Pyrido[2,3-b][1,4]oxazine or tetrahydropyrido[2,3-b][1,4]oxazepine as IAP antagonists

Abstract

To provide pyrido[2,3-b] [1,4] oxazine or tetrahydropyrido[2,3-b][1,4] oxazepine derivatives as antagonists of IAPs.SOLUTION: Disclosed herein are novel 2,3-dihydro-1H-pyrido[2,3-b ][1,4] oxazine or 1,2,3,4-tetrahydropyrido[2,3-b][1,4]oxazepine derivatives used as antagonists of IAPs (Inhibitors Apoptosis Proteins), also known as Smac mimetics. Disclosed herein is the use of these antagonists for inducing or sensitizing cells to the induction of apoptotic cell death, and the use of such compounds for treating proliferative disease such as cancer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] In this specification, IAP (apoptosis inhibitor protein), also known as Smac mimetic, A novel 2,3-dihydro-1H-pyridone [2, 3-b][1,4]oxazine or 1,2,3,4-tetrahydropyrido[2,3-b Derivatives of [1,4]oxazepines are disclosed. In this specification, cells undergo apoptosis. These antagonists are used to induce splenic death or to sensitize to the above induction. The use of such compounds for treating proliferative disorders such as cancer is also disclosed. [Background technology]

[0002] Apoptosis plays an important role in cell development and homeostasis in higher organisms. a strictly regulated process for eliminating damaged or undesirable cells. (Kerr, JF, et al., Br J Cancer, 1972 (26, 239-257). Abnormalities in the apoptotic process are associated with cancer and autoimmunity. It is involved in many human diseases, including epidemics and inflammation (Nicholson, D. W., et al., Nature, 2000, 407, 810-816). In fact, resistance to apoptosis is a characteristic of cancer (Hanahan, D., et al.) al., cell 2000, 100, 57-70;Hanahan, D., et al., cell, 2011, 144, 646-674).

[0003] Apoptosis is triggered by exogenous stimulation of cell death receptors or by intracellular mitochondria. It may be triggered by any of the endogenous stimuli that are produced (Elmore, S. (Toxicol Pathol, 2007, 35, 495-516). Apot - Invasion inhibitor proteins (IAPs) are a group of proteins that inhibit both exogenous and endogenous apoptotic pathways. It is an extremely important negative regulator. IAP was initially identified in baculoviruses. Therefore, it was possible to inhibit apoptosis in infected cells (Birnbau m, MJ, et al., J Virol, 1994, 68, 252 1-2528). The above IAP is a baculovirus IAP repeat (BIR) domain. It is characterized by its presence. The BIR domain is approximately 70-80 amino acids long and is related to the function of IAP. Contains a Zn-binding motif that may promote donating protein-protein interactions. (Yang, YL, Cell Res, 2000, 10, 169-177 The human IAP family consists of eight proteins, namely neuronal IAP (BIR). C1), cellular IAP1 (cIAP1, BIRC2), cellular IAP2 (cIAP2, BIR C3), X-linked IAP (XIAP, BIRC4), Survivin (BIRC5), Yu Biquitin-binding BIR domain enzyme apollon (BIRC6), melanoma IAP (ML- This includes IAP (BIRC7) and IAP-like protein 2 (BIRC8). cIAP1, cIAP2, and XIAP play a direct role in regulating apoptosis. (Salvesen, GS, et al., Nat Rev Mol Cell Bio, 2002, 3, 401-410).

[0004] cIAP1 and cIAP2 (cIAP) are activated through their ubiquitin ligase activity. Caspase-8-dependent exogenous apoptosis pathways, such as those induced by TNF-α. Inhibits (Derakhshan, A., et al., Clin Cance (r Res, 2017, 23, 1379-1387). TNF-α and its receptor T NFR1, cIAPs, and tumor necrosis factor receptor 1-associated death domain (TRADD) When linked, receptor-interacting serine / threonine kinase 1 (RIPK1) and TN F receptor-related factor (TRAF) is recruited to form complex I, which leads to inflammation and proliferation. , and the classical nuclear factor-κB (NF-κB) pathway, which is well known to promote cell survival. This leads to the activation of (Samuel T., et al., J Biol Chem) , 2006, 281, 1080-1090;Vince JE, et a l., J Biol Chem, 2009, 284, 35906-35915; Wang C., et al., Nature, 2001, 412, 346- 351).

[0005] XIAP directly suppresses caspase activation through its BIR domain. It is the only IAP protein that inhibits both exogenous and endogenous apoptotic pathways. (Deveraux QL, et al., Nature, 1997, 3 88, 300-304). The BIR2 domain of XIAP and the linker located before it. The region is the caspase, which is an effective caspase shared by exogenous and endogenous apoptosis. Caspase-3 and -7 associate with the IAP-binding motif (IBM) and active site, and It inhibits the function of and -7 (Chai J., et al., Cell, 2001) , 104, 769-780;Riedl SJ, et al., Cell (2001, 104, 791-800). XIAP uses its BIR3 domain. It binds to procaspase-9, which is an important initiator caspase in the endogenous pathway. It prevents the dimerization and subsequent activation of spase-9 (Shiozaki EN, et al., Mol Cell, 2003, 11, 519-527).

[0006] cIAP1, cIAP2, and XIAP proteins are widely used in various tumor types. It is expressed. Furthermore, the active expression of cIAP and XIAP indicates high-grade cancer. and is associated with a poor prognosis (Che X., et al., Urol Oncol , 2012, 30, 450-456;Yang C., et al., JE xp Clin Cancer Res, 2016, 35, 158). Furthermore, Downregulation or depletion of these IAPs is in response to exogenous or endogenous apoptotic stimulation. It has been shown to restore sensitivity (Gu H., et al., Aging( Albany NY), 2018, 10, 1597-1608). In summary, I Targeting AP proteins offers a potential anti-tumor strategy.

[0007] The second mitochondrion, also known as the low pI direct IAP-binding protein (DIABLO). Doria-derived caspase activator (Smac) promotes apoptosis with cIAP1. It is an endogenous antagonist of cIAP2 and XIAP (Du C., et al.). , Cell, 2000, 102, 33-42;Verhagen AM, et al., Cell, 2000, 102, 43-53). Smac is usually They are sequestered within the mitochondria and released into the cytosol when apoptosis occurs in the cell. In the cytosol, the N-terminal mitochondrial target sequence of Smac is cleaved, and tetrap The ptide (Ala-Val-Pro-Ile) is exposed, which causes Smac to be the B of IAP. This enables interaction with the IR domain (Chai J., et al., N ature, 2000, 406, 855-862). Smac is cIAP1 and c By binding to the BIR3 domain of IAP2, their E3 ubiquitin ligase The activity is stimulated, and the degradation of those proteasomes is induced. Loss of cIAP protein Due to the loss, F has a dead domain containing RIPK1, caspase-8, and complex II. The formation of as-related protein (FADD) is promoted, and TNF-α-mediated apoptosis is induced. (Dueber EC, et al., Science, 2011) (334, 376-380). Dimerized Smac is BIR2 domain of XIAP. It binds to the BIR3 domain and interacts with its caspases-3, -7, and -9. This destroys the caspase, which leads to caspase-dependent apoptosis (Micheau, O., et al., Cell, 2003, 114, 181-190;Chai J. , et al., Cell, 2001, 104, 769-780;Liu Z. ., et al., Nature, 2000, 408, 1004-1008) .

[0008] Smac mimics the N-terminus (Ala-Val-Pro-Ile) of Smac. It is a small molecule containing four amino acids. Similar to Smac, Smac mimetic molecules are BIs of IAP. It binds to the R domain and antagonizes their functions, promoting apoptosis in cancer cells (C hai J., et al., Cell, 2001, 104, 769-780 ;Dueber EC, et al., Science, 2011, 33 4, 376-380;Liu Z., et al., Nature, 2000, 408, 1004-1008;Verhagen AM, et al., Cell, 2000, 102, 43-53). In summary, the Smac mimetic is novel. This group of cancer treatment candidates is a promising one. [Overview of the Initiative] [Means for solving the problem]

[0009] In one embodiment, as used herein, the formula (I) is 2,3-dihydro-1H-pyrido[ 2,3-b][1,4]oxazine or 1,2,3,4-tetrahydropyrid[2,3 -b][1,4]oxazepine derivatives are disclosed. The above embodiments include the following aspects. .

[0010] Appearance 1: Formula (I): [ka] A compound of, During the ceremony, X1 and X2 are independently -O-, -S-, and -NR a -, or -CR a R b - and; m1, m2, and m3 are each independently 0, 1, or 2; R 1a , R 1b , R 1c , R 1d , and R7 may be the same or different and are each independently hydrogen, halogen, -C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, -C 3~8 cycloalkyl, heterocyclyl, aryl, hetero aryl, oxo, -CN, -NO2, -OR a , -SR a , -SO2R a , -COR a ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Choose 1 to 3 R's as you like. d It has been replaced with; n is 0, 1, 2, 3, or 4; R3 and R5 are independently hydrogen, halogen, and -C. 3~8 Cycloalkyl, or -C 1~8 It is alkyl, however, -C 1~8 Alkyl or -C 3~8 Cycloal Kill is optional and involves at least one halogen or -OR a It has been replaced with; R2 and R4 are each independently supplied with hydrogen or -C 1~8 It is alkyl; or R4 and R5, together with the same carbon atom to which they are bonded, form a spiro-3 to 5-membered carbon ring. To form; or One of the existing R2s and one of the existing R4s are both bridges, and in the bridge, 0 Forming the above crosslinks including 1 or 2 -CH2- portions; or R 1b and one of the R4 atoms present together form a 3- to 6-membered carbon ring; or R 1d And one of the existing R4s is a bridge, and in the bridge there is one or two Forming the above crosslink including the -CH2- portion; R6 is hydrogen, halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 a Lukinil, -C 3~8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, o Kiso, -CN, -NO2, -OR a , -SR a , -SO2R a , -COR a , -CO2R a ,-CONR a R b -C(=NR a )NR b Rc 、 -NR a R b 、 -NR a COR b 、 -NR a CONR b R c 、 -NR a CO2R b 、 -NR a SONR b R c 、 -NR a S O2NR b R c 、 -SO2NR a R b 、 or -NR a SO2R b ; provided that the above - C 1~8 alkyl, -C 2~8 alkenyl, -C 2~8 alkynyl, -C 3~8 cyclo alkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with 1 ~3 R d ; R8 and R9 are each independently hydrogen, -C 1~8 alkyl, C 1~8 alkoxy -C 1~8 alkyl -, -C[[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ R a , -CO2R a ,-CONR a R b -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO2R b , -NR a SONR b R c , -NR a SO2NR b R c -SO2NR a R b , or -NR a SO2R b in Yes, however, as per -C above. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkinil, -C 3~8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl cycloalkyl, heterocyclyl, or heteroaryl cycloalkyl, heterocyclyl, or heterocyclyl Each of these can be any choice of 1 to 3 Rs. d It is replaced with, or R 10 and R 11 Both can choose 1 to 3 R's. d Spiro 3-5 members are replaced by Forming a carbon ring; R 12 and R 13 These are, independently, hydrogen and -C. 1~8 Alkyl, -C 2~8 Alkeni Ru, -C 2~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclyl, aryl, he Teroaryl, Oxo, -CN, -NO2, -OR a , -SRa , -SO2R a , -CO R a , -CO2R a ,-CONR a R b -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO2R b , -NR a SONR b R c , -NR a SO2NR b R c -SO2NR a R b , or -NR a SO2R b in Yes, however, as per -C above. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkinil, Each of the following is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound: Select 1 to 3 R d It is replaced with, or R 12 and R 13 Both can choose 1 to 3 R's. d Spiro 3-5 members are replaced by Forming a carbon ring; R 14 and R 15 Each of these is independently either hydrogen or -C 1~8 Selected from alkyl groups; Each R a , R b , and R c These are independently hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenil , -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or hetero It is an aryl, however, as per -C above. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 a Lukinyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl rukinyl Each of these can be any choice of 1 to 3 Rs. d It is replaced with, or (R a and R b ), (R a and R c ), or (R b and R c ) But they combine Together with the atom(s) present, it forms a 3- to 8-membered ring, provided that the above ring is 0, 1, or 2 A further hemoglobin independently selected from nitrogen, oxygen, or optionally oxidized sulfur. It contains multiple ring members (or more), and the above ring can be optionally composed of 1 to 3 R atoms. d Replace with It is done; R d In each of their existences, hydrogen, halogen, and -C exist independently. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclic Ryl, aryl, heteroaryl, oxo, -CN, -NO2, -OR e , -SR a ,- SO2R e -SO2NR e R f , -COR e , -CO2R e ,-CONR e R f , -C (=NR e )NR f R g , -NR eR 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 -N R e SO2R f However, as per -C above 1~8 Alkyl, -C 2~8 Alkenyl, -C2 ~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclyl, aryl, or hetero Each of the aryls can optionally be a halogen, -C 1~8 Alkyl, -OR h , -NR h R i Selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl It is substituted with at least one substituent; R e , R f , R g , R h , and R i These are, independently, hydrogen and -C. 1~8 Alkyl, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkinyl cycloalkyl, heterocyclyl, aryl, aryl-C 1~8 Alkyl-, or It is a heteroaryl. The above compounds, or pharmaceutically acceptable salts thereof, or their stereoisomers, tautomers, Or a prodrug.

[0011] In some embodiments, m2 is 1 and m3 is 1, and R2 and R4 are Both are bridges, and the bridges include 0, 1, or 2 -CH2- portions. To form a bridge; or m2 is 1 and m3 is 2, and R2 and one of the two R4s are both bridges. The above crosslinks include 0, 1, or 2 -CH2- portions; or m2 is 2 and m3 is 1, and R2 and R4 are both bridges, and the above bridge Forming the above crosslinks which include 0, 1, or 2 -CH2- portions; or m2 is 2 and m3 is 2, and one of the two R2s and one of the two R4s are both , a crosslink, wherein the crosslink contains 0, 1, or 2 -CH2- portions. To form.

[0012] In some embodiments, m2 is 1, R 1b Both R4 and R4 are 3-6 membered carbon rings. To form; or m2 is 2, R 1b And one of the two R4s both forms a 3- to 6-membered carbon ring.

[0013] In some embodiments, m2 is 1, R 1d Both R4 and R4 are bridges. , or to form the above crosslink containing one or two -CH2- portions in the above crosslink; or m2 is 2, R 1d And one of the two R4s is a bridge, and in the bridge, 1 Alternatively, the above crosslinks are formed, including two -CH2- portions.

[0014] Appearance 2: Formula (II): [ka] A compound of, During the ceremony, X1 and X2 are independently -O-, -S-, and -NR a -, or -CR a R b - and; m1, m2, and m3 are each independently 0, 1, or 2; R 1a , R 1b , R 1c , R 1d , and R7 may be the same or different. Often, hydrogen, halogen, and -C are considered independently. 1~8 Alkyl, -C 2~8 Alkenil, -C 2~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclyl, aryl, hetero Aryl, Oxo, -CN, -NO2, -OR a , -SR a , -SO2R a , -COR a , -CO2R a ,-CONR a R b -C(=NR a )NR b R c , -NR a R b , -N R a COR b , -NR a CONR b R c , -NR a CO2R b , -NR a SONR b R c , -NR a SO2NR b R c -SO2NR a R b , or -NR a SO2Rb And, However, as per -C above 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkinyl, -C3 ~8 Each of the following is a cycloalkyl, heterocyclyl, aryl, or heteroaryl: Choose 1 to 3 R's as you like. d It has been replaced with; n is 0, 1, 2, 3, or 4; R3 and R5 are independently hydrogen, halogen, and -C. 3~8 Cycloalkyl, or -C 1~8 It is alkyl, however, -C 1~8 Alkyl or -C 3~8 Cycloal Kill is optional and involves at least one halogen or -OR a It has been replaced with; R2 and R4 are each independently supplied with hydrogen or -C 1~8 It is alkyl; or R4 and R5, together with the same carbon atom to which they are bonded, form a spiro-3 to 5-membered carbon ring. To form; or One of the existing R2s and one of the existing R4s are both bridges, and in the bridge, 0 Forming the above crosslinks including 1 or 2 -CH2- portions; or R 1b and one of the R4 atoms present together form a 3- to 6-membered carbon ring; or R 1d And one of the existing R4s is a bridge, and in the bridge there is one or two Forming the above crosslink including the -CH2- portion; R6 is hydrogen, halogen, -C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 a Lukinil, -C 3~8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, o Kiso, -CN, -NO2, -OR a , -SR a , -SO2R a , -COR a , -CO2R a ,-CONR a R b -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO2R b , -NR a SONR b R c , -NR a S O2NR b R c -SO2NR a R b , or -NR a SO2R b However, as stated above - C 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkinyl, -C 3~8 Cycloa Each of the following can be optionally selected: rukyl, heterocyclyl, aryl, or heteroaryl. ~3 R d It has been replaced with; R8 and R9 are independently hydrogen and -C 1~8 Alkyl, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkinyl, or -C 3~8 C It is a chloroalkyl; R 10 and R 11 These are, independently, hydrogen and -C. 1~8 Alkyl, -C2~8 Alkeni Ru, -C 2~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclyl, aryl, he Teroaryl, Oxo, -CN, -NO2, -OR a , -SR a , -SO2R a , -CO R a , -CO2R a ,-CONR a R b -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO2R b , -NR a SONR b R c , -NR a SO2NR b R c -SO2NR a R b , or -NR a SO2R b in Yes, however, as per -C above. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkinil, -C 3~8 Cycloalkyl, heterocyclyl, aryl, or heteroaryl cycloalkyl, heterocyclyl, or heteroaryl cycloalkyl, heterocyclyl, or heterocyclyl Each of these can be any choice of 1 to 3 Rs. d It is replaced with, or R 10 and R 11 Both can choose 1 to 3 R's. d Spiro 3-5 members are replaced by Forming a carbon ring; R 12 and R 13These are, independently, hydrogen and -C. 1~8 Alkyl, -C 2~8 Alkeni Ru, -C 2~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclyl, aryl, he Teroaryl, Oxo, -CN, -NO2, -OR a , -SR a , -SO2R a , -CO R a , -CO2R a ,-CONR a R b -C(=NR a )NR b R c , -NR a R b , -NR a COR b , -NR a CONR b R c , -NR a CO2R b , -NR a SONR b R c , -NR a SO2NR b R c -SO2NR a R b , or -NR a SO2R b in Yes, however, as per -C above. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkinil, Each of the following is a cycloalkyl, heterocyclyl, aryl, or heteroaryl compound: Select 1 to 3 R d It is replaced with, or R 12 and R 13 Both can choose 1 to 3 R's. d Spiro 3-5 members are replaced by Forming a carbon ring; Each Ra , R b , and R c These are independently hydrogen, -C 1~8 Alkyl, -C 2~8 Alkenil , -C 2~8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or hetero It is an aryl, however, as per -C above. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 a Lukinyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl rukinyl Each of these can be any choice of 1 to 3 Rs. d It is replaced with, or (R a and R b ), (R a and R c ), or (R b and R c ) But they combine Together with the atom(s) present, it forms a 3- to 8-membered ring, provided that the above ring is 0, 1, or 2 A further hemoglobin independently selected from nitrogen, oxygen, or optionally oxidized sulfur. It contains multiple ring members (or more), and the above ring can be optionally composed of 1 to 3 R atoms. d Replace with It is done; R d In each of their existences, hydrogen, halogen, and -C exist independently. 1~8 Alkyl, -C 2~8 Alkenyl, -C 2~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclic Ryl, aryl, heteroaryl, oxo, -CN, -NO2, -OR e , -SR a ,- SO2R e -SO2NR e R f , -COR e , -CO2R e ,-CONRe 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 -N R e SO2R f However, as per -C above 1~8 Alkyl, -C 2~8 Alkenyl, -C2 ~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclyl, aryl, or hetero Each of the aryls can optionally be a halogen, -C 1~8 Alkyl, -OR h , -NR h R i Selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl It is substituted with at least one substituent; R e , R f , R g , R h , and R i These are, independently, hydrogen and -C. 1~8 Alkyl, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkinyl cycloalkyl, heterocyclyl, aryl, aryl-C 1~8 Alkyl-, or It is a heteroaryl. The above compounds, or pharmaceutically acceptable salts thereof, or their stereoisomers, tautomers, Or a prodrug.

[0015] In some embodiments, m2 is 1 and m3 is 1, and R2 and R4 are Both are bridges, and the bridges include 0, 1, or 2 -CH2- portions. To form a bridge; or m2 is 1 and m3 is 2, and R2 and one of the two R4s are both bridges. The above crosslinks include 0, 1, or 2 -CH2- portions; or m2 is 2 and m3 is 1, and R2 and R4 are both bridges, and the above bridge Forming the above crosslinks which include 0, 1, or 2 -CH2- portions; or m2 is 2 and m3 is 2, and one of the two R2s and one of the two R4s are both , a crosslink, wherein the crosslink contains 0, 1, or 2 -CH2- portions. To form.

[0016] In some embodiments, m2 is 1, R 1b Both R4 and R4 are 3-6 membered carbon rings. To form; or m2 is 2, R 1b And one of the two R4s both forms a 3- to 6-membered carbon ring.

[0017] In some embodiments, m2 is 1, R 1d Both R4 and R4 are bridges. , or to form the above crosslink containing one or two -CH2- portions in the above crosslink; or m2 is 2, R 1d And one of the two R4s is a bridge, and in the bridge, 1 Alternatively, the above crosslinks are formed, including two -CH2- portions.

[0018] Embodiment 3: X1 is -O-, -S-, -NH-, or -CH2-, as in Embodiment 1 or This is the compound described in 2.

[0019] Embodiment 4: The compound according to Embodiment 3, wherein X1 is -CH2-.

[0020] Embodiment 5: X2 is -O-, -S-, -CH2-, or -NR a -and, R a is H or -C 1~8 It is alkyl (methyl or ethyl), The compound described in embodiment 1 or 2.

[0021] Embodiment 6: X2 is -O- or -NR a -and, R a is hydrogen or -C 1~8 It is alkyl (methyl or ethyl), The compound described in Embodiment 5.

[0022] Embodiment 7: The compound according to Embodiment 1 or 2, wherein m1 is 0.

[0023] Embodiment 8: The compound according to Embodiment 1 or 2, wherein m2 is 1 and m3 is 0 or 1. Compound.

[0024] Embodiment 9: R2, R3, R4, and R5 are each hydrogen, methyl or ethyl, -C H2OH, -CH2OCH3, -CH2OC2H5, -CHF2, -CH2OCH(CH 3) The compound according to embodiment 1 or 2, wherein the compound is 2, cyclopropyl, or CF3.

[0025] Embodiment 10: R4 and R5, together with the same carbon atom to which they are bonded, spiro 3-5 A compound according to embodiment 1 or 2 that forms a member carbon ring.

[0026] Appearance 11: [ka] but, [ka] And in the formula, R 1a , R 1b , R 1c , R 1d , R2, R3, R4, R5, and R a teeth The compound according to embodiment 1 or 2, as defined with respect to formula (I).

[0027] Appearance 12: [ka] but, [ka] And in the formula, R 1c , R 1d R4 and R5 are independently hydrogen or -C 1~8 Alki The compound described in embodiment 11.

[0028] Appearance 13: R 1c And R4 is hydrogen, R 1d And R5 independently of hydrogen or -C 1~ It is 8 alkyl; preferably, R 1c And R4 is hydrogen, R 1d And R5 is methyl The compound described in embodiment 12.

[0029] Appearance 14: R 1a , R 1b , R 1c , R 1d , R2, R3, R4, R5, and Ra gaso Each independently: hydrogen, halogen, -C 1~8 Alkyl (-CH3 or -C2H5, etc.) , or oxo, however, as per -C above 1~8 Alkyl is optionally at least one The compound according to embodiment 11, which is substituted with halogens (for example, 1 to 3 halogens).

[0030] Embodiment 15: R5 is halogen, -C2H5, -CH3, oxo, cyclopropyl, CH F2, -CH2F, -CF3, -CH2OH, -CH2OCH3, -CH2OC2H5, It is -CH2OCH(CH3)2 and R4 is hydrogen or -CH3; or R5 and R4 form a 3- to 5-membered carbon ring together with the bonded carbon atoms; or Both R2 and R4 are bridges, and the bridge includes one -CH2- section. A bridge is formed, and R3 and R5 are each hydrogen; or R 1b And R4 together form a 3-membered carbon ring, and R 1a R5 is hydrogen. or R 1d Both R4 and R4 are crosslinks, and the crosslinks include two -CH2- portions. Forms a crosslink, and R 1c And R5 are hydrogen, The compound described in Embodiment 14.

[0031] Appearance 16: [ka] but, [ka] [ka] The compound according to embodiment 11 or 12.

[0032] Appearance 17: [ka] but, [ka] The compound according to embodiment 1 or 2.

[0033] Embodiment 18: The compound according to Embodiment 17, wherein R7 is a halogen.

[0034] Embodiment 19: The compound according to Embodiment 18, wherein R7 is F.

[0035] Embodiment 20: R6 is hydrogen, -CN, halogen, morpholine, -CONR a R b , -OR a , -NR a R b , -C 3~5 Cycloalkyl, phenyl, or -C 1~8 Alkyl However, as per -C above 1~8 Alkyl or -C 3~5 Cycloalkyl is optional. at least one R d It has been replaced with; R a and R b These are hydrogen and -C, respectively. 3~6 Cycloalkyl, or -C 1~8 Al It's a kill; R d In each of their existences, independently, -CH2F, -CHF2, -CF3, - F, -Cl, -Br, -I, -OH, -NH2, -SH, -CN, -CONH2, -H, -CH3, -C2H5, -C3H7, -CH2OH, -OCH3, -OC2H5, Morpho Rino, [ka] The compound according to embodiment 1 or 2, which is cyclopropyl or otherwise.

[0036] Embodiment 21: R6 is -CONR a R b , -NR a R b , NR a CO-R b , -NR a - SO2-R b , or -OR a and; R a and R b These are hydrogen and -C respectively. 3~6 Cycloalkyl, -C 1~8 Alkyl, 5 Alternatively, a 6-membered heterocyclyl, aryl, or heteroaryl, provided that the above-C 1~8 Alkyl, -C 3~6 Cycloalkyl, 5- or 6-membered heterocyclyl, aryl Alternatively, heteroaryls may have 1 to 3 R's at will. d It is replaced by; or R a and R b However, together with the atom(s) to which they are bonded, they form a 3-8 membered ring, The above ring contains 0, 1, or 2 nitrogen atoms, oxygen atoms, or optionally oxidized sulfur atoms. It contains further heteroatoms independently selected from yellow as ring members (multiple members are possible), and the above ring You can choose 1 to 3 R's. d It has been replaced with; R d However, in each of their existences, hydrogen, halogen, and -C exist independently. 1~8 Alkyl, -C 2~8Alkenyl, -C 2~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclic Ryl, aryl, heteroaryl, oxo, -CN, -NO2, -OR e , -SR a ,- SO2R e -SO2NR e R f , -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 -N R e SO2R f However, as per -C above 1~8 Alkyl, -C 2~8 Alkenyl, -C2 ~8 Alkinyl, -C 3~8 Cycloalkyl, heterocyclyl, aryl, or hetero Each of the aryls can optionally be a halogen, -C 1~8 Alkyl, -OR h , -NR h R i Selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl It is substituted with at least one substituent; R e , R f , Rg , R h , and R i Each of them independently produces hydrogen and -C 1~8 Alkyl, C 1~8 Alkoxy-C 1~8 Alkyl-, -C 2~8 Alkenyl, -C 2~8 Alkinyl cycloalkyl, heterocyclyl, aryl, aryl-C 1~8 Alkyl-, or It is a heteroaryl. The compound according to embodiment 1 or 2.

[0037] Embodiment 22: R6 is -CONR a R b or NR a CO-R b And, R a and R b These are hydrogen and -C, respectively. 1~3 Alkyl, -C 3~6 Cycloalkyl, f Phenyl, 5 or 6-membered heterocyclyl (azetidine, pyrrolidine, piperidine, oxa) Zolidine, isoxazolidine, oxazinan, morpholine, piperazine, tetrahydro (Pyran, or tetrahydrofuran, etc.), however, as per -C above 1~3 Alkyl, -C 3~6 Cycloalkyl, phenyl, 5 or 6-membered heterocycline (azetidine, Helicobacter pylori) Zin, piperidine, oxazolidine, isoxazolidine, oxazinan, morpholine, Piperazine, tetrahydropyran, or tetrahydrofuran (etc.) are optional, Logen, -C 1~3 Alkyl, morpholine, OR e , or -NR e R f Selected from Substituted with at least one substituent; R e and Rf These are independently hydrogen, halogen, and -C 1~8 Alkyl, or C 1~8 Arco Kishi-C 1~8 Alkyl- The compound described in Embodiment 21.

[0038] Aspect 23: R6 is -CONR a R b And, R a and R b These, together with the nitrogen atoms to which they are bonded, form a 4-6 membered ring, however, The ring is independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and It contains 2 further heteroatoms as ring members (multiple are possible), and the above ring can be arbitrarily selected from 1 to 3 R d It has been replaced with; R d In each of their existences, they are independently halogen, -C 1~3 alkyl, or -OR e and; R e These are independently hydrogen, halogen, or -C 1~8 It is alkyl. The compound described in Embodiment 21.

[0039] Appearance 24: R6 is, [ka] [ka] The compound described in embodiment 21.

[0040] Embodiment 25: R6 is hydrogen, halogen, -CN, -CONH2, [ka] Cyclopropyl, -CH2OH, -CF3, -OH, -CH3, or -OC2H5 The compound described in embodiment 20.

[0041] Appearance 26: R 12 and R 13 Each of them independently produces hydrogen or -C 1~8 Alkyl The compound according to embodiment 1 or 2.

[0042] Appearance 27: R 12 is hydrogen or -CH3; R 13 is hydrogen or -CH3. The compound described in embodiment 26.

[0043] Appearance 28: R 10 and R 11 Each of them independently produces hydrogen and -C 1~8 Alkyl, -C 3~ 8-cycloalkyl, -C 5~6 Aryl, 5-6 member heteroaryl, or -CONR a R b However, as per -C above 1~8 Alkyl, -C 3~8 Cycloalkyl, -C 5~6 a A reel, or a 5-6 member heteroaryl, optionally contains 1-3 R d It has been replaced with ; R a and R b Each of these is independently either hydrogen or -C 1~8 It is alkyl; or (R a and R b ) however, together with the nitrogen atom to which they are bonded, they form a 3-6 membered ring, however The above ring contains 0 or 1 additional oxygen atom; the above ring optionally contains 1 R d in It has been replaced; R dIn each of its existences, independently, -C 1~8 Alkyl, halogen, ally Lu, or -OR e However, R e Each of these is independently hydrogen, or -C 1~8 Al It is methyl, phenylethyl, benzyl, or phenyl. The compound according to embodiment 1 or 2.

[0044] Appearance 29: R 10 is hydrogen; R 11 However, -CONR a R b , phenyl, benzyl, pyridinyl, or furyl However, each of the above phenyl, benzyl, pyridinyl, or furyl may be selected at will. 1 to 3 R selected from methyl, methoxy, or halogen d It has been replaced with; R a and R b Each is independently either hydrogen or methyl, or (R a and R b ) form a 5- or 6-membered ring with the nitrogen atom to which they are bonded. However, the above ring contains 0 or 1 further oxygen atom. The compound described in embodiment 28.

[0045] Appearance 30: R 10 is hydrogen; R 11 However, hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, ter t-butyl, 1-methylpropyl, 1,1-dimethylethyl, 1-pentyl, 2-pentyl 3-Pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1 -Butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2- Methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl Tyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3, 3-Dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl Xyl, vinyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -CH 2OCH3, -CH2OCH(CH3)2, -CH2OC2H5, -CH2F, -CHF 2, -CF3, -H, -F, -Cl, -Br, -I, -OH, -NH2, -SH, -CO NH2, -CONHCH3, -CON(CH3)2, [ka] -CH2O-Ph, -CH2-Ph, -CH2O-CH2-Ph, phenyl, 4-methyl Phenyl, 4-methoxyphenyl, 4-F-phenyl, benzyl, pyridinyl (4-pyridinyl Dinyl, 3-pyridinyl, or 2-pyridinyl), or frill (2-frill or (3-frill) The compound described in embodiment 29.

[0046] Appearance 31: R 10 is hydrogen; R 11 However, hydrogen, methyl, ethyl, 2-propyl, -CF3, -CHF2, -CH2C H2OCH3, -CH2OH, -CH2OCH3, -CH2OCH(CH3)2, -CH 2OC2H5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C ONH2, -CONHCH3, -CON(CH3)2, [ka] -CH2O-Ph, -CH2O-CH2-Ph, phenyl, 4-methylphenyl, 4-methylphenyl Toxyphenyl, 4-F-phenyl, benzyl, 4-pyridinyl, 3-pyridinyl, 2- It is pyridinyl, 2-frilled, or 3-frilled. The compound described in embodiment 30.

[0047] Appearance 32: R 10 and R 11 If they are different, R 10 and R 11 carbon atoms to which are bound A compound according to any one of embodiments 1 to 31, wherein the child is in an (S) configuration.

[0048] Appearance 33: R 10 and R 11 The embodiment 1 or 2 describes the configuration in which both of them form a three-membered carbon ring. A compound of [this].

[0049] Appearance 34: [ka] And in the formula, R 1a , R 1b , R 1c , R 1d , R2, R3, R4, R5, R6, R7 , R 10 , R 11 , R 12 , R 13 , and X1 are defined with respect to equation (II) The compound according to embodiment 1 or 2.

[0050] Appearance 35: R 14 and R 15 Each of them independently, hydrogen or -C 1~8 Alkyl (meth A compound according to embodiment 1 or 2, selected from (1 or ethyl).

[0051] Appearance 36: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] The compound described in Embodiment 1, or a pharmaceutically acceptable salt thereof, or its stereoisographic variant. A sexual agent, tautomer, or prodrug.

[0052] In some embodiments, the compounds disclosed herein, or pharmaceuticals A moderately acceptable salt, or its stereoisomer, tautomer, or prodrug, A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier or excipient is disclosed. .

[0053] In some embodiments, this specification describes methods for treating diseases that respond to cIAP inhibition. A law that applies to subjects requiring the above-mentioned treatment method, the compounds disclosed herein, or pharmaceuticals The salt, stereoisomer, tautomer, or prodrug of which is generally acceptable is administered. The above method, including giving, is disclosed.

[0054] In some embodiments, a method for treating cancer altered by cIAPs, For subjects requiring the above treatment method, the compounds disclosed herein, or pharmaceutically acceptable compounds The administration of its salt, or its stereoisomers, tautomers, or prodrugs The above methods, including the above, are disclosed. [Modes for carrying out the invention]

[0055] The following terms have the meanings set forth throughout this specification.

[0056] In this specification, including the attached embodiments, the singular form of words such as "a," "an," and "the" The form is the plural form of the corresponding word unless otherwise explicitly indicated by the context. To include the target.

[0057] "Or" is used unless explicitly indicated otherwise by the context, and the term "and / or" It is used to mean "or" and is used synonymously with "and / or".

[0058] The term "alkyl" refers to a group of elements ranging from 1 to 18, for example, 1 to 12, or even 1 to 10. More specifically, a straight carbon atom containing, for example, 1 to 8, 1 to 6, or 1 to 4 This refers to hydrocarbon groups selected from chain-like and branched saturated hydrocarbon groups. It consists of 1 to 6 carbon atoms. Alkyl alkyl groups containing children (i.e., C 1~6 Examples of alkyl groups include methyl, ethyl, and 1 -propyl, i.e., n-propyl ("n-Pr"), 2-propyl, i.e., isopropyl (i-Pr), 1-butyl, i.e., n-butyl (n-Bu), 2-methyl-1- Propyl, i.e., isobutyl ("i-Bu"), 1-methylpropyl, i.e., sec-bu t-butyl ("sec-Bu"), 1,1-dimethylethyl, i.e., t-butyl ("t-Bu") ), 1-Pentyl, 2-Pentyl, 3-Pentyl, 2-Methyl-2-butyl, 3-methyl -2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2- Hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4- Methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3 Examples include dimethyl-2-butyl and 3,3-dimethyl-2-butyl groups, but these It is not limited to that.

[0059] The term "cycloalkyl" refers to monocyclic groups and condensation, crosslinking, or spirocycloalkyl groups. Selected from saturated cyclic hydrocarbon groups including polycyclic (e.g., bicyclic and tricyclic) groups. It refers to a hydrocarbon group.

[0060] The term "aryl," used alone or in combination with other terms, can be selected from the following: It refers to the base that is used. • Five-membered and six-membered carbocyclic aromatic rings, e.g., phenyl, • At least one ring is a carbocyclic and aromatic system, for example, naphthyl and indanyl. , a 7-12 member bi-ring system, and • At least one ring is a carbocyclic and aromatic system, e.g., fluorenyl, 10~ Tricyclic ring systems, such as 15-membered tricyclic ring systems.

[0061] The terms “aromatic hydrocarbon ring” and “aryl” are used synonymously throughout this disclosure. It is used. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring is 5 It has ~10 ring-forming carbon atoms (i.e., C 5~10 Aryl). Single ring or double ring. Examples of cyclic aromatic hydrocarbon rings include phenyl, naphthal-1-yl, and naphthal-2-yl. Examples include anthracenyl and phenantrenyl, but the work is not limited to these. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthal-1-yl Alternatively, it is a naphthal-2-yl ring or a phenyl ring. In some embodiments, The aromatic hydrocarbon ring is a phenyl ring.

[0062] The term "aryl-alkyl-" refers to a compound further substituted with an aryl group, as defined above. This refers to an aryl-alkyl group. An example of an aryl-alkyl group is aryl-C 1~8 a Examples of methyl compounds include phenylethyl or phenylmethyl (benzyl).

[0063] The term "heteroaryl" refers to a group selected from the following: • At least one heterogen selected from nitrogen (N), sulfur (S), and oxygen (O) Children, for example, 1 to 4, or in some embodiments, 1 to 3, several fruits In its application form, it contains 1-2 heteroatoms, and the remaining ring atom is carbon, 5, 6, and It is a 7-membered aromatic monocyclic ring. • At least one heteroatom selected from N, O, and S, for example, 1 to 4, Or, in some embodiments, 1 to 3, in some embodiments, 1 to 2 A 7-12 membered bicyclic ring containing a heteroatom, with the remaining ring atom being carbon, and at least The above is a ring in which another ring is aromatic and at least one heteroatom is present in the aromatic ring. Biring ring, and • At least one heteroatom selected from N, O, and S, for example, 1 to 4, Or, in some embodiments, 1 to 3, or in other embodiments, 1 or It was an 11-14 member tricyclic ring containing two heteroatoms and the remaining ring atom being carbon. Furthermore, at least one ring is aromatic, and at least one heteroatom is present in the aromatic ring. The above three rings exist.

[0064] If the total number of S atoms and O atoms in the above heteroaryl group exceeds 1, The atoms are not adjacent to each other. In some embodiments, the S in the heteroaryl group The total number of atoms and oxygen atoms is 2 or less. In some embodiments, in an aromatic heterocycle The total number of S atoms and O atoms is 1 or less. Two or more heteroaryl groups are heteroatomic rings. If a member is included, the heteroatoms may be the same or different. The nitrogen atom in the ring(s) of the aryl group may be oxidized to form an N-oxide. The term "C-bonded heteroaryl" as used herein means that the above heteroaryl group is This means that the heteroaryl ring is bonded to the core molecule by a bond from the carbon atom. .

[0065] The terms "aromatic heterocycle" and "heteroaryl" are synonymous throughout this disclosure. It is used. In some embodiments, monocyclic or bicyclic aromatic heterocycles are used. It has 7, 8, 9, or 10 ring-forming members, and contains nitrogen (N), sulfur (S), and oxygen (O). It comprises 1, 2, 3, or 4 heteroatom ring members independently selected from ), and the remaining ring members are It is carbon. In some embodiments, the monocyclic or bicyclic aromatic heterocycle is nitrogen One or two heterogenes independently selected from element (N), sulfur (S), and oxygen (O) It is a monocyclic or bicyclic ring containing sub-ring members. In some embodiments, the above monocyclic ring... Alternatively, a bicyclic aromatic heterocyclic ring is a 5-6 membered heteroaryl ring, while the above ring is monocyclic, and nitrogen One or two heteroatoms independently selected from element (N), sulfur (S), and oxygen (O). It has ring members. In some embodiments, the monocyclic or bicyclic aromatic heterocyclic ring is It is an 8-10 membered heteroaryl ring, and the above ring is bicyclic, consisting of nitrogen, sulfur, and oxygen. It has one or two independently selected heteroatom ring members.

[0066] "heterocyclyl", "heterocyc "le)" or "heterocyclic" are synonymous, and as ring members It contains one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur. The remaining ring members are carbon, and include monocyclic rings, fused rings, bridging rings, and spiro rings, in other words monocyclic heterocyclyl, cross-linked heterocyclyl, spiroheterocyclyl, and condensed heterocyclyl This refers to a non-aromatic heterocyclyl group containing a cyclic group. In this specification, the term "optionally acidic" is used. "Sulfurized sulfur" refers to S, SO, or SO2.

[0067] The compounds disclosed herein may contain a chiral center and therefore have enantiomers. They may exist. "Enantiomers" are mirror images that cannot be superimposed on each other. This refers to two stereoisomers of a compound. The compounds disclosed herein have two or more chiral centers. In that case, they may also exist as diastereomers. Enantiomers and diastereomers Omars belong to a broader group of stereoisomers. They are essentially pure, divided enantiomers, and All such possible stereochemistry as a racemic mixture of these, as well as a mixture of diastereomers. Isomers are intended to be included. Compounds disclosed herein and / or pharmaceutically acceptable It is intended that all stereoisomers of the salt being accepted are included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the compound is not specified, all possible isomers are included.

[0068] As used herein, the term "substantially pure" means that the stereoisomer of interest is 35 times pure. Amount exceeding % by weight, for example exceeding 30% by weight, and even more, for example exceeding 25% by weight, still Furthermore, it must not contain, for example, more than 20% by weight of any other stereoisomer(s). Meaning. In some embodiments, the term “substantially pure” means the intended stereotype. Isomers exceed 10% by weight, for example, exceed 5% by weight, for example, exceed 1% by weight, This means that it does not contain any other stereoisomers(s).

[0069] If a compound disclosed herein contains an olefinic double bond, unless otherwise specified, Such a double bond means that both E and Z geometric isomers are present.

[0070] If the compounds disclosed herein contain a disubstituted cyclohexyl group or a cyclobutyl group, Substituents present on the cyclohexyl ring or cyclobutyl ring are cis and trans. It may also take a cis conformation. The cis conformation is when both substituents are substituted on two carbon atoms. Trans means that the group is located on the upper side of the arrangement, whereas the two substituents are opposite each other. It means being on the side that does the action.

[0071] It can be advantageous to separate multiple reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is obtained by techniques common in the art. The mixture is then separated and / or purified to the desired degree of homogeneity (hereinafter referred to as "separated"). Generally, such separations are performed by multiphase extraction, crystallization from a solvent or solvent mixture, or distillation. This includes sublimation or chromatography. Chromatography can be, for example, reversed-phase and forward-phase. Phase chromatography; size exclusion chromatography; ion exchange chromatography Methods and apparatus for high, medium, and low-pressure liquid chromatography; small-scale analytical chromatography Raffy; Simulated Moving Bed ("SMB") Chromatography and Preparative Thin- or Thick-Layer Chromatography Mathography; as well as small-scale thin-layer chromatography and flash chromatography. It may include any number of methods, including the technique of [name of technique]. Those skilled in the art will know how to achieve the desired separation. The technique with the highest probability of success will be applied.

[0072] A "diastereomer" is a compound that has two or more chiral centers, but they are not mirror images of each other. This refers to the stereoisomers of a compound. Diastereomer mixtures can be chromatographed and / or By methods well known to those skilled in the art, such as fractional crystallization, the individual diastereoes of the above mixture Based on the physicochemical differences of the diastereomers, they can be separated into the individual diastereomers described above. The enantiomers are appropriate optically active compounds (e.g., chiral alcohols or moscheric acid). Diastereomer mixing of enantiomers (such as chlorides) through reaction with chiral auxiliaries. Convert into a substance, separate the diastereomers, and obtain the corresponding pure mirror image of each diastereomer. They can be separated by converting them to isomers (for example, by hydrolysis). The substances can also be separated using a chiral HPLC column.

[0073] "Pharmacologically acceptable salt" means a salt that, within the bounds of sound medical judgment, does not have excessive toxicity, irritation, or Suitable for use in contact with human and lower animal tissues without causing allergic reactions, etc. This refers to a salt that is commensurate with the rational benefit / risk ratio. A pharmaceutically acceptable salt is one disclosed herein. During the final isolation and purification of the compound, free basic functional groups are appropriately removed in-situ or separately. By reacting with an appropriate organic acid, or by reacting an acidic group with an appropriate base It can be manufactured in this way.

[0074] When added to obtain the compounds disclosed herein as acid addition salts, the free base is It can be obtained by basicizing a solution of an acid salt. Conversely, if the product is a free base In some cases, the above liberation is achieved by following conventional procedures for producing acid addition salts from base compounds. By dissolving the base in an appropriate organic solvent and / or water, and treating this solution with acid, Addition salts, for example, pharmaceutically acceptable addition salts can be produced. Those skilled in the art will know that It can be used without conducting any experiments to produce non-toxic, pharmaceutically acceptable addition salts. Let's become aware of the various synthesis methodologies available.

[0075] As defined herein, “a pharmaceutically acceptable salt thereof” means at least one of formula (I) Salts of the compound, and salts of stereoisomers of the compound of formula (I), such as salts of enantiomers, and / or It includes diastereomer salts.

[0076] The terms “administer,” “to administer,” “to treat,” and “to treat” as used herein mean: When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, Exogenous pharmaceuticals, therapeutics, or therapeutics for animals, humans, subjects, cells, tissues, organs, or biological fluids. This means contact with a diagnostic agent or composition. Cell treatment is contact with the above-mentioned cells, Furthermore, it includes the contact of reagents with fluids that are in contact with the cells mentioned above. "Administering" and "treatment" also refer to in vitro and ex vivo procedures, such as cell administration, reagents, This also means treatment with diagnostic agents, binding compounds, or other cells. The word "object" refers to any living organism, preferably an animal, more preferably a mammal (e.g., a rat). These are mice, dogs, cats, and rabbits, and most preferably humans.

[0077] The term "effective dose" or "therapeutic effective dose" refers to the clinical symptoms of a disease or disorder. When administered to a target to treat at least one of the above diseases, disorders, or symptoms, This refers to the amount of active ingredients, such as compounds, that are sufficient to influence such treatment. The therapeutically effective dose is the above compound, the above disease, disorder, and / or the symptoms of the above disease or disorder. Condition, the above-mentioned disease, disability, and / or symptoms of the above-mentioned disease or disability, the year for which treatment is sought This may vary depending on age and / or the weight of the person receiving treatment. The appropriate quantity in the example may be obvious to a person skilled in the art, or can be determined by conventional experimentation. It can be determined by... In some embodiments, the "therapeutic effective dose" is... To treat the disease or disorder as defined above, with less than the disclosure herein. Each of the following is a compound and / or at least one stereoisomer thereof, and / or This is also the amount of that salt that is pharmaceutically acceptable. In the case of combination therapy, the "therapeutic effective dose" is This refers to the total amount of substances used in combination for the effective treatment of a disease, disorder, or illness.

[0078] A pharmaceutical composition comprising the compounds disclosed herein is administered orally to a subject requiring the composition. It can be administered by inhalation, rectal administration, parenteral administration, or topical administration. In this case, the above pharmaceutical composition is a standard solid dosage form, such as tablets, powders, granules, or capsules. Liquid preparations such as water or oil suspensions, or syrups, solutions, and suspensions. It may be other liquid formulations such as drugs; in the case of parenteral administration, the above pharmaceutical composition may be a solution, water-soluble It may be a liquid, an oil suspension concentrate, a freeze-dried powder, etc. The above formulation of the pharmaceutical composition is Preferably, tablets, coated tablets, capsules, suppositories, nasal sprays, or injections, more preferably Alternatively, it may be selected from tablets or capsules. The above pharmaceutical composition is a single, precise dose. It may be administered in units. By adding, the above pharmaceutical composition further contains further active ingredients. That's fine.

[0079] All formulations of the pharmaceutical compositions disclosed herein shall be manufactured by conventional methods in the pharmaceutical field. For example, an active ingredient can be mixed with one or more excipients, and then a desired formulation can be manufactured. It is possible. A "pharmaceutically acceptable excipient" is a conventional excipient suitable for the desired pharmaceutical formulation. Pharmaceutical carriers, for example, vehicles such as diluents, water, and various organic solvents, starch, sucrose, etc. Which fillers; cellulose derivatives, alginates, gelatin, and polyvinylpyrrolidone ( Binders such as PVP; humectants such as glycerin; agar, calcium carbonate, and sodium bicarbonate. Disintegrants such as thorium; absorption enhancers such as quaternary ammonium compounds; hexadecanol Surfactants such as; absorbent carriers such as kaolin and soap clay; Talc, calcium stearate, magnesium stearate, polyethylene glycol This refers to lubricants such as those mentioned above. When added, the above pharmaceutical composition contains dispersed agents, stabilizers, thickeners, Other substances such as complexing agents, buffering agents, penetration enhancers, polymers, aromatic compounds, sweeteners, and colorants. It further contains pharmaceutically acceptable excipients.

[0080] The term "disease" refers to any illness, discomfort, disease, symptom, or sign, while the term "disorder" refers to any disease, discomfort, illness, symptom, or sign. Alternatively, it can be considered synonymous with "disease."

[0081] Throughout this specification and subsequent embodiments, unless otherwise necessary in the context, the term "including" will not be used. "comprise", and "comprises", and "comp Variations such as "rising)" are intended to identify the presence of the feature that follows. This does not preclude the presence or addition of one or more other features used herein. In this case, the term "comprising" is the same as the term "containing". "Includes," and in some cases, "having" can be used as alternatives. It is possible to obtain it.

[0082] Throughout this specification and subsequent embodiments, the term "C" is used. n~m " means that n and m are integers This indicates the number of carbon atoms and the range including the endpoints. For example, C 1~8 , C 1~6 Examples include It can be done.

[0083] Unless otherwise defined elsewhere in this document, all other technologies used herein Terms and scientific terms are defined in the sense generally understood by those skilled in the art to which this invention pertains. It holds.

[0084] General synthesis The compounds disclosed herein (including their salts) are prepared using known organic synthesis techniques. It can be synthesized according to one of a number of possible synthesis routes.

[0085] The reactions for producing the compounds disclosed herein can be easily selected by those skilled in organic synthesis. The reaction can be carried out in any suitable solvent that can be selected. A suitable solvent is one that is warm enough for the reaction to take place. At a temperature that may be, for example, a range from the boiling point of the solvent, the starting material, the intermediate, and The solvent may be substantially inactive with the product. A given reaction can be carried out in a single solvent or multiple solvents. This can be done in a mixture of the following.

[0086] The selection of a suitable protective group can be easily determined by a person skilled in the art.

[0087] The reaction can be carried out by any and appropriate method known in the art, such as NMR, UV, HPLC, L The compound can be monitored by C-MS and TLC. It can be purified by various methods, including silica chromatography.

[0088] Scheme I [ka] The compound of formula (I) can be prepared as shown in scheme I. Compound (ii) is obtained by nucleophilic substitution between iron and compound (i), followed by the addition of iron as a medium. Compound (iii) is obtained by reductive cyclization. Compound (iii) is converted to borane. The compound was converted to compound (iv) by further mediated reduction. The compound was converted in a 3-step procedure. (vi) was obtained. Subsequently, the compound was obtained by Negishi or Suzuki coupling. vii) was obtained. Deprotection and subsequent acylation yielded compound (ix). Compound (ix) was reacted with the main intermediate (x) to obtain compound (xi). Finally, deprotection was performed. Thus, compound (xii), represented by formula (I), was obtained.

[0089] Scheme II [ka] The compound of formula (I) can also be synthesized as shown in scheme II. Compound (ii) was obtained by nucleophilic substitution between i) and the Boc-protected amino alcohol. Compound (iii) is obtained by CN coupling mediated by Cu or Pd, Next, compound (iv) is obtained by Negishi or Suzuki coupling. Compound (v) was obtained by protection. Compound (v) was reacted with 2-chloroacetyl chloride. Compound (vi) was obtained by reacting compound (vi) with the main intermediate (vii) to form compound (vi). (viii) was obtained. Finally, deprotection was performed to obtain compound (ix) represented by formula (I).

[0090] Abbreviation JPEG0007840512000032.jpg226161 [Examples]

[0091] Example 1: 7-(4-fluorobenzyl)-1-(2-((2R,5R)-5-methyl- 2-(((R)-3-methylmorpholino)methyl)piperazine-1-yl)acetyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carbonite Rylgate (Compound 1) [ka] Step 1: 2-((5-bromo-3-nitropyridine-2-yl)oxy)ethyl acetate [ka] 5-Bromo-2-chloro-3-nitropyridine (20g, 84.2 mmol) and 2- A solution of hydroxyethyl acetate (9.6 g, 92.6 mmol) in anhydrous THF (100 mL). Then, slowly add NaH (4.4g, 60% dispersion in mineral oil, 109.5 mmol) at 0°C. The mixture was then added. The resulting solution was stirred at room temperature for 1 hour. This reaction mixture was then diluted with water (20 mL). Quenched and extracted with HCl (100 mL x 3). The combined organic layer was then Na2 Dehydration was performed on SO4, followed by filtration and removal under vacuum. The residue was then subjected to silica gel chromatography. The above product was obtained by purification using PE:siRNA (10:1) (13g, yield 51%). ) LC-MS(M+H) + =305.0, 307.0.

[0092] Step 2: 7-bromo-1H-pyrido[2,3-b][1,4]oxazine-2(3H )-on [ka] 2-((5-bromo-3-nitropyridine-2-yl)oxy)ethyl acetate (13g, In a 300 mL solution of 42.6 mmol AcOH, add 13 g of Fe powder (23) at 70°C. 2 mmol of AcOH was slowly added, and the resulting mixture was stirred at 70°C for 1 hour. The substance was removed under vacuum, and the resulting solid was washed with MeOH (200 mL) and filtered. The procedure was repeated five times. The MeOH phase was concentrated in vacuum to obtain the crude product (9.6 g, yield With a success rate of 98%, this was used directly in the next step: LC-MS(M+H). + = 228 .9, 230.9.

[0093] Step 3: 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4] Kisajin [ka] 7-Bromo-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-one In a 150 mL solution of anhydrous THF (9 g, 39.3 mmol), BH3 (98.3 mmol) was added at room temperature. The solution was added dropwise (mL of 1N THF solution) and stirred at 60°C for 1 hour. The mixture was cooled to room temperature, quenched with MeOH (10 mL), and then 1N HCl was added. The pH was adjusted to 1-2 and stirred at 60°C for 1 hour. The reaction mixture was then cooled to room temperature. Add water (100 mL) and adjust the pH to 8-9. This mixture was then mixed with HCl (100 mL). Extract with 3 mL of solution, combine the organic layers, dehydrate them on Na2SO4, filter, and remove under vacuum. The crude product was obtained by distillation (7.46 g, 88% yield), which was then used directly in the next step. . LC-MS (M+H) + = 215.1, 217.1.

[0094] Step 4: 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4] tert-butyl xazine-1-carboxylate [ka] 7-Bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine ( 6.9g, 32mmol), (Boc)2O(10.5g, 48mmol), DMAP( THF (20) of 3.9g, 32 mmol, and Et3N (6.46g, 64 mmol) The 0 mL solution was stirred at room temperature for 12 hours. The reaction mixture was washed with water (100 mL). The organic layer was extracted with HCl (100 mL x 3) and then dehydrated on Na2SO4. The residue was filtered and removed by distillation under vacuum. The residue was then subjected to silica gel chromatography (PE:EtOA). The above product was obtained by purification using c=5:1 (9g, 90% yield). LC-MS (M+H) + = 315.2, 317.2.

[0095] Step 5: 7-Bromo-1-(tert-butoxycarbonyl)-2,3-dihydro 1H-Pyrido[2,3-b][1,4]oxazine 5-oxide [ka] 7-Bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-carboxylic acid (7g, 22.2 mmol) in a DCM (200mL) solution at room temperature, 3- Add tert-butyl chlorobenzoperoxoate (11.5g, 66.67 mmol). The resulting mixture was stirred at 50°C for 18 hours. The reaction mixture was then cooled to room temperature and solidified. Remove the solids, wash with saturated NaHCO3 aqueous solution (100 mL), and then DCM (100 mL × 3) The organic layer extracted and combined was dehydrated, filtered, and concentrated. The residue was then stored in silica gel. The above product was obtained by purification using chromatography (DCM:MeOH=20:1). (5.8g, yield 78.8%). LC-MS (M+H) + = 331.1, 333.1 .

[0096] Step 6: 7-bromo-6-cyano-2,3-dihydro-1H-pyrido[2,3-b] [1,4] tert-butyl oxazine-1-carboxylate [ka] 7-Bromo-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyri M of [2,3-b][1,4]oxazine 5-oxide (2.9g, 8.8mmol) In 100 mL of eCN solution, under N2 conditions at room temperature, TMSCN (13.04 g, 131.4 ml) was added. (mol) was added, and the resulting solution was stirred at 80°C for 12 hours. This reaction mixture was then subjected to vacuum. The residue was concentrated and then subjected to silica gel chromatography (DCM:MeOH=50:1). The above product was obtained by purification (715 mg, yield 24%). LC-MS(M+H) + = 340.2, 342.2.

[0097] Step 7: 6-Cyano-7-(4-Fluorobenzyl)-2,3-Dihydro-1H-P Lido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] 7-Bromo-6-cyano-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazine-1-carboxylate tert-butyl (715 mg, 2.1 mmol) and bis (Tri-tert-butylphosphine)palladium (54 mg, 0.11 mmol) (4-Fluorobenzyl)zinc(II) chloride (8.4mg) in a 100mL aqueous THF solution. Add 4.2 mmol of 0.5 M THF solution dropwise, and incubate the resulting solution at 60°C for 2 hours. The mixture was stirred. The reaction mixture was quenched with MeOH (5 mL), concentrated under vacuum, and the residue was collected. Purified by silica gel chromatography (PE:dimethyl=5:1), the above raw The product was obtained (470 mg, 61% yield). LC-MS (M+H) + = 370.4.

[0098] Step 8: 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3 -b][1,4]oxazine-6-carbonitriel [ka] 6-Cyano-7-(4-Fluorobenzyl)-2,3-Dihydro-1H-Pyrido[2, 3-b][1,4]oxazine-1-carboxylate tert-butyl (360 mg, 0.9 Add 1,4-dioxane solution (4N, 2) of HCl to 10 mL of DCM solution (8 mmol). 0.5 mL (10 mmol) was added, and the resulting solution was stirred at room temperature for 12 hours. The mixture was concentrated in a vacuum. This mixture was neutralized with an aqueous solution of NaHCO3 and extracted with ethylacetate. The combined organic layer was dehydrated, filtered, and concentrated to obtain the marked compound (260 mg, yield rate 99%). LC-MS (M+H) + = 270.4.

[0099] Step 9: 1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine-6-carbonitrile [ka] 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]Oxazine-6-carbonitride (100 mg, 0.37 mmol) and Et3N 2-chloroacetate (99 mg, 0.98 mmol) in a 10 mL solution of MeCN at room temperature Add tyl chloride (111 mg, 0.98 mmol), and the resulting solution was left at room temperature for 12 hours. The solution was stirred. This solution was concentrated under vacuum, and the residue was separated by TLC (DCM:MeOH=20: The product was purified by (1) to obtain the labeled product (68 mg, yield 53%). LC-MS (M +H) + = 346.3.

[0100] Step 10: Methyl((benzyloxy)carbonyl)-L-ceryl-D-alaninate ト(methyl ((benzyloxy)carbonyl)-L-seryl-D -alaninate) [ka] Cooled (R)-2-aminopropionate methyl hydrochloride (20g, 143. 2 mmol), EDC (33 g, 171.8 mmol), ((benzyl oxy)carbon A mixture of (L)-L-serine (34.3g, 143.2mmol) and DCM (700mL) DIEA (36.9 g, 286.4 mmol) was added dropwise to the mixture. The resulting mixture was then nitrated. The mixture was stirred at ambient temperature for 16 hours under an ambient atmosphere. The mixture was concentrated, and the residue was saturated with sodium carbonate. The solution was diluted with water and extracted with HCl. The combined organic layer was dissolved in 2M HCl. The solution was washed with saturated saline solution, dehydrated on Na2SO4, and concentrated to obtain the above product (2 0g, yield 43%). LC-MS (M+H) + = 325.1.

[0101] Step 11: (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2 ,5-Zeon [ka] Under nitrogen, methyl((benzyloxy)carbonyl)-L-ceryl-D-alaninate (10g, 30.8mmol) contains 10% Pd / C (500mg), MeOH (100 (mL) and cyclohexene (65 mL) were added. This mixture was heated under reflux, and this temperature The mixture was stirred overnight at [temperature]. The reaction mixture was filtered through Celite, and the cake was heated to [temperature] MeOH. Washed with [method]. The combined filtrate was concentrated. The resulting solid was slurryed in 2-butanone. The mixture was then converted to a 10-minute mixture, and petroleum ether was gradually added over 10 minutes. After stirring for 30 minutes, the solid was removed. The cake was filtered and further washed with a PE / 2-butanone (v / v=2 / 1) mixture. The above product was obtained by drying (2.5 g, yield 51%). LC-MS(M+H) + = 159.1.

[0102] Step 12: ((2R,5R)-5-methylpiperazine-2-yl)methanol hydrochloride [ka] (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione (2.5g, 15.8mmol) to which borane THF solution (1M, 126mL, 126. 4 mmol) was added and heated at 70°C for 18 hours. This solution was cooled on ice, and then M eOH (30 mL) was gradually added, followed by 5N HCl (8 mL). The mixture was heated at 70°C for 2 hours, then cooled to room temperature. The resulting solid was filtered, and TH was removed. The product was washed with F and dried to obtain the above product (2.0 g, yield 77%). LC-MS(M+ H) + = 131.1.

[0103] Step 13: (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1 -Tert-butyl carboxylate [ka] ((2R,5R)-5-methylpiperazine-2-yl)methanol hydrochloride (2g) at 0℃ In a 20 mL solution of MeOH (12.0 mmol), add TEA (3.6 g, 36.0 ml) (ol) was added. Then (Boc)2O (6.3g, 28.8 mmol) was added dropwise. The resulting mixture was slowly heated to room temperature and then heated overnight at 50°C. The solution was concentrated, and the residue was dissolved in ethanol (40 mL). NaOH (2.4 g, 60 mmol) Add a 40 mL solution of water to the mixture, heat the reaction mixture at 100°C for 18 hours, and then The mixture was cooled to ambient temperature. This mixture was neutralized to pH approximately 9 with 1N HCl, and then treated with DCM. Extraction was performed. The combined organic layer was dehydrated, filtered, and concentrated to obtain the indicated product (1. 6g, yield 58%). LC-MS (M+H) + = 231.1.

[0104] Step 14: (2R,5R)-4-benzyl-5-(hydroxymethyl)-2-methyl tert-butyl piperazine-1-carboxylate [ka] (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl (1.6g, 6.9mmol), benzaldehyde (805mg, 7. 6 mmol), sodium triacetoxyborohydride (1.8 g, 8.5 mmol), The mixture of sodium and DCM (30 mL) was stirred overnight at room temperature. Then, saturated Na was added to the mixture. The mixture was partitioned between HCO3 solution and DCM. The combined organic layer was dehydrated, filtered, and concentrated. It shrunk. The residue was subjected to silica gel column chromatography (DCM:MeOH=20:1). Therefore, the product was purified to obtain the labeled product (2.0 g, 90% yield). LC-MS(M+H) + = 321.2.

[0105] Step 15: (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpipette tert-butyl radin-1-carboxylate [ka] (2R,5R)-4-benzyl phosphate containing TEA (2.6 mL, 18.4 mmol) at 0°C. 5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-buty In a 30 mL solution of DCM containing 2.0 g, 6.2 mmol of methanesulfonyl chloride, (0.6 mL, 7.4 mmol) was added. This mixture was stirred overnight at room temperature. The reaction mixture was partitioned between NH4Cl solution and DCM. The combined organic layer was then dehydrated. The crude material was filtered and concentrated. The crude material was subjected to silica gel column chromatography (PE:EtOA). The product was purified by LC-M (c=3:1) to obtain the labeled product (1.4g, yield 67%). S (M+H) + = 339.2.

[0106] Step 16: (2R,5S)-4-benzyl-2-methyl-5-(((R)-3-meth (Lumorpholino)methyl)piperazine-1-carboxylate tert-butyl [ka] (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1- MeCN (20 mL) solution of tert-butyl carboxylate (1.4 g, 4.1 mmol) , K2CO3 (1.7g, 12.3mmol), KI (1.4g, 8.4mmol), And (R)-3-methylmorpholine (630 mg, 6.2 mmol) was added. This mixture The mixture was stirred overnight at 70°C. The solids were filtered off, and the filtrate was concentrated. The residue was mixed with water and DCM. The layers were divided amongst themselves. The combined organic layer was dehydrated, filtered, and removed by distillation. The crude residue was siliceous. Purified by DCM:MeOH=40:1, the above raw The product was obtained (1.3g, 78% yield). LC-MS (M+H) + = 404.3.

[0107] Step 17: (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino) Methyl)piperazine-1-carboxylate tert-butyl [ka] (2R,5S)-4-benzyl-2-methyl-5-(((R)-3-methylmorpholino )Methyl)piperazine-1-carboxylate tert-butyl (1.3g, 3.2mmol) To a 20 mL EtOH (EtOH) solution, carefully add Pd / C (130 mg) and a few drops of AcOH. It was added. This mixture was stirred under an H2 atmosphere at ambient temperature for 3 hours. This mixture was concentrated. The organic layer was extracted using DCM. The combined organic layer was washed with saturated NaHCO3 solution and dehydrated. The compound was filtered and concentrated. The resulting labeled compound (1.0 g) was then taken to the next step without purification. Used. LC-MS (M+H)+ = 314.2.

[0108] Step 18: (2R,5S)-4-(2-(6-cyano-7-(4-fluorobenzyl )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl) -2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl) tert-butyl piperazine-1-carboxylate [ka] 1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2,3-dihydro-1 H-Pyrido[2,3-b][1,4]oxazine-6-carbonitrile (68mg, 0. 196 mmol), (2R,5S)-2-methyl-5-(((R)-3-methylmorphol (62 mg, 0.196 mg) methylpiperazine-1-carboxylate tert-butyl ol), KI (65 mg, 0.392 mmol), and K2CO3 (81 mg, 0.58 mmol) A solution of 8 mmol) of MeCN (10 mL) was stirred at room temperature for 2 hours. This reaction mixture was then... The solvent is removed by concentrating in air, and the residue is washed with H2O (10 mL). Extraction was performed using L×3). The combined organic layer was concentrated and preparatively separated by TLC (DCM:MeOH= The compound was purified by 20:1) to obtain the marked compound (80 mg, yield 65.5%). LC- MS (M+H) + = 623.7.

[0109] Step 19: 7-(4-fluorobenzyl)-1-(2-((2R,5R)-5-meth Ru-2-(((R)-3-methylmorpholino)methyl)piperazine-1-yl)acetyl )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carb Nitrile formate (Compound 1) (2R,5S)-4-(2-(6-cyano-7-(4-fluorobenzyl)-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxo Ethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- DCM (10 mL) of tert-butyl 1-carboxylate (80 mg, 0.128 mmol) Add a 1,4-dioxane hydrochloride solution (4N, 2.5 mL) to the solution, and obtain the solution The mixture was stirred at room temperature for 4 hours. This solution was concentrated under vacuum and dissolved in MeOH (10 mL). The pH is adjusted to 8-9 by adding an aqueous solution of NaHCO3, and then concentrated in a vacuum to remove the solvent. Remove and separate the residue using HPLC (gradient eluent: 10%~25% CH3CN / H2O ( The two are purified with 0.1% formic acid (FA) to obtain compound 1 as formate. (30 mg, yield 41%). 1 1HNMR (400 MHz, DMSO-d6) δ 1 1.31 - 9.78 (m, 1H), 8.63 (s,1H), 8.26 (s, 2 H), 7.31 - 7.22 (m, 2H), 7.22- 7.11 (m, 2H), 4.53 - 4.34(m, 2H), 4.17 -3.79 (m, 6H), 3.5 2 - 3.31 (m, 2H), 3.26 - 2.53(m, 10H), 2.23 - 2.09 (m, 1H), 2.04 - 1.92(s, 1H), 1.91 - 1 .78 (m, 1H), 1.08 - 1.01 (m,3H), 0.90 - 0.82 (m, 3H). LC-MS(M+H) + = 523.5.

[0110] Example 2: 1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-((2R,5R)-5-methyl-2 -(((R)-3-methylmorpholino)methyl)piperazine-1-yl)ethane-1-ol Foritate (compound 2) [ka] Step 1: 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3 -b][1,4] tert-butyl oxazine-1-carboxylate [ka] The marked compound (1.56 g) from Step 1 was prepared in the same manner as described in Step 7 of Example 1. In this method, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy tert-butyl sazin-1-carboxylate and zinc (4-fluorobenzyl) chloride (II Prepared from LCMS (M+H). + = 345.2.

[0111] Step 2: 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3 -b][1,4]oxazine [ka] The marked compound (100 mg) from Step 2 was prepared in the same manner as described in Step 8 of Example 1. In this method, 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3- Prepared from [1,4]oxazine-1-carboxylate tert-butyl. LC-MS (M+H) + = 245.2.

[0112] Step 3: 2-Chloro-1-(7-(4-fluorobenzyl)-2,3-dihydro-1 H-Pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one [ka] Step 3: The indicated compound (80 mg) is prepared in the same manner as described in Step 9 of Example 1. By this method, 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b Prepared from [1,4]oxazine and 2-chloroacetyl chloride. LC-MS ( M+H) + = 321.1.

[0113] Step 4: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoye (Tyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1 -Tert-butyl carboxylate [ka] The marked compound (80 mg) in Step 4 is prepared in the same manner as described in Step 18 of Example 1. By this method, 2-chloro-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H -Pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one and (2R ,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- Prepared from tert-butyl 1-carboxylate. LC-MS(M+H) + = 598. 6.

[0114] Step 5: 1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[ 2,3-b][1,4]oxazin-1-yl)-2-((2R,5R)-5-methyl- 2-(((R)-3-methylmorpholino)methyl)piperazine-1-yl)ethane-1- Ongate (compound 2) Compound 2 (20 mg) is used as its formate, and the method is the same as in step 19 of Example 1. In the following way, (2R,5S)-4-(2-(7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoye (Tyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1 Prepared from tert-butyl carboxylate. 1 HNMR (400 MHz, DMSO -d6) δ 8.64 - 8.11 (s, 3H),7.85 (s, 1H), 7.3 0 - 7.19 (m, 2H), 7.18 - 7.04(m, 2H), 4.45 - 4.26 (m, 2H), 4.07 -3.71 (m,6H), 3.52 - 3.3 3 (m, 2H), 3.22 - 3.04 (m,2H), 3.03 - 2.59 ( m, 7H), 2.47 - 2.37 (m, 1H),2.21 - 2.07 (m, 1H), 2.04 - 1.91 (m, 1H), 1.89- 1.74 (m, 1H) , 1.02 (d, J = 5.8 Hz, 3H),0.91 - 0.74 (m, 3H ) LC-MS (M+H) + = 498.6.

[0115] Example 3: 7-(4-fluorobenzyl)-1-(2-((2R,5R)-5-methyl- 2-(((R)-3-methylmorpholino)methyl)piperazine-1-yl)acetyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carboxa Midoformate (Compound 3) [ka] Step 1: 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3 -b][1,4]oxazine-6-carboxamide [ka] 6-cyano-7-(4-fluorobene) in DMSO (6 mL) and H2O (10 mL) (zyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-ca Tert-butyl benzoate (680 mg, 1.84 mmol), KOH (1.55 g, 27.6 mmol) was added, and the resulting solution was stirred at 120°C for 12 hours. The solvent was then removed under vacuum. The residue is removed internally and purified by preparative TLC (DCM:MeOH=30:1) to the indicated value. The product was obtained (40 mg, 7.5% yield). LC-MS (M+H) + = 288.1.

[0116] Step 2: 7-(4-fluorobenzyl)-1-(2-((2R,5R)-5-methyl -2-(((R)-3-methylmorpholino)methyl)piperazine-1-yl)acetyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carboxy Samidofate (compound 3) Compound 3 (30 mg) was used as its formate in steps 9 and 18 of Example 1. In a similar manner to the method described in 19, 7-(4-fluorobenzyl)-2,3-dihydro- 1H-Pyrido[2,3-b][1,4]oxazine-6-carboxamide and (2R,5 S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1- Prepared from tert-butyl carboxylate. 1 HNMR (400 MHz, DMSO- d6) δ 10.26 - 8.03 (m, 4H),7.79 (s, 1H), 7.4 4 (s, 1H), 7.30 - 7.17 (m,2H), 7.14 - 6.99 ( m, 2H), 4.52 - 4.17 (m, 4H),4.13 - 3.72 (m, 4H), 3.54 - 3.29 (m, 2H), 3.17- 3.02 (m, 2H) , 3.01 - 2.76 (m, 4H), 2.73- 2.57 (m, 3H), 2 .48 - 2.35 (m, 1H), 2.21 -2.08 (m, 1H), 2.04 - 1.90 (m,1H), 1.88 - 1.71 (m, 1H), 1.05 - 0 .95 (m, 3H), 0.92 - 0.80 (m,3H). LC-MS (M+H) + = 541.6.

[0117] Example 4: 1-(6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-1H -Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R)-5 -methyl-2-(((R)-3-methylmorpholino)methyl)piperazine-1-yl) Tan-1-one (compound 4) [ka] Step 1: 6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-1H-p Lido[2,3-b][1,4]oxazine [ka] 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1 ,4] In a 15 mL solution of oxazine (612 mg, 2.51 mmol) in DMF, NB S (446 mg, 2.51 mmol) was added in small amounts at 0°C, and the resulting solution was prepared at room temperature. The mixture was stirred for 2 hours. Water (30 mL) was added, and this mixture was extracted with toluene (15 mL x 3). The organic layer was removed. The combined layer was dehydrated, filtered, and concentrated. The residue was subjected to silica gel chromatography. The product was purified by Graphy (DCM:MeOH = 50:1) to obtain the indicated product (35 0 mg, yield 43.2%. LC-MS (M+H) + = 323.0, 325.0.

[0118] Step 2: 6-Bromo-7-(4-Fluorobenzyl)-2,3-Dihydro-1H-P Lido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] 6-Bromo-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazine (350 mg, 1.1 mmol) dissolved in THF (10 mL) TEA (330 mg, 3.3 mmol) was added to the solution. This mixture was cooled to 0°C. Next, (Boc)2O (480 mg, 2.2 mmol) was added dropwise. This mixture was collected at room temperature. The mixture was stirred overnight. This mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography. The product was purified by (PE:Â=3:1) to obtain the marked product (300 mg, yield rate 64%). LC-MS (M+H) + = 423.1, 425.1.

[0119] Step 3: 1-(6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-1 H-Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R)- 5-Methyl-2-(((R)-3-methylmorpholinomethyl)piperazin-1-yl) Ethane-1-one (compound 4) Compound 4 as formate is described in steps 8-9 and 18-19 of Example 1. In a similar manner to the above method, 6-bromo-7-(4-fluorobenzyl)-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl) The salt was prepared from tert-butyl perazine-1-carboxylate. The salt was then prepared using an aqueous solution of NaHCO3. It was neutralized and extracted with HCl. The combined HCl layer was dehydrated and filtered to concentrate It shrunk. The residue was further freeze-dried to obtain compound 4 (27 mg) as a free base. 1 H NMR (400 MHz,DMSO-d6) δ 8.46 (s, 1H), 8.25 (s, 1H), 7.28 - 7.18 (m, 2H),7.17 - 7.09 (m, 2H), 4.52- 4.29 (m, 2H), 4.12 - 3.89 (m, 3H) ), 3.88 - 3.60 (m, 2H), 3.55- 3.09 (m, 4H), 3.08 - 2.58 (m, 7H), 2.45 -2.26 (m, 2H), 2.1 6 (s, 1H), 2.03 - 1.92 (m,1H), 1.85 - 1.73 ( m, 1H), 1.01 - 0.91 (m, 3H),0.91 - 0.74 (m, 3H). LC-MS (M+H) + = 576.5.

[0120] Example 5: 1-(7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-1H -Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R)-5 -methyl-2-(((R)-3-methylmorpholino)methyl)piperazine-1-yl) Tan-1-one (compound 5) [ka] Step 1: 7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-1H-p Lido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] 6-Bromo-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazine-1-carboxylate tert-butyl (300 mg, 0.7 1,4-Dioxy(0.9 mmol) and methylboronic acid (128 mg, 2.13 mmol) In a solution of Sun (20 mL) and H2O (5 mL), Pd(PPh3)4 (82 mg, 0. Add 0.71 mmol) and Cs2CO3 (699 mg, 2.15 mmol) and once obtained... The solution was stirred at 100°C for 12 hours. This reaction solution was cooled to room temperature and H2O(25%) was added. The mixture was washed with (mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was then treated with Na Dehydrated on 2SO4, concentrated in vacuum, and subjected to silica gel chromatography (PE:EtOA). The compound was purified by c=5:1 to obtain the marked compound (250 mg, 98% yield). LC- MS (M+H) + = 359.2.

[0121] Step 2: 1-(7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-1 H-Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R)- 5-Methyl-2-(((R)-3-methylmorpholinomethyl)piperazin-1-yl) Ethane-1-one (compound 5) Compound 5 as the formate is described in steps 8-9 and 18-19 of Example 1. In a similar manner to the above method, 7-(4-fluorobenzyl)-6-methyl-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl) The salt was prepared from tert-butyl perazine-1-carboxylate. The salt was then prepared using an aqueous solution of NaHCO3. It was neutralized and extracted with HCl. The combined HCl layer was dehydrated and filtered to concentrate It shrunk. The residue was further freeze-dried to obtain compound 5 (12.6 mg) as a free base. 1 H NMR (400 MHz, DMSO-d6) δ 8.49 -8.06 (m, 1 H), 7.21 - 7.03 (m, 4H), 4.45- 4.24 (m, 2H), 4.10 - 3.96(m, 2H), 3.92 - 3.84 (m, 2H), 3. 85 - 3.70 (m, 1H), 3.59 - 3.41(m, 3H), 3.29 - 3.15 (m, 1H), 3.07 - 2.65(m, 5H), 2.63 - 2 .53 (m, 2H), 2.31 - 2.18 (m,4H), 2.18 - 2.06 (m, 1H), 2.01- 1.84 (m, 2H), 1.78 - 1.65 (m , 1H), 1.00 - 0.66 (m, 6H). LC-MS(M+H) + = 51 2.3.

[0122] Example 6: 1-(6-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydr Lo-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5 R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine-1- Il-ethane-1-one (compound 6) [ka] Step 1: 6-Cyclopropyl-7-(4-Fluorobenzyl)-2,3-Dihydro 1H-Pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] 6-Bromo-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazine-1-carboxylate tert-butyl (73 mg, 0.17 Toluene (3 mmol) and cyclopropylboronic acid (22 mg, 0.258 mmol) In a solution of (10 mL) and H2O (5 mL), add Pd(OAc)2(2 mg, 0.009 mL). (mol) and tricyclohexylphosphine (5 mg, 0.018 mmol) and K3P Add O4 (109 mg, 0.518 mmol) and the resulting solution under N2 at 80°C. The mixture was stirred for 12 hours. This reaction solution was concentrated under vacuum to remove toluene, and then water (10 mL) was added. The layers were washed and extracted with HCl (10 mL x 3). The combined organic layer was then treated with Na2SO4. 4. Dehydrate, filter, and concentrate to obtain the crude product (78 mg), which is then further purified. It was used in the next step without any issues. LC-MS (M+H) + = 385.3.

[0123] Step 2: 1-(6-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydroxy Dro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R, 5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine-1 -yl)ethane-1-one (compound 6) Compound 6 as formate is described in steps 8-9 and 18-19 of Example 1. In a similar manner to the above method, 6-cyclopropyl-7-(4-fluorobenzyl)-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert -Butyl and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino) Prepared from tert-butyl (Tyl)piperazine-1-carboxylate. The above salt was prepared from NaH The mixture was neutralized with an aqueous CO3 solution and extracted with carboxylic acid. The combined organic layer was dehydrated and filtered. The compound was concentrated. The residue was further freeze-dried to obtain compound 6 (10 mg) as a free base. 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8. 29 (s, 1H), 7.26 - 7.16 (m,2H), 7.16 - 7.06 (m, 2H), 4.43 - 4.19 (m, 2H),4.12 - 3.92 (m, 4H), 3.82- 3.72 (m, 1H), 3.53 - 3.43 (m, 3H) ), 3.29 - 3.17 (m, 1H), 3.05- 2.78 (m, 2H), 2.77 - 2.63 (m, 3H), 2.61 -2.55 (m, 1H), 2.3 1 - 2.05 (m, 4H), 2.01 - 1.86(m, 2H), 1.80 - 1.66 (m, 1H), 0.95 - 0.66 (m,10H). LC-MS (M+ H) + = 538.4.

[0124] Example 7: 1-(7-(4-fluorobenzyl)-6-(trifluoromethyl)-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-(( 2R,5R)-5-methyl-2-(((R)-3-methylmorpholinomethyl)piperazi ¹-1-yl)ethane-1-one (compound 7) [ka] Step 1: 7-(4-fluorobenzyl)-6-(trifluoromethyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert- Butyl [ka] 6-Bromo-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazine-1-carboxylate tert-butyl (110 mg, 0.2 6 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (200 To a 5 mL solution of DMF (1.04 mmol) containing CuI (99 mg, 0.52 mg) The solution was then mixed with ol) and stirred at 120°C for 1 hour. The reaction solution was then cooled to room temperature. The solution was then washed with H2O (10 mL) and extracted with HCl (10 mL x 3). The preserved organic layer was dehydrated with Na2SO4, filtered, concentrated in a vacuum, and the residue was separated into silica gel. The product was purified by microchromatography (PE:alkyl = 5:1) to obtain the indicated product. (73 mg, yield 68%). LC-MS (M+H) + = 413.2.

[0125] Step 2: 1-(7-(4-fluorobenzyl)-6-(trifluoromethyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)pipera Zin-1-yl)ethane-1-one (compound 7) Compound 7 as the formate is described in steps 8-9 and 18-19 of Example 1. In a similar manner to the above method, 7-(4-fluorobenzyl)-6-(trifluoromethyl)- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl and (2R,5S)-2-methyl-5-(((R)-3-methylmorpho Prepared from tert-butyl lino(methyl)piperazine-1-carboxylate. The mixture was neutralized with an aqueous solution of aHCO3 and extracted with toluene. The combined organic layer was dehydrated and filtered. The mixture was then concentrated. The residue was further freeze-dried to obtain compound 7 (26.4 mg) as the free base. I obtained it. 1 H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H) , 7.27 - 7.05 (m, 4H), 4.53- 4.35 (m, 2H), 4 .16 - 3.95 (m, 4H), 3.92 -3.81 (m, 1H), 3.78 - 3.65 (m,1H), 3.53 - 3.37 (m, 2H), 3.19 - 3 .07 (m, 1H), 2.97 - 2.77 (m,4H), 2.76 - 2.57 (m, 3H), 2.47- 2.29 (m, 2H), 2.20 - 2.09 (m , 1H), 2.01 - 1.89 (m, 1H),1.83 - 1.73 (m, 1 H), 0.97 - 0.89 (m, 3H), 0.89- 0.80 (m, 3H). LCMS (M+H) + = 566.3.

[0126] Example 8: 1-(7-(4-fluorobenzyl)-6-(hydroxymethyl)-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2 R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine -1-yl)ethane-1-one (compound 8) [ka] Step 1: 1-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)- 6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine 5- Oxide [ka] The marked compound (1.2g) in Step 1 was prepared in the same manner as described in Step 5 of Example 1. By this method, 7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-1H-pyrid It was prepared from [2,3-b][1,4]oxazine-1-carboxylate tert-butyl. LC-MS (M+H) + = 375.2.

[0127] Step 2: 6-(acetoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydroxymethyl Dro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-b Chill [ka] 1-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-6-methyl -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine 5-oxide( A 1.2g (3.2 mmol) solution in Ac2O (20 mL) was stirred at 130°C for 3 hours. Cool this reaction solution to room temperature, add water (50 mL), and mix this mixture with ¼ (5 mL). Extraction was performed using L×3. The combined organic layer was dehydrated on Na2SO4, filtered, and then removed under vacuum. The mixture was concentrated to obtain a crude product (1.0 g), which was then used directly in the next step without purification. Used. LC-MS (M+H) + = 417.2.

[0128] Step 3: (2R,5S)-4-(2-(6-(acetoxymethyl)-7-(4-full Olobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorphol (no)methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 3 (40 mg) was used in Steps 8-9 and 18 of Example 1. In a similar manner to the method described above, 6-(acetoxymethyl)-7-(4-fluorobenzyl )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carb tert-butyl methyl phosphate and (2R,5S)-2-methyl-5-(((R)-3-methylmethyl methyl phosphate Prepared from tert-butyl methyl piperazine-1-carboxylate. LC- MS (M+H) + = 670.4.

[0129] Step 4: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-6-(Hydro Roxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorphol (no)methyl)piperazine-1-carboxylate tert-butyl [ka] (2R,5S)-4-(2-(6-(acetoxymethyl)-7-(4-fluorobenzyl (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl ) Me of piperazine-1-carboxylate tert-butyl (40 mg, 0.06 mmol) NaOH (12 mg, 0.3 mmol) was added to a solution of OH (5 mL) and H2O (5 mL). Add 10 mL of toluene to the reaction solution and stir the resulting solution at room temperature for 3 hours. Extraction was performed using a 3x filter. The combined organic layer was dehydrated, filtered, and concentrated. The residue was separated into TLs. The product was purified by C(DCM:MeOH=20:1) to obtain the indicated product (20 mg, yield rate 53%). LC-MS (M+H) + = 628.3.

[0130] Step 5: 1-(7-(4-fluorobenzyl)-6-(hydroxymethyl)-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-(( 2R,5R)-5-methyl-2-(((R)-3-methylmorpholinomethyl)piperazi ¹-1-yl)ethane-1-one (compound 8) Compound 8 as formate was prepared in the same manner as described in step 19 of Example 1, ( 2R,5S)-4-(2-(7-(4-fluorobenzyl)-6-(hydroxymethyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)- 2-Oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl) The salt was prepared from tert-butyl perazine-1-carboxylate. The salt was then prepared using an aqueous solution of NaHCO3. The mixture was neutralized and extracted with pharmaceutically acceptable solvents. The combined organic layer was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 8 (5.7 mg) as a free base.1 HNM R (400 MHz, DMSO-d6) δ 8.34(s, 1H), 7.26 - 7 .16 (m, 2H), 7.16 - 7.06 (m,2H), 5.11 (s, 1H ), 4.49 - 4.26 (m, 4H), 4.06- 3.68 (m, 6H), 3.53 - 3.37 (m, 2H), 3.26 -2.60 (m, 10H), 2. 23 - 2.11 (m, 1H), 2.05 - 1.94(m, 1H), 1.91 - 1.80 (m, 1H), 1.10 - 1.01(m, 3H), 0.95 - 0 0.76 (m, 3H). LC-MS (M+H) + = 528.3.

[0131] Example 9: 1-(7-(4-fluorobenzyl)-6-hydroxy-2,3-dihydro- 1H-Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R) -5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl ) Ethane-1-one (compound 9) [ka] Step 1: 1-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine 5-oxide [ka] The marked compound (166 mg) from Step 1 was prepared in the same manner as described in Step 5 of Example 1. In this method, 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3- Prepared from [1,4]oxazine-1-carboxylate tert-butyl. LC-MS (M+H) + = 361.3.

[0132] Step 2: 6-acetoxy-7-(4-fluorobenzyl)-2,3-dihydro-1H -Pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] 1-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine 5-oxide (166 mg, A 0.461 mmol (2 mL) Ac2O solution was stirred at 130°C for 3 hours. The solution was cooled to room temperature, water (5 mL) was added, and the solution was extracted with ¼ (5 mL x 3). The combined organic layer is dehydrated over Na2SO4, filtered, and concentrated in a vacuum to produce the labeled product. The substance (160 mg) was obtained and used directly in the next step without purification. LC- MS(M+H) + = 403.2.

[0133] Step 3: 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3 -b][1,4]oxazine-6-ol [ka] 6-acetoxy-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[ 2,3-b][1,4]oxazine-1-carboxylate tert-butyl (160 mg, 0 To a 0.398 mmol (5 mL) DCM solution, add TFA (1 mL) and obtain the solution The solution was stirred at room temperature for 2 hours. This reaction solution was concentrated under vacuum, and the resulting residue was subjected to preparative TLC. The product was purified by (DCM:MeOH=15:1) to obtain the labeled product (38 mg, yield) 37%). LC-MS (M+H) + = 261.2.

[0134] Step 4: 2-Chloro-1-(7-(4-fluorobenzyl)-6-hydroxy-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane- 1-on [ka] In Step 4, the indicated compound (60 mg) was prepared in the same manner as described in Step 9 of Example 1. By this method, 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b Prepared from [1,4]oxazine-6-ol and 2-chloroacetyl chloride. C-MS (M+H) + = 337.2.

[0135] Step 5: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-6-hydro Xy-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl ) piperazine-1-carboxylate tert-butyl [ka] The marked compound (20 mg) in Step 5 was prepared in the same manner as described in Step 18 of Example 1. In this method, 2-chloro-1-(7-(4-fluorobenzyl)-6-hydroxy-2,3 -Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1 -ONE and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)meth Prepared from tert-butyl piperazine-1-carboxylate. LC-MS (M+H ) + = 614.5.

[0136] Step 6: 1-(7-(4-fluorobenzyl)-6-hydroxy-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R )-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine-1-I (Lu) Ethane-1-one (Compound 9) Compound 9 as formate was prepared in the same manner as described in step 19 of Example 1, ( 2R,5S)-4-(2-(7-(4-fluorobenzyl)-6-hydroxy-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxo Ethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- It was prepared from tert-butyl 1-carboxylate. The above salt was neutralized with an aqueous solution of NaHCO3. Extracted with SiO2. The combined organic layer was dehydrated, filtered, and concentrated. The residue was further processed. The compound 9 was obtained by freeze-drying (5.2 mg). 1 HNMR (400 MHz, DM SO-d6) δ 9.39 (s, 1H), 8.71(s, 1H), 8.17 (s , 1H), 7.34 - 7.15 (m, 2H),7.15 - 7.02 (m, 2 H), 4.45 - 4.25 (m, 2H), 4.03- 3.65 (m, 6H), 3.57 - 3.39(m, 3H), 3.30 - 3.05 (m, 3H), 3. 03 - 2.78 (m, 4H), 2.75 - 2.56(m, 2H), 2.28 - 2.15 (m, 1H), 2.11 - 2.01(m, 1H), 1.99 - 1 .83 (m, 1H), 1.20 - 1.09 (m,3H), 0.96 - 0.79 (m, 3H). LC-MS(M+H) + = 514.5.

[0137] Example 10: 1-(7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1 H-Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R)- 5-Methyl-2-(((R)-3-methylmorpholinomethyl)piperazin-1-yl) Ethane-1-one (compound 10) [ka] Step 1: 2-((5-bromo-3-nitropyridine-2-yl)oxy)propanoic acid ethyl [ka] 5-Bromo-2-chloro-3-nitropyridine (11.87g, 50 mmol) and 2 -Ethyl hydroxypropanoate (8.85g, 75mmol) anhydrous THF (100mL) Add NaH (4g, 60% dispersion in mineral oil, 100 mmol) slowly to the solution at 0°C. It was added. The resulting solution was stirred at room temperature for 1 hour. This reaction mixture was then dissolved in water (20 mL). Quench the mixture, extract with HCl (100 mL x 3), and combine the resulting HCl phase. The residue was dehydrated on Na2SO4, filtered, and removed by distillation under vacuum. The residue was then scanned using silica gel chromatography. The product was purified by Phi (PE:dimethyl=10:1) to obtain the labeled product (8.5g). , yield 53%). LC-MS (M+H) + = 319.0, 321.0.

[0138] Step 2: 7-bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxadi N-2(3H)-on [ka] 2-((5-bromo-3-nitropyridine-2-yl)oxy) ethyl propanoate (8 Add 0.5g, 26.7 mmol) of Fe powder (17) to a 100mL solution of AcOH at 70°C. Slowly add 0.3g (310 mmol) and stir the resulting mixture at 70°C for 1 hour. The AcOH was removed under vacuum, and the resulting solid was washed with MeOH (200 mL) and filtered. This procedure was repeated five times. The MeOH phase was concentrated in a vacuum to obtain the crude product (2 0.2g) was used directly in the next step without purification. LC-MS(M+H ) + = 243.0, 245.0.

[0139] Step 3: 7-bromo-3-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazine [ka] 7-Bromo-3-methyl-1H-pyrido[2,3-b][1,4]oxazine-2(3 In a 50 mL solution of anhydrous THF (2.2 g, 9.05 mmol) of H)-one, at room temperature, Ran's THF solution (1N, 23 mL) was added dropwise, and the resulting solution was stirred at 60°C for 1 hour. Cool the reaction mixture to room temperature, quench with MeOH (10 mL), and 1 N H The pH was adjusted to 1-2 by adding Cl, and the mixture was stirred at 60°C for 1 hour. The reaction mixture was then left at room temperature. Cool to the desired temperature, add water (100 mL), adjust the pH to 8-9, and add HCl (100 mL) Extracted using ×3). The combined HCl layer was dehydrated on Na2SO4, filtered, and then... Removed by distillation in air to obtain the marked product (1.2g), which was then used in the next step without purification. Used. LC-MS (M+H) + = 229.0, 231.0.

[0140] Step 4: 7-bromo-3-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4] tert-butyl oxazine-1-carboxylate [ka] 7-Bromo-3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazine (1g, 4.37mmol), DMAP (0.8g, 6.55mmol), and And in a THF (30 mL) solution of Et3N (0.882 g, 8.72 mmol), at 0°C ( Boc)2O (1.42 g, 6.55 mmol) was added dropwise. This mixture was left at room temperature for 12 hours. The mixture was stirred. The reaction mixture was washed with water (50 mL) and then treated with toluene (50 mL x 3). Extracted. The combined SiO layer was dehydrated on Na2SO4, filtered, and stored in a vacuum. Removed. The residue was purified by silica gel chromatography (PE:SiO=5:1). The product was prepared to obtain the indicated product (0.99 g, 69% yield). LC-MS (M+H) + = 329.2, 331.2.

[0141] Step 5: 7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1H-p Lido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] 7-Bromo-3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazine-1-carboxylate tert-butyl (990 mg, 3 mmol) and bis(t Anhydrous TH400 0.15 mmol of ter-butylphosphine palladium (77 mg, 0.15 mmol) Add (4-fluorobenzyl) zinc chloride solution (0.5N, 1) to F (20 mL) solution. 2 mL (6 mmol) was added dropwise, and the resulting solution was stirred at 60°C for 2 hours. This reaction mixture The substance was quenched with MeOH (5 mL), concentrated in a vacuum, and the residue was subjected to silica gel chromatography. The product was purified by Graph (PE:Â=5:1) to obtain the indicated product (850 mg, yield 79%). LC-MS (M+H) + = 359.4.

[0142] Step 6: 7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1H-p Lido[2,3-b][1,4]oxazine [ka] 7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazine-1-carboxylate tert-butyl (850 mg, 2.3 Add 1,4-dioxane hydrochloride solution (4N, 2.5L) to 10mL of DCM solution (7 mmol). 5 mL (10 mmol) was added, and the resulting solution was stirred at room temperature for 12 hours. The solution was concentrated in a vacuum. NaHCO3 solution (saturated, 20 mL) was added, followed by DCM (20 mL). Extraction was performed using [method]. The combined organic layer was washed with saturated saline solution (20 mL) and then treated with Na2SO4. Dehydration and concentration were performed to obtain the labeled product (550 mg, yield 90%). LC-MS (M+ H) + = 259.1.

[0143] Step 7: 2-Chloro-1-(7-(4-fluorobenzyl)-3-methyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1- on [ka] The marked compound (110 mg) in Step 7 is prepared in the same manner as described in Step 9 of Example 1. By this method, 7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1H-pyri It was prepared from do[2,3-b][1,4]oxazine and 2-chloroacetyl chloride. LC-MS (M+H) + = 334.9.

[0144] Step 8: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-3-methyl -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)- 2-Oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl) Perazine-1-carboxylate tert-butyl [ka] The marked compound (45 mg) in Step 8 was prepared in the same manner as described in Step 18 of Example 1. By this method, 2-chloro-1-(7-(4-fluorobenzyl)-3-methyl-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-ol n and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl) Prepared from tert-butyl piperazine-1-carboxylate. LC-MS(M+H) + = 612.3.

[0145] Step 9: 1-(7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1 H-Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R)- 5-Methyl-2-(((R)-3-methylmorpholinomethyl)piperazin-1-yl) Ethane-1-one (compound 10) Compound 10 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-(7-(4-fluorobenzyl)-3-methyl-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoye (Tyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1 Prepared from tert-butyl carboxylate. The above salt was neutralized with an aqueous solution of NaHCO3. Extraction was performed using tOAc. The combined organic layer was dehydrated, filtered, and concentrated. The residue was further... Compound 10 (8 mg) was obtained as a free base by freeze-drying. 1 HNMR (400 M Hz, DMSO-d6) δ 8.28 (s, 1H),7.85 (s, 1H), 7 .26 (s, 2H), 7.14 - 7.12 (m,2H), 4.48 (s, 1H) ), 4.09 - 4.05 (m, 2H), 3.88(s, 2H), 3.55 (s , 1H), 3.49 - 3.47 (m, 3H),3.26 - 3.20 (m, 1 H), 2.93 (s, 1H), 2.79 - 2.76(m, 3H), 2.70 - 2.59 (m, 4H),2.32 - 2.26 (m, 1H), 2.16 (brs , 2H), 2.01 - 1.94 (m, 1H),1.77 - 1.72 (m, 1 H), 1.34 - 1.28 (m, 3H), 0.91- 0.82 (m, 6H). LC-MS (M+H) + = 512.0.

[0146] Example 11: 1-(6-bromo-7-(4-fluorobenzyl)-3-methyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2 R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine -1-yl)ethane-1-one (compound 11) [ka] Step 1: 6-bromo-7-(4-fluorobenzyl)-3-methyl-2,3-dihydr Lo-1H-pyrido[2,3-b][1,4]oxazine [ka] 7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazine (620 mg, 2.4 mmol) dissolved in DMF (15 mL) Add NBS (428 mg, 2.4 mmol) to the solution at 0°C, and allow the resulting solution to rise at room temperature for 2 minutes. Stirred for a while. Water (30 mL) was added and extracted with alkyl (15 mL x 3). The combined organic layer was concentrated and subjected to silica gel chromatography (PE:.''=3:1 The product was purified by LC-MS (M+) to obtain the marked product (350 mg, yield 43%). H) + = 337.0, 339.0.

[0147] Step 2: 1-(6-bromo-7-(4-fluorobenzyl)-3-methyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-chloro Ethane-1-on [ka] The marked compound (140 mg) from Step 2 was prepared in the same manner as described in Step 9 of Example 1. By this method, 6-bromo-7-(4-fluorobenzyl)-3-methyl-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine and 2-chloroacetyl chloride Prepared using LC-MS (M+H). + =413.3, 415.3.

[0148] Step 3: (2R,5S)-4-(2-(6-bromo-7-(4-fluorobenzyl) -3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino )Methyl)piperazine-1-carboxylate tert-butyl [ka] The marked compound (80 mg) in Step 3 is prepared in the same manner as described in Step 18 of Example 1. By this method, 1-(6-bromo-7-(4-fluorobenzyl)-3-methyl-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-chloro Tan-1-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorphol Prepared from tert-butyl methylpiperazine-1-carboxylate. LC-MS (M+H) + = 690.3, 692.3.

[0149] Step 4: 1-(6-bromo-7-(4-fluorobenzyl)-3-methyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2 R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine -1-yl)ethane-1-one (compound 11) Compound 11 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-(6-bromo-7-(4-fluorobenzyl)-3-methyl -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)- 2-Oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl) The salt was prepared from tert-butyl perazine-1-carboxylate. The salt was then prepared using an aqueous solution of NaHCO3. The mixture was neutralized and extracted with pharmaceutically acceptable solvents. The combined organic layer was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 11 (10 mg) as a free base. 1 HNM R (400 MHz, DMSO-d6) δ 8.42(s, 1H), 7.23 (s , 2H), 7.23 - 7.14 (m, 2H),4.55 (s, 1H), 4.1 3 - 4.09 (m, 2H), 3.97 (s,2H), 3.59 (brs, 1H ), 3.55 - 3.42 (m, 3H), 3.27- 3.21 (m, 1H), 2.95 (brs, 1H), 2.77 - 2.74(m, 3H), 2.65 - 2 .59 (m, 3H), 2.30 - 2.23 (m,1H), 2.16 (brs, 2H), 2.00 - 1.95 (m, 2H), 1.76- 1.73 (m, 1H) , 1.33 (d, J = 4.0 Hz, 3H),0.86 (d, J = 8.0 H z, 6 H). LC-MS (M+H) + = 590.0, 592.0.

[0150] Example 12: 1-(6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2- ((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)pipette Radin-1-yl)ethane-1-one (compound 12) [ka] Step 1: 2-Bromo-N-(5-Bromo-2-hydroxypyridine-3-yl)-2 -Methylpropanamide [ka] 3-amino-5-bromopyridine-2-ol (4g, 21.2 mmol) THF( TEA (6.4 g, 63.5 mmol) was added to 40 mL of solution. This mixture was 0 Cool to °C, and add 2-bromo-2-methylpropanoyl bromide (5.3g, 23.3mm). (ol) was added dropwise. This mixture was slowly heated to room temperature and stirred for 2 hours. The substance was concentrated, diluted with water, and extracted with HCl. The combined organic layer was dehydrated and filtered. The residue was then concentrated. The residue was subjected to silica gel column chromatography (PE:.'' = 1:1 The product was purified by LC-MS (M+) to obtain the labeled product (4.2 g, yield 60%). H) + = 336.9.

[0151] Step 2: 7-bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4] Xazidine-2-(3H)-one [ka] 2-Bromo-N-(5-Bromo-2-hydroxypyridine-3-yl)-2-methyl K2CO3 is added to a 100 mL solution of lopanamide (4.2 g, 12.5 mmol) in DMF. 3 (5.2g, 37.5 mmol) was added. This mixture was heated to 70°C for 8 hours. The mixture was stirred. After cooling, it was concentrated, diluted with H2O, and extracted with toluene. The combined organic layers were dehydrated, filtered, and removed by distillation. The residue was then subjected to silica gel column chromatography. The product was purified by Fi (DCM:MeOH=30:1) to obtain the labeled product (1.6g). , yield 50%). LC-MS (M+H) + =257.0, 259.0.

[0152] Step 3: 7-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrido[2,3 -b][1,4]oxazine [ka] The marked compound (830 mg) in Step 3 was prepared in the same manner as described in Step 3 of Example 1. By this method, 7-bromo-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxy Prepared from sazin-2(3H)-one. LC-MS (M+H)+ =243.0, 2 45.0.

[0153] Step 4: 7-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrido[2,3 -b][1,4] tert-butyl oxazine-1-carboxylate [ka] The indicated compound (830 mg) in Step 4 was prepared in the same manner as described in Step 4 of Example 10. By the method described above, 7-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrido[2,3 Prepared from -b][1,4]oxazine. LC-MS (M+H) + = 342.9, 344.9.

[0154] Step 5: 7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1 H-Pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] The indicated compound (500 mg) in Step 5 was prepared in the same manner as described in Step 5 of Example 10. By the method described above, 7-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrido[2,3 Prepared from -b][1,4]oxazine-1-carbocite tert-butyl. LC- MS (M+H) + = 373.0.

[0155] Step 6: 7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazine [ka] The marked compound (280 mg) in Step 6 was prepared in the same manner as in Step 6 of Example 10. By the method described above, 7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1 From H-pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl Prepared using LC-MS (M+H). + = 273.0.

[0156] Step 7: 6-Bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] The marked compound (230 mg) in Step 7 was prepared in the same manner as described in Step 1 of Example 11. By the method described, 7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-1 Prepared from H-pyrido[2,3-b][1,4]oxazine. LC-MS(M+H) + = 351.0, 353.0.

[0157] Step 8: 1-(6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2- Chloroethane-1-one [ka] The marked compound (100 mg) in Step 8 is prepared in the same manner as described in Step 9 of Example 1. By this method, 6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloroacetylchloro Prepared from lidocaine. LC-MS (M+H) + = 427.0, 429.0.

[0158] Step 9: (2R, 5S)-4-(2-(6-bromo-7-(4-fluorobenzyl) -3,3-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxa Zin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmol tert-butyl methylpiperazine-1-carboxylate [ka] The marked compound (85 mg) in Step 9 was prepared in the same manner as described in Step 18 of Example 1. In this method, 1-(6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2- Loroethane-1-one and (2R,5S)-2-methyl-5-(((R)-3-methylmethyl Prepared from tert-butyl methyl piperazine-1-carboxylate. LC- MS (M+H) + = 704.0, 706.0.

[0159] Step 10: 1-(6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2 -((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) Perazine-1-yl)ethane-1-one (compound 12) Compound 12 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-(6-bromo-7-(4-fluorobenzyl)-3,3-di Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-i (R)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)meth The salt was prepared from tert-butyl piperazine-1-carboxylate. The above salt was prepared using NaHCO3. The mixture was neutralized with an aqueous solution and extracted with carboxylic acid. The combined organic layer was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 12 (15 mg) as a free base. 1 H NMR (400 MHz,DMSO-d6) δ 8.38 (s, 1H), 7.24 (s, 2H), 7.17 - 7.13 (m, 2H),4.14 (d, J = 15 .6 Hz, 1H), 3.97 (s, 3H), 3.57- 3.47 (m, 4H) , 3.26 (t, J = 9.7 Hz, 1H),2.96 (brs, 1H), 2 .78 - 2.75 (m, 4H), 2.57 -2.55(m, 2H), 2.30 - 2.27 (m, 1H), 2.15 (s, 2H),2.02 - 1.88 (m, 2H), 1.77(d, J = 12.4 Hz, 1H), 1.36 (s, 3H) , 1.30 (s, 3H), 0.91 - 0.81(m, 6H). LC-MS (M +H) + = 604.0, 606.0.

[0160] Example 13: 2-((2R,5R)-2-(((1S,4S)-2-oxa-5-azabi Cyclo[2.2.1]heptan-5-yl)methyl)5-methylpiperazine-1-yl )-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3- b) [1,4]oxazine-1-yl)ethane-1-one (compound 13) [ka] Step 1: (2R,5S)-5-(((1S,4S)-2-oxa-5-azabicyclo [2.2.1] Heptan-5-yl)methyl)-4-benzyl-2-methylpiperazine- 1-Tert-butyl carboxylate [ka] The marked compound (110 mg) in Step 1 was prepared in the same manner as described in Step 16 of Example 1. By the method described, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane salt Salts and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine Prepared from tert-butyl carboxylate. LC-MS(M+H) + = 402 .0.

[0161] Step 2: (2R,5S)-5-(((1S,4S)-2-oxa-5-azabicyclo [2.2.1] Heptan-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl [ka] The marked compound (60 mg) in Step 2 was prepared in the same manner as described in Step 17 of Example 1. In this method, (2R,5S)-5-(((1S,4S)-2-oxa-5-azabicyclo[ 2.2.1] Heptan-5-yl)methyl)-4-benzyl-2-methylpiperazine-1 Prepared from tert-butyl carboxylate. LC-MS(M+H) + =312.0.

[0162] Step 3: (2R,5S)-5-(((1S,4S)-2-oxa-5-azabicyclo [2.2.1] Heptan-5-yl(methyl)-4-(2-(7-(4-fluorobendi (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound (30 mg) in Step 3 was prepared in the same manner as described in Step 18 of Example 1. In this method, (2R,5S)-5-(((1S,4S)-2-oxa-5-azabicyclo[ 2.2.1] Heptan-5-yl(methyl)-2-methylpiperazine-1-carboxylic acid ert-butyl and 2-chloro-1-(7-(4-fluorobenzyl)-2,3-dihydr Low-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one Prepared using LC-MS (M+H). + = 596.0.

[0163] Step 4: 2-((2R,5R)-2-(((1S,4S)-2-Oxa-5-Azabi Cyclo[2.2.1]heptan-5-yl)methyl)5-methylpiperazine-1-yl )-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3- b) [1,4]oxazine-1-yl)ethane-1-one (compound 13) Compound 13 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-5-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1 ]heptan-5-yl(methyl)-4-(2-(7-(4-fluorobenzyl)-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-ox Prepared from tert-butyl soethyl-2-methylpiperazine-1-carboxylate. The salt was neutralized with an aqueous NaHCO3 solution and extracted with ethyl acetate. The combined organic layer was then decontaminated. The mixture was diluted with water, filtered, and concentrated. The residue was further freeze-dried to obtain compound 13 (8 mg) as a free base. It was obtained as such. 1 H NMR (400MHz, CD3OD) δ 8.44 (s, 1H) , 7.79 (s, 1H), 7.23 (s, 2H),7.04 - 7.01 (m, 2H), 4.44- 4.41 (m, 2H), 4.31 (s, 1H), 4.10 - 4.07 (m,2H), 3.93 (brs, 3H), 3.79 (brs, 1 H), 3.56 - 3.53 (m, 1H), 3.47(d, J = 7.2 Hz, 1H), 3.37 (s, 1H), 2.99 (d,J = 12.0 Hz, 1H), 2.80 - 2.77(m, 4H), 2.64 (s, 1H), 2.55 - 2. 26 (m, 4H), 1.66 (d, J = 9.2Hz, 1H), 1.54 (d , J = 9.3 Hz, 1H), 1.03 (s,3H). LC-MS (M+H) + = 496.3.

[0164] Example 14: 2-((2R,5R)-2-(((1R,4R)-2-oxa-5-azabi Cyclo[2.2.1]heptan-5-yl)methyl)5-methylpiperazine-1-yl )-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3- b) [1,4]oxazine-1-yl)ethane-1-one (compound 14) [ka] Step 1: (2R,5S)-5-(((1R,4R)-2-oxa-5-azabicyclo [2.2.1] Heptan-5-yl)methyl)-4-benzyl-2-methylpiperazine- 1-Tert-butyl carboxylate [ka] The marked compound (100 mg) in Step 1 was used in the same manner as described in Step 16 of Example 1. (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane salt Salts and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine Prepared from tert-butyl carboxylate. LC-MS(M+H) + = 402 .0.

[0165] Step 2: (2R,5S)-5-(((1R,4R)-2-oxa-5-azabicyclo [2.2.1] Heptan-5-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl [ka] The marked compound (60 mg) in Step 2 was prepared in the same manner as described in Step 17 of Example 1. In this method, (2R,5S)-5-(((1R,4R)-2-oxa-5-azabicyclo[ 2.2.1] Heptan-5-yl)methyl)-4-benzyl-2-methylpiperazine-1 Prepared from tert-butyl carboxylate. LC-MS(M+H) + = 312.0 .

[0166] Step 3: (2R,5S)-5-(((1R,4R)-2-oxa-5-azabicyclo [2.2.1] Heptan-5-yl(methyl)-4-(2-(7-(4-fluorobendi (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound (30 mg) in Step 3 was prepared in the same manner as described in Step 18 of Example 1. In this method, (2R,5S)-5-(((1R,4R)-2-oxa-5-azabicyclo[ 2.2.1] Heptan-5-yl(methyl)-2-methylpiperazine-1-carboxylic acid ert-butyl and 2-chloro-1-(7-(4-fluorobenzyl)-2,3-dihydr Low-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one Prepared using LC-MS (M+H). + = 596.0.

[0167] Step 4: 2-((2R,5R)-2-(((1R,4R)-2-Oxa-5-Azabi Cyclo[2.2.1]heptan-5-yl)methyl)5-methylpiperazine-1-yl )-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3- b) [1,4]oxazine-1-yl)ethane-1-one (compound 14) Compound 14 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-5-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1 ]heptan-5-yl(methyl)-4-(2-(7-(4-fluorobenzyl)-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-ox Prepared from tert-butyl soethyl-2-methylpiperazine-1-carboxylate. The salt was neutralized with an aqueous NaHCO3 solution and extracted with ethyl acetate. The combined organic layer was then decontaminated. The mixture was diluted with water, filtered, and concentrated. The residue was further freeze-dried to obtain compound 14 (5 mg) as a free base. It was obtained as such. 1 H NMR (400MHz, CD3OD) δ 8.54 (s, 1H) , 7.80 (s, 1H), 7.22 (s, 2H),7.04 - 7.02 (m, 2H), 4.42(brs, 2H), 4.19 (s, 1H), 4.01 - 3. 97 (m, 2H), 3.92 (s, 2H), 3.88- 3.87 (m, 2H) , 3.70 (d, J = 16.6 Hz, 1H),3.46 (d, J = 7.6 Hz, 1H), 2.97 (d, J = 12.2Hz, 1H), 2.90 - 2. 86 (m, 1H), 2.80 - 2.72 (m,4H), 2.68 (s, 1H) , 2.54 -2.51 (m, 2H), 2.45(d, J = 12.3 Hz, 1 H), 2.31 (d, J = 9.4 Hz, 1H),1.51 (s, 2H), 1 .10-1.05 (m, 3H). LC-MS (M+H) + = 496.3.

[0168] Example 15: (S)-4-(difluoromethyl)-3-(((2R,5R)-1-(2- (7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]Oxazin-1-yl)-2-oxoethyl)-5-methylpiperazine-2-yl )Methyl)oxazolidine-2-one (compound 15) [ka] Step 1: (2R,5R)-4-benzyl-5-(((S)-4-(difluoromethyl )-2-oxoxazolidine-3-yl)methyl)-2-methylpiperazine-1-cal tert-butyl benzoate [ka] The marked compound (120 mg) in Step 1 was prepared in the same manner as described in Step 16 of Example 1. In the following manner, (S)-4-(difluoromethyl)oxazolidine-2-one and (2R, 5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylic acid Prepared from tert-butyl. LC-MS (M+H) + = 440.0.

[0169] Step 2: (2R,5R)-5-(((S)-4-(difluoromethyl)-2-oxo Oxazolidine-3-yl)methyl)-2-methylpiperazine-1-carboxylic acid -butyl [ka] The marked compound (45 mg) in Step 2 was prepared in the same manner as described in Step 17 of Example 1. By this method, (2R,5R)-4-benzyl-5-(((S)-4-(difluoromethyl) -2-oxoxazolidine-3-yl)methyl)2-methylpiperazine-1-carb Prepared from tert-butyl phosphate. LC-MS (M+H) + = 350.0.

[0170] Step 3: (2R,5R)-5-(((S)-4-(difluoromethyl)-2-oxo Oxazolidine-3-yl)methyl)-4-(2-(7-(4-fluorobenzyl)-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2- Oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound (15 mg) in Step 3 is prepared in the same manner as described in Step 18 of Example 1. In this method, (2R,5R)-5-(((S)-4-(difluoromethyl)-2-oxo Xazolidine-3-yl)methyl)-2-methylpiperazine-1-carboxylic acid tert- Butyl and 2-chloro-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H - Prepared from pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one . LC-MS (M+H) + = 634.3.

[0171] Step 4: (S)-4-(difluoromethyl)-3-(((2R,5R)-1-(2- (7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]Oxazin-1-yl)-2-oxoethyl)-5-methylpiperazine-2-yl )Methyl)oxazolidine-2-one (compound 15) Compound 15 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5R)-5-(((S)-4-(difluoromethyl)-2-oxoxazolidi (-3-yl)methyl)-4-(2-(7-(4-fluorobenzyl)-2,3-dihydr L-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl Prepared from tert-butyl methylpiperazine-1-carboxylate. The above salt was N The mixture was neutralized with an aqueous solution of aHCO3 and extracted with toluene. The combined organic layer was dehydrated and filtered. The mixture was then concentrated. The residue was further freeze-dried to obtain compound 15 (5 mg) as a free base. Ta. 1 H NMR (400 MHz,CD3OD) δ 8.54 (s, 1H), 7. 80 (s, 1H), 7.23 (s, 2H), 7.03- 7.01 (m, 2H) , 6.09 (t, J = 54.8 Hz, 1H),4.43 (s, 3H), 4. 29 - 4.21 (m, 2H), 4.08 (s,1H), 3.92 (s, 2H) , 3.88 - 3.84 (m, 3H), 3.70-3.66 (m, 2H), 3. 21 - 3.17 (m, 2H), 2.96 - 2.82(m, 3H), 2.59 (t, J = 11.3 Hz, 1H), 2.47(s, 1H), 1.05 (d, J = 4.0 Hz, 3H). LC-MS (M+H) + = 534.3.

[0172] Example 16: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho Linol(methyl)-5-methylpiperazine-1-yl)-1-(7-(4-fluorobendi (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl ) Ethane-1-one (compound 16) [ka] Step 1: (2R, 5S)-4-Benzyl-5-(((3R, 5R)-3, 5-Dimethicone Lumorpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound (80 mg) in Step 1 was prepared in the same manner as described in Step 16 of Example 1. By this method, (3R,5R)-3,5-dimethylmorpholine hydrochloride and (2R,5R)-4 -benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylic acid tert- Prepared from butyl. LC-MS (M+H) + = 418.3.

[0173] Step 2: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) Methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound (40 mg) in Step 2 was prepared in the same manner as described in Step 17 of Example 1. By this method, (2R,5S)-4-benzyl-5-(((3R,5R)-3,5-dimethyl Prepared from morpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl Manufactured. LC-MS (M+H) + = 328.5.

[0174] Step 3: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) Methyl)-4-(2-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyri [2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methyl tert-butyl piperazine-1-carboxylate [ka] The marked compound (20 mg) in Step 3 is prepared in the same manner as described in Step 18 of Example 1. In this method, (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) (Tyl)-2-methylpiperazine-1-carboxylate tert-butyl and 2-chloro-1- (7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1 Prepared from [4]oxazine-1-yl)ethane-1-one. LC-MS(M+H) + = 612.3.

[0175] Step 4: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho Linol(methyl)-5-methylpiperazine-1-yl)-1-(7-(4-fluorobendi (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl ) Ethane-1-one (compound 16) Compound 16 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4 -(2-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine- Prepared from tert-butyl 1-carboxylate. The above salt was neutralized with NaHCO3 and EtO Extracted with Ac. The combined organic layer was dehydrated, filtered, and concentrated. The residue was then frozen. After drying, compound 16 (4 mg) was obtained as a free base. 1 HNMR (400 MHz , CD3OD) δ 8.28(s, 1H), 7.82 (s, 1H), 7.27 - 7.19 (m, 2H),7.13 - 7.05 (m, 2H), 4.36 (brs , 1H), 4.30 (brs, 1H), 4.04- 3.96 (m, 2H), 3 .85 (brs, 2H), 3.83 - 3.73(m, 1H), 3.50 - 3. 41 (m, 1H), 3.41 - 3.34 (m,2H), 3.04 (brs, 2 H), 2.90 - 2.82 (m, 1H), 2.73(brs, 1H), 2.6 5 (brs, 2H), 2.59 - 2.51 (m,2H), 2.28 - 2.18 (m, 1H), 2.18- 2.08 (m, 1H), 2.00 - 1.88 (m , 2H), 1.21 (brs, 1H), 0.89- 0.75 (m, 9H). L C-MS (M+H) + = 512.3.

[0176] Example 17: 1-(6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro- 1H-Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R) -5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl ) Ethane-1-one (compound 17) [ka] Step 1: 6-Ethoxy-3-nitropyridine-2-amine [ka] 100 mL of ethanol contains NaH (1.2 g, 60% dispersion in mineral oil, 30 mmol) The mixture was slowly added and stirred at room temperature for 10 minutes. 2-amino-6-chloro-3-nitrop Add lysine (5g, 28.9 mmol) in small increments, and stir the mixture at ambient temperature for 30 minutes. Mixed. After concentration, water was added and extracted with ethyl acetate. The combined organic layer was dehydrated and filtered. The residue was passed through and concentrated. The residue was subjected to silica gel column chromatography (PE: Â15=3: The product was purified by (1) to obtain the labeled product (3.0 g, yield 56%). LC-MS (M +H) + = 184.1.

[0177] Step 2: 5-bromo-6-ethoxy-3-nitropyridine-2-amine [ka] 6-Ethoxy-3-nitropyridine-2-amine (3.0g, 16.4mmol) 0 mL of DMF was added. This mixture was cooled to 0°C. NBS (3.2 g, 18.04 mmol was added to the cooled mixture described above in small amounts. The new mixture was slowly brought to room temperature. The mixture was heated and stirred for 2 hours. This mixture was diluted with water and extracted with ethyl acetate. The stopped organic layer was washed with an aqueous solution of Na2S2O3, dehydrated, filtered, and concentrated. The residue was then silicified. Purified by Kagel column chromatography (PE:dimethyl=3:1), and marked as follows: The product was obtained (3.4 g, 80% yield). LC-MS (M+H) + = 262.0,2 64.0.

[0178] Step 3: 3-Bromo-6-chloro-2-ethoxy-5-nitropyridine [ka] 5-Bromo-6-ethoxy-3-nitropyridine-2-amine (3.4g, 13.02 To a solution of 60 mL of HCl ( mmol) in CH3CN, add CuCl (2.57 g, 26.0 mmol) ) and t-BuONO (2.68 g, 26.0 mmol) were added. This mixture was 65 The mixture was heated to °C and stirred for 1.5 hours. This mixture was diluted with water and extracted with toluene. The combined organic layers were dehydrated, filtered, and concentrated. The resulting residue was then processed using silica gel. The product was purified by chromatography (PE:dimethyl=5:1) to obtain the indicated product. 2g, yield 55%). LC-MS (M+H) + = 280.9.

[0179] Step 4: 2-((5-bromo-6-ethoxy-3-nitropyridine-2-yl)oxy C) Ethyl acetate [ka] 3-Bromo-6-chloro-2-ethoxy-5-nitropyridine (2g, 7.14mmo) l) and 2-hydroxyethyl acetate (880 mg, 8.5 mmol) are mixed in a solution at 0°C for 6 0% NaH (340 mg, 8.5 mmol) was added in small amounts. The resulting mixture was then heated in a chamber. Slowly heated to warm and stirred overnight. Carefully quenched and diluted this mixture, and E Extraction was performed using tOAc. The combined organic layer was dehydrated, filtered, and concentrated. The residue was silica. Purified by gel column chromatography (PE:dimethyl=5:1), the following product was obtained. The product was obtained (2g, 80% yield). LC-MS (M+H) + = 349.0.

[0180] Step 5: 7-bromo-6-ethoxy-1H-pyrido[2,3-b][1,4]oxa Jin-2(3H)-on [ka] In Step 5, prepare the marked compound (1 g, crude) in the same manner as described in Step 2 of Example 1. In this method, 2-((5-bromo-6-ethoxy-3-nitropyridine-2-yl)oxy Prepared from ethyl acetate. The crude substance was used in the next step without purification. LC- MS (M+H) + = 273.0, 275.0.

[0181] Step 6: 7-bromo-6-ethoxy-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazine [ka] 7-Bromo-6-ethoxy-2,3-dihydro-1H-pyrido[2,3-b][1,4 ]Oxazine (500 mg, crude) was prepared in the same manner as described in step 3 of Example 1. And then, 7-bromo-6-ethoxy-1H-pyrido[2,3-b][1,4]oxazine-2 Prepared from (3H)-one. The crude product was used in the next step without purification. LC -MS (M+H) + = 259.0, 261.0.

[0182] Step 7: 7-bromo-6-ethoxy-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazine-1-carboxylate tert-butyl [ka] The marked compound (400 mg) in Step 7 is prepared in the same manner as described in Step 4 of Example 1. By this method, 7-bromo-6-ethoxy-2,3-dihydro-1H-pyrido[2,3-b] Prepared from [1,4]oxazine. LC-MS (M+H) + =359.1, 361 .1.

[0183] Step 8: 6-Ethoxy-7-(4-Fluorobenzyl)-2,3-Dihydro-1H- Pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] The marked compound (300 mg) in Step 8 is prepared in the same manner as described in Step 7 of Example 1. By this method, 7-bromo-6-ethoxy-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazine-1-carboxylate tert-butyl and (4-fluorobenzyl) Prepared from zinc(II) chloride. LC-MS (M+H) + = 389.2.

[0184] Step 9: 6-Ethoxy-7-(4-Fluorobenzyl)-2,3-Dihydro-1H- Pyrido[2,3-b][1,4]oxazine [ka] The marked compound (210 mg) in Step 9 was prepared in the same manner as described in Step 8 of Example 1. By this method, 6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-1H-p Prepared from tert-butyl lido[2,3-b][1,4]oxazine-1-carboxylate. . LC-MS (M+H) + = 289.1.

[0185] Step 10: 2-Chloro-1-(6-ethoxy-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane- 1-on [ka] The marked compound (120 mg) in Step 10 is prepared in the same manner as described in Step 9 of Example 1. In the following method, 6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-1H- Prepared from pyrido[2,3-b][1,4]oxazine and 2-chloroacetyl chloride. . LC-MS (M+H) + =365.1.

[0186] Step 11: (2R,5S)-4-(2-(6-ethoxy-7-(4-fluorobenzyme (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl ) piperazine-1-carboxylate tert-butyl [ka] The marked compound (100 mg) in Step 11 was prepared using the method described in Step 18 of Example 1. In a similar manner, 2-chloro-1-(6-ethoxy-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane- 1-ONE and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino) Prepared from tert-butyl (Tyl)piperazine-1-carboxylate. LC-MS(M+ H) + = 642.4.

[0187] Step 12: 1-(6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R )-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine-1-I (Lu) Ethane-1-one (Compound 17) Compound 17 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-(6-ethoxy-7-(4-fluorobenzyl)-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxo Ethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- It was prepared from tert-butyl 1-carboxylate. The above salt was neutralized with an aqueous solution of NaHCO3. Extracted with SiO2. The combined organic layer was dehydrated, filtered, and concentrated. The residue was further processed. The compound was freeze-dried to obtain compound 17 (53 mg) as a free base. 1 HNMR (400 MHz, DMSO-d6)δ 8.25 (s, 1H), 7.20 - 7.17 (m , 2H), 7.10 - 7.06 (m, 2H),4.37 - 4.27 (m, 2 H), 4.18 (q, J = 8.0 Hz, 2H),3.93 - 3.70 (m, 6H), 3.50 - 3.39 (m, 3H), 3.22- 3.03 (m, 5H) , 3.00 - 2.77 (m, 4H), 2.70- 2.54 (m, 2H), 2 .05 - 2.01 (m, 1H), 1.92 -1.87 (m, 1H), 1.23 (t, J = 8.0Hz, 3H), 1.14 (d, J = 8.0Hz, 3H) , 0.92-0.86 (m, 3H). LC-MS (M+H)+ = 542.3.

[0188] Example 18: 1-(8-(4-fluorobenzyl)-3,4-dihydropyrido[2,3- b][1,4]Oxazepine-1(2H)-yl)-2-((2R,5R)-5-methyl -2-(((R)-3-methylmorpholino)methyl)piperazine-1-yl)ethane-1 -On (compound 18) [ka] Step 1: N-(3-((3,5-dibromopyridine-2-yl)oxy)propyl) -4-methylbenzenesulfonamide [ka] N-(3-hydroxypropyl)-4-methylbenzenesulfonamide under nitrogen at 0°C (7.6g, 33 mmol) THF (150 mL) solution, NaH (1.44 g, 60 %, 36 mmol) was added and stirred for 30 minutes. Then 3,5-dibromo-2-fluorine Lopyridine (7.65 g, 30 mmol) was added in small amounts, and the mixture was stirred overnight at 70°C. The reaction mixture was quenched with water, and the resulting mixture was extracted with toluene (80 mL x 3). The combined organic layers were washed with saturated saline solution, dehydrated over Na2SO4, filtered, and then drained. Removed. The residue was analyzed by silica gel column chromatography (PE:SiO=2:1). The product was purified to obtain the indicated product (2.4g, yield 17%). LC-MS(M+H) + = 464.9.

[0189] Step 2: 8-bromo-1-tosyl-1,2,3,4-tetrahydropyrido[2,3- b][1,4]Oxazepine [ka] N-(3-((3,5-dibromopyridine-2-yl)oxy)propyl)-4-methyl Benzenesulfonamide (2.2g, 4.74mmol), picolinic acid (466mg, 3.79 mmol), CuI (1.08 g, 5.69 mmol), and K2CO3 (1. DMSO (20 mL) was added to a mixture of 96 g (14.2 mmol). This mixture was then subjected to nitration. The mixture was stirred at 140°C for 3 hours under an ambient atmosphere. This mixture was cooled and diluted with water, then toluene was added. Extraction was performed using (80 mL x 3). The combined organic layer was washed with saturated saline solution and Na2SO4. The residue was dehydrated, filtered, and removed by distillation. The residue was then subjected to silica gel column chromatography (PE: The product was purified using ammonium (5:1 ratio) to obtain the labeled product (1.03 g, 57% yield). LC-MS (M+H) + =383.0, 385.0.

[0190] Step 3: 8-(4-fluorobenzyl)-1-tosyl-1,2,3,4-tetrahydr Lopiride[2,3-b][1,4]oxazepine [ka] The marked compound (630 mg) in Step 3 is prepared in the same manner as described in Step 7 of Example 1. By this method, 8-bromo-1-tosyl-1,2,3,4-tetrahydropyrido[2,3-b Prepared from [1,4]oxazepine and (4-fluorobenzyl)zinc(II) chloride LC-MS (M+H) + = 413.1.

[0191] Step 4: 8-(4-fluorobenzyl)-1,2,3,4-tetrahydropyrido[2 ,3-b][1,4]Oxazepine [ka] 8-(4-fluorobenzyl)-1-tosyl-1,2,3,4-tetrahydro at 80℃ Metabolism of pyrido[2,3-b][1,4]oxazepine (350 mg, 0.85 mmol) Mg (204 mg, 8.5 mmol) was added in small amounts to a 10 mL solution of Nol. This mixture was stirred overnight at 80°C. The precipitate was filtered off, and the filtrate was removed by distillation. The residue was silica gel. Purified by column chromatography (DCM:MeOH=50:1), the product is produced. The substance was obtained (80 mg, 36% yield). LC-MS (M+H) + = 259.1.

[0192] Step 5: 2-Chloro-1-(8-(4-fluorobenzyl)-3,4-dihydropyryl [2,3-b][1,4]oxazepine-1(2H)-yl)ethane-1-one [ka] The compound indicated in Step 5 (50 mg, crude) was prepared using the method described in Step 9 of Example 1. In a similar manner, 8-(4-fluorobenzyl)-1,2,3,4-tetrahydropyrid [ Prepared from 2,3-b][1,4]oxazepine and 2-chloroacetyl chloride. Crude The refined substance was used directly in the next step without purification. LC-MS(M+H) + = 335.1.

[0193] Step 6: (2R,5S)-4-(2-(8-(4-fluorobenzyl)-3,4-di Hydropyrido[2,3-b][1,4]oxazepine-1(2H)-yl)-2-oxo Ethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1-Tert-butyl carboxylate [ka] The marked compound (70 mg) in Step 6 was prepared in the same manner as described in Step 18 of Example 1. By this method, 2-chloro-1-(8-(4-fluorobenzyl)-3,4-dihydropyrid [2,3-b][1,4]Oxazepine-1(2H)-yl)ethane-1-one and (2 R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine Prepared from tert-butyl carboxylate. LC-MS(M+H) + = 612 .4.

[0194] Step 7: 1-(8-(4-fluorobenzyl)-3,4-dihydropyrido[2,3- b][1,4]Oxazepine-1(2H)-yl)-2-((2R,5R)-5-methyl -2-(((R)-3-methylmorpholino)methyl)piperazine-1-yl)ethane-1 -On (compound 18) Compound 18 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-(8-(4-fluorobenzyl)-3,4-dihydropyrid [2,3-b][1,4]Oxazepine-1(2H)-yl)-2-oxoethyl)-2 -methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carbone Prepared from tert-butyl acid. The above salt was neutralized with an aqueous solution of NaHCO3 and then treated with ammonium compounds. Extracted. The combined organic layer was dehydrated, filtered, and concentrated. The residue was further freeze-dried. Compound 18 (25 mg) was then obtained as a free base. 1 HNMR (400 MHz, C D3OD) δ 8.14 (s, 1H), 7.77(s, 1H), 7.29 (s, 2H), 7.06 (s, 2H), 4.70 (s,1H), 4.46 (s, 1H) ), 4.19 (s, 1H), 4.01 (s, 2H),3.90 (s, 1H), 3.58 (s, 1H), 3.45 (s, 1H),3.04 - 2.63 (m, 9 H), 2.52 (s, 1H), 2.34 - 2.21(m, 3H), 2.09 ( s, 1H), 1.88 - 1.77 (m, 2H),1.58 (s, 1H), 1. 01 (s, 3H), 0.84 (s, 3H). LC-MS(M+H) + = 512 .3.

[0195] Example 19: 1-(7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R)- 5-Methyl-2-(((R)-3-methylmorpholinomethyl)piperazin-1-yl) Ethane-1-one (compound 19) [ka] Step 1: (1-((3,5-dibromopyridine-2-yl)oxy)propane-2- tert-butyl ylcarbamate [ka] (1-hydroxypropan-2-yl)carbamate tert-butyl (2g, 11. 4 mmol) and 3,5-dibromo-2-fluoropyridine (2.6 g, 10.3 mmol) 40 mL of THF was added to the mixture in (1). This mixture was cooled to 0°C. NaH( 456 mg (60% dispersion in mineral oil, 11.4 mmol) was added in small amounts. The mixture was slowly heated to room temperature and stirred overnight. This mixture was then carefully quenched and diluted. The mixture was separated and extracted with HCl. The combined organic layer was dehydrated, filtered, and removed by distillation. Crude soil The product is purified by silica gel column chromatography (PE:SiO=8:1). The indicated product was obtained (4g, 95% yield). LC-MS(M+H) + =409.0 .

[0196] Step 2: 7-bromo-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4] tert-butyl oxazine-1-carboxylate [ka] The marked compound (300 mg) in Step 2 was prepared in the same manner as described in Step 2 of Example 18. In the following way, (1-((3,5-dibromopyridine-2-yl)oxy)propane-2- Prepared from tert-butyl ylcarbamate. LC-MS(M+H) + =329 .0.

[0197] Step 3: 7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-p Lido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] The marked compound (260 mg) in Step 3 is prepared in the same manner as described in Step 7 of Example 1. In this method, 7-bromo-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][ 1,4]Oxazine-1-carboxylate tert-butyl and (4-fluorobenzyl) salts Prepared from zinc(II) oxide. LC-MS (M+H) + = 359.2.

[0198] Step 4: 7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-p Lido[2,3-b][1,4]oxazine [ka] The marked compound (200 mg) in Step 4 is prepared in the same manner as described in Step 8 of Example 1. By this method, 7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyri Prepared from do[2,3-b][1,4]oxazine-1-carboxylate tert-butyl The crude material was used in the next step without purification. LC-MS(M+H) + =2 59.1.

[0199] Step 5: 2-Chloro-1-(7-(4-fluorobenzyl)-2-methyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1- on [ka] The marked compound (150 mg) in Step 5 is prepared in the same manner as described in Step 9 of Example 1. By this method, 7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyri It was prepared from do[2,3-b][1,4]oxazine and 2-chloroacetyl chloride. LC-MS (M+H) + = 335.1.

[0200] Step 6: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-2-methyl -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)- 2-Oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl) Perazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 6 (100 mg, a mixture of diastereomers, 1 / 1 ratio) is used in the actual In a manner similar to that described in step 18 of Example 1, 2-chloro-1-(7-(4-flu Olobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4 ]Oxazin-1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(( (R)-3-methylmorpholino)methyl)piperazine-1-carboxylate tert-butyl Prepared from: LC-MS (M+H) + = 612.3.

[0201] Step 7: 1-(7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-Pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R,5R)- 5-Methyl-2-(((R)-3-methylmorpholinomethyl)piperazin-1-yl) Ethane-1-one (compound 19) Compound 19 as formate (a mixture of diastereomers, in a 1 / 1 ratio) was used in Example 1. In the same manner as described in Step 19, (2R, 5S)-4-(2-(7-(4-Full Olobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4 ]Oxazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methyl It was prepared from tert-butyl methyl((Tylmorpholino)methyl)piperazine-1-carboxylate. The above salts were neutralized with an aqueous solution of NaHCO3 and extracted with ammonium compounds. The combined organic layers were then collected. The solution was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 19 (20 mg, dias). A mixture of teleomers (in a 1:1 ratio) was obtained as a free base. 1 HNMR (400 MHz , DMSO-d6) δ 8.25 (s, 1H),7.84 (d, J = 12.0 Hz, 1H), 7.30 - 7.22 (m, 2H),7.16 - 7.09 (m, 2H), 4.77- 4.67 (m, 1H), 4.35 - 4.19 (m, 2H) ), 4.07 - 4.03 (m, 1H), 3.88(s, 2H), 3.59 - 3.46 (m, 3H), 2.98 - 2.51 (m,8H), 2.33 - 2.1 7 (m, 3H), 2.06 - 1.89 (m,2H), 1.76 (t, J = 1 2.0 Hz, 1H), 1.19 - 1.12 (m,3H), 0.91 - 0.82 (m, 6H). LC-MS(M+H) + = 512.3.

[0202] Example 19A: 1-((S)-7-(4-fluorobenzyl)-2-methyl-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R ,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine- 1-yl)ethane-1-one (compound 19A) [ka] Compound 19A as formate was prepared in the same manner as described in Example 19, in Step 1 (S)-(1-hydroxypropan-2-yl)carbami is a chiral starting material in this context. tert-butyl methyl phosphate and (2R,5S)-2-methyl-5-(((R)-3-methylmethyl methyl phosphate Prepared from tert-butyl ruhorino(methyl)piperazine-1-carboxylate. The above salt It was neutralized with an aqueous solution of NaHCO3 and extracted with ethyl acetate. The combined organic layer was dehydrated. The mixture was filtered and concentrated. The residue was further freeze-dried to obtain compound 19A (23 mg) as a free base. It was obtained as such. 1 H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1 H), 7.82 (s, 1H), 7.26 - 7.22(m, 2H), 7.13 - 7.08 (m, 2H),4.74 (s, 1H), 4.32 - 4.29 (m, 1H), 4.19 - 4.16 (m, 1H), 4.05- 4.00 (m, 1H) , 3.85 (s, 2H), 3.49 - 3.45(m, 3H), 3.29 - 3 .23 (m, 1H), 2.95 (bro, 1H),2.82 - 2.64 (m, 3H), 2.59 - 2.53 (m, 2H), 2.30- 2.12 (m, 4H) , 1.95 (t, J = 12.0 Hz, 2H),1.71 (d, J = 8.0 Hz, 1H), 1.15 - 1.10 (m, 3H),0.85 - 0.83 (m, 6H). LC-MS(M+H) + = 512.5.

[0203] Example 19B: 1-((R)-7-(4-fluorobenzyl)-2-methyl-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R ,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine- 1-yl)ethane-1-one (compound 19B) [ka] Compound 19B as formate was prepared in the same manner as described in Example 19, in Step 1 (R)-(1-hydroxypropan-2-yl)carbami is a chiral starting material in tert-butyl methyl phosphate and (2R,5S)-2-methyl-5-(((R)-3-methylmethyl methyl phosphate Prepared from tert-butyl ruhorino(methyl)piperazine-1-carboxylate. The above salt It was neutralized with an aqueous solution of NaHCO3 and extracted with ethyl acetate. The combined organic layer was dehydrated. The mixture was filtered and concentrated. The residue was further freeze-dried to obtain compound 19B (15 mg) as a free base. It was obtained as such. 1 H NMR (400MHz, DMSO-d6) δ 8.25 (s, 1 H), 7.83 (s, 1H), 7.27 - 7.24(m, 2H), 7.14 - 7.09 (m, 2H),4.67 (s, 1H), 4.38 - 4.19 (m, 3H), 3.88 (s, 2H), 3.58 - 3.51(m, 2H), 3.31 - 3.16 (m, 2H), 3.00 (s, 1H),2.88 - 2.72 (m, 3H), 2.63(s, 2H), 2.32 (s, 2H), 2.17 (s, 2H) ), 2.00 (s, 2H), 1.79 - 1.76(m, 1H), 1.21 - 1.11 (m, 3H), 0.93 - 0.81 (m,6H). LC-MS (M+H ) + = 512.5.

[0204] Example 20: 1-(7'-(4-fluorobenzyl)-1'H,3'H-spiro[cyclo Propane-1,2'-pyrido[2,3-b][1,4]oxazine]-1'-yl)-2 -((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) Perazin-1-yl)ethane-1-one hydrochloride (compound 20) [ka] Step 1: (1-(((3,5-dibromopyridine-2-yl)oxy)methyl) tert-butyl ropropylcarbamate [ka] The marked compound (3.9g) in Step 1 was prepared in the same manner as described in Step 1 of Example 19. By this method, (1-(hydroxymethyl)cyclopropyl)carbamate tert-butyl It was prepared from 3,5-dibromo-2-fluoropyridine. LC-MS(M+H) + = 423.0.

[0205] Step 2: 7'-Bromo-1'H,3'H-Spiro[Cyclopropane-1,2'-Pyryl [2,3-b][1,4]oxazine]-1'-carboxylate tert-butyl [ka] (1-(((3,5-dibromopyridine-2-yl)oxy)methyl)cyclopropyl ) tert-butyl carbamate (1.69g, 4 mmol), CuI (762mg, 4 mmol) mmol), picolinic acid (492 mg, 4 mmol), and Cs2CO3 (2.6 g, 8 mmol). DMSO (15 mL) was added to a mixture of mmol. This mixture was subjected to a nitrogen atmosphere for 12 minutes. The mixture was stirred at 0°C for 2 hours. After cooling to room temperature, the mixture was treated with water to obtain the final mixture. The material was extracted with toluene (80 mL x 3). The combined organic layer was washed with saturated saline solution. The residue was dehydrated on Na2SO4, filtered, and removed by distillation. The residue was then chromatographed using silica gel column chromatography. The product was purified by (PE / Â=5:1) to obtain the indicated product (360 mg, yield rate 27%). LC-MS (M+H) + = 341.0, 343.0.

[0206] Step 3: 7'-(4-fluorobenzyl)-1'H,3'H-spiro[cyclopropane n-1,2'-pyrido[2,3-b][1,4]oxazine]-1'-carboxylic acid t-butyl [ka] The marked compound (230 mg) in Step 3 is prepared in the same manner as described in Step 7 of Example 1. In this method, 7'-bromo-1'H,3'H-spiro[cyclopropane-1,2'-pyrid [2,3-b][1,4]oxazine]-1'-carboxylate tert-butyl and (4- Prepared from zinc(II) fluorobenzyl chloride. LC-MS(M+H) + = 37 1.1.

[0207] Step 4: 7'-(4-fluorobenzyl)-1'H,3'H-spiro[cyclopropane n-1,2'-pyrido[2,3-b][1,4]oxazine] [ka] In Step 4, the indicated compound (45 mg) was prepared in the same manner as described in Step 8 of Example 1. By this method, 7'-(4-fluorobenzyl)-1'H,3'H-spiro[cyclopropane- 1,2'-Pyrido[2,3-b][1,4]oxazine]-1'-carboxylic acid tert- Prepared from butyl. LC-MS (M+H) + = 271.1.

[0208] Step 5: 2-Chloro-1-(7'-(4-fluorobenzyl)-1'H,3'H- Pyrro[cyclopropane-1,2'-pyrido[2,3-b][1,4]oxazine]-1' -Il)Ethan-1-one [ka] The marked compound (60 mg, crude) in Step 5 was prepared using the method described in Step 9 of Example 1. In a similar manner, 7'-(4-fluorobenzyl)-1'H,3'H-spiro[cyclopro Pan-1,2'-pyrido[2,3-b][1,4]oxazine] and 2-chloroacetyl Prepared from chloride. The crude substance was used directly in the next step without purification. LC -MS (M+H) + = 347.1.

[0209] Step 6: (2R,5S)-4-(2-(7'-(4-fluorobenzyl)-1'H, 3'H-Spiro[cyclopropane-1,2'-Pyrido[2,3-b][1,4]oxadi [n]-1'-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmethyl (ruhorino)methyl)piperazine-1-carboxylate tert-butyl [ka] The marked compound (100 mg) in Step 6 is prepared in the same manner as described in Step 18 of Example 1. In the following method, 2-chloro-1-(7'-(4-fluorobenzyl)-1'H,3'H- Pyrro[cyclopropane-1,2'-pyrido[2,3-b][1,4]oxazine]-1' -yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R)-3-methyl Prepared from tert-butyl methyl (Lumorpholino)piperazine-1-carboxylate. C-MS (M+H) + = 624.4.

[0210] Step 7: 1-(7'-(4-fluorobenzyl)-1'H,3'H-spiro[cyclo Propane-1,2'-pyrido[2,3-b][1,4]oxazine]-1'-yl)-2 -((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) Perazin-1-yl)ethane-1-one hydrochloride (compound 20) Compound 20 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-(7'-(4-fluorobenzyl)-1'H,3'H-spi Ro[cyclopropane-1,2'-pyrido[2,3-b][1,4]oxazine]-1'- (Iyl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino) Prepared from tert-butyl (Tyl)piperazine-1-carboxylate. The above salt was prepared from NaHCO₃ The solution was neutralized with aqueous solution 3 and extracted with carboxylic acid. The combined organic layer was dehydrated, filtered, and concentrated. It shrunk. The residue was acidified with 1N HCl and freeze-dried to obtain compound 20 (23 mg). It was obtained as a hydrochloride salt. 1 H NMR(400 MHz, DMSO-d6) δ 8.35 ( s, 2H), 7.89 (d, J = 2.2 Hz,1H), 7.55 (d, J = 1.9 Hz, 1H), 7.30 - 7.21 (m, 2H), 7.15 - 7.0 6 (m, 2H), 4.30 (s, 2H), 3.95- 3.76 (m, 4H), 3.47 (d, J= 11.3 Hz, 1H), 3.41 (d, J = 8.4 H z, 1H), 3.15 - 3.13 (m, 1H),2.95 (s, 1H), 2. 86 - 2.59 (m, 6H), 2.48 - 2.41(m, 1H), 2.25 (t, J = 11.2 Hz, 1H), 2.05(s, 1H), 1.87 (t, J = 10.3 Hz, 1H), 1.67 (d,J = 13.3 Hz, 1H), 1 .05 (s, 3H), 0.96 - 0.81 (m,4H), 0.66 (s, 3H) ) LC-MS (M+H) + = 524.4.

[0211] Example 21: 1-(7-(4-fluorobenzyl)-6-(1-hydroxycycloprop (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)meth (Lu)piperazine-1-yl)ethane-1-one (compound 21) [ka] Step 1: 7-(4-fluorobenzyl)-6-(hydroxymethyl)-2,3-dihy Dro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-b Chill [ka] 6-(acetoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H - Pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl (5g) To a 12 mmol solution, THF / H2O (60 mL, v / v=1 / 1) was added. The mixture was cooled to 0°C. LiOH·H2O (1.0g, 24 mmol) was added in small amounts. The mixture was added. This mixture was stirred at room temperature for 2 hours. This mixture was concentrated and extracted with toluene. The combined organic layer was dehydrated, filtered, and concentrated to obtain the crude labeled product (4. 5g) was used directly in the next step without further purification. LC-MS(M +H) + = 375.2.

[0212] Step 2: 1-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carboxylic acid [ka] 7-(4-fluorobenzyl)-6-(hydroxymethyl)-2,3-dihydro-1H -Pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl(1. MeCN(2g, 3.2 mmol) and TEMPO(64 mg, 0.41 mmol) To the 0 mL solution, phosphate buffer (20 mL, pH=7.4) was added. Then NaClO Aqueous solution of 2 (1.8g, 15.9 mmol, 10 mL) and NaClO (1.2g, 15 0.9 mmol, 10 mL) was added. This mixture was stirred overnight at room temperature. The pH was adjusted to 8 by adding 1M NaOH. This mixture was then cooled on ice to saturated N2. Pour the solution into an aqueous a2S2O3 solution and continue stirring for 30 minutes. Add 1N HCl. The pH was adjusted to 3, and the aqueous phase was extracted using DCM (30 mL x 3). The chamber is washed with saturated saline solution, dehydrated over Na2SO4, filtered, and distilled to obtain the crude labeled raw material. The resulting product (1.3g) was used directly in the next step without further purification. LC-MS (M+H) + = 389.2.

[0213] Step 3: 7-(4-fluorobenzyl)-6-(methoxy(methyl)carbamoyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carbone tert-butyl acid [ka] 1-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine-6-carboxylic acid (600m g, 1.55 mmol), N,O-dimethylhydroxylamine hydrochloride (252 mg, 2 0.58 mmol), DIPEA (333 mg, 2.58 mmol), and HATU (58 The reaction mixture (9 mg, 1.55 mmol) in DMF (10 mL) was stirred overnight at room temperature. This mixture was treated with water and extracted with toluene (30 mL x 3). It was then combined into one. The organic layer was washed with saturated saline solution, dehydrated over Na2SO4, filtered, and removed by distillation. The residue was then dried. The product was purified by microchromatography (PE:siRNA=2:1) ​​to obtain the labeled product. (640 mg, yield 98%). LC-MS (M+H) + = 432.2.

[0214] Step 4: 6-acetyl-7-(4-fluorobenzyl)-2,3-dihydro-1H- Pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] Under nitrogen, at -78°C, 7-(4-fluorobenzyl)-6-(methoxy(methyl)calcium Bamoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1 -Tert-butyl carboxylate (640 mg, 1.53 mmol) in THF (20 mL) Add MeLi (1.4 mL, 1.6 M hexane solution, 2.24 mmol) to the solution. The mixture was stirred at the same temperature for 2 hours. This reaction mixture was quenched with a saturated aqueous solution of NH4Cl. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layer was then treated with saturated saline solution. The residue was washed, dehydrated over Na2SO4, filtered, and removed by distillation. The residue was then subjected to column chromatography. The product was purified by (PE:Â1=2:1) ​​to obtain the labeled product (380 mg, yield) 64%). 1 H NMR (400MHz, DMSO-d6) δ 8.14 (s, 1H ), 7.17 (dd, J = 8.1, 5.6 Hz,2H), 7.08 (t, J = 8.9 Hz, 2H), 4.37 (s, 2H),4.24 (s, 2H), 3. 84 (s, 2H), 2.50 (s, 3H), 1.42(s, 9H). LC-MS (M+H) + = 387.1.

[0215] Step 5: 6-(1-((tert-butyldimethylsilyl)oxy)vinyl)-7- (4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4] tert-butyl oxazine-1-carboxylate [ka] 6-acetyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyri at 0℃ [2,3-b][1,4]oxazine-1-carboxylate tert-butyl (380mg) DCM (20m³) of Et3N (298mg, 2.95mm³) (0.98mm³) L) In the solution, add tert-butyldimethylsilyl trifluoromethanesulfonate ( 390 mg (1.48 mmol) was added and stirred overnight at room temperature. This mixture was then treated with DCM. Dilution, washing with water and saturated saline, dehydration over Na2SO4, filtration, and distillation. Residue The product was purified by column chromatography (PE:siRNA=1:2) to produce the indicated product. We obtained the substance (415 mg, 84% yield). 1 1H NMR (400 MHz, DMSO-d6) ) δ 7.92 (s, 1H), 7.18 - 7.05(m, 4H), 4.56 ( s, 1H), 4.52 (s, 1H), 4.31(s, 2H), 4.06 (s, 2H), 3.78 (s, 2H), 1.38 (s,9H), 0.87 (s, 9H) ), 0.11 (s, 6H). LC-MS (M+H) + = 501.1.

[0216] Step 6: 6-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl )-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][ [1,4]Oxazine [ka] Et2Zn in hexane solution (3.32 mL, 1 M, 3.32 mmol) at 0°C under nitrogen. CH2I2 (1.8g, 6.64 mmol) was added to the mixture and stirred for 30 minutes. 6-(1-((tert-butyldimethylsilyl)oxy)vinyl)-7-(4-fluorine Robenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- DCM of 1-tert-butyl carboxylate (415 mg, 0.83 mmol) (15 mL) The solution was added dropwise, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was then saturated with NH4Cl. Quenched with a well-formed aqueous solution and extracted with DCM (20 mL x 2). The combined organic layer was then saturated. The solution was washed with saline solution, dehydrated over Na2SO4, filtered, and removed by distillation. The residue was then subjected to column chromatography. The product was purified by Graphy (DCM:MeOH = 20:1) to obtain the indicated product (18 0 mg, yield 52%. 1 H NMR(400 MHz, DMSO-d6) δ 7.26 - 7.04 (m,4H), 6.48 (s, 1H), 5.94 (s, 1H), 4.18 (s, 2H), 4.11 (s, 2H),3.20 (s, 2H), 0. 88 (d, J = 5.6 Hz, 4H), 0.77(s, 9H), 0.14 (s , 6H). LC-MS (M+H) + = 415.2.

[0217] Step 7: 1-(6-(1-((tert-butyldimethylsilyl)oxy)cyclo Ropyr)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-1-yl)-2-chloroethane-1-one [ka] The compound indicated in Step 7 (210 mg, crude) was prepared according to the method described in Step 9 of Example 1. In a similar manner, 6-(1-((tert-butyldimethylsilyl)oxy)cyclopro Pyr)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b Prepared from [1,4]oxazine and 2-chloroacetyl chloride. The crude product was purified. It was used directly in the next step without any further processing. LC-MS (M+H) + = 491.1.

[0218] Step 8: (2R,5S)-4-(2-(6-(1-((tert-butyldimethyl sulfite (Lyl)oxy)cyclopropyl)-7-(4-fluorobenzyl)-2,3-dihydro- 1H-Pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)- 2-Methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carb tert-butyl phosphate [ka] The compound indicated in Step 8 (230 mg, 69% yield) was used in Step 18 of Example 1. Using the same method as described above, 1-(6-(1-((tert-butyldimethylsilyl)oxy (Cyclopropyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyri do[2,3-b][1,4]oxazin-1-yl)-2-chloroethane-1-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piper Prepared from tert-butyl din-1-carboxylate. LC-MS(M+H) + = 7 68.4.

[0219] Step 9: 1-(7-(4-fluorobenzyl)-6-(1-hydroxycycloprop (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)meth (Lu)piperazine-1-yl)ethane-1-one (compound 21) (2R,5S)-4-(2-(6-(1-((tert-butyldimethylsilyl)oxy (Cyclopropyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyri [2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methyl -5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid ter t-butyl (230 mg, 0.3 mmol) in methanol (3 mL) solution, HCl at 0°C 1 liter of 1,4-dioxane solution (3 mL, 4 M) was added. The mixture was stirred at room temperature for 4 hours. Mixed. The solvent was removed by distillation, the residue was washed with an aqueous NaHCO3 solution, and extracted with EA. The trapped layer was dehydrated, filtered, and concentrated. The residue was subjected to silica gel column chromatography. The product was purified by (DCM:MeOH=10:1) to obtain the labeled product (60 mg, yield) 36%). 1 H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1H ), 7.24 (s, 2H), 7.10 (t, J= 8.0 Hz, 2H), 6. 03 (s, 1H), 4.43 - 4.23 (m,3H), 4.15 (d, J = 15.5 Hz, 1H), 3.97 - 3.93 (m,2H), 3.74 (s, 1 H), 3.61 (d, J = 15.7 Hz, 1H),3.45 (d, J = 10 .1Hz, 1H), 3.36 (s, 1H), 3.17- 3.12 (m, 1H) , 2.28 -2.78 (m, 4H), 2.66(d, J = 9.9 Hz, 2H ), 2.56 (d, J = 10.6 Hz, 1H),2.33 - 2.30 (m, 2H), 2.12 (s, 1H), 1.93 (s,1H), 1.74 (d, J = 10.7 Hz, 1H),0.90 - 0.83 (m, 10H). LC-MS (M +H) + = 554.3.

[0220] Example 22: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazine-1-yl)ethane-1-one (compound 22) [ka] Compound 22 as formate is added to step 1 in the same manner as described in Example 19. The corresponding chiral starting material is (S)-(1-hydroxypropan-2-yl) tert-butyl rubamate and (2R,5S)-5-(((3R,5R)-3,5-di Methylmorpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl Prepared from the above salt. The salt was neutralized with an aqueous solution of NaHCO3 and extracted with ammonium compounds. The retained organic layer was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 22(2 24 mg (41% yield) was obtained as free base. 1 1HNMR (400 MHz, DMS) O-d6) δ 8.20 (s, 1H), 7.85(s, 1H), 7.30 - 7. 18 (m, 2H), 7.17 - 7.06 (m,2H), 4.81 - 4.63 (m, 1H), 4.38 - 4.27 (m, 1H),4.25 - 4.14 (m, 1H), 3.98- 3.90 (m, 1H), 3.87 (s, 2H), 3.53 - 3.38 (m, 3H), 3.16 - 3.02 (m, 2H), 2.99 - 2 .88 (m, 1H), 2.84 - 2.74 (m,1H), 2.73 - 2.64 (m, 2H), 2.63- 2.54 (m, 2H), 2.26 (t, J = 10 .7 Hz, 1H), 2.13 (t, J = 10.8Hz, 1H), 2.08 - 1.88 (m, 2H), 1.17 (d, J =6.0 Hz, 3H), 0.93 - 0.76 (m, 9H). LC-MS (M+H) + = 526.6.

[0221] Example 23: 1-((S)-2-((benzyloxy)methyl)-7-(4-fluorobe (Nzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1- Il)-2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino )methyl)-5-methylpiperazine-1-yl)ethane-1-one (compound 23) [ka] Step 1: (S)-(1-(benzyloxy)-3-((3,5-dibromopyridine- 2-yl)oxy)propan-2-yl)carbamate tert-butyl [ka] The marked compound (19 g, 95% yield) from Step 1 is used as described in Step 1 of Example 19. By the same method as above, (R)-(1-(benzyloxy)-3-hydroxypropane-2 -Tert-butyl yl-carbamate and 3,5-dibromo-2-fluoropyridine Prepared using LC-MS (M+H). + = 515.0.

[0222] Step 2: (S)-2-((benzyloxy)methyl)-7-bromo-2,3-dihydr Ro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyric acid Ru [ka] The marked compound (2.5g, 38% yield) from Step 2 is described in Step 2 of Example 18. In a similar manner to the above method, (S)-(1-(benzyloxy)-3-((3,5-dibromo From pyridine-2-yl)oxy)propan-2-yl)carbamate tert-butyl Prepared using LC-MS (M+H). + = 435.0.

[0223] Step 3: (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carb tert-butyl phosphate [ka] The marked compound from Step 3 (1.5 g, 56% yield) is used as described in Step 7 of Example 1. By the same method as above, (S)-2-((benzyloxy)methyl)-7-bromo-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid ter Prepared from t-butyl and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 465.2.

[0224] Step 4: (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] The marked compound (1.1 g, 94% yield) from Step 4 is used as described in Step 8 of Example 1. In a similar manner, (S)-2-((benzyloxy)methyl)-7-(4-fluoro Benzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1 Prepared from tert-butyl carboxylate. LC-MS(M+H) + = 365.2 .

[0225] Step 5: (S)-1-(2-((benzyloxy)methyl)-7-(4-fluorobe (Nzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1- Il-2-chloroethane-1-one [ka] The marked compound (750 mg, 56% yield) from Step 5 is described in Step 9 of Example 1. In a similar manner to the above method, (S)-2-(benzyloxy)methyl)-7-(4-fluoro benzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and Prepared from 2-chloroacetyl chloride. LC-MS (M+H) + = 441.1.

[0226] Step 6: (2R,5S)-4-(2-((S)-2-((benzyloxy)methyl) -7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]Oxazin-1-yl)-2-oxoethyl)-5-(((3R,5R)-3,5 -dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert- Chill [ka] The compound indicated in Step 6 (520 mg, 86% yield) is used in Step 18 of Example 1. In the same manner as described above, (S)-1-(2-((benzyloxy)methyl)-7-(4 -Fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy Sajin-1-yl)-2-chloroethane-1-one and (2R,5S)-5-(((3R ,5R)-3,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carb Prepared from tert-butyl phosphate. LC-MS (M+H) + = 732.4.

[0227] Step 7: 1-((S)-2-((benzyloxy)methyl)-7-(4-fluorobe (Nzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1- Il)-2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino )methyl)-5-methylpiperazine-1-yl)ethane-1-one (compound 23) Compound 23 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-((S)-2-((benzyloxy)methyl)-7-(4- Fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxa Zin-1-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmethyl Prepared from tert-butyl methyl-2-methylpiperazine-1-carboxylate. The above salt was neutralized with an aqueous solution of NaHCO3 and extracted with ammonium compounds. The bed was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 23 (210 mg). , 47% yielded as free base. 1 1H NMR (400 MHz, DMSO-d6) ) δ 8.31 (s, 1H), 7.83 (s,1H), 7.3 - 7.23 (m , 5H), 7.23 - 7.16 (m, 2H),7.15 - 7.08 (m, 2 H), 4.97 (brs, 1H), 4.58 -4.52 (m, 1H), 4.5 1 - 4.39 (m, 2H), 4.27 - 4.20(m, 1H), 4.19 - 4.11 (m, 1H), 3.88 (s, 2H),3.55 - 3.49 (m, 1 H), 3.48 - 3.41 (m, 3H), 3.31- 3.24 (m, 2H), 3.11 (brs,2H), 3.05 - 2.98 (m, 1H), 2.83 - 2.72 (m, 1H), 2.68 - 2.53 (m,4H), 2.38 (brs , 1H), 2.27 - 2.17 (m, 1H),2.08 - 1.98 (m, 1 H), 1.98 - 1.90 (m, 1H), 0.85(d, J = 4.5 Hz, 3H), 0.80 (d, J = 5.6 Hz, 6H). LC-MS(M+H) + = 632.4.

[0228] Example 24: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyri do[2,3-b][1,4]oxazine-1-yl)ethane-1-one (compound 24) [ka] Step 1: (S)-(1-((3,5-dibromo-6-methylpyridine-2-yl)o tert-butyl xypropan-2-yl carbamate [ka] The marked compound (4.2g, 75% yield) from Step 1 is described in Step 1 of Example 19. In a similar manner to the above method, (S)-(1-hydroxypropan-2-yl)carbamate t Prepared from ert-butyl and 3,5-dibromo-2-fluoro-6-methylpyridine LC-MS (M+H) + = 423.0.

[0229] Step 2: (S)-7-bromo-2,6-dimethyl-2,3-dihydro-1H-pyrid [2,3-b][1,4] tert-butyl oxazine-1-carboxylate [ka] The compound indicated in Step 2 (890 mg, yield 15%) is used in Step 2 of Example 18. By the same method as described above, (S)-(1-((3,5-dibromo-6-methylpyridine- It was prepared from tert-butyl 2-yl)oxy)propan-2-yl)carbamate. LC-MS (M+H) + = 343.1.

[0230] Step 3: (S)-7-(4-fluorobenzyl)-2,6-dimethyl-2,3-dihydroxy Dro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-b Chill [ka] The marked compound (1.0 g, 90% yield) from Step 3 is used as described in Step 7 of Example 1. By the same method, (S)-7-bromo-2,6-dimethyl-2,3-dihydro-1H -Pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl and ( Prepared from 4-fluorobenzyl zinc(II) chloride. LC-MS(M+H) + = 373.2.

[0231] Step 4: (S)-1-(tert-butoxycarbonyl)-7-(4-fluorobene) Zyl)-2,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazine 5-oxide [ka] The marked compound from Step 4 (900 mg, 65% yield) is described in Step 5 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2,6-dimethyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid t Prepared from ert-butyl and 3-chloroperbenzoic acid. LC-MS(M+H) + = 389.2.

[0232] Step 5: (S)-6-(acetoxymethyl)-7-(4-fluorobenzyl)-2- Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-ca tert-butyl benzoate [ka] The compound indicated in Step 5 (855 mg, yield 86%) is described in Step 2 of Example 8. In a similar manner to the above method, (S)-1-(tert-butoxycarbonyl)-7-(4-fu Luolobenzyl)-2,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4] Prepared from oxazine 5-oxide and Ac2O. LC-MS(M+H) + = 431.2.

[0233] Step 6: (S)-(7-(4-fluorobenzyl)-2-methyl-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-6-yl)methylacetate [ka] The compound indicated in Step 6 (462 mg, 70% yield) is described in Step 8 of Example 1. In a similar manner to the above method, (S)-6-(acetoxymethyl)-7-(4-fluorobenz (Lu)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi Prepared from tert-butyl nitrate. LC-MS(M+H) + = 33 1.1.

[0234] Step 7: (S)-(1-(2-chloroacetyl)-7-(4-fluorobenzyl)- 2-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6 -yl)methylacetate [ka] The compound indicated in Step 7 (570 mg, 90% yield) is described in Step 9 of Example 1. In a similar manner to the above method, (S)-(7-(4-fluorobenzyl)-2-methyl-2,3 -Dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-yl)methylacetate Prepared from tate and 2-chloroacetyl chloride. LC-MS(M+H) + = 4 07.1.

[0235] Step 8: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-5-(((3R,5R)-3 ,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid -butyl [ka] The compound indicated in Step 8 (252 mg, 51% yield) was used in Step 18 of Example 1. Using the same method as described above, (S)-(1-(2-chloroacetyl)-7-(4-fluoro Benzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]o Xazazine-6-yl)methylacetate and (2R,5S)-5-(((3R,5R)- 3,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid Prepared from t-butyl. LC-MS (M+H) + = 698.5.

[0236] Step 9: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) Methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl (Lu)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid -butyl [ka] The compound indicated in Step 9 (240 mg, 100% yield) is used in Step 4 of Example 8. Using the same method as described above, (2R,5S)-4-(2-((S)-6-(acetoxymeth (Lu)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[ 2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-(((3R ,5R)-3,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carb Prepared from tert-butyl phosphate. LC-MS (M+H) + = 656.5.

[0237] Step 10: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmol (Forino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-Fur) Olobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H- Lido[2,3-b][1,4]oxazin-1-yl)ethane-1-one (compound 24) Compound 24 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4 -(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl Tyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl From )-2-oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl Prepared. The above salt was neutralized with an aqueous NaHCO3 solution and extracted with ammonium compounds. Combined into one. The organic layer was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 24 (97m). g (48% yield) was obtained as free base. 1 HNMR (400 MHz, DMSO-d 6) δ 8.12 (s, 1H), 7.28 - 7.17(m, 2H), 7.16 - 7.04 (m, 2H), 5.15 - 5.01(m, 1H), 4.72 (s, 1H), 4.50- 4.37 (m, 2H), 4.33 (d, J = 10.6H z, 1H), 4.20 (d, J = 10.9 Hz,1H), 3.97 (s, 2 H), 3.94 - 3.83 (m, 1H), 3.54- 3.37 (m, 3H), 3.18 - 3.02(m, 2H), 2.97 - 2.88 (m, 1H), 2. 82 - 2.71 (m, 1H), 2.71 - 2.63(m, 2H), 2.62 - 2.53 (m, 2H), 2.31 - 2.19(m, 1H), 2.18 - 2 .05 (m, 1H), 2.02 - 1.89 (m,2H), 1.19 (d, J = 5.7 Hz, 3H), 0.92 - 0.75(m, 9H). LC-MS (M+ H) + = 556.6.

[0238] Example 25: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl) -2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-Iyl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorphol (Methyl)piperazine-1-yl)ethane-1-one (compound 25) [ka] Step 1: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R) -3-methylmorpholino)methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 1 (259 mg, yield 54%) was used in Step 18 of Example 1. Using the same method as described above, (S)-(1-(2-chloroacetyl)-7-(4-fluoro Benzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]o ((2R,5S)-2-Methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl )-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl was prepared. LC-MS (M+H) + = 684.5

[0239] Step 2: (2R,5S)-4-(2-((S)-7-(4-Fluorobenzyl)-6 -(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]oxazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R) -3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl [Chemical formula] The title compound of Step 2 (240 mg, yield 90%) was prepared in the same manner as described in Step 4 of Example 8 from (2R,5S)-4-(2-((S)-6-(acetoxymethyl )-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methyl-5- (((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl (((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl. LC-MS (M+H) = 642.5 +

[0240] Step 3: 1-((S)-7-(4-Fluorobenzyl)-6-(hydroxymethyl) -2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin- 1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino no)methyl)piperazin-1-yl)ethan-1-one (Compound 25)​ Compound 25 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2((S)-7(4-fluorobenzyl)-6-(hydrox (Cymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4] Xazazine-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methyl Prepared from tert-butyl morpholino(methyl)piperazine-1-carboxylate. The salt was neutralized with an aqueous solution of NaHCO3 and extracted with ethyl acetate. The combined organic layer was then dehydrated. The mixture was filtered and concentrated. The residue was further freeze-dried to obtain compound 25 (103 mg, yield 51%). %) was obtained as a free base. 1 1HNMR (400 MHz, DMSO-d6) δ 8. 18 (s, 1H), 7.26 - 7.17 (m,2H), 7.16 - 7.06 (m, 2H), 5.12 - 5.04 (m, 1H),4.77 (s, 1H), 4 .50 - 4.37 (m, 2H), 4.37 -4.28 (m, 1H), 4.26 - 4.15 (m, 1H), 4.07 - 4.00 (m, 1H), 3.97 (s , 2H), 3.56 - 3.40 (m, 3H),3.31 - 3.24 (m, 1 H), 3.05 - 2.92 (m, 1H), 2.88- 2.53 (m, 6H), 2.36 - 2.23(m, 1H), 2.23 - 2.07 (m, 2H), 2. 03 - 1.84 (m, 2H), 1.79 - 1.67(m, 1H), 1.16 (d, J = 5.9 Hz, 3H), 0.93 -0.77 (m, 6H). LC-M S (M+H) + = 542.5.

[0241] Example 26: 1-((S)-2-cyclopropyl-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)pipera Zin-1-yl)ethane-1-one (compound 26) [ka] Step 1: (S)-2-amino-2-cyclopropylethane-1-ol [ka] (S)-2-amino-2-cyclopropylacetic acid (6.9g, 60 mmol) anhydrous TH Add LiAlH4 (4.56g, 120 mmol) to F (190mL) solution slowly at 0°C. The mixture was added. The resulting solution was stirred at room temperature for 1 hour. This reaction mixture was then mixed with water (20 mL). Quenched and extracted with toluene (100 mL x 3). Combined into one EtOA The c phase was dehydrated over Na2SO4, filtered, and removed under vacuum to obtain the crude product (6.4g). This was then used in the next step without further purification. LC-MS(M+H) + = 102.0.

[0242] Step 2: (S)-1-Cyclopropyl-2-((3,5-Dibromopyridine-2-I (L)oxy)ethane-1-amine [ka] 3,5-Dibromo-2-fluoropyridine (5g, 20mmol) and (S)-2-A Anhydrous THF of Mino-2-cyclopropylethane-1-ol (2.5g, 25mmol) Slowly add NaH (2g, 60%, 50 mmol) to the (100 mL) solution at 0°C. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (20 mL). The butyl phase was extracted with HCl (100 mL x 3). The combined HCl phase was then treated with Na2SO4. The residue was dehydrated on 4, filtered, and removed by distillation under vacuum. The residue was then subjected to silica gel chromatography (DC). The above product was obtained by purification using M:MeOH=10:1 (6.5g, 2 steps). Yield of 97%. LC-MS (M+H) + = 334.9, 336.9.

[0243] Step 3: (S)-(1-Cyclopropyl-2-((3,5-Dibromopyridine-2- tert-butyl ethyl oxycarbamate [ka] (S)-1-cyclopropyl-2-((3,5-dibromopy) in DCM (100 mL) Lysine-2-yl(oxy)ethane-1-amine (6.5g, 19.3 mmol), (B oc)2O (6.3g, 29mmol), DMAP (0.1g, 0.82mmol), and Et3N (5.8g, 58 mmol) was stirred at room temperature for 12 hours. This reaction mixture was then mixed with water. Wash with (50 mL), extract with DCM (50 mL x 3), and combine the DCM phase into one N The residue was dehydrated on a2SO4, filtered, and removed by distillation under vacuum. The residue was then subjected to silica gel chromatography. The product was purified by (PE:Ã=5:1) to obtain the product (6.5g, yield 77%). %). LC-MS (M+H) + = 434.9, 436.9.

[0244] Step 4: (S)-7-Bromo-2-cyclopropyl-2,3-dihydro-1H-pyrido [2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl

Chemical Structure

[0245] Step 5: (S)-2-Cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert- butyl

Chemical Structure

[0246] Step 6: (S)-2-Cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

Chemical Structure

[0247] Step 7: (S)-2-chloro-1-(2-cyclopropyl-7-(4-fluorobene (zyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-i Ethane-1-on [ka] The marked compound (520 mg, 68% yield) from Step 7 is used as described in Step 9 of Example 1. (S)-2-cyclopropyl-7-(4-fluorobenzyl)-2, 3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloroacetyl Prepared from luchloride. LC-MS (M+H) + = 361.1.

[0248] Step 8: (2R,5S)-4-(2-((S)-2-cyclopropyl-7-(4-F Luolobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpho (Lino)methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 8 (300 mg, 66% yield) was used in Step 18 of Example 1. In the same manner as described above, (S)-2-chloro-1-(2-cyclopropyl-7-(4- Fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxa Zin-1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R)- Prepared from 3-methylmorpholino)methyl)piperazine-1-carboxylate tert-butyl . LC-MS (M+H) + = 638.9.

[0249] Step 9: 1-((S)-2-cyclopropyl-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)pipera Zin-1-yl)ethane-1-one (compound 26) Compound 26 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-((S)-2-cyclopropyl-7-(4-fluorobendi (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl Prepared from tert-butyl piperazine-1-carboxylate. The above salt was dissolved in NaHCO3 water. The solution was neutralized and extracted with ∙. The combined organic layer was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 26 (190 mg, 75% yield) as the free base. I obtained it. 1 H NMR (400MHz, DMSO-d6) δ 8.11 (s, 1H) , 7.86 (d, J = 1.8 Hz, 1H),7.29 - 7.25 (m, 2H ), 7.15 - 7.10 (m, 2H), 4.49- 4.46 (m, 1H), 4.24 - 4.21 (m, 1H), 4.14 -4.00 (m, 2H), 3.8 9 (s, 2H), 3.56 - 5.48 (m,2H), 3.40 - 3.37 ( m, 2H), 3.02 (brs, 1H), 2.85- 2.82 (m, 1H), 2.71 (brs, 2H), 2.58 - 2.54(m, 3H), 2.35 - 2 .09 (m, 3H), 2.04 (brs, 1H),1.77 (s, 1H), 0 .85 (d, J = 6.1 Hz, 3H), 0.80(brs, 4H), 0.52 (d, J = 5.9Hz, 1H), 0.44 (s, 3H). LC-MS (M+H ) + = 538.9.

[0250] Example 27: 1-((S)-2-cyclopropyl-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5 -Methylpiperazine-1-yl)ethane-1-one (compound 27) [ka] Step 1: (2R,5S)-4-(2-((S)-2-cyclopropyl-7-(4-F Luolobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmol (Forino)methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound from Step 1 (300 mg, 64% yield) is used in Step 18 of Example 1. In the same manner as described above, (S)-2-chloro-1-(2-cyclopropyl-7-(4- Fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxa Zin-1-yl)ethane-1-one and (2R,5S)-5-(((3R,5R)-3, 5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert- Prepared from butyl. LC-MS (M+H) + = 652.9.

[0251] Step 2: 1-((S)-2-cyclopropyl-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5 -Methylpiperazine-1-yl)ethane-1-one (compound 27) Compound 27 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-((S)-2-cyclopropyl-7-(4-fluorobendi (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmorpholino)meth Prepared from tert-butyl methylpiperazine-1-carboxylate. The above salt The mixture was neutralized with an aqueous solution of NaHCO3 and extracted with carboxylic acid. The combined organic layer was dehydrated. The mixture was filtered and concentrated. The residue was further freeze-dried to obtain compound 27 (210 mg, 83% yield). It was obtained as a free base. 1 H NMR(400 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.87(s, 1H), 7.28 - 7.25 (m, 2H), 7.12 (t, J = 8.8 Hz, 2H), 4.49- 4.47 (m, 1H) , 4.23 - 4.21 (m, 1H), 4.11- 4.09 (m, 1H), 3 .96 - 3.93 (m, 1H), 3.89 (s,2H), 3.50 - 3.48 (m, 2H), 3.25(s, 1H), 3.15 (brs, 2H), 3.04 - 3.01 (m, 1H), 2.76 - 2.68(m, 3H), 2.52 (br s, 2H), 2.40 (brs, 1H), 2.22- 2.19 (m, 1H), 2.07 - 2.02 (m, 1H), 1.96 -1.91 (m, 1H), 0.8 4 (brs, 10H), 0.53 - 0.51 (m,2H), 0.45 (s, 2 H). LC-MS (M+H) + = 552.9.

[0252] Example 28: 1-((S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydroxy Dro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R, 5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine-1 -yl)ethane-1-one (compound 28) [ka] Step 1: (S)-(1-((3,5-dibromopyridine-2-yl)oxy) pig tert-butyl 2-yl carbamate [ka] The marked compound (12 g, 94% yield) from Step 1 is used as described in Step 1 of Example 19. In the same manner as the method, (S)-(1-hydroxybutan-2-yl)carbamate ter Prepared from t-butyl and 3,5-dibromo-2-fluoropyridine. LC-MS ( M+H) + = 423.0.

[0253] Step 2: (S)-7-bromo-2-ethyl-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] The marked compound (1.1g, 11% yield) from Step 2 is described in Step 2 of Example 19. In a similar manner to the above method, (S)-(1-((3,5-dibromopyridine-2-yl) Prepared from tert-butyl butan-2-yl carbamate. LC-MS (M +H) + = 343.1.

[0254] Step 3: (S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro- 1H-Pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] The marked compound (1 g, 82% yield) from Step 3 was prepared according to the method described in Step 7 of Example 1. In a similar manner, (S)-7-bromo-2-ethyl-2,3-dihydro-1H-pyrido[ 2,3-b][1,4]oxazine-1-carboxylate tert-butyl and (4-fluorine Prepared from lobenzyl zinc(II) chloride. LC-MS(M+H) + = 373.2 .

[0255] Step 4: (S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazine [ka] The marked compound from Step 4 (700 mg, 95% yield) is described in Step 8 of Example 1. In a similar manner to the above method, (S)-2-ethyl-7-(4-fluorobenzyl)-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert - Prepared from butyl. LC-MS (M+H) + = 273.2.

[0256] Step 5: (S)-2-chloro-1-(2-ethyl-7-(4-fluorobenzyl)- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethanol n-1-on [ka] The compound indicated in Step 5 (550 mg, 61% yield) is described in Step 9 of Example 1. In a similar manner to the above method, (S)-2-ethyl-7-(4-fluorobenzyl)-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloroacetyl Prepared from loride. LC-MS (M+H) + = 349.2.

[0257] Step 6: (2R,5S)-4-(2-((S)-2-ethyl-7-(4-fluorobe (Nzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1- (Iyl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino) tert-butyl piperazine-1-carboxylate [ka] The compound indicated in Step 6 (760 mg, yield 77%) was used in Step 18 of Example 1. In the same manner as described above, (S)-2-chloro-1-(2-ethyl-7-(4-fluoro Benzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1 -yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R)-3-methyl Prepared from tert-butyl methyl (Lumorpholino)piperazine-1-carboxylate. C-MS (M+H) + = 626.4.

[0258] Step 7: 1-((S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydroxy Dro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-((2R, 5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine-1 -yl)ethane-1-one (compound 28) Compound 28 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-((S)-2-ethyl-7-(4-fluorobenzyl)-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2- Oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piper Prepared from tert-butyl din-1-carboxylate. The above salt was dissolved in an aqueous solution of NaHCO3. The mixture was blended and extracted with pharmaceutically acceptable phosphate. The combined organic layer was dehydrated, filtered, and concentrated. Residue The compound was further freeze-dried to obtain compound 28 (290 mg, 45% yield) as a free base. 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7. 84 (s, 1H), 7.25 (dd, J = 8.4,5.6 Hz, 2H), 7 .12 (t, J = 8.8 Hz, 2H), 4.45(d, J = 11.7 Hz, 2H), 4.20(d, J = 11.3 Hz, 1H), 4.09(d, J = 14.4 Hz, 1H), 3.88 (s, 2H),3.51 (s, 2H), 3. 42 (d, J = 15.9 Hz, 1H), 2.99(s, 1H), 2.82 ( d, J = 9.9 Hz, 2H), 2.73 (d,J = 11.5 Hz, 1H), 2.71 - 2.56(m, 4H), 2.27 (t, J = 10.8 Hz, 1H ), 2.16 (s, 2H), 2.00 (s, 1H),1.76 (s, 1H), 1.46 (s, 2H), 0.87 - 0.81 (m,9H). LC-MS (M+H ) + = 526.5.

[0259] Example 29: 1-((S)-2-benzyl-7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R ,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine- 1-yl)ethane-1-one (compound 29) [ka] Step 1: (S)-(1-((3,5-dibromopyridine-2-yl)oxy)-3- tert-butyl phenylpropan-2-yl carbamate [ka] N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]carbamate t ert-butyl (4.7g, 18.9mmol) and 3,5-dibromo-2-fluoropropyl Lysine (4.4g, 17.1 mmol) in THF (80mL) solution, under a nitrogen atmosphere, 0 At °C, NaH (865 mg, 21.6 mmol, 60%) was added in small amounts. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. Once the reaction was complete, the reaction mixture was removed. The mixture was quenched by adding water (60 mL). The resulting solution was then mixed with ethyl acetate (60 mL). Extraction was performed using L×3. The organic phase was combined, washed with saturated saline solution, and dehydrogenated on Na2SO4. The solvent was diluted. The solvent was concentrated under reduced pressure, and the residue was flash-chromatographed (DCM:EtO). The product was purified by Ac=3:1 to obtain the labeled product (9.9g, yield 73%). LC- MS (M+H) + = 485.0.

[0260] Step 2: (S)-2-benzyl-7-bromo-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] (S)-(1-((3,5-dibromopyridine-2-yl)oxy)-3-phenylp tert-butyl ropan-2-yl)carbamate (1.5g, 3.1mmol) In a 10 mL solution of F, add CuI (190 mg, 1.0 mmol) and Cs2CO3 (at room temperature). (2.1g, 6.4 mmol) and DMEDA (105 mg, 1.3 mmol) were added. The resulting mixture was stirred under a nitrogen atmosphere at 80°C for 16 hours. The resulting mixture was filtered, and the filter cake was washed with DCM (2 × 10 mL). The residue was concentrated under reduced pressure and subjected to flash chromatography (PE:siRNA=5:1). Therefore, the product was purified to obtain the indicated product (260 mg, yield 20%). LC-MS (M+H ) + = 405.1.

[0261] Step 3: (S)-2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] (S)-2-benzyl-7-bromo-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazine-1-carboxylate tert-butyl (260 mg, 0.6 mmol) ), chloro[(4-fluorophenyl)methyl]zinc (180 mg, 0.8 mmol), and Pd(t-Bu3P)2 (14 mg, 0.03 mmol) in THF (10 mL) solution The mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. Once the reaction was complete, this reaction mixture was removed. The mixture was quenched by adding MeOH (5 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (10 mL). The resulting mixture was filtered and filtered. The sample was washed with DCM (2 × 10 mL). The solvent was concentrated under reduced pressure, and the residue was flash-clotted. The product was purified by matrix (PE:Â=3:1) to obtain the indicated product (2 00 mg, yield 81%. LC-MS (M+H) + = 435.2.

[0262] Step 4: (S)-2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine [ka] (S)-2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-p Lido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl (200m 1,4-dioxide (g, 0.5 mmol) of HCl (gas) in a 5 mL DCM solution at 0°C. A xane solution (1.2 mL, 4.8 mmol, 4 M) was added dropwise. The resulting mixture was left at room temperature. The mixture was stirred for 3 hours. Once the reaction was complete, the resulting mixture was concentrated under reduced pressure. The mixture was diluted with saturated NaHCO3 solution (15 mL) and toluene (2 × 20 mL) Extraction was performed. The organic phase was combined, washed with saturated saline solution, and dehydrated on Na2SO4. The medium was concentrated under reduced pressure, and the residue was flash-chromatographed (PE:.'' = 1:1 The product was purified by LC-MS (M) to obtain the labeled product (120 mg, yield 78%). +H) + = 335.0.

[0263] Step 5: (S)-1-(2-benzyl-7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-chloro Tan-1-on [ka] The compound indicated in Step 5 (83 mg, crude) was prepared using the method described in Step 9 of Example 1. In a similar manner, (S)-2-benzyl-7-(4-fluorobenzyl)-2,3-dihydr Ro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloroacetyl chloride Prepared from [source]. This crude substance was used directly in the next step without purification. LC-MS (M+H) + = 411.0.

[0264] Step 6: (2R,5S)-4-(2-((S)-2-benzyl-7-(4-fluoro Benzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1 -yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino) Methyl)piperazine-1-carboxylate tert-butyl [ka] The marked compound (90 mg, 64% yield) from Step 6 is described in Step 18 of Example 1. Prepare in the same manner as the method described above, (S)-1-(2-benzyl-7-(4-fluorobenzyl (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-chloroethane-1-one and (2R,5S)-2-methyl-5-(((R)-3 -methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl was obtained. C-MS (M+H) + = 688.4.

[0265] Step 7: 1-((S)-2-benzyl-7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R ,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine- 1-yl)ethane-1-one (compound 29) (2R,5S)-4-(2-((S)-2-benzyl-7-(4-fluorobenzyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)- 2-Oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl) DCM of perazine-1-carboxylate tert-butyl (90 mg, 0.13 mmol) (3 mL) solution, 1,4-dioxane solution (0.5 mL, 2 mm) with HCl (gas) at 0°C. (4M) was added dropwise. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was then concentrated under reduced pressure. The resulting mixture was then prepared as a saturated NaHCO3 solution (1 Diluted with 0 mL. The resulting mixture was extracted with HCl (2 × 15 mL). Organic phase The samples were combined, washed with saturated saline solution, and dehydrated over Na2SO4. The solvent was concentrated under reduced pressure. The residue was then processed under the following conditions, namely, column XBridge Shield RP1 8 OBD columns, 30 × 150 mm, 5 μm; mobile phase, acetonitrile / water (10 mm) (Containing ol / L NH4HCO3 and 0.1% NH3·H2O), 25%~5% in 8 minutes Purified by preparative HPLC with a 5% gradient and a UV 254 nm detector. (The compound is shown.) (29 mg, yield 38%) was obtained. 1 1H NMR (400 MHz, DMSO-d6) δ 8.24(s, 1H), 7.92 (s, 1H), 7.34-7.25 (m, 2H), 7.26 (s, 3H), 7.21-7.10(m, 2H), 7.08 ( s, 2H), 4.76 (s, 1H), 4.37(d, J = 11.2 Hz, 1 H), 4.28-4.20 (m, 1H), 3.93(d, J = 2.2 Hz, 2 H), 3.69 (s, 1H), 3.51 (s,2H), 3.37 (d, J = 9.4 Hz, 2H), 3.00 (s, 1H),2.88 (s, 2H), 2.8 7-2.78 (m, 1H), 2.64-2.57 (m,4H), 2.44-2.2 8 (m, 2H), 2.29-2.07 (m, 2H),1.99 (s, 1H), 1.84 (t, J = 10.6 Hz, 1H),1.71-1.64 (m, 1H) , 0.82 (d, J = 6.2 Hz, 6H). LC-MS(M+H) + = 588 .2.

[0266] Example 30: 1-((S)-7-(4-fluorobenzyl)-2-(p-tolyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)pipera Zin-1-yl)ethane-1-one (compound 30) [ka] Step 1: (S)-2-amino-2-(p-tolyl)ethane-1-ol [ka] (S)-amino(4-methylphenyl)acetic acid (1.9g, 11.5 mmol) THF (30 mL) solution, LiAlH4 (17.5 mL, 17.5 mL) in a nitrogen atmosphere at 0°C. (mol, 1M) was added dropwise. The resulting mixture was stirred under a nitrogen atmosphere at 70°C for 16 hours. Once the reaction is complete, this reaction mixture can be converted by adding NaOH (2M) at 0°C. The mixture was then quenched. The resulting mixture was filtered, and the filter cake was washed with THF (2 × 10 mL). The filtrate was concentrated under reduced pressure. The aqueous layer was extracted with CH2Cl2 (2 × 30 mL). Organic The phases were combined, washed with saturated saline solution, and dehydrated over Na2SO4. The solvent was concentrated under reduced pressure. The compound was reduced to obtain the indicated compound (800 mg, 46% yield). LC-MS (M+H) + = 152.2.

[0267] Step 2: (S)-(2-hydroxy-1-(p-tolyl)ethyl)carbamate te rt -butyl [ka] (S)-2-amino-2-(p-tolyl)ethane-1-ol (800mg, 5.3mg) To a THF (20 mL) solution of (mol) and TEA (1.4 g, 13.2 mmol), add nitrogen Under atmospheric conditions, Boc2O (1.7 g, 7.9 mmol) was added in small amounts at 0°C. The mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours. Once the reaction was complete, the reaction mixture was removed. The mixture was quenched by adding saturated NaHCO3 solution (20 mL). The resulting solution was then converted to C Extraction was performed with H2Cl2 (2 × 30 mL). The organic phase was combined and washed with saturated saline solution. The solution was dehydrated on Na2SO4. The solvent was concentrated under reduced pressure, and the residue was examined by flash chromatography. The compound was purified by (DCM:MeOH=10:1) to obtain the marked compound (850 mg, yield 64%). LC-MS (M+H) + = 252.1.

[0268] Step 3: (S)-(2-((3,5-dibromopyridine-2-yl)oxy)-1- (p-tolyl)ethyl) tert-butyl carbamate [ka] The marked compound from Step 3 (1.3g, 86% yield) is described in Step 1 of Example 29. In a similar manner to the above method, (S)-(2-hydroxy-1-(p-tolyl)ethyl)carb Prepared from tert-butyl minate and 3,5-dibromo-2-fluoropyridine. C-MS (M+H) + = 485.0.

[0269] Step 4: (S)-7-bromo-2-(p-tril)-2,3-dihydro-1H-pyryl [2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 4 (350 mg, 31% yield) is used in Step 2 of Example 29. Using the same method as described above, (S)-(2-((3,5-dibromopyridine-2-yl) Prepared from tert-butyl xy)-1-(p-tolyl)ethyl)carbamate. LC -MS (M+H) + = 405.2.

[0270] Step 5: (S)-7-(4-fluorobenzyl)-2-(p-tril)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert- Butyl [ka] The compound indicated in Step 5 (275 mg, yield 73%) was used in Step 3 of Example 29. Using the same method as described above, (S)-7-bromo-2-(p-tolyl)-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl Prepared from (4-fluorobenzyl)zinc(II) chloride. LC-MS(M+H) + = 435.3.

[0271] Step 6: (S)-7-(4-fluorobenzyl)-2-(p-tril)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine [ka] The compound indicated in Step 6 (180 mg, 84% yield) is used in Step 4 of Example 29. Using the same method as described above, (S)-7-(4-fluorobenzyl)-2-(p-tril) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carbone Prepared from tert-butyl acid. LC-MS (M+H) + = 335.1.

[0272] Step 7: (S)-2-chloro-1-(7-(4-fluorobenzyl)-2-(p- Ryl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-i Ethane-1-on [ka] The compound indicated in Step 7 (162 mg, 73% yield) is described in Step 9 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2-(p-tril)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloro Prepared from cetyl chloride. LC-MS (M+H) + = 411.2.

[0273] Step 8: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2 -(p-tolyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpho (Lino)methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 8 (90 mg, 64% yield) is described in Step 18 of Example 1. In a similar manner to the above method, (S)-2-chloro-1-(7-(4-fluorobenzyl)-2 -(p-tolyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R)-3 Prepared from methylmorpholino(methyl)piperazine-1-carboxylate tert-butyl. . LC-MS (M+H) + = 688.4.

[0274] Step 9: 1-((S)-7-(4-fluorobenzyl)-2-(p-tril)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)pipera Zin-1-yl)ethane-1-one (compound 30) (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-(p- Ryl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-i (R)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)meth (L) Piperazine-1-carboxylate tert-butyl (90 mg, 0.13 mmol) To CM (3 mL) solution, add 0.5 mL of 1,4-dioxane solution (HCl (gas) at 0°C, 2 mmol (4M) was added dropwise. The resulting mixture was stirred at room temperature for 3 hours. The reaction was complete. The resulting mixture was then concentrated under reduced pressure. The solution was diluted with 10 mL of liquid. The resulting mixture was extracted with HCl (2 × 15 mL). The organic phases were combined, washed with saturated saline solution, and dehydrated over Na2SO4. The solvent was then subjected to reduced pressure. The residue was concentrated and then processed under the following conditions: column XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase, acetonitrile / water (1 (Containing 0 mmol / L NH4HCO3 and 0.1% NH3·H2O), 25 minutes Gradient of %~55%; Purified by preparative HPLC with a UV 254 nm detector. The compound (29 mg, 38% yield) was obtained. 1 HNMR (400 MHz, DMSO- d6) δ 8.24 (s, 1H), 7.92 (s, 1H), 7.34-7.25 (m, 2H), 7.26 (s, 3H), 7.21-7.10(m, 2H), 7. 08 (s, 2H), 4.76 (s, 1H), 4.37(d, J = 11.2H z, 1H), 4.28-4.20 (m, 1H),3.93 (d, J = 2.2H z, 2H), 3.69 (s, 1H), 3.51(s, 2H), 3.37 (d, J = 9.4 Hz, 2H), 3.00 (s, 1H),2.88 (s, 2H), 2.87-2.78 (m, 1H), 2.64-2.57(m, 4H), 2.44- 2.28 (m, 2H), 2.29-2.07 (m,2H), 1.99 (s, 1H ), 1.84 (t, J = 10.6 Hz, 1H),1.71-1.64 (m, 1 H), 0.82 (d, J = 6.2 Hz, 6H). LC-MS(M+H) + = 5 88.2.

[0275] Example 31: (S)-7-(4-fluorobenzyl)-2-methyl-1-(2-((2R ,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine- 1-yl)acetyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy Sadin-6-carboxamide (compound 31) [ka] Step 1: (S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-ca tert-butyl benzoate [ka] Take the marked compound (3g, 90% yield) from Step 1 as described in Step 1 of Example 21. In the same manner as the method, (S)-6-(acetoxymethyl)-7-(4-fluorobenzyl) -2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- Prepared from tert-butyl 1-carboxylate. LC-MS(M+H) + = 389. 2.

[0276] Step 2: (S)-1-(tert-butoxycarbonyl)-7-(4-fluorobene) Zyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxa Zin-6-carboxylic acid [ka] The marked compound (2g, crude) in Step 2 was prepared in the same manner as described in Step 2 of Example 21. In the following method, (S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-ca Prepared from tert-butyl benzoate. LC-MS (M+H) + = 403.2.

[0277] Step 3: (S)-6-carbamoyl-7-(4-fluorobenzyl)-2-methyl- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl [ka] (S)-1-(tert-butoxycarbonyl)-7-(4- Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]Oxazine-6-carboxylic acid (430 mg, 1.1 mmol), NH4Cl (28 9 mg, 5.3 mmol), DIPEA (276 mg, 2.1 mmol), and HATU The reaction mixture (407 mg, 1.1 mmol) was stirred overnight at room temperature. This mixture was then mixed with water. The sample was processed and extracted with toluene (30 mL x 3). The combined organic layer was then treated with saturated saline solution. The residue was washed, dehydrated over Na2SO4, filtered, and removed by distillation. The residue was then subjected to column chromatography. The product was purified by (PE:siRNA=2:1) ​​to obtain the labeled product (340 mg, yield) 79%). LC-MS (M+H) + = 402.1.

[0278] Step 4: (S)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro 1H-Pyrido[2,3-b][1,4]oxazine-6-carboxamide [ka] The compound indicated in Step 4 (255 mg, 100% yield) is used in Step 8 of Example 1. In the same manner as described above, (S)-6-carbamoyl-7-(4-fluorobenzyl)- 2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1 Prepared from tert-butyl carboxylate. LC-MS(M+H) + = 302.1 .

[0279] Step 5: (S)-1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2 -methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6- Carboxamide [ka] The marked compound (200 mg, 62% yield) from Step 5 is described in Step 9 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2-methyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carboxamide and Prepared from 2-chloroacetyl chloride. LC-MS (M+H) + = 378.1.

[0280] Step 6: (2R, 5S)-4-(2-((S)-6-Carbamoil-7-(4-Full Olobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4 ]Oxazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methyl (Tylmorpholino)methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 6 (150 mg, 88% yield) is used in Step 18 of Example 1. Using the same method as described above, (S)-1-(2-chloroacetyl)-7-(4-fluorobe (Nzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy Sazin-6-carboxamide and (2R,5S)-2-methyl-5-(((R)-3-methyl It was prepared from tert-butyl methyl((Tylmorpholino)methyl)piperazine-1-carboxylate. LC-MS (M+H) + = 655.3.

[0281] Step 7: (S)-7-(4-fluorobenzyl)-2-methyl-1-(2-((2R ,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine- 1-yl)acetyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy Sadin-6-carboxamide (compound 31) Compound 31 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-((S)-6-carbamoyl-7-(4-fluorobenzyl )-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorphol Prepared from tert-butyl ((n)methyl)piperazine-1-carboxylate. The above salt was prepared from Na The mixture was neutralized with an aqueous HCO3 solution and extracted with carboxylic acid. The combined organic layer was dehydrated and filtered. The compound was then concentrated. The residue was further freeze-dried to release compound 31 (53 mg, 41% yield). It was obtained as a base. 1 H NMR (400MHz, DMSO-d6) δ 8.37 (s , 1H), 7.80 (s, 1H), 7.44 (s,1H), 7.30 - 7.1 7 (m, 2H), 7.08 (t, J = 8.8Hz, 2H), 4.79 (s, 1H), 4.39 -4.26 (m, 4H), 4.07(d, J = 15.6 Hz , 1H), 3.55 - 3.45 (m, 3H),3.30 - 3.17 (m, 1 H), 2.97 (t, J = 9.7 Hz, 1H),2.83 - 2.72 (m, 4H), 2.60 - 2.56 (m, 2H), 2.37- 2.06 (m, 4H) , 1.96 (t, J = 9.4 Hz, 1H),1.74 (d, J = 11.6 Hz, 1H), 1.19 (d, J = 6.4 Hz,3H), 0.86 (d, J = 5.8 Hz, 6H). LC-MS (M+H) + = 555.5.

[0282] Example 32: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5- Dimethylmorpholino(methyl)-5-methylpiperazine-1-yl)acetyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazine-6-carboxamide (compound 32) [ka] Step 1: (2R, 5S)-4-(2-((S)-6-Carbamoil-7-(4-Full Olobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4 ]Oxazine-1-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-di Methylmorpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound from Step 1 (100 mg, 60% yield) is used in Step 18 of Example 1. Using the same method as described above, (S)-1-(2-chloroacetyl)-7-(4-fluorobe (Nzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy Sazin-6-carboxamide and (2R,5S)-5-(((3R,5R)-3,5-di Methylmorpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl Prepared from: LC-MS (M+H) + = 669.3.

[0283] Step 2: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5- Dimethylmorpholino(methyl)-5-methylpiperazine-1-yl)acetyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazine-6-carboxamide (compound 32) Compound 32 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-4-(2-((S)-6-carbamoyl-7-(4-fluorobenzyl )-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmorpho Prepared from tert-butyl linomethyl-2-methylpiperazine-1-carboxylate The above salt was neutralized with an aqueous solution of NaHCO3 and extracted with ammonium compounds. The organic layer was then combined. The mixture was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 32 (15 mg, yield). 17% was obtained as free base. 1 1HNMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.80 (s, 1H),7.44 (s, 1H), 7. 22 (s, 2H), 7.08 (t, J = 8.8Hz, 2H), 4.75 (s , 1H), 4.43 - 4.21 (m, 4H),3.96 (d, J = 15.4 Hz, 1H), 3.52 (d, J = 15.3Hz, 1H), 3.42 (d, J = 9.2 Hz, 2H), 3.08 (s, 2H),2.94 (d, J = 10 .5 Hz, 1H), 2.77 (d, J = 8.4Hz, 1H), 2.71 - 2 .55 (m, 5H), 2.30 - 2.18 (m,2H), 1.96 (d, J = 8.6 Hz, 1H), 1.24 - 1.18(m, 4H), 0.87 (d, J = 5.8 Hz, 3H), 0.83 (d, J= 6.0 Hz, 6H). LC- MS (M+H) + = 569.5.

[0284] Example 33: 1-((S)-7-(4-fluorobenzyl)-2-isobutyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2 R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine -1-yl)ethane-1-one (compound 33) [ka] Step 1: (S)-(1-((3,5-dibromopyridine-2-yl)oxy)-4- tert-butyl methylpentan-2-yl carbamate [ka] The marked compound (6g, 83% yield) in Step 1 was prepared according to the method described in Step 1 of Example 29. (S)-(1-hydroxy-4-methylpentan-2-yl)carbamyl by the same method as the law. Prepared from tert-butyl phosphate and 3,5-dibromo-2-fluoropyridine. LC -MS (M+H) + = 451.0.

[0285] Step 2: (S)-7-bromo-2-isobutyl-2,3-dihydro-1H-pyrido[ 2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 2 (760 mg, yield 15%) is used in Step 2 of Example 29. Using the same method as described above, (S)-(1-((3,5-dibromopyridine-2-yl) It was prepared from tert-butyl xy)-4-methylpentan-2-yl)carbamate. LC-MS (M+H) + = 371.1.

[0286] Step 3: (S)-7-(4-fluorobenzyl)-2-isobutyl-2,3-dihydr Ro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyric acid Ru [ka] The compound indicated in Step 3 (600 mg, yield 69%) is used in Step 3 of Example 29. By the same method as described above, (S)-7-bromo-2-isobutyl-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl and Prepared from (4-fluorobenzyl)zinc(II) chloride. LC-MS(M+H) + = 401.2.

[0287] Step 4: (S)-7-(4-fluorobenzyl)-2-isobutyl-2,3-dihydr Lo-1H-pyrido[2,3-b][1,4]oxazine [ka] The marked compound (350 mg, 91% yield) from Step 4 is used in Step 4 of Example 29. Using the same method as described above, (S)-7-(4-fluorobenzyl)-2-isobutyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid t Prepared from ert-butyl. LC-MS (M+H) + = 301.1.

[0288] Step 5: (S)-2-chloro-1-(7-(4-fluorobenzyl)-2-isobutyl (Lu-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl) Ethane-1-on [ka] The compound indicated in Step 5 (330 mg, 90% yield) is described in Step 9 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2-isobutyl-2, 3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloroacetyl Prepared from luchloride. LC-MS (M+H) + = 377.1.

[0289] Step 6: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2 -Isobutyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino )Methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 6 (300 mg, 57% yield) was used in Step 18 of Example 1. In the same manner as described above, (S)-2-chloro-1-(7-(4-fluorobenzyl)- 2-Isobutyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R)-3- Prepared from methylmorpholino(methyl)piperazine-1-carboxylate tert-butyl LC-MS (M+H) + = 654.5.

[0290] Step 7: 1-((S)-7-(4-fluorobenzyl)-2-isobutyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2 R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine -1-yl)ethane-1-one (compound 33) Compound 33 (13 mg, 6% yield) was prepared in the same manner as described in step 7 of Example 29. By law, (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-iso Butyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-i (R)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)meth Prepared from tert-butyl piperazine-1-carboxylate. 1 HNMR (300 MHz, DMSO-d6)δ 8.09 (s, 1H), 7.83 (d, J = 2 .1 Hz, 1H), 7.28-.16 (m, 2H),7.16-7.04 (m, 2H), 4.65-4.11 (m, 3H), 3.99(d, J = 15.9 Hz , 1H), 3.86 (s, 2H), 2.92 (s,2H), 2.82-2.65 (m, 4H), 2.58-2.49(m, 2H), 2.36-2.14 (m, 3 H), 2.11-1.87 (m, 3H), 1.66(s, 3H), 1.28 (d , J = 34.5 Hz, 3H), 0.91-0.80(m, 12H). LC-MS (M+H) + = 554.4.

[0291] Example 34: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazine-1-yl)ethane-1-one (compound 34) [ka] Step 1: (S)-(1-(benzyloxy)-3-((3-bromo-5-chloropyriol) tert-butyl hydroxy propane-2-yl carbamate [ka] The marked compound from Step 1 (19.5g, 78% yield) is used in Step 1 of Example 29. (R)-(1-(benzyloxy)-3-hydroxypropane -2-yl)carbamate tert-butyl and 3-bromo-5-chloro-2-fluoro Prepared from pyridine. LC-MS (M+H) + = 471.0.

[0292] Step 2: (S)-2-((benzyloxy)methyl)-7-chloro-2,3-dihydr Ro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyric acid Ru [ka] (S)-(1-(benzyloxy)-3-((3-bromo-5-chloropyridine-2- tert-butyl oxypropan-2-yl carbamate (19.5g, 41 In a 200 mL solution of dioxane (0.9 mmol), add XantPhos (4.9 g, 8. (4 mmol), Cs2CO3 (41.0 g, 125.9 mmol), and Pd2 (dba )3 (3.8g, 4.2 mmol) was added. The resulting mixture was heated under a nitrogen atmosphere at 100°C. The mixture was stirred at °C for 4 hours. Once the reaction was complete, water (200 mL) was added. The reaction mixture was quenched. The resulting solution was extracted with ethyl acetate (250 mL x 2). The organic phases were combined, washed with saturated saline solution, and dehydrated over Na2SO4. The solvent was then subjected to reduced pressure. The residue was concentrated and then subjected to flash chromatography (PE:Â=5:1). The compound was purified to obtain the labeled compound (14.3 g, 87% yield). LC-MS (M+H) + = 391.1.

[0293] Step 3: (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carb tert-butyl phosphate [ka] Under a nitrogen atmosphere, (S)-2-((benzyloxy)methyl)-7-chloro-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert -Butyl (14.3g, 36.6mmol), [1,3-bis[2,6-bis(propane [-2-yl)phenyl]-2,3-dihydro-1H-imidazole-2-yl]dichloro (3-Chloropyridine-1-ium-1-yl)palladium (1.2g, 1.8mmol) ), and THF (200 mL) and NMP of LiBr (9.5 g, 109.7 mmol) Add 15.4g of chloro[(4-fluorophenyl)methyl]zinc to a 300mL solution. (73.2 mmol) was added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was completed, and then 2.5% w / w citric acid (600 mL) was added. Then I quenched this reaction mixture. I extracted the resulting solution with ethyl acetate (600 mL x 3). The organic phase was removed. It was combined, washed with saturated saline solution, and dehydrated over Na2SO4. The solution was concentrated under reduced pressure, and the residue was subjected to flash chromatography (PE:SiO=1:1). The compound was purified by LC-MS (M+H) to obtain the marked compound (15g, 74% yield). + = 465.2.

[0294] Step 4: (S)-7-(4-fluorobenzyl)-2-(hydroxymethyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid te rt-butyl [ka] (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid ter t-butyl (15g, 32.3 mmol) in MeOH (150mL) and AcOH (30 Pd / C (8.6 g, 8.0 mmol, 10%) was added to a solution of (mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. Once the reaction was complete, this mixture was removed. The material was filtered through a Celite pad and concentrated under reduced pressure. The residue was then treated with a saturated NaHCO3 solution. The solution was made basic at pH=8. The resulting mixture was extracted with CH2Cl2 (200 mL x 3). The organic phases were combined, washed with saturated saline solution, and dehydrated over Na2SO4. The solvent was then reduced under reduced pressure. Flash chromatography is used to concentrate the solution and elute the residue with DCM:MeOH (10:1). The compound was purified by LC-MS to obtain the marked compound (11.0 g, yield 90%). M+H) + = 375.1.

[0295] Step 5: (R)-7-(4-fluorobenzyl)-2-(((methylsulfonyl)o Xy(methyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-Tert-butyl carboxylate [ka] (S)-7-(4-fluorobenzyl)-2-(hydroxymethyl)-2,3-dihyde Ro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyric acid DCM of 2.5g, 6.7 mmol and TEA (1.3g, 13.3 mmol) MsCl (1.2 g, 10.0 mmol) was added to the 40 mL solution at 0°C. The octopus was stirred under a nitrogen atmosphere at room temperature for 6 hours. Once the reaction was complete, the resulting mixture was obtained. The mixture was concentrated under reduced pressure. The residue was subjected to flash column chromatography (PE:EtO). The compound was purified by Ac=4:1 to obtain the labeled compound (3g, 92% yield). LC-MS (M+H) + = 453.0.

[0296] Step 6: (R)-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyri [2,3-b][1,4]oxazin-2-yl)methylmethanesulfonate [ka] The marked compound (2g, 85% yield) in Step 6 was prepared according to the method described in Step 4 of Example 29. In the same manner as the method, (R)-7-(4-fluorobenzyl)-2-(((methylsulfon (Lu)oxy)methyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy Prepared from tert-butyl sazin-1-carboxylate. LC-MS(M+H) + = 353.1.

[0297] Step 7: (S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] (R)-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3 -b][1,4]Oxazin-2-yl)methylmethanesulfonate (280mg, 0. MeOH (15 mL) solution of 8 mmol) and NaOMe (430 mg, 7.9 mmol) The liquid was stirred under a nitrogen atmosphere at 80°C for 16 hours. Once the reaction was complete, the resulting mixture was obtained. The mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (15 mL) and ethyl acetate (20 Extraction was performed using 3 mL of solution. The organic phase was combined, washed with saturated saline solution, and then extracted on Na2SO4. Dehydrated. The solvent was concentrated under reduced pressure, and the residue was subjected to flash column chromatography (DCM). The compound was purified using ammonium compounds (170 mg, 74% yield) in a ratio of 2:3. ) LC-MS (M+H) + = 289.1.

[0298] Step 8: (S)-2-chloro-1-(7-(4-fluorobenzyl)-2-(methoxy (Dimethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1 -yl)ethan-1-one

Chemical formula

[0299] Step 9: (2R,5S)-5-(((3R,5R)-3,5-Dimethylmorpholino) methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-(methoxymethyl )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl) -2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl

Chemical formula

[0300] Step 10: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmol (Forino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-Fur) Olobenzyl)-2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazine-1-yl)ethane-1-one (compound 34) Compound 34 (30 mg, 85% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) (Tyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-(methoxymethyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)- Prepared from tert-butyl 2-oxoethyl)-2-methylpiperazine-1-carboxylate did. 1 H NMR (300 MHz,DMSO-d6) δ 8.27 (s, 1H), 7.84 (s, 1H), 7.30-7.18 (m, 2H), 7.18-7.05 (m, 2H), 4.88 (s, 1H), 4.50(d, J = 11.4 Hz, 1H), 4.20 (d, J = 11.4, 2.7Hz, 1H), 4.08 (d, J = 15.0 Hz, 1H), 3.87 (s, 2H), 3.53-3.43 (m , 2H), 3.41-3.32 (m, 3H), 3.23(s, 3H), 3.21 -3.09 (m, 2H), 3.06-2.96 (m,1H), 2.87-2.62 (m, 4H), 2.59-2.50(m, 2H), 2.46-2.39 (m, 1 H), 2.30-2.17 (m, 1H), 2.17-2.04(m, 1H), 2 .01-1.88 (m, 1H), 0.91-0.79(m, 9H). LC-MS ( M+H) + = 556.3.

[0301] Example 35: 1-((S)-7-(4-fluorobenzyl)-2-(methoxymethyl)- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2 -((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) Perazine-1-yl)ethane-1-one (compound 35) [ka] Step 1: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2 -(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy (Sazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmethyl (ruhorino)methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 1 (115 mg, yield 59%) was used in Step 18 of Example 1. In the same manner as described above, (S)-2-chloro-1-(7-(4-fluorobenzyl)- 2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]o Xazazine-1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R From )-3-methylmorpholino)methyl)piperazine-1-carboxylate tert-butyl Prepared using LC-MS (M+H). + = 642.5.

[0302] Step 2: 1-((S)-7-(4-fluorobenzyl)-2-(methoxymethyl)- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2 -((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) Perazine-1-yl)ethane-1-one (compound 35) Compound 35 (57 mg, 59% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2- (Methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxa Zin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmol It was prepared from tert-butyl methyl piperazine-1-carboxylate. 1 HN MR (300 MHz, chloroform-d) δ 8.48 (s, 1H), 7.84 ( s, 1H), 7.23-7.10 (m, 2H),7.06-6.92 (m, 2H) ), 5.11 (t, J = 7.5 Hz, 1H),4.66-4.53 (m, 2H ), 4.23 (dd, J = 11.3, 2.8Hz, 1H), 3.89 (s, 2H), 3.76-3.51 (m, 3H), 3.51-3.29(m, 2H), 3.30 (s, 3H), 3.27-3.09 (m,2H), 3.09-2.88 (m, 2H), 2.87-2.74 (m, 2H),2.78-2.65 (m, 1 H), 2.62-2.54 (m, 1H), 2.53(s, 2H), 2.39-2 .28 (m, 1H), 2.23-2.02 (m,2H), 1.96-1.85 ( m, 1H), 1.02 (d, J = 6.3 Hz,3H), 0.96 (d, J = 6.3 Hz, 3H). LC-MS(M+H) + = 542.3.

[0303] Example 36: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-2-(Ethoxymethyl) (Tyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazine-1-yl)ethane-1-one (compound 36) [ka] Step 1: (S)-2-(ethoxymethyl)-7-(4-fluorobenzyl)-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] The marked compound from Step 1 (140 mg, 66% yield) was used in Step 7 of Example 34. (R)-(7-(4-fluorobenzyl)-2,3-dihydro- 1H-Pyrido[2,3-b][1,4]oxazin-2-yl)methylmethanesulfonate Prepared from t and sodium ethoxide. LC-MS (M+H) + = 303.3.

[0304] Step 2: (S)-2-chloro-1-(2-(ethoxymethyl)-7-(4-fluoro Benzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1 -Il)Ethan-1-one [ka] The marked compound (95 mg, 54% yield) from Step 2 is used as described in Step 9 of Example 1. By the same method, (S)-2-(ethoxymethyl)-7-(4-fluorobenzyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloro Prepared from acetyl chloride. LC-MS (M+H) + = 379.1.

[0305] Step 3: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) Methyl)-4-(2-((S)-2-(ethoxymethyl)-7-(4-fluorobenzyl )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl) (-2-oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 3 (155 mg, 77% yield) is used in Step 18 of Example 1. By the same method as described above, (S)-2-chloro-1-(2-(ethoxymethyl)-7-( 4-Fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4] Xazazine-1-yl)ethane-1-one and (2R,5S)-5-(((3R,5R)- 3,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid Prepared from t-butyl. LC-MS (M+H) + = 670.4.

[0306] Step 4: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-2-(Ethoxymethyl) (Tyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazine-1-yl)ethane-1-one (compound 36) Compound 36 (21 mg, 15% yield) was prepared in the same manner as described in step 7 of Example 29. The method is (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)meth (Lu)-4-(2-((S)-2-(ethoxymethyl)-7-(4-fluorobenzyl)- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2 Prepared from tert-butyl methylpiperazine-1-carboxylate (-oxoethyl) Ta. 1 ¹H NMR (300 MHz, chloroform-d) δ 8.50 (s, 1H), 7.83 (s, 1H), 7.21-7.11 (m,2H), 6.98 (t, J = 8.5 Hz, 2H), 5.09 (t, J =7.4 Hz, 1H), 4.62 (d, J = 11.3 Hz, 1H), 4.52(d, J = 13.7 Hz, 1H ), 4.24 (d, J = 11.4, 2.8 Hz,1H), 3.89 (s, 2 H), 3.63 (d, J = 10.9, 3.0Hz, 2H), 3.56-3.4 6 (m, 1H), 3.51-3.37 (m, 3H),3.42-3.26 (m, 2H), 3.21 (d, J = 10.5 Hz,1H), 3.12 (d, J = 1 3.7 Hz, 1H), 2.98-2.87 (m,1H), 2.86-2.77 ( m, 3H), 2.72 (d, J = 11.5,2.9 Hz, 1H), 2.58- 2.41 (m, 2H), 2.18-2.00 (m,2H), 1.14 (t, J = 7.0 Hz, 3H), 1.02 (d, J =6.2 Hz, 3H), 0.96 (d, J = 6.4 Hz, 6H). LC-MS (M+H) + = 570.5.

[0307] Example 37: 1-((S)-2-(ethoxymethyl)-7-(4-fluorobenzyl)- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2 -((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) Perazine-1-yl)ethane-1-one (compound 37) [ka] Step 1: (2R,5S)-4-(2-((S)-2-(ethoxymethyl)-7-(4 -Fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy (Sazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmethyl (ruhorino)methyl)piperazine-1-carboxylate tert-butyl [ka] The marked compound from Step 1 (150 mg, 85% yield) is used in Step 18 of Example 1. By the same method as described above, (S)-2-chloro-1-(2-(ethoxymethyl)-7-( 4-Fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4] Xazazine-1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R From )-3-methylmorpholino)methyl)piperazine-1-carboxylate tert-butyl Prepared using LC-MS (M+H). + = 656.4.

[0308] Step 2: 1-((S)-2-(ethoxymethyl)-7-(4-fluorobenzyl)- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2 -((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) Perazine-1-yl)ethane-1-one (compound 37) Compound 37 (40 mg, 47% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-4-(2-((S)-2-(ethoxymethyl)-7-(4- Fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxa Zin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmol It was prepared from tert-butyl methyl piperazine-1-carboxylate. 1 HN MR (300 MHz, DMSO-d6) δ 8.27(s, 1H), 7.83 ( s, 1H), 7.29-7.17 (m, 2H),7.17-7.02 (m, 2H) ), 4.79 (s, 1H), 4.48 (dd,J = 11.5, 1.3 Hz, 1H), 4.27-4.10 (m, 2H), 3.86(s, 2H), 3.60- 3.47 (m, 2H), 3.44-3.17 (m,7H), 3.07-2.92 (m, 2H), 2.86-2.56 (m, 5H),2.44-2.25 (m, 2 H), 2.22-2.16 (m, 1H), 2.15-2.03(m, 1H), 1 .87-1.77 (m, 1H), 1.02 (t,J = 7.0 Hz, 3H), 0 .93 (d, J = 6.2 Hz, 3H), 0.81(s, 3H). LC-MS ( M+H)+ = 556.3.

[0309] Example 38: 1-((S)-7-(4-fluorobenzyl)-2-(isopropoxymethic (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)meth (Lu)piperazine-1-yl)ethane-1-one (compound 38) [ka] Step 1: (S)-7-(4-fluorobenzyl)-2-(isopropoxymethyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] The marked compound from Step 1 (240 mg, 87% yield) was used in Step 7 of Example 34. By the same method as described above, (R)-(7-(4-fluorobenzyl)-2,3-dihydro -1H-Pyrido[2,3-b][1,4]oxazin-2-yl)methylmethanesulfone Prepared from phosphate and sodium isopropoxide. LC-MS(M+H) + = 31 7.1.

[0310] Step 2: (S)-2-chloro-1-(7-(4-fluorobenzyl)-2-(isopropyl Ropoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (N-1-Il) Ethan-1-O [ka] The compound indicated in Step 2 (225 mg, 90% yield) is described in Step 9 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2-(isopropoxy Methyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2 - Prepared from chloroacetyl chloride. LC-MS (M+H) + = 393.0.

[0311] Step 3: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2 -(isopropoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4 ]Oxazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methyl (Tylmorpholino)methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 3 (150 mg, 86% yield) is used in Step 18 of Example 1. In the same manner as described above, (S)-2-chloro-1-(7-(4-fluorobenzyl)- 2-(isopropoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1, 4] Oxazin-1-yl)ethane-1-one and (2R,5S)-2-methyl-5-( ((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-buty Prepared from LC-MS (M+H). + = 670.4.

[0312] Step 4: 1-((S)-7-(4-fluorobenzyl)-2-(isopropoxymethic (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)meth (Lu)piperazine-1-yl)ethane-1-one (compound 38) Compound 38 (63 mg, 73% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2- (isopropoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methyl Prepared from tert-butyl methyl (rumorpholino)piperazine-1-carboxylate. 1 ¹H NMR (300 MHz, chloroform-d) δ 8.50 (s, 1H), 7.8 3 (s, 1H), 7.20-7.09 (m, 2H),7.04-6.91 (m, 2H), 4.99-4.93 (m, 1H), 4.66-4.52(m, 2H), 4.23 (d, J = 11.3, 2.9 Hz,1H), 3.88 (s, 2H), 3.74-3.34(m, 6H), 3.26-3.01 (m, 2H), 3.00 -2.88 (m, 1H), 2.87-2.67 (m,3H), 2.62-2.50 (m, 2H), 2.33(s, 1H), 2.25-2.03 (m, 2H), 2 .01 (s, 1H), 1.95-1.85 (m,1H), 1.09 (d, J = 6.1 Hz, 3H), 1.06-0.99 (m,6H), 0.96 (d, J = 6.3 Hz, 3H). LC-MS (M+H) + = 570.3.

[0313] Example 39: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-(isopropoxymethyl)-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazin-1-yl)ethane-1-one (compound 39) [ka] Step 1: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) Methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-(isopropoxy Methyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1- (Iyl)-2-oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound from Step 1 (150 mg, 86% yield) is used in Step 18 of Example 1. Methods similar to those described, (S)-2-chloro-1-(7-(4-fluorobenzyl)-2 -(isopropoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4 ]Oxazine-1-yl)ethane-1-one and (2R,5S)-5-(((3R,5R )-3,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid Prepared with ert-butyl. LC-MS (M+H) + = 684.4.

[0314] Step 2: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-(isopropoxymethyl)-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazin-1-yl)ethane-1-one (compound 39) Compound 39 (60 mg, 72% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) (Tyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-(isopropoxymethyl (Tyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-i (L)-2-oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl Then it was prepared. 1 ¹H NMR (300 MHz, chloroform-d) δ 8.51 (s, 1H), 7.83 (s, 1H), 7.20-7.09(m, 2H), 7.03- 6.91 (m, 2H), 5.05-4.96 (m,1H), 4.65-4.47 (m, 2H), 4.27-4.19 (m, 1H),3.88 (s, 2H), 3. 68-3.57 (m, 2H), 3.55-3.36(m, 3H), 3.36-3. 26 (m, 2H), 3.22 (d, J = 9.8Hz, 1H), 3.10 (d , J = 13.7 Hz, 1H), 2.98-2.87(m, 1H), 2.85- 2.66 (m, 3H), 2.57-2.44 (m,2H), 2.16-2.02 (m, 2H), 1.10 (d, J = 6.1 Hz,3H), 1.05-0.99 (m, 6H), 0.96 (d, J = 6.4 Hz,6H). LC-MS (M+H ) + = 584.3.

[0315] Example 40: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-(phenoxymethyl)-2,3-dihydro-1H-pyrido[2,3- b) [1,4]oxazine-1-yl)ethane-1-one (compound 40) [ka] Step 1: (S)-7-(4-fluorobenzyl)-2-(phenoxymethyl)-2, 3-dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] The marked compound from Step 1 (240 mg, 80% yield) was used in Step 7 of Example 34. By the same method as described above, (R)-(7-(4-fluorobenzyl)-2,3-dihydro -1H-Pyrido[2,3-b][1,4]oxazin-2-yl)methylmethanesulfone Prepared from phosphate and sodium phenolate. LC-MS(M+H) + = 351. 0.

[0316] Step 2: (S)-2-chloro-1-(7-(4-fluorobenzyl)-2-(pheno Xymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-Iyl)Ethane-1-O1 [ka] The compound indicated in Step 2 (160 mg, 80% yield) is described in Step 9 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2-(phenoxymethic (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2-C Prepared from loloacetyl chloride. LC-MS (M+H) + = 427.2.

[0317] Step 3: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) Methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-(phenoxymethyl (Lu)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl )-2-oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The compound labeled in Step 3 (100 mg, 46% yield) is used in Step 18 of Example 1. In the same manner as described above, (S)-2-chloro-1-(7-(4-fluorobenzyl)- 2-(phenoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazine-1-yl)ethane-1-one and (2R,5S)-5-(((3R,5R) -3,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid Prepared from rt-butyl. LC-MS (M+H) + = 718.5.

[0318] Step 4: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-(phenoxymethyl)-2,3-dihydro-1H-pyrido[2,3- b) [1,4]oxazine-1-yl)ethane-1-one (compound 40) Compound 40 (48 mg, 56% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) (Tyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-(phenoxymethyl )-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl) Prepared from tert-butyl methylpiperazine-1-carboxylate (-2-oxoethyl) It was made. 1 ¹H NMR (300 MHz, chloroform-d) δ 8.47 (s, 1H ), 7.84 (s, 1H), 7.30-7.19(m, 2H), 7.19-7. 09 (m, 2H), 7.03-6.91 (m, 3H),6.85-6.76 (m , 2H), 5.41 (s, 1H), 4.78-4.61(m, 2H), 4.38 -4.30 (m, 1H), 4.13-3.95 (m,2H), 3.88 (s, 2 H), 3.65-3.55 (m, 2H), 3.34-3.23(m, 2H), 3 .23-3.10 (m, 2H), 2.97-2.85(m, 1H), 2.76 ( s, 4H), 2.57-2.43 (m, 2H),2.17-2.01 (m, 2H) ), 1.01 (d, J = 6.2 Hz, 3H),0.89 (d, J = 6.4 Hz, 6H). LC-MS (M+H) + = 618.5.

[0319] Example 41: 1-((S)-7-(4-fluorobenzyl)-2-(phenoxymethyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)- 2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) Piperazine-1-yl)ethane-1-one (compound 41) [ka] Step 1: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2 -(phenoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]o Xazazine-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methyl Morpholino(methyl)piperazine-1-carboxylate tert-butyl [ka] The marked compound (97 mg, 46% yield) from Step 1 is described in Step 18 of Example 1. In a similar manner to the above method, (S)-2-chloro-1-(7-(4-fluorobenzyl)-2 -(phenoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]o Xazazine-1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R From )-3-methylmorpholino)methyl)piperazine-1-carboxylate tert-butyl Prepared using LC-MS (M+H). + = 704.5.

[0320] Step 2: 1-((S)-7-(4-fluorobenzyl)-2-(phenoxymethyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)- 2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) Piperazine-1-yl)ethane-1-one (compound 41) Compound 41 (45 mg, 49% yield) was prepared in the same manner as described in Step 7 of Example 29. In this method, (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2- (phenoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy (Sazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmethyl Prepared from tert-butyl methyl piperazine-1-carboxylate. 1 H NMR (300 MHz, chloroform-d) δ 8.47 (s, 1H), 7.84 (s, 1H), 7.30-7.19 (m, 2H),7.19-7.09 (m, 2 H), 7.03-6.91 (m, 3H), 6.87-6.75(m, 2H), 5 .41 (t, J = 7.5 Hz, 1H), 4.74(dd, J = 11.5, 1 .5 Hz, 2H), 4.38-4.30 (m, 1H),4.11-3.92 (m , 2H), 3.88 (s, 2H), 3.73-3.63(m, 1H), 3.63 -3.48 (m, 2H), 3.21-3.09 (m,2H), 3.06-2.86 (m, 2H), 2.82-2.68(m, 3H), 2.56 (t, J = 10. 9 Hz, 1H), 2.48 (s, 1H), 2.29(s, 1H), 2.20- 1.98 (m, 3H), 1.96-1.84 (m,1H), 1.01 (d, J = 6.3 Hz, 3H), 0.86 (d, J =6.3 Hz, 3H). LC-MS (M+H) + = 604.4.

[0321] Example 42: 1-((S)-2-cyclohexyl-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)pipera Zin-1-yl)ethane-1-one (compound 42) [ka] Step 1: 3-Bromo-2-Fluoro-5-(4-Fluorobenzyl)pyridine [ka] 3,5-Dibromo-2-Fluoropyridine (9.5g, 37.2mmol), Xant Phos(650mg, 1.1 mmol), and Pd2(dba)3(70mg, 0.0 In a 75 mL solution of 7 mmol THF, chloro(4-fluorocarbon) was dissolved over 5 minutes at room temperature. Add a drop of zinc( The mixture was added. The resulting mixture was stirred at 40°C for 6 hours under a nitrogen atmosphere. The reaction was completed. The resulting mixture was then concentrated under reduced pressure, and the residue was subjected to flash column chromatography. The compound was purified using (PE:toluene=20:1) to obtain the marked compound (2.8g, yield) 31%). LC-MS (M+H) + = 284.0.

[0322] Step 2: (S)-(2-((3-bromo-5-(4-fluorobenzyl)pyridine- 2-Iyl)oxy)-1-cyclohexylethyl)carbamate tert-butyl [ka] The compound indicated in Step 2 (270 mg, 63% yield) is used in Step 1 of Example 29. Using the same method as described above, 3-bromo-2-fluoro-5-(4-fluorobenzyl) Lysine and (S)-(1-cyclohexyl-2-hydroxyethyl)carbamate ter Prepared from t-butyl. LC-MS (M+H) + = 507.1.

[0323] Step 3: (S)-2-cyclohexyl-7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert- Butyl [ka] The compound indicated in Step 3 (195 mg, yield 86%) is used in Step 2 of Example 34. Using the same method as described above, (S)-(2-((3-bromo-5-(4-fluorobenzyl )pyridine-2-yl)oxy)-1-cyclohexylethyl)carbamate tert- Prepared from butyl. LC-MS (M+H) + = 427.3.

[0324] Step 4: (S)-2-cyclohexyl-7-(4-fluorobenzyl)-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazine [ka] The compound indicated in Step 4 (130 mg, 89% yield) is used in Step 4 of Example 29. Using the same method as described above, (S)-2-cyclohexyl-7-(4-fluorobenzyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carbone Prepared from tert-butyl acid. LC-MS (M+H) + = 327.1.

[0325] Step 5: (S)-2-chloro-1-(2-cyclohexyl-7-(4-fluorobene (zyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-i Ethane-1-on [ka] The compound indicated in Step 5 (105 mg, 88% yield) is described in Step 9 of Example 1. In a similar manner to the above method, (S)-2-cyclohexyl-7-(4-fluorobenzyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloro Prepared from cetyl chloride. LC-MS (M+H) + = 403.2.

[0326] Step 6: (2R, 5S)-4-(2-((S)-2-Cyclohexyl-7-(4-F Luolobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpho (Lino)methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 6 (40 mg, 30% yield) is described in Step 18 of Example 1. In a similar manner to the above method, (S)-2-chloro-1-(2-cyclohexyl-7-(4-flu Luolobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R)-3 Prepared from methylmorpholino(methyl)piperazine-1-carboxylate tert-butyl. . LC-MS (M+H) + = 680.5.

[0327] Step 7: 1-((S)-2-cyclohexyl-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)pipera Zin-1-yl)ethane-1-one (compound 42) Compound 42 (12 mg, 24% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-4-(2-((S)-2-cyclohexyl-7-(4-full Olobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorphol It was prepared from tert-butyl methylpiperazine-1-carboxylate. 1 HNMR (300 MHz, chloroform-d) δ 8.26 (s, 1H), 7.83 (s, 1H), 7.18-7.08 (m, 2H), 7.04-6.92(m, 2H), 4.67 (d, J = 11.3 Hz, 1H),4.53-4.30 (m, 2H) , 4.17 (dd, J = 11.3, 2.7 Hz,1H), 3.90 (s, 2 H), 3.74-3.45 (m, 3H), 3.19(s, 1H), 3.04 (d , J = 8.4 Hz, 2H), 2.89-2.65(m, 4H), 2.53 (d , J = 7.7 Hz, 2H), 2.34 (s,3H), 2.15 (s, 2H) , 2.02-1.89 (m, 3H), 1.79-1.70(m, 1H), 1.3 9 (s, 1H), 1.26-0.63 (m, 12H). LC-MS(M+H) + = 580.5.

[0328] Example 43: 1-((S)-2-cyclohexyl-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5 -Methylpiperazine-1-yl)ethane-1-one (compound 43) [ka] Step 1: (2R, 5S)-4-(2-((S)-2-Cyclohexyl-7-(4-F Luolobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmol (Forino)methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound (61 mg, 41% yield) from Step 1 is described in Step 18 of Example 1. In a similar manner to the above method, (S)-2-chloro-1-(2-cyclohexyl-7-(4-flu Luolobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-Il)Ethane-1-Ole and (2R,5S)-5-(((3R,5R)-3,5 -dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert- Prepared from chill. LC-MS (M+H) + = 694.4.

[0329] Step 2: 1-((S)-2-cyclohexyl-7-(4-fluorobenzyl)-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-( (2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5 -Methylpiperazine-1-yl)ethane-1-one (compound 43) Compound 43 (15 mg, 27% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-4-(2-((S)-2-cyclohexyl-7-(4-full Olobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmorpho Prepared from tert-butyl linomethyl-2-methylpiperazine-1-carboxylate . 1 ¹H NMR (300 MHz, chloroform-d) δ 8.26 (s, 1H), 7 .84 (s, 1H), 7.14 (t, J = 7.1Hz, 2H), 6.98 ( t, J = 8.6 Hz, 2H), 4.68 (d,J = 11.3 Hz, 1H), 4.38 (s, 2H),4.22-4.12 (m, 1H), 3.90 (s, 2 H), 3.62 (d, J = 10.9 Hz, 2H),3.36-3.21 (m, 3H), 3.13-2.96 (m, 1H), 2.80(s, 4H), 2.69 ( d, J = 11.3 Hz, 1H), 2.47 (d, J = 10.1 Hz, 2H) , 2.25-1.92 (m, 4H), 1.77-1.53(m, 3H), 1.4 9-1.36 (m, 1H), 1.15-1.11 (m,2H), 1.06-0.8 6 (m, 13H). LC-MS (M+H) + = 594.3.

[0330] Example 44: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4 Oxazine-1-yl)ethane-1-one (compound 44) [ka] Step 1: (S)-(2-((3-bromo-5-chloropyridine-2-yl)oxy) tert-butyl phenylethyl carbamate (-1-phenylethyl)carbamate [ka] The marked compound (2.1g, 38% yield) from Step 1 is described in Step 1 of Example 34. (S)-(2-hydroxy-1-phenylethyl)carbamate Prepared from tert-butyl and 3-bromo-5-chloro-2-fluoropyridine. C-MS (M+H) + = 427.0.

[0331] Step 2: (S)-7-chloro-2-phenyl-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 2 (1.5g, 88% yield) is described in Step 2 of Example 34. In a similar manner to the above method, (S)-(2-((3-bromo-5-chloropyridine-2-yl Prepared from tert-butyl hydroxy-1-phenylethyl carbamate. LC- MS (M+H)+ = 347.1.

[0332] Step 3: (S)-7-(4-fluorobenzyl)-2-phenyl-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 3 (750 mg, 41% yield) is used in Step 3 of Example 34. Using the same method as described above, (S)-7-chloro-2-phenyl-2,3-dihydro-1H - Prepared from pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl Manufactured. LC-MS (M+H) + = 421.1.

[0333] Step 4: (S)-7-(4-fluorobenzyl)-2-phenyl-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine [ka] The compound indicated in Step 4 (550 mg, 96% yield) is used in Step 4 of Example 29. By the same method as described above, (S)-7-(4-fluorobenzyl)-2-phenyl-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid te Prepared from rt-butyl. LC-MS (M+H) + = 321.1.

[0334] Step 5: (S)-2-chloro-1-(7-(4-fluorobenzyl)-2-phenyl -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl) Tan-1-on [ka] The compound indicated in Step 5 (350 mg, 51% yield) is described in Step 9 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2-phenyl-2,3 -Dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloroacetyl Prepared from chloride. LC-MS (M+H) + = 397.1.

[0335] Step 6: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) Methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-phenyl-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-ox Soethyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 6 (150 mg, 57% yield) is used in Step 18 of Example 1. In the same manner as described above, (S)-2-chloro-1-(7-(4-fluorobenzyl)- 2-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine 1-Il)ethane-1-one and (2R,5S)-5-(((3R,5R)-3,5-j Methylmorpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl Prepared from: LC-MS (M+H) + = 688.4.

[0336] Step 7: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4 Oxazine-1-yl)ethane-1-one (compound 44) Compound 44 (51 mg, 66% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) (Tyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-phenyl-2,3- Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxo It was prepared from tert-butyl ethyl-2-methylpiperazine-1-carboxylate. 1 H NMR (300 MHz,DMSO- d6) δ 8.62 (s, 1H), 7.82 (d, J = 2.1Hz, 1H), 7.39-7.27 (m, 3H), 7.24 -7.11 (m, 4H), 7.08-6.94 (m,2H), 6.01 (s, 1 H), 4.86 (d, J = 11.7, 1.9Hz, 1H), 4.57-4.4 7 (m, 1H), 4.29 (d, J = 14.4Hz, 1H), 3.92 (s , 2H), 3.55 (dd, J = 11.0,2.9 Hz, 2H), 3.31 (d, J = 11.6 Hz, 1H), 3.25-3.14(m, 3H), 2.9 6 (d, J = 9.0 Hz, 1H), 2.82(dd, J = 11.9, 2.9 Hz, 1H), 2.74-2.65(m, 1H), 2.69-2.63 (m, 3 H), 2.63-2.44 (m, 2H), 2.37(t, J = 11.3 Hz, 1H), 2.07-1.95 (m, 1H), 1.18(d, J = 6.3 Hz, 3H), 0.78 (d, J = 6.3 Hz, 6H). LC-MS(M+H) + = 588.3.

[0337] Example 45: 1-((S)-7-(4-fluorobenzyl)-2-phenyl-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R ,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine- 1-yl)ethane-1-one (compound 45) [ka] Step 1: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2 -phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1 -yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino) Methyl)piperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 1 (150 mg, 58% yield) is used in Step 18 of Example 1. In the same manner as described above, (S)-2-chloro-1-(7-(4-fluorobenzyl)- 2-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine 1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R)-3-methyl It was prepared from tert-butyl methyl((Tylmorpholino)methyl)piperazine-1-carboxylate. LC-MS (M+H) + = 674.4.

[0338] Step 2: 1-((S)-7-(4-fluorobenzyl)-2-phenyl-2,3-di Hydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R ,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazine- 1-yl)ethane-1-one (compound 45) Compound 45 (44 mg, 35% yield) as a free base was added to step 7 of Example 29. Using the same method as described, (2R,5S)-4-(2-((S)-7-(4-fluoro benzyl)-2-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazin-1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methyl Prepared from tert-butyl methyl (rumorpholino)piperazine-1-carboxylate. 1 ¹H NMR (300 MHz, chloroform-d) δ 8.63 (s, 1H), 7.8 0 (s, 1H), 7.35-7.11 (m, 7H),7.06-6.95 (m, 2H), 6.23 (s, 1H), 4.94 (d,J = 11.5, 1.9 Hz, 1H), 4.54(d, J = 11.6, 3.0 Hz, 2H), 3.92 (s , 2H), 3.60 (d, J = 11.5 Hz,1H), 3.54-3.47 ( m, 1H), 3.51-3.42 (m, 1H),3.18-3.10 (m, 1H) ), 3.08-2.99 (m, 1H), 2.98(dd, J = 11.4, 2. 3 Hz, 1H), 2.89-2.76 (m, 2H),2.76-2.67 (m, 2H), 2.55 (t, J = 10.9 Hz,1H), 2.50 (s, 1H), 2.22-2.17(m, 1H), 2.09 (t, J = 10.9 Hz, 1H) , 2.01-1.91 (m, 1H), 1.83 (dd,J = 13.4, 3.1 Hz, 1H), 1.04 (d, J = 6.2 Hz,3H), 0.58 (d, J = 6.3 Hz, 3H). LC-MS (M+H) + = 574.3.

[0339] Example 46: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]Oxazine-1-yl)ethane-1-one (compound 46) [ka] Step 1: (S)-(1-((3-bromo-5-(4-fluorobenzyl)pyridine- 2-yl)oxy)-3-methylbutan-2-yl)carbamate tert-butyl [ka] The marked compound (2.4g, 75% yield) from Step 1 is described in Step 1 of Example 29. In a similar manner to the above method, 3-bromo-2-fluoro-5-(4-fluorobenzyl)pyri Zin and (S)-(1-hydroxy-3-methylbutan-2-yl)carbamate ter Prepared from t-butyl. LC-MS (M+H) + = 467.1.

[0340] Step 2: (S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihy Dro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-b Chill [ka] The compound indicated in Step 2 (370 mg, 95% yield) is used in Step 2 of Example 34. Using the same method as described above, (S)-(1-((3-bromo-5-(4-fluorobenzyl Pyridine-2-yl)oxy)-3-methylbutan-2-yl)carbamate tert - Prepared from butyl. LC-MS (M+H) + = 387.2.

[0341] Step 3: (S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihy Dro-1H-pyrido[2,3-b][1,4]oxazine [ka] The compound indicated in Step 3 (240 mg, 92% yield) was used in Step 4 of Example 29. In the same manner as described above, (S)-7-(4-fluorobenzyl)-2-isopropyl- 2,3-Dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid Prepared from tert-butyl. LC-MS (M+H) + = 287.1.

[0342] Step 4: (S)-2-chloro-1-(7-(4-fluorobenzyl)-2-isopro Pyr-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl ) Ethane-1-one [ka] The compound indicated in Step 4 (250 mg, 83% yield) is described in Step 9 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2-isopropyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2-chloroacetate Prepared from tyl chloride. LC-MS (M+H) + = 363.1.

[0343] Step 5: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) Methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-isopropyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2- Oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 5 (95 mg, 45% yield) is described in Step 18 of Example 1. In a similar manner to the above method, (S)-2-chloro-1-(7-(4-fluorobenzyl)-2 -Isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)ethane-1-one and (2R,5S)-5-(((3R,5R)-3,5- Dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert-buty Prepared from LC-MS (M+H). + = 654.3.

[0344] Step 6: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-2-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]Oxazine-1-yl)ethane-1-one (compound 46) Compound 46 (30 mg, 31% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) (Tyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-isopropyl-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-o It was prepared from xoethyl)-2-methylpiperazine-1-carboxylate tert-butyl. 1 ¹H NMR (300 MHz, chloroform-d) δ 8.8.26 (s, 1H), 7.83 (s, 1H), 7.19-7.08 (m, 2H), 7.03-6.92 (m, 2H), 4.66 (d, J = 11.2Hz, 1H), 4.38 (s, 1H), 4.25-4.15 (m, 1H), 3.90(s, 2H), 3.66- 3.57 (m, 2H), 3.33-3.27 (m,2H), 3.21 (s, 1H ), 2.78 (s, 4H), 2.72-2.62(m, 1H), 2.58-2. 24 (m, 2H), 2.15-2.02 (m, 1H),2.02-1.89 (m , 4H), 1.06 (d, J = 6.4 Hz,3H), 1.03-0.84 (m , 12H). LC-MS (M+H) + = 554.4.

[0345] Example 47: 1-((S)-7-(4-fluorobenzyl)-2-isopropyl-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-(( 2R,5R)-5-methyl-2-(((R)-3-methylmorpholinomethyl)piperazi n-1-i (Lu) Ethane-1-one (Compound 47) [ka] Step 1: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2 -Isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorphol (no)methyl)piperazine-1-carboxylate tert-butyl [ka] The marked compound (95 mg, 45% yield) from Step 1 is described in Step 18 of Example 1. In a similar manner to the above method, (S)-2-chloro-1-(7-(4-fluorobenzyl)-2 -Isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)ethane-1-one and (2R,5S)-2-methyl-5-(((R)-3- Prepared from methylmorpholino(methyl)piperazine-1-carboxylate tert-butyl LC-MS (M+H) + = 640.3.

[0346] Step 2: 1-((S)-7-(4-fluorobenzyl)-2-isopropyl-2,3 -dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)-2-(( 2R,5R)-5-methyl-2-(((R)-3-methylmorpholinomethyl)piperazi ¹-1-yl)ethane-1-one (compound 47) Compound 47 (36 mg, 44% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2- Isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine 1-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino Prepared from tert-butyl methylpiperazine-1-carboxylate. 1 HNMR ( 300 MHz, chloroform-d) δ 8.26 (s, 1H), 7.87-7.80 (m, 1H), 7.19-7.08(m, 2H), 7.05-6.92 (m, 2 H), 4.65 (dd, J = 11.4, 1.4Hz, 1H), 4.59-4. 28 (m, 2H), 4.27-4.16 (m, 1H),3.90 (s, 2H), 3.75-3.49(m, 3H), 3.26-2.96 (m, 3H), 2.90 -2.63 (m, 4H), 2.60-2.40 (m,2H), 2.33 (s, 1 H), 2.15 (s, 1H), 2.05-1.76(m, 4H), 1.02 (d d, J = 19.5, 6.4 Hz, 6H), 0.90(s, 6H). LC-MS (M+H) + = 540.5.

[0347] Example 48: 2-((2R,5R)-2-((3,3-dimethylmorpholino)methyl)- 5-Methylpiperazine-1-yl)-1-((S)-7-(4-fluorobenzyl)-6 -(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)ethane-1-one (compound 48) [ka] Step 1: (2R,5S)-4-benzyl-5-((3,3-dimethylmorpholino)me tert-butyl methylpiperazine-1-carboxylate (Tyl)-2-methylpiperazine-1-carboxylate [ka] The marked compound from Step 1 (500 mg, 81% yield) is used in Step 16 of Example 1. Using the same method as described above, 3,3-dimethylmorpholine and (2R,5R)-4-benzyl 5-(chloromethyl)-2-methylpiperazine-1-carboxylate tert-butyl Prepared using LC-MS (M+H). + = 418.4.

[0348] Step 2: (2R,5S)-5-((3,3-dimethylmorpholino)methyl)-2-methyl Chill tert-butyl piperazine-1-carboxylate [ka] The compound indicated in Step 2 (350 mg, crude) was prepared according to the method described in Step 17 of Example 1. In the same manner as the method, (2R,5S)-4-benzyl-5-((3,3-dimethylmorphol It was prepared from tert-butyl methyl-2-methylpiperazine-1-carboxylate. LC-MS (M+H) + = 328.3.

[0349] Step 3: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-5-((3,3-dimethylmethylmethyl Ruhorino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound in Step 3 (550 mg, yield 59% in 2 steps) was used in Example 1. In a similar manner to the method described in Step 18, (S)-(1-(2-chloroacetyl)-7- (4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazin-6-yl)methylacetate and (2R,5S)-5-((3 ,3-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid - Prepared from butyl. LC-MS (M+H) + = 698.4.

[0350] Step 4: ((S)-1-(2-((2R,5R)-2-((3,3-dimethylmorpho Linol(methyl)-5-methylpiperazine-1-yl)acetyl)-7-(4-fluorob (Nzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy (Sadin-6-yl)methylacetate [ka] The compound indicated in Step 4 (120 mg, 70% yield) is described in Step 8 of Example 1. In a similar manner to the above method, (2R,5S)-4-(2-((S)-6-(acetoxymethyl )-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-((3,3- Dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert-buty Prepared from LC-MS (M+H). + = 598.4.

[0351] Step 5: 2-((2R,5R)-2-((3,3-dimethylmorpholino)methyl)- 5-Methylpiperazine-1-yl)-1-((S)-7-(4-fluorobenzyl)-6 -(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)ethane-1-one (compound 48) ((S)-1-(2-((2R,5R)-2-((3,3-dimethylmorpholino)meth (L)-5-methylpiperazine-1-yl)acetyl)-7-(4-fluorobenzyl)- 2-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6 -Iyl)methylacetate (120 mg, 0.2 mmol) in a THF (5 mL) solution, A solution of LiOH (10 mg, 0.4 mmol) in H2O (5 mL) was added. The resulting mixture The mixture was stirred at room temperature for 1 hour. Once the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was collected under the following conditions, namely, column XBridge Shield RP1 8 OBD columns, 30 x 150 mm, 5 μm; mobile phase: acetonitrile / water (10 mm) (ol / L NH4HCO3 and 0.1% NH3·H2O), 23% to 53% in 8 minutes Gradient; Purified by preparative HPLC with UV 254 nm detector. The marked compound (47m g, yielding 42% was obtained. 1 ¹H NMR (300 MHz, chloroform-d) δ 8. 39 (brs, 1H), 7.14-7.03 (m,2H), 7.03-6.91 (m, 2 H),4.95 (s, 1 H), 4.64-4.47 (m, 2 H), 4.45-4.35 (m, 1 H), 4.35-4.24(m, 1 H), 4.19 -4.08 (m, 1H), 3.82 (s, 2H), 3.68-3.60 (m, 2H), 3.33-3.07 (m, 4H), 2.89-2.76(m, 1H) , 2.76-2.67 (m, 1 H), 2.57-2.40(m, 4 H), 2. 44-2.36 (m, 1 H), 2.23-2.01(m, 2 H), 1.36-1 .28 (m, 3 H), 1.05-0.98 (m,3 H), 0.98-0.89 (m, 6 H). LC-MS (M+H) + = 556.3.

[0352] Example 49: 2-((2R,5R)-2-(((2S,5R)-2,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyri do[2,3-b][1,4]oxazin-1-yl)ethane-1-one (compound 49) [ka] Step 1: (2R,5S)-4-Benzyl-5-(((2S,5R)-2,5-Dimethicone Lumorpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound from Step 1 (460 mg, 51% yield) is used in Step 16 of Example 1. Using the same method as described above, (2S,5R)-dimethylmorpholine and (2R,5R)-4 -benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylic acid tert- Prepared from butyl. LC-MS (M+H) + = 418.3.

[0353] Step 2: (2R,5S)-5-(((2S,5R)-2,5-dimethylmorpholino) Methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound from Step 2 (280 mg, 78% yield) was used in Step 17 of Example 1. Using the same method as described above, (2R,5S)-4-benzyl-5-(((2S,5R)-2 ,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid - Prepared from butyl. LC-MS (M+H) + = 328.3.

[0354] Step 3: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-5-(((2S,5R)-2 ,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid -butyl [ka] The compound indicated in Step 3 (150 mg, 62% yield) is used in Step 18 of Example 1. Using the same method as described above, (S)-(1-(2-chloroacetyl)-7-(4-fluoro Benzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]o Xazazine-6-yl)methylacetate and (2R,5S)-5-(((2S,5R)- 2,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid Prepared from t-butyl. LC-MS (M+H) + = 698.3.

[0355] Step 4: (2R,5S)-5-(((2S,5R)-2,5-dimethylmorpholino) Methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl (Lu)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid -butyl [ka] The compound indicated in Step 4 (130 mg, 92% yield) is described in Step 4 of Example 8. In a similar manner to the above method, (2R,5S)-4-(2-((S)-6-(acetoxymethyl )-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-(((2S, 5R)-2,5-dimethylmorpholino)methyl)-2-methylpiperazine-1-carbone Purified from tert-butyl acid. LC-MS (M+H) + = 656.3.

[0356] Step 5: 2-((2R,5R)-2-(((2S,5R)-2,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyri do[2,3-b][1,4]oxazin-1-yl)ethane-1-one (compound 49) Compound 49 as formate was prepared in the same manner as described in step 19 of Example 1. (2R,5S)-5-(((2S,5R)-2,5-dimethylmorpholino)methyl)-4 -(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl Tyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl From )-2-oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl Prepared. The above salt was neutralized with an aqueous NaHCO3 solution and extracted with ammonium compounds. Combined into one. The organic layer was dehydrated, filtered, and concentrated. The residue was further freeze-dried to obtain compound 49 (15m). g, yield 14%) was obtained as free base. 1 HNMR (400 MHz, DMSO-d 6) δ 8.22 (s, 1H), 7.21 - 7.17(m, 2H), 7.14 - 7.09 (m, 2H), 5.07 (t, J= 5.6 Hz, 1H), 4.7 9 (s, 1H), 4.43 - 4.32 (m,3H), 4.22 - 4.20 ( m, 1H), 4.06 - 4.00 (m, 2H),3.95 - 3.91 (m, 1H), 3.57 - 3.55 (m, 1H), 3.50- 3.47 (m, 1H) , 3.39 - 3.37 (m, 1H), 3.01- 2.96 (m, 1H), 2 .89 - 2.86 (m, 2H), 2.77 -2.74 (m, 1H), 2.71 (brs, 2H),2.60 (brs, 1H), 2.55 (brs, 1H), 2.32 - 2.27 (m, 1H), 2.21 -2.18 (m, 1H), 1.9 6 (brs, 1H), 1.64 - 1.55 (m,2H), 1.16 (d, J = 6.4 Hz, 3H), 0.97 (d, J =6.2 Hz, 3H), 0.86 (d, J = 6.2 Hz, 6H). LC-MS (M+H) + = 556.5.

[0357] Example 50: 2-((2R,5R)-2-((7-oxa-4-azaspiro[2.5]o Cutane-4-yl)methyl)-5-methylpiperazine-1-yl)-1-((S)-7- (4-Fluorobenzyl)-6-(Hydroxymethyl)-2-methyl-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one (chemical Compound 50) [ka] Step 1: (2R, 5S)-5-((7-Oxa-4-Azaspiro[2.5]Octane -4-yl)methyl)-4-benzyl-2-methylpiperazine-1-carboxylic acid -butyl [ka] The marked compound from Step 1 (500 mg, 81% yield) is used in Step 16 of Example 1. Using the same method as described, (2R,5R)-4-benzyl-5-(chloromethyl)-2- Methylpiperazine-1-carboxylate tert-butyl and 7-oxa-4-azaspiro 2.5] Prepared from octane. LC-MS (M+H) + = 416.3.

[0358] Step 2: (2R,5S)-5-((7-Oxa-4-Azaspiro[2.5]Octane -4-yl)methyl)2-methylpiperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 2 (320 mg, crude) was prepared according to the method described in Step 17 of Example 1. In a similar manner to the method, (2R,5S)-5-((7-oxa-4-azaspiro[2.5]o Cutan-4-yl)methyl)-4-benzyl-2-methylpiperazine-1-carboxylic acid Prepared from ert-butyl. LC-MS (M+H) + = 326.2.

[0359] Step 3: (2R, 5S)-5-((7-Oxa-4-Azaspiro[2.5]Octane -4-yl(methyl)-4-(2-((S)-6-(acetoxymethyl)-7-(4-flu Luolobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1, 4] Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carb tert-butyl phosphate [ka] The marked compound in Step 3 (448 mg, yield 53% in 2 steps) was used in Example 1. In a similar manner to the method described in Step 18, (S)-(1-(2-chloroacetyl)-7- (4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazin-6-yl)methylacetate and (2R,5S)-5-((7 -Oxa-4-azaspiro[2.5]octan-4-yl)methyl)-2-methylpiper Prepared from tert-butyl din-1-carboxylate. LC-MS(M+H) + = 6 96.4.

[0360] Step 4: (2R, 5S)-5-((7-Oxa-4-Azaspiro[2.5]Octane -4-yl)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-( (Droxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1, 4] Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carb tert-butyl phosphate [ka] The compound indicated in Step 4 (240 mg, composition) was prepared according to the method described in Step 4 of Example 8. In a similar manner, (2R,5S)-5-((7-oxa-4-azaspiro[2.5]oc Tan-4-yl)methyl)-4-(2-((S)-6-(acetoxymethyl)-7-(4 -Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][ [1,4]Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1- Prepared from tert-butyl benzoate. LC-MS (M+H) + = 654.4.

[0361] Step 5: 2-((2R,5R)-2-((7-Oxa-4-Azaspiro[2.5]O Cutane-4-yl)methyl)-5-methylpiperazine-1-yl)-1-((S)-7- (4-Fluorobenzyl)-6-(Hydroxymethyl)-2-methyl-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one (chemical Compound 50) Compound 50 (25 mg, 11% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-((7-oxa-4-azaspiro[2.5]octane- 4-Il(methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(Hyd Roxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4 Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carbone Prepared from tert-butyl acid. 1 HNMR (300 MHz, chloroform-d) δ 8.40 (brs, 1 H), 7.15-7.04(m, 2 H), 7.04- 6.92 (m, 2 H), 4.91 (s, 1 H),4.66-4.47 (m, 2 H), 4.44-4.24(m, 2 H), 4.18-4.07 (m, 1 H), 3.83 (s, 2H), 3.69-3.63 (m,2H), 3.43-3.30 (m, 2 H), 3.20-2.98 (m, 2 H),2.89-2.76 (m, 4H), 2.76-2.66 (m, 1H), 2.55-2.34(m, 3H) , 2.18-2.05 (m, 1 H), 1.36-1.27(m, 3 H), 1. 05-0.97 (m, 3H), 0.64-0.41(m, 4H). LC-MS ( M+H) + = 554.4.

[0362] Example 51: 2-((2R,5R)-2-(((R)-3-ethylmorpholino)methyl) -5-methylpiperazine-1-yl)-1-((S)-7-(4-fluorobenzyl)- 6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazine-1-yl)ethane-1-one (compound 51) [ka] Step 1: (2R,5S)-4-benzyl-5-(((R)-3-ethylmorpholino) Methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 1 (550 mg, yield 89%) was used in Step 16 of Example 1. (R)-3-ethylmorpholine and (2R,5R)-4-ben Zyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylate tert-butyl Prepared from: LC-MS (M+H) + = 418.3.

[0363] Step 2: (2R,5S)-5-(((R)-3-ethylmorpholino)methyl)-2- Methylpiperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 2 (350 mg, crude) was prepared according to the method described in Step 17 of Example 1. In the same manner as the method, (2R,5S)-4-benzyl-5-(((R)-3-ethylmorpho Prepared from tert-butyl linomethyl-2-methylpiperazine-1-carboxylate LC-MS (M+H) + = 328.3.

[0364] Step 3: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-5-(((R)-3-ethyl Morpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound in Step 3 (534 mg, yield 58% in 2 steps) was used in Example 1. (2R,5S)-5-(((R)-3-ethyl Morpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl and ( S)-(1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)methyl Prepared from acetate. LC-MS (M+H) + = 698.4.

[0365] Step 4: (2R,5S)-5-(((R)-3-ethylmorpholino)methyl)-4- (2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-meth (Lu-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl) (-2-oxoethyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 4 (250 mg, 88% yield) is described in Step 4 of Example 8. In a similar manner to the above method, (2R,5S)-4-(2-((S)-6-(acetoxymethyl )-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-(((R)- 3-Ethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert- Prepared from chill. LC-MS (M+H) + = 656.4.

[0366] Step 5: 2-((2R,5R)-2-(((R)-3-ethylmorpholino)methyl) -5-methylpiperazine-1-yl)-1-((S)-7-(4-fluorobenzyl)- 6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazine-1-yl)ethane-1-one (compound 51) Compound 51 (52 mg, 24% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((R)-3-ethylmorpholino)methyl)-4-( 2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-yl)- Prepared from tert-butyl 2-oxoethyl)-2-methylpiperazine-1-carboxylate did. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.49 (brs, 1 H), 7.16-7.08(m, 2 H), 7.05-6.95 (m, 2 H), 5.01 (s, 1 H), 4.67-4.52 (m,2 H), 4.52-4.36 (m, 2 H),4.36-4.26 (m, 1 H), 3.85 (s, 2 H), 3.79-3.65 (m, 2 H), 3.59-3.50(m, 1 H), 3.37 -3.21 (m, 2 H), 3.05-2.99 (m,1 H), 2.98-2.8 9 (m, 1H), 2.88-2.83 (m, 2H), 2.79-2.70 (m , 1 H), 2.68-2.54 (m, 2 H),2.21-2.12 (m, 3 H ), 2.02-1.94 (m, 1 H), 1.70-1.54(m, 1 H), 1 .36-1.29 (m, 4 H), 1.07-1.00(m, 3 H), 0.92- 0.84 (m, 3 H). LC-MS (M+H) + = 556.4.

[0367] Example 52: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl) -2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-yl)-2-((2R,5R)-2-(((R)-3-(methoxymethyl)morphol (N)methyl)-5-methylpiperazine-1-yl)ethane-1-one (compound 52) [ka] Step 1: (2R,5S)-4-benzyl-5-(((R)-3-(methoxymethyl) Morpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound from Step 1 (500 mg, 78% yield) is used in Step 16 of Example 1. (R)-3-(methoxymethyl)morpholine and (2R,5R) are obtained by the same method as described above. -4-benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylic acid Prepared from t-butyl. LC-MS (M+H) + = 434.3.

[0368] Step 2: (2R,5S)-5-(((R)-3-(methoxymethyl)morpholino) tert-butyl methylpiperazine-1-carboxylate (Tyl)-2-methylpiperazine-1-carboxylate [ka] The compound indicated in Step 2 (300 mg, crude) was prepared according to the method described in Step 17 of Example 1. In a similar manner to the method, (2R,5S)-4-benzyl-5-(((R)-3-(methoxym (Til)morpholino)methyl)-2-methylpiperazine-1-carboxylate tert-butyl Prepared from: LC-MS (M+H) + = 344.2.

[0369] Step 3: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-5-(((R)-3-(meth Xymethyl(morpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert- Butyl [ka] Step 3: The marked compound (425 mg, 51% yield in 2 steps) is used in Example 1. In a similar manner to the method described in Step 18, (2R,5S)-5-(((R)-3-(Meth Xymethyl(morpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert- Butyl and (S)-(1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2 -methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6- Prepared from methyl acetate. LC-MS (M+H) + = 714.4.

[0370] Step 4: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-6 -(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-5-(((R)-3-(meth Xymethyl(morpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert- Butyl [ka] The compound indicated in Step 4 (170 mg, 60% yield) is described in Step 4 of Example 8. In a similar manner to the above method, (2R,5S)-4-(2-((S)-6-(acetoxymethyl )-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-(((R)- 3-(methoxymethyl)morpholino)methyl)-2-methylpiperazine-1-carboxylic acid Prepared from tert-butyl. LC-MS (M+H) + = 672.4.

[0371] Step 5: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl) -2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-yl)-2-((2R,5R)-2-(((R)-3-(methoxymethyl)morphol (N)methyl)-5-methylpiperazine-1-yl)ethane-1-one (compound 52) Compound 52 (45 mg, 26% yield) as a free base was added to step 7 of Example 29. Using the same method as described, (2R,5S)-4-(2-((S)-7-(4-fluoro Benzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrid [2,3-b][1,4]Oxazin-1-yl)-2-oxoethyl)-5-(((R )-3-(methoxymethyl)morpholino)methyl)-2-methylpiperazine-1-carb Prepared from tert-butyl phosphate. 1 HNMR (300 MHz, chloroform-d ) δ 8.41 (brs, 1 H), 7.17-7.06(m, 2 H), 7.06 -6.94 (m, 2H), 4.97 (s, 1H), 4.68-4.46 (m, 3 H), 4.45-4.27 (m, 2 H), 3.86(s, 2 H), 3.77 -3.60 (m, 2 H), 3.58-3.42 (m,3 H), 3.39-3.3 3 (m, 2 H), 3.26 (s, 3 H),3.14-2.83 (m, 4 H) , 2.83-2.51 (m, 3 H), 2.41(s, 1 H), 2.32-1. 91 (m, 3 H), 1.36-1.28 (m,3 H), 1.07-0.99 ( m, 3 H). LC-MS (M+H) + = 572.4.

[0372] Example 53: 2-((2R,5R)-2-(((R)-3-(ethoxymethyl)morphol (((S)-7-(4-fluoro))methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluoro Benzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrid [2,3-b][1,4]Oxazin-1-yl)ethane-1-one (compound 53) [ka] Step 1: (R)-4-Benzyl-3-(ethoxymethyl)morpholine

Chem.

[0373] Step 2: (R)-3-(Ethoxymethyl)morpholine

Chem.

[0374] Step 3: (2R,5S)-4-benzyl-5-(((R)-3-(ethoxymethyl) Morpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] Step 3: The marked compound (338 mg, 51% yield in 2 steps) was added to the sample from Example 1. In a manner similar to that described in Step 16, (R)-3-(ethoxymethyl)morpholine and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1- Prepared from tert-butyl carboxylate. LC-MS (M+H) + = 448.3.

[0375] Step 4: (2R,5S)-5-(((R)-3-(ethoxymethyl)morpholino) tert-butyl methylpiperazine-1-carboxylate (Tyl)-2-methylpiperazine-1-carboxylate [ka] The compound indicated in Step 4 (280 mg, crude) was prepared according to the method described in Step 17 of Example 1. In the same manner as the method, (2R,5S)-4-benzyl-5-(((R)-3-(ethoxymethyl (Til)morpholino)methyl)-2-methylpiperazine-1-carboxylate tert-butyl Prepared from: LC-MS (M+H) + = 358.3.

[0376] Step 5: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-5-(((R)-3-(Eth Xymethyl(morpholino(methyl)-2-methylpiperazine-1-carboxylic acid tert- Butyl [ka] The compound indicated in Step 5 (307 mg, 55% yield) is described in Step 18 of Example 1. In a similar manner to the above method, (2R,5S)-5-(((R)-3-(ethoxymethyl)mol (Forino)methyl)-2-methylpiperazine-1-carboxylate tert-butyl and (S) -(1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3 -Dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-yl)methylacetate Prepared from tate. LC-MS (M+H) + = 728.4.

[0377] Step 6: (2R,5S)-5-(((R)-3-(ethoxymethyl)morpholino) (Tyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl )-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert- Butyl [ka] The marked compound (101 mg, 87% yield) from Step 6 is described in Step 4 of Example 8. In a similar manner to the above method, (2R,5S)-4-(2-((S)-6-(acetoxymethyl )-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-(((R)- 3-(ethoxymethyl)morpholino)methyl)-2-methylpiperazine-1-carboxylic acid Prepared from tert-butyl. LC-MS (M+H) + = 686.5.

[0378] Step 7: 2-((2R,5R)-2-(((R)-3-(ethoxymethyl)morphoyl (((S)-7-(4-fluoro))methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluoro Benzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrid [2,3-b][1,4]Oxazin-1-yl)ethane-1-one (compound 53) Compound 53 (54 mg, 42% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((R)-3-(ethoxymethyl)morpholino)meth (Lu)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl) -2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert- Prepared from chill. 1 H NMR(400 MHz, DMSO-d6) δ 8.19 ( brs, 1H), 7.26-7.17 (m, 2H), 7.17-7.07 (m, 2 H), 5.12-5.04(m, 1 H), 4.75 (s, 1 H), 4.4 9-4.30 (m, 3 H), 4.25-4.17(m, 1 H), 4.02-3. 93 (m, 3 H), 3.68-3.53 (m,2 H), 3.46-3.33 ( m, 4 H), 3.32-3.23 (m, 2 H),2.90-2.81 (m, 1 H), 2.81-2.73 (m, 3 H), 2.66-2.53(m, 2 H), 2.34-2.18 (m, 3 H), 2.08-1.98(m, 1 H), 1.96 -1.87 (m, 1 H), 1.21-1.15 (m,3 H), 1.10-1.0 2 (m, 3H), 0.89-0.83 (m, 3H). LC-MS (M+H) + = 586.4.

[0379] Example 54: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl) -2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-yl)-2-((2R,5R)-2-(((R)-3-(hydroxymethyl)morpho Lino(methyl)-5-methylpiperazine-1-yl)ethane-1-one (compound 54) [ka] Step 1: (S)-4-benzyl-3-(((tert-butyldimethylsilyl) oxy Methylmorpholine [ka] [(3R)-4-benzylmorpholin-3-yl]methanol (425mg, 2.1mg) In a 10 mL solution of DMF (350 mg, 5.2 mmol) and imidazole (mol) Under a nitrogen atmosphere, TBDMSCl (375 mg, 2.5 mmol) was added in small amounts at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours until the reaction was complete. Then, this reaction mixture was quenched with H2O at room temperature. The resulting mixture was toluene ( Extraction was performed using 2 x 30 mL. The organic phase was combined and washed with saturated saline solution, then Na2SO4 The solution was dehydrated above. The solvent was removed under reduced pressure, and the residue was subjected to flash column chromatography (P The compound was purified using E:alkyl=4:1 to obtain the marked compound (342 mg, yield 76%). %). LC-MS (M+H) + = 322.2.

[0380] Step 2: (S)-3-(((tert-butyldimethylsilyl)oxy)methyl) Ruhorin [ka] The compound indicated in Step 2 (200 mg, crude) was prepared according to the method described in Step 2 of Example 53. In the same manner as the method, (S)-4-benzyl-3-(((tert-butyldimethylsilyl Prepared from oxymethylmorpholine. LC-MS(M+H) + = 232.2 .

[0381] Step 3: (2R, 5S)-4-benzyl-5-(((S)-3-(((tert-bu Tyldimethylsilyl(oxy)methyl(morpholino)methyl)-2-methylpiperazine- 1-Tert-butyl carboxylate [ka] The marked compound in Step 3 (281 mg, yield 49% in 2 steps) was used in Example 1. In a similar manner to the method described in TEP 16, (S)-3-(((tert-butyldimethyl Silyl(oxy)methyl(morpholine) and (2R,5R)-4-benzyl-5-(chloro Prepared from tert-butyl methyl-2-methylpiperazine-1-carboxylate. LC -MS (M+H) + = 534.4.

[0382] Step 4: (2R,5S)-5-(((S)-3-(((tert-butyldimethyl syl methyl syl Lyl(oxy)methyl(morpholino)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl [ka] The compound indicated in Step 4 (220 mg, crude) was prepared according to the method described in Step 17 of Example 1. In the same manner as the law, (2R,5S)-4-benzyl-5-(((S)-3-(((ter t-butyldimethylsilyl(oxy)methyl(morpholino)methyl)-2-methylpiper Prepared from tert-butyl din-1-carboxylate. LC-MS(M+H) + = 4 44.3.

[0383] Step 5: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-5-(((S)-3-((( tert-butyldimethylsilyl(oxy)methyl(morpholino)methyl)-2-methyl tert-butyl piperazine-1-carboxylate [ka] The marked compound in Step 5 (250 mg, yield 58% in 2 steps) was used in Example 1. In the same manner as described in Step 18, (2R, 5S)-5-(((S)-3-((( tert-butyldimethylsilyl(oxy)methyl(morpholino)methyl)-2-methyl tert-butyl piperazine-1-carboxylate and (S)-(1-(2-chloroacetyl )-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2 Prepared from ,3-b][1,4]oxazine-6-yl)methyl acetate. LC-M S (M+H) + = 814.5.

[0384] Step 6: (2R,5S)-5-(((S)-3-(((tert-butyldimethyl syl methyl syl (Lyl)oxy)methyl)morpholino)methyl)-4-(2-((S)-7-(4-Fluor) Robenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyri [2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methyl tert-butyl piperazine-1-carboxylate [ka] The compound indicated in Step 6 (162 mg, 68% yield) is described in Step 4 of Example 8. In a similar manner to the above method, (2R,5S)-4-(2-((S)-6-(acetoxymethyl )-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-(((S)- 3-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)methyl)- Prepared from 2-methylpiperazine-1-carboxylate tert-butyl. LC-MS ( M+H) + = 772.4.

[0385] Step 7: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl) -2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-yl)-2-((2R,5R)-2-(((R)-3-(hydroxymethyl)morpho Lino(methyl)-5-methylpiperazine-1-yl)ethane-1-one (compound 54) Compound 54 (70 mg, 59% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((S)-3-(((tert-butyldimethylsil (L)oxy)methyl)morpholino)methyl)-4-(2((S)-7(4-fluoro) Benzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrid [2,3-b][1,4]Oxazin-1-yl)-2-oxoethyl)-2-methylpropyl It was prepared from perazine-1-carboxylate tert-butyl. 1 HNMR (400MHz, Chloroform-d)δ8.43(brs,1H),7.16-7.07(m,2H),7 .05-6.96(m,2H),4.88(s,1H),4.67-4.51(m,2H ),4.49-4.29(m,3H),3.96-3.67(m,6H),3.65-3 .48(m,3H),3.30-3.22(m,1H),3.13-3.00(m,2H ),2.99-2.86(m,2H),2.84-2.77(m,1H),2.67-2 .63(m,2H),2.40-2.35(m,1H),2.31-2.21(m,1H ),2.18-2.08(m,2H),1.35-1.29(m,3H),1.08-1 0.02 (m, 3H). LC-MS (M+H) + = 558.3.

[0386] Example 55: 2-((2R,5R)-2-(((S)-3-(difluoromethyl)morpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyri do[2,3-b][1,4]oxazine-1-yl)ethane-1-one (compound 55) [ka] Step 1: (S)-4-benzylmorpholine-3-carbaldehyde [ka] A 10 mL solution of DMSO (1.95 mL, 27.5 mmol) in DCM was prepared under a nitrogen atmosphere. Under gas pressure, at -78°C, oxalyl chloride (1.16 mL, 13.6 mmol) is dissolved in DCM. 5 mL of the solution was added dropwise. The resulting mixture was stirred under a nitrogen atmosphere at -78°C for 15 minutes. The above mixture was then heated at -78°C to [(3R)-4-benzylmorpholin-3-yl]meth A 5 mL solution of DCM containing 950 mg of Nol (4.6 mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at -78°C for a further 30 minutes. TEA (7.6) was added to the above mixture. 0 mL (54.7 mmol) was added dropwise over 10 minutes at -78°C. The resulting mixture was then heated to -7 The mixture was stirred for another hour at 8°C. Once the reaction was complete, the reaction mixture was heated to room temperature until saturated. The mixture was quenched with NaHCO3 solution. The resulting mixture was extracted with DCM (2 × 50 mL). The organic phases were combined, washed with saturated saline solution, and dehydrated over Na2SO4. The solvent was then reduced under reduced pressure. Remove below, and the residue is subjected to flash chromatography (PE:dimethyl=3:1). The compound was purified to obtain the indicated compound (455 mg, yield 48%). LC-MS(M+H) + = 206.2.

[0387] Step 2: (S)-4-benzyl-3-(difluoromethyl)morpholine [ka] (S)-4-benzylmorpholine-3-carbaldehyde (455 mg, 2.2 mmol) In a DCM solution of ) under a nitrogen atmosphere at 0°C, diethylaminosulfur trifluoride (345 (mg, 2.2 mmol) was added dropwise. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was then quenched at room temperature with a saturated NaHCO3 solution. The resulting mixture The organic phase was extracted using DCM (2 × 30 mL). The organic phase was combined and washed with saturated saline solution, and N The residue was dehydrated on a2SO4. The solvent was removed under reduced pressure, and the residue was flash-chromatographed. The compound was purified by (PE:dimethyl=2:1) ​​to obtain the marked compound (260 mg, yield) 51%). LC-MS (M+H) + = 228.1.

[0388] Step 3: (S)-3-(difluoromethyl)morpholine hydrochloride [ka] (S)-4-benzyl-3-(difluoromethyl)morpholine (260 mg, 1.1 mg) In a 12 mL solution of (mol) MeOH, add Pd / C (250 mg, 0.2) under a nitrogen atmosphere. 10% mmol was added. This mixture was then subjected to a hydrogen atmosphere using a hydrogen balloon. The mixture was hydrogenated at room temperature for 16 hours. Once the reaction was complete, the mixture was passed through a Celite pad. The mixture was then filtered. To the above mixture, a HCl dioxane solution (2 mL, 8 mmol, at room temperature) was added. 4M was added dropwise. The resulting mixture was stirred at room temperature for a further 30 minutes. The compound was concentrated under reduced pressure to obtain the indicated compound (200 mg, crude), and without purification, it was used as follows: Used in stepping. LC-MS (M+H) + = 138.1.

[0389] Step 4: (2R,5S)-4-benzyl-5-(((S)-3-(difluoromethyl Morpholino(methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] In Step 4, the marked compound (225 mg, yield 44% in 2 steps) was added to the solution of Example 1. (S)-3-(difluoromethyl)morpholine Hydrochloride and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazi Prepared from tert-butyl nitrate. LC-MS(M+H) + = 44 0.3.

[0390] Step 5: (2R,5S)-5-(((S)-3-(difluoromethyl)morpholino) Methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 5 (180 mg, crude) was prepared according to the method described in Step 17 of Example 1. In the same manner as the method, (2R,5S)-4-benzyl-5-(((S)-3-(difluoro Methyl(morpholino)methyl)-2-methylpiperazine-1-carboxylic acid tert-buty Prepared from LC-MS (M+H). + = 350.2.

[0391] Step 6: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b] [1,4]Oxazin-1-yl)-2-oxoethyl)-5-(((S)-3-(difu (Morphomethyl)morpholino(methyl)-2-methylpiperazine-1-carboxylic acid -butyl [ka] The marked compound of Step 6 (220 mg, yield 59% in 2 steps) was used in Example 1. In a similar manner to the method described in Step 18, (2R, 5S)-5-(((S)-3-(Jif (Morphomethyl)morpholino(methyl)-2-methylpiperazine-1-carboxylic acid -Butyl and (S)-(1-(2-chloroacetyl)-7-(4-fluorobenzyl)- 2-Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6 Prepared from -yl)methyl acetate. LC-MS (M+H) + = 720.4.

[0392] Step 7: (2R,5S)-5-(((S)-3-(difluoromethyl)morpholino) Methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl (Lu)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxadi (1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid -butyl [ka] The compound indicated in Step 7 (134 mg, 65% yield) is described in Step 4 of Example 8. In a similar manner to the above method, (2R,5S)-4-(2-((S)-6-(acetoxymethyl )-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-(((S)- 3-(difluoromethyl)morpholino)methyl)-2-methylpiperazine-1-carbone Prepared from tert-butyl acid. LC-MS (M+H) + = 678.3.

[0393] Step 8: 2-((2R,5R)-2-(((S)-3-(difluoromethyl)morpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyri do[2,3-b][1,4]oxazine-1-yl)ethane-1-one (compound 55) Compound 55 (53 mg, 46% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((S)-3-(difluoromethyl)morpholino) (Tyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl )-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert- It was prepared from butyl. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.41(b rs,1H),7.14-7.04(m,2H),7.03-6.92(m,2H),6 .32-5.87(m,1H),5.06-4.77(m,1H),4.64-4.50 (m,2H),4.44-4.35(m,1H),4.35-4.25(m,1H),4 .10-4.02(m,1H),3.83(s,2H),3.82-3.57(m,4H ),3.23-3.07(m,2H),2.95-2.79(m,3H),2.78-2 .64(m,2H),2.62-2.36(m,4H),2.19-2.07(m,1H ),1.35-1.23(m,3H),1.06-0.99(m,3H). LC-MS (M+H) + = 578.4.

[0394] Example 56: 2-((2R,5R)-2-((8-oxa-5-azaspiro[3.5]no Nan-5-yl)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-( 4-Fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro 1H-Pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one (compound) Item 56) [ka] Step 1: (2R, 5S)-5-((8-Oxa-5-Azaspiro[3.5]nonan- 5-Il(methyl)-4-benzyl-2-methylpiperazine-1-carboxylic acid tert- Butyl [ka] The marked compound from Step 1 (500 mg, 78% yield) is used in Step 16 of Example 1. In the same manner as described above, 8-oxa-5-azaspiro[3,5]nonane and (2R,5 R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylic acid Prepared from ert-butyl. LC-MS (M+H)+ = 430.3.

[0395] Step 2: (2R, 5S)-5-((8-Oxa-5-Azaspiro[3.5]nonan- 5-Il(methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The compound indicated in Step 2 (300 mg, crude) was prepared according to the method described in Step 17 of Example 1. In a similar manner to the method, (2R,5S)-5-((8-oxa-5-azaspiro[3.5]no Nan-5-yl)methyl)-4-benzyl-2-methylpiperazine-1-carboxylic acid te Prepared from rt-butyl. LC-MS (M+H) + = 340.3.

[0396] Step 3: (2R, 5S)-5-((8-Oxa-5-Azaspiro[3.5]nonan- 5-(yl)methyl)-4-(2-((S)-6-(acetoxymethyl)-7-(4-flu) Olobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4 Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carbone tert-butyl acid [ka] The marked compound in Step 3 (350 mg, 42% yield in 2 steps) was used in Example 1. In a similar manner to the method described in step 18, (2R,5S)-5-((8-oxa-5-a Zaspiro[3.5]nonan-5-yl)methyl)2-methylpiperazine-1-carbone tert-butyl acid and (S)-(1-(2-chloroacetyl)-7-(4-fluorobenzoate) (Nzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy Prepared from sazin-6-yl)methyl acetate. LC-MS(M+H) + = 71 0.4.

[0397] Step 4: (2R, 5S)-5-((8-Oxa-5-Azaspiro[3.5]nonan- 5-Il(methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(Hydro Roxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4 Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carbone tert-butyl acid [ka] The compound indicated in Step 4 (250 mg, 75% yield) is described in Step 4 of Example 8. Using a method similar to the above, (2R,5S)-5-((8-oxa-5-azaspiro[3.5 ]nonan-5-yl(methyl)-4-(2-((S)-6-(acetoxymethyl)-7- (4-Fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b [1,4]Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1 Prepared from tert-butyl carboxylate. LC-MS(M+H) + = 668.4 .

[0398] Step 5: 2-((2R,5R)-2-((8-Oxa-5-Azaspiro[3.5]no Nan-5-yl)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-( 4-Fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro 1H-Pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one (compound) Item 56) Compound 56 (59 mg, 28% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-((8-oxa-5-azaspiro[3,5]nonane-5 -Iyl(methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydro Xymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid Prepared from tert-butyl. 1 HNMR (300 MHz, chloroform-d) δ8. 45(brs,1H),7.17-7.06(m,2H),7.06-6.93(m,2 H),4.97(s,1H),4.66-4.50(m,2H),4.47-4.37( m,1H),4.37-4.24(m,2H),3.85(s,2H),3.72-3. 56(m,3H),3.48-3.38(m,1H),3.22-3.08(m,2H) ,2.93-2.66(m,3H),2.63-2.32(m,4H),2.32-2. 20(m,1H),2.17-2.00(m,3H),1.87-1.49(m,4H) ,1.37-1.29(m,3H),1.07-0.99(m,3H). LC-MS( M+H) + = 568.3.

[0399] Example 57: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl) -2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methyl (Tylmorpholino)methyl)piperazine-1-yl)ethane-1-one (compound 57) [ka] Step 1: (S)-(1-(benzyloxy)-3-((3,5-dibromo-6-meth Lupyridine-2-yl)oxy)propan-2-yl)carbamate tert-butyl [ka] The marked compound (9.8g, 99% yield) from Step 1 is described in Step 1 of Example 19. In a similar manner to the above method, (R)-(1-(benzyloxy)-3-hydroxypropane- 2-Il)carbamate tert-butyl and 3,5-dibromo-2-chloro-6-methyl Prepared from lupyridine. LC-MS (M+H) + = 529.0.

[0400] Step 2: (S)-2-((benzyloxy)methyl)-7-bromo-6-methyl-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid t ert-butyl [ka] The marked compound (4g, 74% yield) in Step 2 was prepared according to the method described in Step 2 of Example 34. In the same manner as the method, (S)-(1-(benzyloxy)-3-((3,5-dibromo-6 -Methylpyridine-2-yl)oxy)propan-2-yl)carbamate tert- Prepared from chill. LC-MS (M+H) + = 449.1.

[0401] Step 3: (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl )-6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine -1-Tert-butyl carboxylate [ka] The marked compound from Step 3 (2.9 g, 91% yield) is used as described in Step 7 of Example 1. In the same manner as the method, (S)-2-((benzyloxy)methyl)-7-bromo-6-methyl Tyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-cal It was prepared from tert-butyl benzoate and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 479.2.

[0402] Step 4: (S)-7-(4-fluorobenzyl)-2-(hydroxymethyl)-6- Methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-ca tert-butyl benzoate [ka] The marked compound (2g, 84% yield) in Step 4 was prepared according to the method described in Step 4 of Example 34. In the same manner as the method, (S)-2-((benzyloxy)methyl)-7-(4-fluorobe (Nzyl)-6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy Prepared from tert-butyl sazin-1-carboxylate. LC-MS(M+H) + = 389.2.

[0403] Step 5: (R)-7-(4-fluorobenzyl)-6-methyl-2-(((methyls Ruhonyl)oxy)methyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4 tert-butyl oxazine-1-carboxylate [ka] The compound indicated in Step 5 (2.3g, yield 99%) is used in Step 5 of Example 34. Using the same method as described above, (S)-7-(4-fluorobenzyl)-2-(hydroxymethyl (Tyl)-6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxa Prepared from tert-butyl din-1-carboxylate and MsCl. LC-MS(M+ H) + = 467.2.

[0404] Step 6: (R)-(7-(4-fluorobenzyl)-6-methyl-2,3-dihydro -1H-Pyrido[2,3-b][1,4]oxazin-2-yl)methylmethanesulfone te [ka] The marked compound (1.4g, 75% yield) from Step 6 is described in Step 6 of Example 34. In a similar manner to the above method, (R)-7-(4-fluorobenzyl)-6-methyl-2-(( (methylsulfonyl)oxy)methyl)-2,3-dihydro-1H-pyrido[2,3-b [1,4]oxazine-1-carboxylate tert-butyl was used to prepare the solution. LC-M S (M+H) + = 367.1.

[0405] Step 7: (S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-6-methyl Tyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine [ka] The compound indicated in Step 7 (665 mg, yield 58%) is used in Step 7 of Example 34. By the same method as described above, (R)-(7-(4-fluorobenzyl)-6-methyl-2, 3-Dihydro-1H-pyrido[2,3-b][1,4]oxazin-2-yl)methylmethyl Prepared from tansulfonate and sodium methoxide. LC-MS(M+H) + = 303.1.

[0406] Step 8: (S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-6-methyl Tyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-cal tert-butyl benzoate [ka] The compound indicated in Step 8 (590 mg, 79% yield) is described in Step 4 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2-(methoxymethyl )-6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine Prepared from: LC-MS (M+H) + = 403.2.

[0407] Step 9: (S)-1-(tert-butoxycarbonyl)-7-(4-fluorobene) Zyl)-2-(methoxymethyl)-6-methyl-2,3-dihydro-1H-pyrido[2, 3-b][1,4]oxazine 5-oxide [ka] The compound indicated in Step 9 (457 mg, 74% yield) is described in Step 5 of Example 1. In a similar manner to the above method, (S)-7-(4-fluorobenzyl)-2-(methoxymethyl )-6-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine Prepared from tert-butyl carboxylate. LC-MS(M+H) + = 419 .2.

[0408] Step 10: (S)-6-(acetoxymethyl)-7-(4-fluorobenzyl)-2 -(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxy tert-butyl carboxylate (sazine-1-carboxylate) [ka] The marked compound (409 mg, 93% yield) from Step 10 was used in Step 2 of Example 8. Using the same method as described above, (S)-1-(tert-butoxycarbonyl)-7-(4- Fluorobenzyl)-2-(methoxymethyl)-6-methyl-2,3-dihydro-1H- Prepared from pyrido[2,3-b][1,4]oxazine 5-oxide. LC-MS ( M+H) + = 461.2.

[0409] Step 11: (S)-(7-(4-fluorobenzyl)-2-(methoxymethyl)-2 ,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)methyl acetate [ka] The compound indicated in Step 11 (298 mg, 98% yield) is used in Step 8 of Example 1. By the same method as described above, (S)-6-(acetoxymethyl)-7-(4-fluoroben Zyl)-2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1 Prepared from tert-butyl oxazine-1-carboxylate. LC-MS(M+ H) + = 361.1.

[0410] Step 12: (S)-(1-(2-chloroacetyl)-7-(4-fluorobenzyl) -2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4] Oxazine-6-yl)methylacetate [ka] The marked compound (400 mg, crude) in Step 12 was prepared according to the method described in Step 9 of Example 1. In the same manner as the method, (S)-(7-(4-fluorobenzyl)-2-(methoxymethyl) -2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-yl) Prepared from chloroacetyl acetate and 2-chloroacetyl chloride. LC-MS(M+H) + = 437.1.

[0411] Step 13: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7- (4-Fluorobenzyl)-2-(Methoxymethyl)-2,3-Dihydro-1H-Pyrid [2,3-b][1,4]Oxazin-1-yl)-2-oxoethyl)-2-methyl- 5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert -butyl [ka] The marked compound (400 mg, crude) from Step 13 is prepared according to Step 18 of Example 1. By the same method as above, (S)-(1-(2-chloroacetyl)-7-(4-fluorobene Zyl)-2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1 ,4]Oxazin-6-yl)methylacetate and (2R,5S)-2-methyl-5- (((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert- Prepared from chill. LC-MS (M+H) + = 714.4.

[0412] Step 14: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)- 6-(hydroxymethyl)-2-(methoxymethyl)-2,3-dihydro-1H-pyrid [2,3-b][1,4]Oxazin-1-yl)-2-oxoethyl)-2-methyl- 5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert -butyl [ka] The marked compound (110 mg, 61% yield) from Step 14 was used in the same manner as in Step 4 of Example 8. In the following method, (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-(Methoxymethyl)-2,3-dihydro-1H-pyrido[ 2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methyl-5 -(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert- Prepared from butyl. LC-MS (M+H) + = 672.4.

[0413] Step 15: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl )-2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4 ]Oxazin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3- Methylmorpholino(methyl)piperazine-1-yl)ethane-1-one (compound 57) Compound 57 (20 mg, 15% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-6- (Hydroxymethyl)-2-(Methoxymethyl)-2,3-dihydro-1H-pyrido[2 ,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methyl-5- (((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert- Prepared from chill. 1 H NMR(300 MHz, DMSO-d6) δ 8.22 ( brs, 1H), 7.25-7.14 (m, 2H), 7.17-7.04 (m, 2H), 5.14-5.04(m, 1H), 4.85 (s, 1H), 4.5 4-4.45 (m, 1 H), 4.45-4.33(m, 2 H), 4.25-4. 09 (m, 2 H), 3.96 (s, 2 H),3.54-3.45 (m, 2 H) ), 3.49-3.33 (m, 1H), 3.30-3.24(m, 2H), 3. 21 (s, 3 H), 3.07-2.95 (m,1 H), 2.93-2.74 ( m, 2 H), 2.73-2.53 (m, 4H),2.39-2.12 (m, 3 H), 2.10-1.96 (m, 1 H), 1.82-1.71(m, 1 H), 1.22 (s, 1 H), 0.92-0.85 (m,3 H), 0.85-0.79 (m, 3H). LC-MS(M+H) + = 572.0.

[0414] Example 58: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-6-(hydroxymethyl)-2-(methoxymethyl)-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one (chemical Compound 58) [ka] Step 1: (2R,5S)-4-(2-((S)-6-(acetoxymethyl)-7-( 4-Fluorobenzyl)-2-(Methoxymethyl)-2,3-dihydro-1H-pyrido[ 2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-(((3R ,5R)-3,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carb tert-butyl phosphate [ka] Take the compound labeled in Step 1 (400 mg, crude) as described in Step 18 of Example 1. In a similar manner to the method, (S)-(1-(2-chloroacetyl)-7-(4-fluorobenzyl (Lu)-2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1, 4) Oxazin-6-yl)methyl acetate and (2R,5S)-5-(((3R,5 R)-3,5-dimethylmorpholino(methyl)-2-methylpiperazine-1-carboxylic acid Prepared from tert-butyl. LC-MS (M+H) + = 728.4.

[0415] Step 2: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) Methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl (Lu)-2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1, 4] Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carb tert-butyl phosphate [ka] The compound indicated in Step 2 (109 mg, 59% yield) is described in Step 4 of Example 8. In a similar manner to the above method, (2R,5S)-4-(2-((S)-6-(acetoxymethyl )-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-1H -Pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5- (((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine- Prepared from tert-butyl 1-carboxylate. LC-MS(M+H) + = 686. 4.

[0416] Step 3: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpho (Lino)methyl)-5-methylpiperazine-1-yl)-1-((S)-7-(4-fluor) Robenzyl)-6-(hydroxymethyl)-2-(methoxymethyl)-2,3-dihydro -1H-pyrido[2,3-b][1,4]oxazine-1-yl)ethane-1-one (chemical Compound 58) Compound 58 (29 mg, 32% yield) was prepared in the same manner as described in step 7 of Example 29. In this method, (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) (Tyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl )-2-(methoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4 Oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carbone Prepared from tert-butyl acid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.20 (brs, 1 H), 7.25-7.17(m, 2 H), 7.21- 7.07 (m, 2 H), 5.13-5.06 (m,1 H), 4.86 (s, 1 H), 4.55-4.36(m, 3 H), 4.26-4.18 (m, 1 H), 4.09-3.95 (m, 3H), 3.52-3.44(m, 2H), 3.43 -3.38 (m, 2H), 3.24 (s, 3H), 3.19-3.11 (m, 2H), 3.09-2.98 (m, 1H), 2.84-2.75(m, 1H) , 2.73-2.51 (m, 5 H), 2.50-2.44(m, 1 H), 2. 30-2.20 (m, 1 H), 2.19-2.10(m, 1 H), 2.00-1 .90 (m, 1 H), 0.90-0.80 (m,9 H). LC-MS (M+H) + = 586.3.

[0417] Example 59: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl) -2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine- 1-Iyl)-2-((2R,5R)-2-(((S)-3-(isopropoxymethyl)mo Ruhorino(methyl)-5-methylpiperazine-1-yl)ethane-1-one (compound 59) ) [ka] Step 1: (S)-(4-benzylmorpholin-3-yl)methylmethanesulfonate [ka] The compound indicated in Step 1 (335 mg, 61% yield) was used in Step 5 of Example 34. In the same manner as described above, (R)-(4-benzylmorpholine-3-yl)methanol and Prepared from MsCl. LC-MS (M+H) + = 286.1.

[0418] Step 2: (S)-4-benzyl-3-(isopropoxymethyl)morpholine [ka] The compound indicated in Step 2 (230 mg, 78% yield) was used in Step 7 of Example 34. (S)-(4-benzylmorpholin-3-yl)methylmethane by the same method as described above. Prepared from sulfonates and sodium isopropoxide. LC-MS(M+H) + = 250.2.

[0419] Step 3: (S)-3-(isopropoxymethyl)morpholine [ka] The compound indicated in Step 3 (160 mg, crude) was prepared according to the method described in Step 2 of Example 53. In a similar manner to the law, (S)-4-benzyl-3-(isopropoxymethyl)morpholine Prepared using LC-MS (M+H). + = 160.1.

[0420] Step 4: (2R, 5S)-4-benzyl-5-(((S)-3-(isopropoxymethicone) (Til)morpholino)methyl)-2-methylpiperazine-1-carboxylate tert-butyl [ka] The marked compound (310 mg, 46% yield in 2 steps) from Step 4 was used in Example 1. In a manner similar to that described in TEP 16, (S)-3-(isopropoxymethyl)morpho Phosphorus and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine Prepared from tert-butyl carboxylate. LC-MS(M+H) + = 462 .3.

[0421] Step 5: (2R,5S)-5-(((S)-3-(...

Claims

1. Equation (I): 【Chemistry 1】 A compound thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, During the ceremony, X １ and X ２ These are independently -O-, -S-, and -NR ａ - or -CR ａ R ｂ - and; I understand １ , m ２ , and m ３ Each of these is independently 0, 1, or 2; R １ａ 、R １ｂ 、R １ｃ 、R １ｄ 、and R ７ may be the same or different and each independently is hydrogen, halogen, -C １～８ alkyl, -C ２～８ alkenyl, -C ２～８ alkynyl, -C ３～８ cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ )NR ｂ R ｃ , -NR ａ R ｂ , -NR ａ COR ｂ , -NR ａ CONR ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO<00​​​​​​​​​​​​​​​​​​​​​​​​​​​ n is 0, 1, 2, 3, or 4; R ３ and R ５ These are, independently, hydrogen, halogen, and -C. ３～８ Cycloalkyl, or -C １～８ Alkyl, and the aforementioned -C １～８ Alkyl or -C ３～８ Cycloalkyl groups optionally contain at least one halogen or -OR ａ It has been replaced with; R ２ and R ４ Each of these is independently either hydrogen or -C １～８ It is alkyl; or R ４ and R ５ However, they form a spiro-3 to 5-membered carbon ring with the same carbon atom to which they are bonded; or R exists ２ One of the existing R ４ One of them is a crosslink, and the crosslink contains 0, 1, or 2 -CH ２ - Forming the aforementioned crosslink including a portion; or R １ｂ and existing R ４ One of them together forms a 3- to 6-membered carbon ring; or R １ｄ and existing R ４ One of them is a crosslink, and in the crosslink, one or two -CH ２ - Forming the crosslink including the portion; R ６ is hydrogen, halogen, -C １～８ alkyl, -C ２～８ alkenyl, -C ２～８ alkynyl, -C ３～８ cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ )NR ｂ R ｃ , -NR ａ R ｂ , -NR ａ COR ｂ , -NR ａ CONR ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ NR ｂ R ｃ , -SO ２ NR ａ R ｂ , or -NR ａ SO ２ R ｂ and each of the -C １～８ alkyl, -C ２～８ alkenyl, -C ２～８ alkynyl, -C ３～８ cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 to 3 R ｄ ; R ８ and R ９ These are, independently, hydrogen and -C. １～８ Alkyl, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, or -C ３～８ It is cycloalkyl; R １０ and R １１ These are, independently, hydrogen and -C. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) NR ｂ R ｃ , -NR ａ R ｂ , -NR ａ COR ｂ , -NR ａ CONR ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ NR ｂ R ｃ , -SO ２ NR ａ R ｂ , or -NR ａ SO ２ R ｂ And the above-C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally contain 1 to 3 R groups. ｄ It is replaced with, or R １０ and R １１ Both can choose 1 to 3 R's. ｄ It forms a spiro-3 to 5-membered carbon ring that is substituted with; R １２ and R １３ These are, independently, hydrogen and -C. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) NR ｂ R ｃ , -NR ａ R ｂ , -NR ａ COR ｂ , -NR ａ CONR ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ NR ｂ R ｃ , -SO ２ NR ａ R ｂ , or -NR ａ SO ２ R ｂ And the above-C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally contain 1 to 3 R groups. ｄ It is replaced with, or R １２ and R １３ Both have 1 to 3 R ｄ They form a spiro 3-5 membered carbon ring which is optionally substituted; R １４ and R １５ Each of these is independently either hydrogen or -C １～８ Selected from alkyl groups; Each R ａ , R ｂ , and R ｃ These are independently hydrogen, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally contain 1 to 3 R groups. ｄ It is replaced with, or (R ａ and R ｂ ), (R ａ and R ｃ ), or (R ｂ and R ｃ ) together with the atom(s) to which they are bonded form a 3- to 8-membered ring, the ring containing 0, 1, or 2 further heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the ring optionally contains 1 to 3 R ｄ It has been replaced with; R ｄ In each of their existences, they are independently hydrogen, halogen, and -C. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ｅ , -SR ａ , -SO ２ R ｅ , -SO ２ NR ｅ R ｆ , -COR ｅ , -CO ２ R 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 CO ２ R ｆ , -NR ｅ SONR ｆ R ｇ , -NR ｅ SO ２ NR ｆ R ｇ , or -NR ｅ SO ２ R ｆ And the above-C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally be a halogen, -C １～８ Alkyl, -OR ｈ , -NR ｈ R ｉ , substituted with at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ｅ , R ｆ , R ｇ , R ｈ , and R ｉ These are, independently, hydrogen and -C. １～８ Alkyl, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkynyl, cycloalkyl, heterocyclyl, aryl, aryl-C １～８ Alkyl- or heteroaryl, However, the above compound is as follows: Table 3A 【change】 Not a compound selected from, or a pharmaceutically acceptable salt or tautomer thereof, The aforementioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof.

2. Formula (II) or (III): 【Chemistry 2】 【Chemistry 16】 A compound thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, During the ceremony, X １ and X ２ These are independently -O-, -S-, and -NR ａ - or -CR ａ R ｂ - and; I understand １ , m ２ , and m ３ Each of these is independently 0, 1, or 2; R １ａ , R １ｂ , R １ｃ , and R １ｄ These may be the same or different, and each may independently be hydrogen, halogen, and -C. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) NR ｂ R ｃ , -NR ａ R ｂ , -NR ａ COR ｂ , -NR ａ CONR ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ NR ｂ R ｃ , -SO ２ NR ａ R ｂ , or -NR ａ SO ２ R ｂ And the above-C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally contain 1 to 3 R groups. ｄ It has been replaced with; R ７ It is a halogen; n is 0, 1, 2, 3, or 4; R ３ and R ５ These are, independently, hydrogen, halogen, and -C. ３～８ Cycloalkyl, or -C １～８ Alkyl, and the aforementioned -C １～８ Alkyl or -C ３～８ Cycloalkyl groups optionally contain at least one halogen or -OR ａ It has been replaced with; R ２ and R ４ Each of these is independently either hydrogen or -C １～８ It is alkyl; or R ４ and R ５ However, they form a spiro-3 to 5-membered carbon ring with the same carbon atom to which they are bonded; or R exists ２ One of the existing R ４ One of them is a crosslink, and the crosslink contains 0, 1, or 2 -CH ２ - Forming the aforementioned crosslink including a portion; or R １ｂ and existing R ４ One of them together forms a 3- to 6-membered carbon ring; or R １ｄ and existing R ４ One of them is a crosslink, and in the crosslink, one or two -CH ２ - Forming the crosslink including the portion; R ６ is hydrogen, halogen, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) NR ｂ R ｃ , -NR ａ R ｂ , -NR ａ COR ｂ , -NR ａ CONR ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ NR ｂ R ｃ , -SO ２ NR ａ R ｂ , or -NR ａ SO ２ R ｂ And the above-C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally contain 1 to 3 R groups. ｄ It has been replaced with; R ８ and R ９ These are, independently, hydrogen and -C. １～８ Alkyl, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkinyl, or -C ３～８ It is cycloalkyl; R １０ and R １１ These are, independently, hydrogen and -C. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) NR ｂ R ｃ , -NR ａ R ｂ , -NR ａ COR ｂ , -NR ａ CONR ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ NR ｂ R ｃ , -SO ２ NR ａ R ｂ , or -NR ａ SO ２ R ｂ And the above-C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally contain 1 to 3 R groups. ｄ It is replaced with, or R １０ and R １１ Both have 1 to 3 R ｄ They form a spiro 3-5 membered carbon ring which is optionally substituted; R １２ and R １３ These are, independently, hydrogen and -C. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ａ , -SR ａ , -SO ２ R ａ , -COR ａ , -CO ２ R ａ , -CONR ａ R ｂ , -C(=NR ａ ) NR ｂ R ｃ , -NR ａ R ｂ , -NR ａ COR ｂ , -NR ａ CONR ｂ R ｃ , -NR ａ CO ２ R ｂ , -NR ａ SONR ｂ R ｃ , -NR ａ SO ２ NR ｂ R ｃ , -SO ２ NR ａ R ｂ , or -NR ａ SO ２ R ｂ And the above-C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally contain 1 to 3 R groups. ｄ It is replaced with, or R １２ and R １３ Both have 1 to 3 R ｄ They form a spiro 3-5 membered carbon ring which is optionally substituted; Each R ａ , R ｂ , and R ｃ These are independently hydrogen, -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the -C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally contain 1 to 3 R groups. ｄ It is replaced with, or (R ａ and R ｂ ), (R ａ and R ｃ ), or (R ｂ and R ｃ ) together with the atom(s) to which they are bonded form a 3- to 8-membered ring, the ring containing 0, 1, or 2 further heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the ring optionally contains 1 to 3 R ｄ It has been replaced with; R ｄ In each of their existences, they are independently hydrogen, halogen, and -C. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ｅ , -SR ａ , -SO ２ R ｅ , -SO ２ NR ｅ R ｆ , -COR ｅ , -CO ２ R 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 CO ２ R ｆ , -NR ｅ SONR ｆ R ｇ , -NR ｅ SO ２ NR ｆ R ｇ , or -NR ｅ SO ２ R ｆ And the above-C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally be a halogen, -C １～８ Alkyl, -OR ｈ , -NR ｈ R ｉ , substituted with at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ｅ , R ｆ , R ｇ , R ｈ , and R ｉ These are, independently, hydrogen and -C. １～８ Alkyl, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkynyl, cycloalkyl, heterocyclyl, aryl, aryl-C １～８ Alkyl- or heteroaryl, However, the above compound is as follows: Table 3B 【change】 Not a compound selected from, or a pharmaceutically acceptable salt or tautomer thereof, The aforementioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof.

3. X ２ However, it is -O-, -NH-, -N(methyl)-, or -N(ethyl); I understand １ is 0; I understand ２ is 1; and I understand ３ is 0 or 1, The compound according to claim 1 or 2.

4. R ３ , and R ５ These are hydrogen, methyl or ethyl, and -CH, respectively. ２ OH, -CH ２ OCH ３ ien-CH ２ OC ２ H ５ ,-CHF ２ ien-CH ２ OCH(CH ３ ) ２ , cyclopropyl, or CF ３ is; or R ４ and R ５ The compound according to claim 1 or 2, wherein they form a spiro-3 to 5-membered carbon ring together with the same carbon atom to which they are bonded. 【Request Item 5】 【Chemistry 3】 but, 【Chemistry 4】 And; In the formula, R １ａ , R １ｂ , R １ｃ , and R １ｄ Each of these independently produces hydrogen, halogen, and -C. １～８ Alkyl or oxo, and the -C １～８ The alkyl group is optionally substituted with at least one halogen; R ２ , R ３ , R ４ , R ５ , and R ａ The compound according to claim 1 or 2, wherein is as defined with respect to formula (I).

6. R １ｃ and R ４ is hydrogen, R １ｄ and R ５ These independently produce hydrogen, or -C １～８ The compound according to claim 5, wherein it is alkyl.

7. (i) R ５ However, halogen, -C ２ H ５ ien-CH ３ Cyclopropyl, CHF ２ ien-CH ２ F, -CF ３ ien-CH ２ OH, -CH ２ OCH ３ ien-CH ２ OC ２ H ５ ien-CH ２ OCH(CH ３ ) ２ And R ４ is hydrogen or -CH ３ is; or (ii) R ５ and R ４ However, together with the bonded carbon atoms, they form a 3- to 5-membered carbon ring; or (iii) R ２ and R ４ Both are crosslinks, and one -CH is present in the crosslink. ２ - Forms the crosslink including the portion, and R ３ and R ５ Each of them is hydrogen; or (iv)R １ｂ and R ４ They together form a three-membered carbon ring, and R １ａ and R ５ Each of them is hydrogen; or (v) R １ｄ and R ４ Both are crosslinks, and in the crosslink there are two -CH ２ - Forms the crosslink including the portion, and R １ｃ and R ５ Each of them is hydrogen. The compound according to claim 5. 【Request Item 8】 【Chemistry 7】 but, 【Chemistry 8-1】 【Chemistry 8-2】 The compound according to claim 5. 【Request Item 9】 【Chemistry 9】 but, 【Chemistry 10】 And; R ７ The compound according to claim 1 or 2, wherein F is present.

10. R ６ However, hydrogen, -CN, halogen, morpholine, -CONR ａ R ｂ , -NR ａ COR ｂ , -NR ａ SO ２ R ｂ , -OR ａ , -NR ａ R ｂ , -C ３～５ Cycloalkyl, phenyl, or -C １～８ Alkyl, and the aforementioned -C １～８ Alkyl or -C ３～５ Cycloalkyl groups optionally have at least one R ｄ It has been replaced with; R ａ and R ｂ These are hydrogen and -C, respectively. ３～６ Cycloalkyl, or -C １～８ It is alkyl; R ｄ Each of these entities exists independently of the other, -CH ２ F, -CHF ２ , -CF ３ , -F, -Cl, -Br, -I, -OH, -NH ２ , -SH, -CN, -CONH ２ -H, -CH ３ , -C ２ H ５ , -C ３ H ７ ien-CH ２ OH, -OCH ３ , -OC ２ H ５ Morpholino, 【Chemistry 11】 The compound according to claim 1 or 2, which is otherwise cyclopropyl.

11. R ６ However, hydrogen, halogen, -CN, -CONH ２ , 【Chemistry 13】 Cyclopropyl, -CH ２ OH, -CF ３ -OH, -CH ３ , or -OC ２ H ５ The compound according to claim 10.

12. R ６ However, -CONR ａ R ｂ , -NR ａ R ｂ , -NR ａ CO-R ｂ , -NR ａ -SO ２ -R ｂ , or -OR ａ And; R ａ and R ｂ These are hydrogen and -C respectively. ３～６ Cycloalkyl, -C １～８ Alkyl, 5 or 6-membered heterocyclyl, aryl, or heteroaryl, and the -C １～８ Alkyl, -C ３～６ Each of the cycloalkyl, 5- or 6-membered heterocyclyl, aryl, or heteroaryl groups may optionally contain 1 to 3 R groups. ｄ It is replaced by; or R ａ and R ｂ However, together with the atom(s) to which they are bonded, they form a 3- to 8-membered ring, and the ring(s) contain 0, 1, or 2 further heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the ring(s) optionally contain 1 to 3 R ｄ It has been replaced with; R ｄ However, in each of their existences, hydrogen, halogen, and -C exist independently. １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ２ , -OR ｅ , -SR ａ , -SO ２ R ｅ , -SO ２ NR ｅ R ｆ , -COR ｅ , -CO ２ R 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 CO ２ R ｆ , -NR ｅ SONR ｆ R ｇ , -NR ｅ SO ２ NR ｆ R ｇ , or -NR ｅ SO ２ R ｆ And the above-C １～８ Alkyl, -C ２～８ Alkenyl, -C ２～８ Alkinyl, -C ３～８ Each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl groups may optionally be a halogen, -C １～８ Alkyl, -OR ｈ , -NR ｈ R ｉ , substituted with at least one substituent selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ｅ , R ｆ , R ｇ , R ｈ , and R ｉ Each of them independently produces hydrogen and -C １～８ Alkyl, C １～８ Alkoxy-C １～８ Alkyl-, -C ２～８ Alkenyl, -C ２～８ Alkynyl, cycloalkyl, heterocyclyl, aryl, aryl-C １～８ It is alkyl- or heteroaryl; Optional, R ６ ga-CONR ａ R ｂ And, R ａ and R ｂ These atoms, together with the nitrogen atoms to which they are bonded, form a 4-6 membered ring, the ring containing 0, 1, or 2 further heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the ring optionally contains 1-3 R ｄ It has been replaced with; R ｄ In each of their existences, they are independently halogen, -C １～３ Alkyl, or -OR ｅ And; R ｅ These are independently hydrogen, halogen, or -C １～８ It is alkyl. The compound according to claim 1 or 2.

13. R ６ but, 【Chemistry 12-1】 【Chemistry 12-2】 The compound according to claim 12.

14. R １２ and R １３ Each of them independently produces hydrogen or -C １～８ It is alkyl; R １０ and R １１ Each of them independently produces hydrogen and -C １～８ Alkyl, -C ３～８ Cycloalkyl, -C ５～６ Aryl, 5-6 member heteroaryl, or -CONR ａ R ｂ And the above-C １～８ Alkyl, -C ３～８ Cycloalkyl, -C ５～６ Each aryl or 5-6 member heteroaryl may optionally contain 1 to 3 R ｄ It has been replaced with; R ａ and R ｂ Each of these is independently either hydrogen or -C １～８ It is alkyl; or (R ａ and R ｂ ) together with the nitrogen atom to which they are bonded, form a 3- to 6-membered ring, the ring containing 0 or 1 further oxygen atom; the ring optionally contains 1 R ｄ It has been replaced with; R ｄ In each of its existences, independently, -C １～８ Alkyl, halogen, aryl, or -OR ｅ And R ｅ These are, independently, hydrogen or -C. １～８ The compound according to claim 1 or 2, wherein the compound is alkyl, phenylethyl, benzyl, or phenyl.

15. R １２ is hydrogen or -CH ３ And; R １３ is hydrogen or -CH ３ And; R １０ is hydrogen; R １１ However, -CONR ａ R ｂ , phenyl, benzyl, pyridinyl, or furyl, each of which phenyl, benzyl, pyridinyl, or furyl is optionally selected from methyl, methoxy, or halogen, with 1 to 3 R ｄ It has been replaced with; R ａ and R ｂ Each is independently either hydrogen or methyl, or (R ａ and R ｂ ) together with the nitrogen atom to which they are bonded, form a 5- or 6-membered ring, and the ring contains 0 or 1 further oxygen atom. The compound according to claim 14.

16. R １０ is hydrogen; R １１ However, hydrogen, methyl, ethyl, 2-propyl, -CF ３ ,-CHF ２ ien-CH ２ CH ２ OCH ３ ien-CH ２ OH, -CH ２ OCH ３ ien-CH ２ OCH(CH ３ ) ２ ien-CH ２ OC ２ H ５ Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , 【Chemistry 15】 -CH ２ O-Ph, -CH ２ O-CH ２ -Ph, phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-F-phenyl, benzyl, 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, 2-furyl, or 3-furyl R １０ and R １１ The compound according to claim 15, wherein both members form a three-membered carbon ring.

17. R １０ and R １１ If they are different, R １０ and R １１ The compound according to claim 16, wherein the carbon atom to which the compound is bonded is in an (S) configuration. 【Request Item 18】 【Table 1-1】 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 A compound selected from, or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

20. A composition for use in the treatment of a disease responding to inhibition of cIAP, comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer or tautomer thereof, wherein optionally the disease is cancer.

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