Cl2(49 mg, 67.3 umol), and Na2CO3(142 mg, 1.4 mmol) in ACN (10 mL) / H2O (2 mL) was heated at 120 °C for 20 min under microwave irradiation. 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 to 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.

[1237] Step 5: N-(4'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide

[1238]

[1239] 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. The mixture was then stirred at room temperature for 12 h. After the reaction was completed, 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 to 30:1) to give N-(4'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridin]-6'-yl)acetamide (150 mg, 39%). 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.88 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 4.34 (s, 2H), 4.13 - 4.05 (m, 2H), 3.97 - 3.89 (m, 2H), 2.21 (s, 3H). MS (ESI) m / e [M+1] + 347.

[1240] Step 6: N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3'- bipyridin]-6'-yl)acetamide

[1241]

[1242] A mixture of N-(4'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridinyl]-6'- yl)acetamide (150 mg, 432 umol), 3-(methylsulfonyl)aniline (147 mg, 865 umol), Pd2(dba)3(39 mg, 43 umol), Xant-Phos (25 mg, 43 umol), and Cs2CO3(421 mg, 1.3 mmol) in dioxane (5 mL) was heated at 110 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by neutral prep-HPLC (column: Phenomenex Gemini-NX 150x30mm x 5um; Phase: A-H2O (10 mM NH4HCO3); B-ACN; B%: 10%-40% in 20 min) to give N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-(3-oxomorpholino)-[2,3'- bipyridinyl]-6'-yl)acetamide (5.6 mg, 2.7%). 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 10.52 (s, 1H), 8.84 (s, 1H), 8.71 (s, 1H), 8.20 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.69-7.64 (m, 2H), 7.63-7.58 (m, 1H), 4.29 (s, 2H), 4.08-4.01 (m, 2H), 3.91-3.84 (m, 2H), 3.30 (s, 3H), 2.09 (s, 3H). MS (ESI) m / e [M+l] + 482.

[1243] Example G2: Synthesis of N-(4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3- oxomorpholino)-[2,3'-bipyridinyl]-6'-yl)acetamide

[1244]

[1245] Step 1: tert-Butyl (6'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridinyl]-4'- yl)carbamate

[1246]

[1247] 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 umol), Pd(PPh3)4 (1.1 g, 977 umol), and Sn2Me6 (4.8 g, 14.7 mmol) in 1,4-dioxane (30 mL) was heated at 100 °C for 12 h under nitrogen atmosphere. After cooling to room temperature, the mixture was quenched with 10% KF solution (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1 to 1:2) to give tert-butyl (6'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridin]-4'- yl)carbamate (1.1 g, 28%). 1 H NMR (400 MHz, DMSO-d6) d 11.96 (s, 1H), 8.87 (s, 1H), 8.86 - 8.83 (m, 1H), 8.28 (s, 1H), 8.24 - 8.18 (m, 1H), 8.17 - 8.10 (m, 1H), 4.29 (s, 2H), 4.08 - 3.99 (m, 2H), 3.93 - 3.86 (m, 2H), 1.50 (s, 9H). MS (ESI) m / e [M+1] + 405.

[1248] Step 2: tert-Butyl (6'-acetamido-5-(3-oxomorpholino)-[2,3'-bipyridin]-4'- yl)carbamate

[1249]

[1250] A mixture of tert-butyl (6'-chloro-5-(3-oxomorpholino)-[2,3'-bipyridinyl]-4'- yl)carbamate (500 mg, 1.2 mmol), acetamide (146 mg, 2.5 mmol), Pd2(dba)3 (113 mg, 123 umol), Xantphos (72 mg, 124 umol) and Cs2CO3 (808 mg, 2.5 mmol) in 1,4-dioxane (10 mL) was heated at 110 °C for 12 h under 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 to 30:1) to give tert-butyl (6'-acetamido-5-(3-oxomorpholino)-[2,3'-bipyridinyl]-4'- yl)carbamate (300 mg, 57%). MS (ESI) m / e [M+1] + 428.

[1251] Step 3: N-(4'-amino-5-(3-oxomorpholino)-[2,3'-bipyridinyl]-6'- yl)acetamide

[1252]

[1253] A mixture of tert-butyl (6'-acetamido-5-(3-oxomorpholino)-[2,3'-bipyridinyl]-4'- yl)carbamate (300 mg, 703 umol) in HCl / EA (20 mL, v:v = 1:9) was stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed in vacuo and the residue was purified by preparative HPLC [Column: Phenomenex Gemini-NX C18 75x30mmx 3um; Mobile Phase: [A-10 mM NH4HCO3 in H2O; B-ACN] B%: 5%-45% in 8 min] to give N-(4'-amino-5-(3-oxomorpholino)-[2,3'-bipyridinyl]-6'- yl)acetamide (98 mg, 43%). 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 7.96-7.86 (m, 2H), 7.55-7.45 (m, 3H), 4.22 (s, 2H), 3.99-3.95 (m, 2H), 3.82-3.78 (m, 2H), 2.03 (s, 3H). MS (ESI) m / e [M+1] + 328.

[1254] Step 4: N-(4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-(3-oxomorpholino)- [2,3'-bipyridinyl]-6'-yl)acetamide

[1255]

[1256] A mixture of N-(4',5-diamino-[2,3'-bipyridinyl]-6'-yl)acetamide (98 mg, 0.40 mmol), 2-bromo-6-(methylsulfonyl)pyridine (96 mg, 0.41 mmol), Pd2(dba)3(18 mg, 0.02 mmol), BINAP (23 mg, 0.04 mmol), and K3PO4(174 mg, 0.82 mmol) in 1,4-dioxane (10 mL) was heated to 100 °C for 4 h under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under vacuum. 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'-bipyridinyl]-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 (...

Claims

1. A compound of Formula (I-A) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: X is N; L 1 is a direct bond, R 1 is -C 1-6 alkyl, -haloC 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkoxy, -C 3-6 cycloalkyl, or -NR m R n ; R 2 and R 4 each independently is hydrogen, halogen, -C 1-6 alkyl, or -C 1-6 alkoxy; R 3 is - hydrogen, cyano, halogen; --C 1-4 alkyl, optionally substituted with at least one substituent independently selected from halogen, 3- to 6-membered heterocyclyl, or -OR h wherein said 3- to 6-membered heterocyclyl is selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl, thiazolidinyl or azetidinyl, each optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy, and R h is hydrogen, C 1-6 alkyl, tetrahydrofuranyl or thiazolidinyl; --C 3-6 cycloalkyl, optionally substituted by at least one substituent independently selected from cyano, -oxo, halogen, NR m R n , hydroxy, -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted by at least one substituent independently selected from cyano, halogen, hydroxy, -NH2, -C 1-6 alkyl or C 1-6 alkoxy; - heterocyclyl selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or azetidinyl, which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, C 1-6 alkyl, -C 1-6 alkoxy, -NR m R n , or -C(O)NR m R n , and wherein -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from the group consisting of cyano, halo, hydroxy, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from the group consisting of cyano, halo, hydroxy, -NH2, -C --OR e wherein R e is -C 1-6 alkyl, -C 3-6 cycloalkyl, 4- to 6-membered monocyclic saturated heterocyclyl comprising one oxygen atom as a ring member, or phenyl, wherein i) -C 1-6 alkyl is optionally substituted with deuterium, cyano, -oxo-, halogen, hydroxyl, -NR m R n , -C 1-6 alkoxy-, optionally substituted with cyano, -oxo, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n substituted -C 3-6 cycloalkyl, optionally substituted with cyano, halo, hydroxy, -C 1-6 alkyl or -C 1-6 alkoxy; and, ii) -C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with cyano, -oxo, halogen, hydroxyl, NR m R n , C 1-6 alkyl, C 1-6 alkoxy or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy; - phenyl; or - 5- to 6-membered heteroaryl selected from pyridyl, pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n , wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or C 1-6 alkoxy; R 5 is hydrogen or C 1-6 alkyl; Cy 1 is a. said 5- to 7-membered monocyclic heteroaryl comprising 1, 2, 3 or 4 heteroatoms selected from oxygen (O), nitrogen (N) or sulfur (S) as ring member(s), said monocyclic heteroaryl is optionally substituted with one or two substituents selected from: i. halogen; ii. cyano; iii.-C 1-6 alkyl, optionally substituted with halogen, hydroxyl, -C 1-6 alkoxy, -C(O)R m , or -NR m R n substituted; iv. heterocyclyl selected from tetrahydrofuranyl, morpholinyl, 2-oxa-5- azabicyclo[2.2.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, isoindolinyl, which is optionally substituted with halogen, C 1-6 alkyl-, -C 1-6 alkoxy-substituted -C 1-6 alkyl, or oxo; v.-C 3-6 cycloalkyl optionally substituted with halogen, -oxo, -C 1-6 alkyl, C 1-6 alkoxy-, or -C 1-6 alkoxy-substituted -C 1-6 alkyl-substituted; or vi.-OR j , where R j It is -C 1-6 Alkyl, -C 1-6 Alkoxy-substituted -C 1-6 Alkyl or tetrahydrofuranyl; vii. oxo; b. the 7- to 14-membered bicyclic or tricyclic heteroaryl comprising 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, or sulfur as ring members, each of which is optionally substituted with halogen, -C 1-6 alkyl, -NH2, or -C(O)C 1-6 alkyl, each of which is optionally enriched in deuterium; wherein R m and R n are independently selected from hydrogen or -C 1-3 alkyl; or (R 1 and R 2 ) or (R 2 and R 3 ) or (R 3 and R 4 ) together with the atoms to which they are attached form a fused 5- to 7-membered ring system comprising 0-2 oxygen heteroatoms as one or more ring members and optionally and independently substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -haloC 1-6 alkoxy, or -C 3-6 cycloalkyl; any of said alkyl or alkoxy groups is optionally enriched with deuterium.

2. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is -C 1-3 alkyl, -NR m R n or -C 3-6 cycloalkyl.

3. The compound of claim 1 or 2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is -NH2, methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclopentyl.

4. The compound of claim 1 or 2, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are each independently hydrogen, fluoro, methyl, methoxy, ethoxy, or isopropoxy.

5. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 is - hydrogen, cyano, halogen; -- C 1-4 alkyl, optionally substituted with at least one substituent independently selected from the group consisting of halogen, hydroxy, C 1-3 alkoxy; --C 3-6 cycloalkyl, optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, -NR m R n , hydroxy, -C 1-6 alkyl, or -C 1-6 alkoxy, wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxy, -NH2, -C 1-6 alkyl or -C 1-3 alkoxy; - heterocyclyl selected from morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, 1,4-dioxanyl, piperidinyl or azetidinyl, which heterocyclyl is optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, C1-4alkyl, -C1-4alkoxy, -NR 1-6 R 1-6 R m R n , or -C(O)NR m R n , and wherein -C 1-6 alkyl or C 1-6 alkoxy is substituted with at least one substituent independently selected from the group consisting of cyano, halo, hydroxy, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from the group consisting of cyano, halo, hydroxy, -NH2, -C --OR e wherein R e is -C 1-6 alkyl, -C 3-6 cycloalkyl, 4- to 6-membered monocyclic saturated heterocyclyl comprising one oxygen atom as a ring member, or phenyl, wherein i) -C 1-6 alkyl is optionally substituted with cyano, -oxo-, halogen, hydroxy, -NR m R n , -C 1-6 alkoxy-, 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 substituted -C 3-6 cycloalkyl, optionally substituted with cyano, halogen, hydroxy, -C 1-6 alkyl or -C 1-6 alkoxy-substituted 4- to 6-membered monocyclic heterocyclyl containing one heteroatom as a ring member selected from the group consisting of oxygen, nitrogen and sulfur; and, ii) -C 3-6 cycloalkyl or 3- to 6-membered heterocyclyl is optionally substituted with cyano, -oxo, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n substituted, wherein -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy; - phenyl; or - 5- to 6-membered heteroaryl selected from pyridyl, pyridazinyl, pyrazinyl, thiazolyl or isoxazolyl, each optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , -C 1-6 alkyl, -C 1-6 alkoxy or -C(O)NR m R n , wherein the -C 1-6 alkyl or -C 1-6 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy; and wherein R m and R n are independently selected from hydrogen or -C 1-3 alkyl.

6. The compound of claim 5, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 is - hydrogen, cyano, halogen; - methyl, ethyl, propyl or butyl, each optionally substituted with at least one substituent independently selected from halogen, hydroxyl, methoxy, ethoxy, propoxy, or 2,4-dioxothiazolidin-3-yl; cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each optionally 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 alkoxy substituted, wherein -C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with at least one member independently selected from cyano, halo, hydroxy, -NH2, -C 1-3 alkyl or -C 1-3 substituted by substituents of alkoxy; - heterocyclyl 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, - 4-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, each of which is optionally substituted with at least one independently selected from cyano, -oxo, halogen, hydroxyl, -C 1-6 alkyl, -C 1-6 alkoxy, -NR m R n , or -C(O)NR m R n substituted by at least one substituent independently selected from the group consisting of cyano, halo, hydroxy, -NH2, -C 1-6 alkyl or -C 1-6 alkoxy; and wherein -C 1-6 alkyl or -C 1-6 alkoxy is substituted by at least one substituent independently selected from the group consisting of cyano, halo, hydroxy, -NH2, -C --OR e wherein R e is i) methyl, ethyl, propyl (iso-propyl), butyl, pentyl or hexyl, each optionally substituted with deuterium, cyano, -oxo-, halogen, hydroxy, -NR m R n , -C 1-3 alkyl, -C m alkyl, -C n alkyl, -C 1-3 alkyl, -C 1-3 alkyl, -C(O)NR m R n substituted -C 3-6 cycloalkyl, or optionally substituted with cyano, halogen, hydroxy, -C 1-3 alkyl or -C 1-3 alkoxy-substituted 4- to 6-membered monocyclic heterocyclyl comprising one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur as a ring member; 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 optionally substituted with cyano, -oxo, halo, hydroxyl, -NR m R n , -C 1-3 alkyl, -C 1-3 alkoxy, or -C(O)NR m R n substituted, wherein -C 1-3 alkyl or -C 1-3 alkoxy is substituted with at least one substituent independently selected from cyano, halo, hydroxyl, -NH2, -C 1-3 alkyl, or -C 1-3 alkoxy; - phenyl; or - 5- to 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 optionally substituted with at least one substituent independently selected from cyano, -oxo, halogen, hydroxyl, -NR m R n , -C 1-3 alkyl, -C 1-3 alkoxy, or -C(O)NR m R n , wherein -C 1-3 alkyl or -C 1-3 alkoxy is substituted with at least one substituent independently selected from cyano, halogen, hydroxyl, -NH2, -C 1-3 alkyl, or C 1-3 alkoxy; and wherein R m and R n are independently selected from hydrogen or -C 1-3 alkyl.

7. The compound of claim 5, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 3 is - hydrogen; - methyl, 1-methoxyethyl, 2-hydroxypropan-2-yl, 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, 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; - 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; - 4-methylpyridin-3-yl, 5-methylpyridazin-4-yl, 5-methoxypyridazin-4-yl, 3,5-dimethylisoxazol-4-yl, 4-methoxypyridin-3-yl, 4-(2-hydroxyprop-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.

8. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the atoms to which they are attached form a fused ring system selected from ; or R 2 and R 3 together with the atoms to which they are attached form a fused ring system ; R 3 and R 4 together with the atoms to which they are attached form a fused ring system selected from ; and wherein each fused ring system is optionally and independently substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -haloC 1-6 alkyl, -haloC 1-6 alkoxy, or -C 3-6 cycloalkyl.

9. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Cy 1 is a. pyrazolyl, triazolyl, imidazolyl, thiazolyl, oxazolyl, furanyl, pyridyl, pyridazinyl, pyrazinyl, or pyrimidinyl, optionally substituted with one or two substituents selected from: i. halogen; ii. cyano; iii.-C 1-6 alkyl, optionally substituted with halogen, hydroxyl, -C 1-6 alkoxy, or -NR m R n substituted; iv. tetrahydrofuranyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 8-oxa-3- azabicyclo[3.2.1]octanyl, or isoindolinyl, each optionally substituted with methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-butyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, or oxo; v.-C 3-6 Cycloalkyl groups, optionally converted to halogen, -oxo, or -C 1-6 Alkyl, C 1-6 Alkoxy-, or -C 1-6 alkoxy-substituted -C 1-6 alkyl-substituted; or vi. -OR j wherein R j is -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 alkyl, or tetrahydrofuranyl; vii. oxo; b. 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-pyrano[4,3-c]thiazolyl, 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]dioxolino[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 optionally substituted with halo, -C(O)C 1-6 alkyl, -NH2, or -C(O)C 1-6 alkyl; any of said alkyl groups is optionally enriched in deuterium.

10. The compound of claim 9, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein tetrahydrofuranyl is tetrahydrofuran-3-yl, morpholinyl is morpholino, 2-oxa-5- azabicyclo[2.2.1]heptanyl is 2-oxa-5-azabicyclo[2.2.1]heptan-2-yl, 8-oxa-3-azabicyclo[3.2.1]octanyl is 8-oxa-3-azabicyclo[3.2.1]octan-8-yl, or isoindolinyl is isoindolin-2-yl.

11. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Cy 1 is a. b. c. d. e. f. g. h.

12. A compound, wherein the compound is selected from: N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide; (A1) N-[4-[(3-methylsulfonylphenyl)amino]-5-(oxolan-2-yl)pyridin-2-yl]acetamide; (A2) N-(5-(1 H-imidazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (A3) N-(5-(5-methylpyrazin-2-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2- yl)acetamide; (A4) N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(pyrazin-2-yl)pyridin-2-yl)acetamide; (A5) N-(5-(2,6-dimethylpyrimidin-4-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2- yl)acetamide; (A6) N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(2-oxopyrrolidin-1 -yl)pyridin-2- yl)acetamide; (A7) N-(5-(1 -methyl-1 H-pyrazol-4-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (A8) N-(5-(furan-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (A9) N-(5-(1 -methyl-1 H-1,2,4-triazol-3-yl)-4-((3-(methylsulfonyl)phenyl)amino)pyridin-2- yl)acetamide; (A10) N-(4-((3-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)acetamide; (A11) N-(4-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1H-pyrazol-1-yl)pyridin-2-yl)acetamide; (A12) N-(4-((4-methyl-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-(2-morpholino-2-oxoethyl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (A13) N-(5-(1-(2-hydroxyethyl)-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (A14) N-(5-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)-4-((4-methyl-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (A15) N-(6-cyano-4'-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (A16) N-(5-cyano-4'-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (A17) N-(5-(1H-imidazol-1-yl)-4-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (A18) N-(5-(1-cyclobutyl-1H-pyrazole-3-yl)-4-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (A19) N-(5-(2-aminopropyl-2-yl)-4'-((4-methyl-6-(methanesulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (A20) N-(5-(1H-imidazol-4-yl)-4-((4-(2-methoxyethoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (A21) N-(5-(1H-imidazol-4-yl)-4-((4-methyl-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (A22) N-(5-(1H-imidazol-4-yl)-4-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (A23) N-(4-((6-(methanesulfonyl)pyridin-2-yl)amino)-5-(pyridazin-3-yl)pyridin-2-yl)acetamide; (A24) N-(4-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6- methoxypyridazin-3-yl)pyridin-2-yl)acetamide; (A25) N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(6-methoxypyridazin-3- yl)pyridin-2-yl)acetamide; (A26) N-(4-((4-((2S,6R)-2,6-dimethylmorpholino)-6-(methylsulfonyl)pyridin-2-yl)amino)-5- (6-methoxypyridazin-3-yl)pyridin-2-yl)acetamide; (A27) N-(5-(6-methoxypyridazin-3-yl)-4-((6-(methylsulfonyl)-[l,3]dioxolo[4,5-c]pyridin-4- yl)amino)pyridin-2-yl)acetamide; (A28) N-(5-(6-isopropoxypyridazin-3-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (A29) N-(5-(6-isopropoxypyridazin-3-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (A30) N-(5-(6-isopropoxypyridazin-3-yl)-4-(4-(methoxy-d3)-6-(methylsulfonyl)pyridin-2- ylamino)pyridin-2-yl)acetamide; (A31) N-(4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (Bl) N-(4-((6-(methylsulfonyl)pyridin-2-yl)amino)-[3,3'-bipyridin]-6-yl)acetamide; (B2) N-(4'-((6-sulfamoylpyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (B4) N-(4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (B5) N-(4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'- yl)acetamide; (B6) N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'- yl)acetamide; (B7) N-(4-(methoxymethyl)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'- yl)acetamide; (B8) N-(4-(2-hydroxypropan-2-yl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'- yl)acetamide; (B9) N-(4-(2-hydroxypropan-2-yl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'- yl)acetamide; (B9) N-(4-(2-hydroxypropan-2-yl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (B10) N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-morpholino-[2,3'-bipyridinyl]-6'- yl)acetamide; (B11) N-(5-(2,2-dimethylmorpholino)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridinyl]-6'-yl)acetamide; (B12) N-(5-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-4'-((4-isopropoxy-6- (methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide; (B16) N-(4-chloro-5-(2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (B17) N-(4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2- (methoxymethyl)morpholino)-[2,3'-bipyridinyl]-6'-yl)acetamide; (B18) N4'-(3-(methylsulfonyl)phenyl)-[2,3'-bipyridinyl]-4',6'-diamine; (B19) N-(4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridinyl]-6'-yl)cyclopropanecarboxamide; (B20) (S)-N-(4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((tetrahydrofuran-3- yl)oxy)-[2,3'-bipyridinyl]-6'-yl)acetamide; (B21) N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((tetrahydrofuran- 3-yl)oxy)-[2,3'-bipyridinyl]-6'-yl)acetamide; (B22) N-(4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-5-((tetrahydrofuran-3-yl)oxy)-[2,3'- bipyridinyl]-6'-yl)acetamide; (B23) N-(5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4'-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide; (B24) N-(5-(2,5-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (B25) N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C1) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide;(C2) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide;(C3) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(C4) N-(4'-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((cis)- 2,6-dimethylmorpholino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(C5) N-(4'-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-((cis)-2,6- dimethylmorpholino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(C6) N-(5-((trans)-2,6-dimethylmorpholino)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(C7) N-(5-(cis-2,6-dimethylmorpholino)-4'-((7-(methylsulfonyl)-2,3-dihydro-[l,4]dioxino[2,3- c]pyridin-5-yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(C8) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(C9) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-ethoxy-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(C10) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin- 2-yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(Cll) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((4-((R)-2-hydroxypropoxy)-6-(methylsulfonyl) pyridin-2-yl)amino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(C12) N-(4'-((4-((R)-sec-butoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-((cis)-2,6- dimethylmorpholino)-[2,3'-bipyridinyl]-6'-yl)acetamide;(C13) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-(5-((cis)-2,6-dimethylmorpholino)-4'-((3-fluoro-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridinyl]-6'-yl)acetamide; (C15) N-( N-(5-(cis-2,6-dimethylmorpholino)-4'-((4-(3-methoxyazetidin-l-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide;(C25) N-(5-(2-methoxyethoxy)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide;(D1) N-(5-(2-methoxyethoxy)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'- bipyridin]-6'-yl)acetamide;(D2) N-(5-(2-methoxyethoxy)-4'-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)- [2,3'-bipyridin]-6'-yl)acetamide;(D3) N-(5-(2-methoxyethoxy)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridin]-6'-yl)acetamide;(D4) N-(4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2- methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide;(D5) N-(4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2- methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide;(D6) (R)-N-(5-(2-methoxyethoxy)-4'-((4-(2-methoxypropoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide;(D7) N-(5-(2-methoxyethoxy)-4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide;(D8) N-(4'-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2- methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide;(D9) N-(4'-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(2- methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide;(D10) N-(4'-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2- methoxyethoxy)-[2,3'-bipyridin]-6'-yl)acetamide;(D11) N-(5-(methoxymethyl)-4'-((3-(methylsulfonyl)phenyl)amino)-[2,3'-bipyridin]-6'- yl)acetamide; (El) N-(5-(methoxymethyl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridin]-6'-yl)acetamide; (E2) (R)-N-(5-(methoxymethyl)-4'-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (E3) N-(4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)- [2,3'-bipyridin]-6'-yl)acetamide; (E4) N-(4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5- (methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide; (E5) N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5- (methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide; (E6) N-(4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(methoxymethyl)- [2,3'-bipyridin]-6'-yl)acetamide; (E7) N-(4'-((4-((lr,3r)-3-hydroxycyclobutyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)- 5-(methoxymethyl)-[2,3'-bipyridin]-6'-yl)acetamide; (E8) N-(5-(methoxymethyl)-4'-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridin]-6'-yl)acetamide; (E9) N-(4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(trifluoromethyl)- [2,3'-bipyridin]-6'-yl)acetamide; (Fl) N-(4'-((3-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'-bipyridin]-6'- yl)acetamide; (F2) N-(4'-((3-methyl-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'- bipyridin]-6'-yl)acetamide; (F3) N-(4'-((3-cyano-5-(methylsulfonyl)phenyl)amino)-5-(trifluoromethyl)-[2,3'- bipyridin]-6'-yl)acetamide; (F4) N-(4'-((3-((trans)-3-hydroxycyclobutyloxy)-5-(methylsulfonyl)phenyl)amino)-5- (trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide; (F5) N-(4'-((3-((trans)-3-hydroxycyclobutyloxy)-5-(methylsulfonyl)phenyl)amino)-5- (trifluoromethyl)-[2,3'-bipyridin]-6'-yl)acetamide; (F5) N-(4'-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5- (trifluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide; (F6) N-(4'-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5- (trifluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide; (F7) N-(4'-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5- (trifluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide; (F8) N-(4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5- (trifluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide; (F9) N-(4'-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5- (trifluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide; (F10) N-(4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5- (trifluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide; (F11) N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5- (trifluoromethyl)-[2,3'-bipyridine]-6'-yl)acetamide; (F12) N-(5-fluoro-4'-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)- [2,3'-bipyridine]-6'-yl)acetamide; (F13) N-(5-fluoro-4'-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridine]-6'-yl)acetamide; (F14) N-(5-fluoro-4'-((3-((trans)-3-hydroxycyclobutyloxy)-5- (methylsulfonyl)phenyl)amino)-[2,3'-bipyridine]-6'-yl)acetamide; (F15) N-(5-fluoro-4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridine]-6'-yl)acetamide; (F16) N-(5-fluoro-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridine]-6'-yl)acetamide; (F17) N-(5-fluoro-4'-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridine]-6'-yl)acetamide; (F18) N-(4'-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-fluoro- [2,3'-bipyridine]-6'-yl)acetamide; (F19) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (F22) N-(5-fluoro-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl) N-(5-(2-hydroxypropyl)-4'-((6-(methylsulfonyl)pyridin-2-yl)amino)-[2,3'- bipyridin]-6'-yl)acetamide; (H5) N-(5-(2-hydroxypropyl)-4'-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H6) N-(5-(2-hydroxypropyl)-4'-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H7) N-(4'-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2- hydroxypropyl)-[2,3'-bipyridin]-6'-yl)acetamide; (H8) N-(5-(2-hydroxypropyl)-4'-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridin]-6'-yl)acetamide; (H9) N-(4'-((4-(trans)-3-hydroxycyclobutyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)- 5-(2-hydroxypropyl)-[2,3'-bipyridin]-6'-yl)acetamide; (H10) N-(5-(2-hydroxypropyl)-4'-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)- [2,3'-bipyridin]-6'-yl)acetamide; (H11) N-(5-(2-hydroxypropyl)-4'-((6-(methylsulfonyl)-4-(oxetan-3-ylmethoxy)pyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H12) N-(5-(2-hydroxypropyl)-4'-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H13) N-(4'-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropyl)- [2,3'-bipyridin]-6'-yl)acetamide; (H14) N-(5-(2-hydroxypropyl)-4'-((3-(2-methoxyethoxy)-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridin]-6'-yl)acetamide; (H15) N-(5-(2-hydroxypropyl)-4'-((3-(methoxymethyl)-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridin]-6'-yl)acetamide; (H16) N-(5-(2-hydroxypropyl)-4'-((3-(3-hydroxypyrrolidin-1-yl)-5-(methylsulfonyl)phenyl) amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H17) N-(5-(2-hydroxypropan-2-yl)-4'-((3-methyl-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridin]-6'-yl)acetamide; (H21) N-(4'-((3-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(2- hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H22) N-(4'-((3-cyclopropoxy-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2- yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H23) N-(5-(2-hydroxypropan-2-yl)-4'-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)- [2,3'-bipyridin]-6'-yl)acetamide; (H24) N-(4'-((3-(difluoromethyl)-5-(methylsulfonyl)phenyl)amino)-5-(2-hydroxypropan-2- yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H25) N-(5-(2-hydroxypropan-2-yl)-4'-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H26) N-(5-(2-hydroxypropan-2-yl)-4'-((6-(methylsulfonyl)-4-(oxetan-3-yloxy)pyridin-2- yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H27) N-(4'-((4-(cis-3-hydroxycyclobutyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2- hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H28) N-(5-(2-hydroxypropan-2-yl)-4'-((4-(3-methoxycyclobutyloxy)-6-(methylsulfonyl)pyridin- 2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H29) N-(4'-((4-(cyclopropylmethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2- hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H30) ​ ​ ​ N-(4'-((4-cyclobutoxy-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropyl-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H31) N-(5-(2-hydroxypropyl-2-yl)-4'-((3-methyl-6-(methanesulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H32) N-(4'-((4-ethoxy-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropyl-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H33) N-(4'-((5-fluoro-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropyl-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H34) N-(5-(2-hydroxypropyl-2-yl)-4'-((2-methyl-5-(methanesulfonyl)phenyl)amino)-[2,3'-bipyridine]-6'-yl)acetamide; (H35) N-(4'-((6-(ethylsulfonyl)-4-isopropoxypyridin-2-yl)amino)-5-(2-hydroxypropyl-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H36) N-(5-(2-hydroxypropyl-2-yl)-4'-((7-(methanesulfonyl)-2,3-dihydro-[1,4]dioxinro[2,3-c]pyridin-5-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H37) (R)-N-(5-(2-hydroxypropyl-2-yl)-4'-((4-(2-hydroxypropoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H38) N-(5-(2-hydroxypropyl-2-yl)-4'-((6-(methanesulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H39) N-(5-(2-hydroxypropyl-2-yl)-4'-((4-isobutoxy-6-(methanesulfonyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-yl)acetamide; (H40) (S)-N-(4'-((4-(sec-butoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropyl-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H41) (R)-N-(4'-((4-(sec-butoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(2-hydroxypropyl-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; (H42) N-(5-(2-hydroxypropyl-2-yl)-4'-((3-isopropoxy-5-(methanesulfonyl)phenyl)amino)-[2,3'-bipyridine]-6'-yl)acetamide; (H43) N-(5-(1-methyl-1H-pyrazole-3-yl)-4-((4-methyl-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (J1) N-(4-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J2) N-(4-((4-(cyclopropylmethoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J3) N-(5-(1-methyl-1H-pyrazole-3-yl)-4-((6-aminosulfonylpyridin-2-yl)amino)pyridin-2-yl)acetamide; (J4) N-(4-((6-(ethylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazole-3-yl)pyridin-2-yl)acetamide; (J5) N-(5-(1-methyl-1H-pyrazole-3-yl)-4-((3-(methanesulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (J6) N-(4-((3-cyano-5-(methanesulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazole-3-yl)pyridin-2-yl)acetamide; (J7) N-(5-(1-methyl-1H-pyrazole-3-yl)-4-((3-methyl-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (J8) N-(4-((3-methoxy-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazole-3-yl)pyridin-2-yl)acetamide; (J9) N-(5-(1-methyl-1H-pyrazole-3-yl)-4-((3-(methanesulfonyl)-5-(trifluoromethoxy)phenyl)amino)pyridin-2-yl)acetamide; (J10) N-(5-(1-methyl-1H-pyrazole-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (J11) N-(4-((4-(2-methoxyethoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J12) N-(4-((4-(2-methoxypropoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J13) (R)-N-(4-((4-(2-methoxypropoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J14) N-(4-((4-(2-hydroxyethoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J15) N-(4-((4-((trans)-3-hydroxycyclobutyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J16) N-(4-((4-((trans)-3-hydroxycyclobutyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J17) N-(4-((4-(3-methoxycyclobutyloxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J18) N-(4-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J19) N-(4-((4-(cyano methoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J20) N-(4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J21) N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(oxetan-3-yloxy)pyridin-2-yl)amino)pyridin-2-yl)acetamide;(J22) N-(4-((3-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J23) N-(4-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J24) N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(oxetan-3-ylmethoxy)pyridin-2-yl)amino)pyridin-2-yl)acetamide;(J25) N-(4-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J26) N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((3-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide;(J27) N-(4-((6-(cyclopropylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J28) N-(4-((6-(isopropylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide;(J29) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazol-3- yl)pyridin-2-yl)acetamide; (J31) N-(4-((3-chloro-5-(methylsulfonyl N-(4-((4-cyclopentyloxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl- 1 H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J45) N-(4-((4-cyclopentyloxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl- 1 H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J45) N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-((tetrahydrofuran-3- yl)oxy)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (J46) (R)-N-(4-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1- methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J47) N-(4-((4-(2,3-dihydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1- methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J48) N-(4-((3-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H- pyrazol-3-yl)pyridin-2-yl)acetamide; (J49) N-(4-((5-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H- pyrazol-3-yl)pyridin-2-yl)acetamide; (J50) N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((5-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (J51) N-(5-(1-methyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-4-(trifluoromethyl)pyridin- 2-yl)amino)pyridin-2-yl)acetamide; (J52) N-(4-((6-(ethylsulfonyl)-4-isopropoxy pyridin-2-yl)amino)-5-(1-methyl-1H- pyrazol-3-yl)pyridin-2-yl)acetamide; (J53) N-(4-((5-fluoro-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol- 3-yl)pyridin-2-yl)acetamide; (J54) (S)-N-(4-((3-(2-hydroxypropoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl- 1 H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J55) N-(4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl-1H- pyrazol-3-yl)pyridin-2-yl)acetamide; (J56) (R)-N-(4-((3-(2-hydroxypropoxy)-5-(methylsulfonyl)phenyl)amino)-5-(1-methyl- 1 H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J57) N-(4-((4-(difluoromethoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J58) N-(4-((4-isobutoxy-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J59) (S)-N-(4-((4-(sec-butoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J60) 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; (J61) N-(4-((3-(difluoromethoxy)-5-(methanesulfonyl)phenyl)amino)-5-(1-methyl-1H-pyrazole-3-yl)pyridin-2-yl)acetamide; (J62) N-(4-((3-(difluoromethoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J63) N-(5-(1-methyl-1H-pyrazole-3-yl)-4-((7-(methanesulfonyl)-2,3-dihydro-[1,4]dioxinro[2,3-c]pyridin-5-yl)amino)pyridin-2-yl)acetamide; (J64) (R)-N-(4-((4-(sec-butoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (J65) N-(5-(1-cyclopropyl-1H-pyrazole-3-yl)-4-((6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M1) N-(5-(1-cyclopropyl-1H-pyrazole-3-yl)-4-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M2) N-(5-(1-cyclopropyl-1H-pyrazole-3-yl)-4-((4-methyl-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M3) N-(5-(1-cyclopropyl-1H-pyrazole-3-yl)-4-((4-(2-methoxyethoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M4) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M5) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((4-isopropoxy-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M6) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((4-(methoxymethyl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M7) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((3-(methanesulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (M8) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((3-methoxy-5-(methanesulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (M9) N-(4-((3-cyano-5-(methanesulfonyl)phenyl)amino)-5-(1-ethyl-1H-pyrazole-3-yl)pyridin-2-yl)acetamide; (M10) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((3-methyl-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (M11) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((3-(methoxymethyl)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (M12) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((3-(methanesulfonyl)-5-(trifluoromethyl)phenyl)amino)pyridin-2-yl)acetamide; (M13) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((3-(2-methoxyethoxy)-5-(methanesulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (M14) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((3-(2-hydroxyethoxy)-5-(methanesulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (M15) N-(4-((3-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl)amino)-5-(1-ethyl-1H-pyrazole-3-yl)pyridin-2-yl)acetamide; (M16) N-(4-((4-(cyclopentyloxy)-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (M17) N-(4-((4-ethoxy-6-(methanesulfonyl)pyridin-2-yl)amino)-5-(1-ethyl-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (M18) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((4-(2-hydroxyethoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M19) N-(5-(1-ethyl-1H-pyrazole-3-yl)-4-((4-(2-methoxyethoxy)-6-(methanesulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M20) N-(5-(l-ethyl-lH-pyrazol-3-yl)-4-((3-isopropoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (M21) N-(5-(l-isopropyl-lH-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (M22) N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(l-isopropyl-lH- pyrazol-3-yl)pyridin-2-yl)acetamide; (M23) N-(5-(l-isopropyl-lH-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (M24) N-(5-(l-isopropyl-lH-pyrazol-3-yl)-4-((3-(methylsulfonyl)-5- (trifluoromethyl)phenyl)amino)pyridin-2-yl)acetamide; (M25) N-(4-((3-isopropoxy-5-(methylsulfonyl)phenyl)amino)-5-(l-isopropyl-lH- pyrazol-3-yl)pyridin-2-yl)acetamide; (M26) N-(5-(l-isopropyl-lH-pyrazol-3-yl)-4-((3-methoxy-5- (methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (M27) N-(4-((4-(2-hydroxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(l- isopropyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide; (M28) N-(4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)-5-(l- isopropyl-lH-pyrazol-3-yl)pyridin-2-yl)acetamide; (M29) N-(4-((3-(methylsulfonyl)phenyl)amino)-5-(l-(tetrahydrofuran-3-yl)-lH-pyrazol- 3-yl)pyridin-2-yl)acetamide; (M30) N-(4-((4-methyl-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(l-(tetrahydrofuran-3- yl)-lH-pyrazol-3-yl)pyridin-2-yl)acetamide; (M31) (R)-N-(4-((3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)amino)-5-(l- (tetrahydrofuran-3-yl)-lH-pyrazol-3-yl)pyridin-2-yl)acetamide; (M32) (S)-N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(l- (tetrahydrofuran-3-yl)-lH-pyrazol-3-yl)pyridin-2-yl)acetamide; (M33) (R)-N-(4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(l- (tetrahydrofuran-3-yl)-lH-pyrazol-3-yl)pyridin-2-yl)acetamide; (M34) (R)-N-(4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (M35) N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (N1) N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (N2) N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((3-(2-hydroxyethoxy)-5-(methylsulfonyl)phenyl)amino)pyridin-2-yl)acetamide; (N3) N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (N4) N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (N5) (R)-N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-(2-methoxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (N6) N-(5-(1,5-dimethyl-1H-pyrazol-3-yl)-4-((4-ethoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (N7) N-(5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)-4-((6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (O1) N-(4-((4-(2-methoxyethoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (O2) N-(4-((4-(2-hydroxypropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl-5-morpholino-1H-pyrazol-3-yl)pyridin-2-yl)acetamide; (O3) 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; (Q1) N-(5-([1,3]dioxolo[4,5-b]pyridin-5-yl)-4-((4-isopropoxy-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q2) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(3,4-dihydro-2H-pyrido[4,3-b][l,4]oxazin-7-yl)-4-((4-isopropoxy-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q4) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-methyl-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q3) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) N-(5-([ 1,3]thiazolo[ 5,4-c]pyridin-2-yl)-4-((4-methoxy-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; (Q 16) 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; (Q25) 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; (Q25) 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; (Q25) 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; (Q25) 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; (Q25) 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; (Q25) 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; (Q25) 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; (Q25) 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; (Q25) 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; (Q25) 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; (Q25) N-(5-(3,3-dimethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)- 4-(oxetan-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q39) (R)-N-(5-(3,3-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; (Q45) (S)-N-(5-(3,3-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; (Q46) (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; (Q43) (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; (Q44) (R)-N-(5-(3,3-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; (Q45) (S)-N-(5-(3,3-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; (Q46) 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; (Q47) 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; (Q48) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-methoxyazetidin-1-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q49) (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]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q50) (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]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q51) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(4-methoxyazetidin-1-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q52) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((cis)-3-methoxycyclobutyl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q53) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans)-3-methoxycyclobutyl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q54) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(4-hydroxy-4-methylpiperidin-1-yl)- 6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q55) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-hydroxy-3-methylazetidin-1-yl)- 6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q56) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-hydroxy-3-methylpyrrolidin-1- yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q57) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-hydroxy-3-methylpyrrolidin-1- yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q57) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((6-(methylsulfonyl)-4- (tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q58) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-(2- hydroxyethoxy)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q59) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((6-(methylsulfonyl)-4- (1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q60) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-(2- hydroxyethoxy)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q61) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-methyl-6'-(methylsulfonyl)- [3,4'-bipyridinyl]-2'-yl)amino)pyridin-2-yl)acetamide; (Q62) N-(4-((4-cyano-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q63) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-methyl-6-(methylsulfonyl)- 3-oxo-3,4-dihydropyrazin-2-yl)amino)pyridin-2-yl)acetamide; (Q64) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-methoxy- piperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q65) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-methoxy- piperidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q66) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-ethoxyazetidin- 1 -yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q67) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-ethoxyazetidin- 1 -yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q68) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((6-(methylsulfonyl)-4- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q69) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((6-(methylsulfonyl)-4- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q70) (S)-1-(2-((2-acetamido-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)pyridin-4- yl)amino)-6-(methylsulfonyl)pyridin-4-yl)pyrrolidine-2-carboxamide; (Q71) (R)-1-(2-((2-acetamido-5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)pyridin-4- yl)amino)-6-(methylsulfonyl)pyridin-4-yl)pyrrolidine-2-carboxamide; (Q72) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-(methoxymethyl) azetidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q73) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-(methoxymethyl) azetidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q74) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((6-(methylsulfonyl)-4- (tetrahydro-2H-pyran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q75) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((6-(methylsulfonyl)- 4-(tetrahydro-2H-pyran-3-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q76) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((5-(3-methoxypyrrolidin- 1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q77) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((5-(3-methoxypyrrolidin- 1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q78) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((6-(methylsulfonyl)-5- (tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q79) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(5-methylpyridazin-4-yl)- 6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q80) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(5-methoxypyridazin-4- yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q81) 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]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q82) 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]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q83) 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]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q84) N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxepino[2,3-b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q90) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxepino[2,3-b]pyridin-6-yl)-4-((3-(3- methoxypyrrolidin- 1 -yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q91) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxepino[2,3-b]pyridin-6-yl)-4-((3-(3- methoxypyrrolidin- 1 -yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q92) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxepino[2,3-b]pyridin-6-yl)-4-((3-(3- methoxypyrrolidin- 1 -yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q91) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxepino[2,3-b]pyridin-6-yl)-4-((3-(3- methoxypyrrolidin- 1 -yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q92) N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxepino[2,3-b]pyridin-6-yl)-4-((6- (methylsulfonyl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q90) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxepino[2,3-b]pyridin-6-yl)-4-((3-(3- methoxypyrrolidin- 1 -yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q91) (R)-N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxepino[2,3-b]pyridin-6-yl)-4-((3-(3- methoxypyrrolidin- 1 -yl)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q92) cis-N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxepino[2,3-b]pyridin-6-yl)-4-((4-((cis- 4-hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q93) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-((trans-4- hydroxycyclohexyl)oxy)-6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2- yl)acetamide; (Q94) (S)-N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-methylpyrrolidin-1-yl)- 6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q103) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((6-(methylsulfonyl)-4- (pyrrolidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q104) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(2-hydroxypropan-2-yl)-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide; (Q105) 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]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q106) (S)-N-(4-((4-(3-(cyanomethoxy)pyrrolidin-1-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)- 5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q107) N-(4-((6-cyano-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)-5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q108) N-(4-((2-cyano-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)-5-(2,2-dimethyl-2,3- dihydro-[1,4]dioxepin-6-yl)pyridin-2-yl)acetamide; (Q109) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((4-(3-methylpyrazin-2-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q110) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepin-6-yl)-4-((6-(methylsulfonyl)-4-(2,2,6,6- tetramethyltetrahydro-2H-pyran-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q111) (R)-N-(4-((4-(2,2-dichlorocyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl- 2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (Q112) (S)-N-(4-((4-(2,2-dichlorocyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl- 2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (Q113) N-(4-((4-(5-cyanopyridazin-4-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (Q114) N-(4-((4-cyano-6'-(methylsulfonyl)-[3,4'-bipyridin]-2'-yl)amino)-5-(2,2-dimethyl-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (Q115) N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-(5-fluoropyridazin-4-yl)- 6-(methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q116) N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((4-fluoro-6'-(methylsulfonyl)- [3,4'-bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide; (Q117) N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((6'-(methylsulfonyl)-[2,4'- bipyridin]-2'-yl)amino)pyridin-2-yl)acetamide; (Q118) N-(5-(2,2-dimethyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)-4-((6-(methylsulfonyl)-4- (thiazol-4-yl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; (Q119) N-(4-((4-(l-cyanocyclopropyl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(2,2-dimethyl-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-6-yl)pyridin-2-yl)acetamide; (Q120) N-(5-(2,2-dimethyl-2,3-dihydro-[1,4]dioxepino[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]dioxepino[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]dioxepino[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]dioxepino[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]dioxepino[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]dioxepino[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]dioxepino[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-((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-(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-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)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-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)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-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)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-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)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-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)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-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)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-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)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-6-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-yl)acetamide; N-(4-((5,5-dioxo-3,4-dihydro-2H-[1,4]oxathiEPino[3,2-b]pyridin-7-yl)amino)-5-(1-methyl- 1 H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-hydroxypropan-2-yl)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl- 1 H-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- 1 H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(4-((4-(2-hydroxy-2-methylpropoxy)-6-(methylsulfonyl)pyridin-2-yl)amino)-5-(1-methyl- 1 H-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 -dioxido-3,4-dihydro-2H-thiopyrano[2,3-b]pyridin-7-yl)amino)-5-(1 -methyl- 1 H-pyrazol-3-yl)pyridin-2-yl)acetamide; N-(5-(1 -methyl- 1 H-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- 1 H-pyrazol-3-yl)-4-((6-(methylsulfonyl)-[ 1,3]dioxolo[4,5-c]pyridin-4- yl)amino)pyridin-2-yl)acetamide; N-(5-(1 -methyl- 1 H-pyrazol-3-yl)-4-((6-(methylsulfonyl)imidazo[ 1,2-a]pyrazin-8-yl)amino) pyridin-2-yl)acetamide; N-(5-(1 -methyl- 1 H-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-hydroxyprop-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-hydroxytetrahydrofuran-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-(3-hydroxytetrahydrofuran-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-(3-hydroxytetrahydrofuran-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-(3-hydroxytetrahydrofuran-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-(3-hydroxytetrahydrofuran-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-(3-hydroxytetrahydrofuran-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-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)pyridin-2-yl)acetamide; N-(5-(6,7-dihydro-4H-thiopyran-2-yl)-4-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6- (methylsulfonyl)pyridin-2-yl)amino)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]phthalazine-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]phthalazine-2(7H)- yl)pyridin-2-yl)acetamide; N-(4'-((4-(3-(hydroxymethyl)tetrahydrofuran-3-yl)-6-(methylsulfonyl)pyridin-2- yl)amino)-5-(l-oxoisoindolin-2-yl)-[2,3'-bipyridin]-6'-yl)acetamide; N-(5-(2,3-dihydropyrazolo[5,l-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,l-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-l,6'-pyrazolo[5,l-b][l,3]oxazin]-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-(lH-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-(lH-benzo[d]imidazol-2-yl)-4-((4-methyl-6-(methylsulfonyl)pyridin-2- yl)amino)pyridin-2-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-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(((tetrahydrofuran-3- yl)oxy)methyl)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-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(((tetrahydrofuran-3- yl)oxy)methyl)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-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(((tetrahydrofuran-3- yl)oxy)methyl)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-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(((tetrahydrofuran-3- yl)oxy)methyl)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-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(((tetrahydrofuran-3- yl)oxy)methyl)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-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(((tetrahydrofuran-3- yl)oxy)methyl)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-(2,6-dimethylmorpholino)-4'-((6-(methylsulfonyl)-4-(((tetrahydrofuran-3- yl)oxy)methyl)pyridin-2-yl)amino)-[2,3'-bipyridin]-6'-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-methyl-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- c]pyrimidin-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-methyl-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- c]pyrimidin-2-yl)pyridin-2-yl)acetamide; 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, or a pharmaceutically acceptable salt or stereoisomer thereof.

13. A pharmaceutical composition comprising one or more compounds of any one of claims 1-12, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. Use of a compound of any one of claims 1-12, or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disease. ​

Images