Pyrido[2,3-b][1,4]oxazin or tetrahydropyrido[2,3-b][1,4]oxazepines as iap antagonists

Abstract

Disclosed herein are novel 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazepine or 1,2,3,4-tetrahydropyrido[2,3-b][l,4]oxazepine derivatives that act as antagonists of IAP (inhibitor of apoptosis proteins), also known as Smac mimetics. Disclosed herein are uses of these antagonists for inducing or sensitizing cells to induce apoptotic cell death, as well as uses of such compounds for treating proliferative diseases, such as cancer.

Description

TECHNICAL FIELD

[0001] Disclosed herein are novel 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin or 1,2,3,4- tetrahydropyrido[2,3-b][l,4]oxazepine derivatives that act as antagonists of IAPs (inhibitors of apoptosis proteins), also known as Smac mimetics. Disclosed herein are uses of these antagonists for inducing or sensitizing cells to induce apoptotic cell death, as well as uses of such compounds for treating proliferative diseases, such as cancer. BACKGROUND

[0002] Apoptosis plays a key role in the development and homeostasis of cells in higher organisms and is a tightly controlled process to eliminate damaged or unwanted cells (Kerr, J.F. et al., Br J Cancer, 1972, 26, 239-257). Abnormalities in the apoptotic process are associated with many human diseases, including cancer, autoimmune diseases and inflammation (Nicholson, D.W. et al., Nature, 2000, 407, 810-816). Indeed, resistance to apoptosis is a hallmark of cancer (Hanahan, D. et al., cell 2000, 100, 57-70; Hanahan, D. et al., cell, 2011, 144, 646-674).

[0003] Apoptosis can be triggered by extrinsic stimulation of death receptors or intrinsic stimulation by mitochondrial release of cytochrome c (Elmore, S., Toxicol Pathol, 2007, 35, 495-516). Inhibitors of apoptosis proteins (IAPs) are a class of key negative regulators of both extrinsic and intrinsic apoptotic pathways. IAPs were first discovered in baculoviruses and were able to inhibit apoptosis in infected cells (Birnbaum, M.J. et al., J Virol, 1994, 68, 2521-2528). IAPs are characterized by the presence of baculovirus IAP repeat (BIR) domains. BIR domains are approximately 70-80 amino acids in length and contain Zn-binding motifs that can facilitate protein-protein interactions involved in IAP function (Yang, Y.L., Cell Res, 2000, 10, 169-177). The human IAP family comprises eight proteins: neuronal IAP (BIRC1), cellular IAP1 (cIAP1, BIRC2), cellular IAP2 (cIAP2, BIRC3), X-linked IAP (XIAP, BIRC4), survivin (BIRC5), ubiquitin-binding BIR domain enzyme apollon (BIRC6), melanoma IAP (ML-IAP, BIRC7), and IAP-like protein 2 (BIRC8). Of these, cIAP1, cIAP2, and XIAP play a direct role in the regulation of apoptosis (Salvesen, G.S. et al., Nat Rev Mol Cell Bio, 2002, 3, 401-410).

[0004] cIAP1 and cIAP2 (cIAPs) inhibit the caspase-8-dependent extrinsic apoptotic pathway, such as the pathway induced by TNF-a, through their ubiquitin ligase activity (Derakhshan, A. et al., Clin Cancer Res, 2017, 23, 1379-1387). Upon ligation of TNF-a to its receptor TNFR1, cIAPs, and tumor necrosis factor receptor type 1-associated death domain (TRADD), receptor-interacting serine / threonine kinase 1 (RIPK1) and TNF receptor-associated factors (TRAFs) are recruited to form complex I, leading to activation of the canonical nuclear factor-kappa B (NF-kB) pathway, which is well known to promote inflammation, proliferation, and cell survival (Samuel T. et al., J Biol Chem, 2006, 281, 1080-1090; Vince J.E. et al., J Biol Chem, 2009, 284, 35906-35915; Wang C. et al., Nature, 2001, 412, 346-351).

[0005] XIAP is the only IAP protein that inhibits both extrinsic and intrinsic apoptotic pathways by directly countering caspase activation through their BIR domains (Deveraux Q.L. et al., Nature, 1997, 388, 300-304). The BIR2 domain and the preceding linker of XIAP are associated with the active sites of IAP binding motifs (IBM) and caspase-3 and -7, executioner caspases shared by extrinsic and intrinsic apoptosis, and inhibit their functions (Chai J. et al., Cell, 2001, 104, 769-780; Riedl S.J. et al., Cell, 2001, 104, 791-800). XIAP binds to pro-caspase-9 via its BIR3 domain and prevents dimerization and subsequent activation of caspase-9, a key initiator caspase in the intrinsic pathway (Shiozaki E.N. et al., Mol Cell, 2003, 11, 519-527).

[0006] The cIAP1, cIAP2 and XIAP proteins are widely expressed in various tumor types. Moreover, positive expression of cIAP and XIAP is associated with high-grade cancers and poor prognosis (Che X. et al., Urol Oncol, 2012, 30, 450-456; Yang C. et al., J Exp Clin Cancer Res, 2016, 35, 158). Furthermore, downregulation or depletion of these IAPs has been shown to restore sensitivity to extrinsic or intrinsic apoptotic stimuli (Gu H. et al., Aging (Albany NY), 2018, 10, 1597-1608). Taken together, targeting IAP proteins provides a potential anti-tumor strategy.

[0007] Second mitochondria-derived caspase activator (Smac), also known as direct IAP binding protein with low pi (DIABLO), is an endogenous antagonist of cIAPl, cIAP2 and XIAP to promote apoptosis (Du C. et al., Cell, 2000, 102, 33-42; Verhagen A.M. et al., Cell, 2000, 102, 43-53). Smac is normally sequestered in mitochondria and released into the cytoplasm when a cell undergoes apoptosis. In the cytoplasm, the N-terminal mitochondrial targeting sequence of Smac is cleaved to expose a tetrapeptide (Ala-Val-Pro-Ile) that allows Smac to interact with the BIR domains of IAPs (Chai J. et al., Nature, 2000, 406, 855-862). Binding of Smac to the BIR3 domain of cIAPl and cIAP2 stimulates their E3 ubiquitin ligase activity and induces their proteasomal degradation. Loss of cIAP proteins promotes the formation of complex II containing RIPK1, caspase-8 and Fas death domain-associated protein (FADD) and triggers TNF-a-mediated apoptosis (Dueber E.C. et al., Science, 2011, 334, 376-380). Dimerized Smac binds to the BIR2 and BIR3 domains of XIAP and disrupts its interaction with caspases-3, -7 and -9, leading 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 mimetics are small molecules containing 4 amino acids that mimic the N-terminus of Smac (Ala-Val-Pro-Ile). Similar to Smac, Smac mimetics bind to the BIR domains of IAPs and antagonize their effects to promote apoptosis of cancer cells (Chai J. et al., Cell, 2001, 104, 769-780; Dueber E.C. et al., Science, 2011, 334, 376-380; Liu Z. et al., Nature, 2000, 408, 1004-1008; Verhagen A.M. et al., Cell, 2000, 102, 43-53). In summary, Smac mimetics become a new class of cancer therapeutic candidates. SUMMARY

[0009] In one embodiment, disclosed herein is a 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin or 1,2,3,4-tetrahydropyrido[2,3-b][l,4]oxazepine derivative of Formula (I). This embodiment includes the following aspects:

[0010] Aspect 1 : A compound of Formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer, or prodrug thereof,

[0013] wherein

[0014] X1and X2are each independently -O-, -S-, -NR a - or -CR a R b -;

[0015] m1, m2, and m3 are each independently 0, 1, or 2;

[0016] R 1a , R 1b , R 1c , R 1d , and R7, which can be the same or different, are each independently hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, 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 , -NR a COR b , -NR a CONR b R c , -NR a CO2R b , -NR a SONR b R c , -NR a SO2NR b Rc -SO2NR a R b or -NR a SO2R b , said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with 1-3 R d ;

[0017] n is 0, 1, 2, 3 or 4;

[0018] R3and R5are each independently hydrogen, halogen, -C 3-8 cycloalkyl or -C 1-8 alkyl, said -C 1-8 alkyl or -C 3-8 cycloalkyl is optionally substituted with at least one halogen or -OR a ;

[0019] R2and R4are each independently hydrogen or -C 1-8 alkyl; or

[0020] R4and R5together with the same carbon atom to which they are attached form a 3- to 5-membered spiro carbocyclic ring; or

[0021] R2at one occurrence and R4at one occurrence together form a bridge comprising zero, one or two -CH2- moieties in the bridge; or

[0022] or R 1b and R4at one occurrence together form a 3- to 6-membered carbocyclic ring;

[0023] or R 1d and R4at one occurrence together form a bridge comprising one or two -CH2- moieties in the bridge;

[0024] R6is hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -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 SO2NR b R c -SO2NR a R b or -NR a SO2R b , said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl or heteroaryl is each optionally substituted with 1-3 R d ;

[0025] R8and R9are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl or C 3-8 cycloalkyl;

[0026] R 10 and R 11 are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, 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 , -NR a COR b , -NR a CONRb 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 , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with 1-3 R d ;or

[0027] R 10 and R 11 Together they form a 3- to 5-membered spirocarbocyclic ring, which is optionally substituted with 1-3 R d ;

[0028] R 12 and R 13 are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl, heteroaryl, 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 、-NR a COR b 、-NR a CONR b R c 、-NR a CO2R b 、-NR a SONR b R c 、-NR a SO2NR b Rc -SO2NR a R b or -NR a SO2R b , said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1-3 R d ; or

[0029] R 12 and R 13 together form a 3- to 5-membered spiro carbocyclic ring, optionally substituted with 1-3 R d ;

[0030] R 14 and R 15 are each independently selected from hydrogen or -C 1-8 alkyl;

[0031] R a , R b , and R c are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1-3 R d ; or

[0032] (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 attached form a 3- to 8-membered ring comprising 0, 1, or 2 additional heteroatoms as a ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring is optionally substituted with 1-3 R d ;

[0033] R d is independently at each occurrence hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR e , -SRa -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 -NR e SO2R f , said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, -C 1-8 alkyl, -OR h , -NR h R i , cycloalkyl, heterocyclyl, aryl or heteroaryl; and

[0034] R e , R f , R g , R h and R i are each independently hydrogen, -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.

[0035] In some embodiments, m2 is 1 and m3 is 1, R2and R4together form a bridge comprising zero, one or two -CH2- moieties in the bridge; or m2 is 1 and m3 is 2, R2and one of the two R4together form a bridge comprising zero, one or two -CH2- moieties in the bridge; or m2 is 2 and m3 is 1, one of the two R2and R4together form a bridge comprising zero, one or two -CH2- moieties in the bridge; or m2 is 2 and m3 is 2, one of the two R2and one of the two R4together form a bridge comprising zero, one or two -CH2- moieties in the bridge.

[0036] In some embodiments, m2 is 1, R 1b and R4together form a 3- to 6-membered carbocyclic ring; or m2 is 2, R 1b and one of the two R4together form a 3- to 6-membered carbocyclic ring.

[0037] In some embodiments, m2 is 1, R 1d and R4together form a bridge comprising one or two -CH2- moieties in the bridge; or m2 is 2, R 1d and one of the two R4together form a bridge comprising one or two -CH2- moieties in the bridge.

[0038] Aspect 2: A compound of Formula (II):

[0039]

[0040] or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer or prodrug thereof,

[0041] wherein

[0042] X1and X2are each independently -O-, -S-, -NR a - or -CR a R b -;

[0043] m1, m2 and m3 are each independently 0, 1 or 2;

[0044] R 1a , R 1b , R 1c , R 1d and R7, which can be the same or different, are each independently hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR a , -SR a , -SO2Ra -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 SO2NR b R c -SO2NR a R b or -NR a SO2R b , said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl or heteroaryl is each optionally substituted with 1-3 R d ;

[0045] n is 0, 1, 2, 3 or 4;

[0046] R3and R5are each independently hydrogen, halogen, -C 3-8 cycloalkyl or -C 1-8 alkyl, said -C 1-8 alkyl or -C 3-8 cycloalkyl is optionally substituted with at least one halogen or -OR a ;

[0047] R2and R4are each independently hydrogen or -C 1-8 alkyl; or

[0048] R4and R5together with the same carbon atom to which they are attached form a 3- to 5-membered spiro carbocyclic ring; or

[0049] R2at one occurrence and R4at one occurrence together form a bridge comprising zero, one or two -CH2- moieties in the bridge; or

[0050] or R 1b and R4at one occurrence together form a 3- to 6-membered carbocyclic ring;

[0051] or R 1d and R4in one of its occurrences together form a bridge comprising one or two -CH2- moieties in the bridge;

[0052] R6is hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, 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 , -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 , each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with 1-3 R d ;

[0053] R8and R9are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl or C 3-8 cycloalkyl;

[0054] R 10 and R 11each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, 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 , -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 , said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1-3 R d ; or

[0055] R 10 and R 11 together form a 3- to 5-membered spiro carbocyclic ring optionally substituted with 1-3 R d ;

[0056] R 12 and R 13 each independently are hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR a , -SR a , -SO2Ra -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 SO2NR b R c -SO2NR a R b or -NR a SO2R b , said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1-3 R d ; or

[0057] R 12 and R 13 together form a 3- to 5-membered spiro carbocyclic ring, optionally substituted with 1-3 R d ;

[0058] R a , R b , and R c are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with 1-3 R d ; or

[0059] (R a and R b ), (R a and R c ), or (R b and R c) together with the atom or atoms to which they are attached form a 3 to 8 membered ring comprising 0, 1 or 2 additional heteroatoms as one or more ring members independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring optionally substituted with 1-3 R d ;

[0060] R d is independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, 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 -NR e SO2R f , the-C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C 1-8 Alkyl, -OR h 、-NR h R i , cycloalkyl, heterocyclyl, aryl or heteroaryl; and

[0061] R e 、R f 、R g, R h , and R i each independently is hydrogen, -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.

[0062] In some embodiments, m2 is 1 and m3 is 1, R2and R4together form a bridge comprising zero, one, or two -CH2- moieties in the bridge; or m2 is 1 and m3 is 2, R2and one of the two R4together form a bridge comprising zero, one, or two -CH2- moieties in the bridge; or m2 is 2 and m3 is 1, one of the two R2and R4together form a bridge comprising zero, one, or two -CH2- moieties in the bridge; or m2 is 2 and m3 is 2, one of the two R2and one of the two R4together form a bridge comprising zero, one, or two -CH2- moieties in the bridge.

[0063] In some embodiments, m2 is 1, R 1b and R4together form a 3- to 6-membered carbocyclic ring; or m2 is 2, R 1b and one of the two R4together form a 3- to 6-membered carbocyclic ring.

[0064] In some embodiments, m2 is 1, R 1d and R4together form a bridge comprising one or two -CH2- moieties in the bridge; or m2 is 2, R 1d and one of the two R4together form a bridge comprising one or two -CH2- moieties in the bridge.

[0065] Aspect 3: The compound according to Aspect 1 or 2, wherein X1is -O-, -S-, -NH-, or -CH2-.

[0066] Aspect 4: The compound according to Aspect 3, wherein X1is -CH2-.

[0067] Aspect 5: The compound according to Aspect 1 or 2, wherein X2is -O-, -S-, -CH2-, or -NR a ; R a is H or -C 1-8 alkyl (methyl or ethyl).

[0068] Aspect 6: The compound according to Aspect 5, wherein X2is -O- or -NR a -; R a is hydrogen or -C 1-8 alkyl (methyl or ethyl).

[0069] Aspect 7: The compound according to Aspect 1 or 2, wherein ml is 0.

[0070] Aspect 8: The compound according to Aspect 1 or 2, wherein m2 is 1; and m3 is 0 or 1.

[0071] Aspect 9: The compound according to Aspect 1 or 2, wherein R2, R3, R4, and R5 are each hydrogen, methyl or ethyl, -CH2OH, -CH2OCH3, -CH2OC2H5, -CHF2, -CH2OCH(CH3)2, cyclopropyl, or CF3.

[0072] Aspect 10: The compound according to Aspect 1 or 2, wherein R4 and R5 together with the same carbon atom to which they are attached form a 3- to 5-membered spiro carbocyclic ring.

[0073] Aspect 11 : The compound according to Aspect 1 or 2, wherein is

[0074] wherein R 1a , R 1b , R 1c , R 1d , R2, R3, R4, R5 and R a are as defined for formula (I).

[0075] Aspect 12: The compound according to Aspect 11, wherein is wherein R 1c , R 1d , R4 and R5 are independently hydrogen or -C 1-8 alkyl.

[0076] Aspect 13: The compound according to Aspect 12, wherein R 1c and R4 are hydrogen, R 1d and R5 are independently hydrogen or -C 1-8 alkyl; preferably, R 1c and R4 are hydrogen, R 1d and R5 are methyl.

[0077] Aspect 14: The compound according to Aspect 11, wherein R 1a , R 1b , R 1c , R 1d , R2, R3, R4, R5 and R a are each independently hydrogen, halogen, -C 1-8 alkyl (e.g. -CH3 or -C2H5) or oxo, wherein the -C 1-8alkyl is optionally substituted with at least one halo (e.g., 1-3 halo).

[0078] Aspect 15: The compound according to Aspect 14, wherein R5is halo, -C2H5, -CH3, oxo, cyclopropyl, CHF2, -CH2F, -CF3, -CH2OH, -CH2OCH3, -CH2OC2H5, -CH2OCH(CH3)2; and R4is hydrogen or -CH3; or R5and R4together with the carbon atom to which they are attached form a 3- to 5-membered carbocyclic ring; or R2and R4together form a bridge comprising one -CH2- moiety in the bridge, and R3and R5are each hydrogen; or R 1b and R4together form a 3-membered carbocyclic ring, and R 1a and R5are each hydrogen; or R 1d and R4together form a bridge comprising two -CH2- moieties in the bridge, and R 1c and R5are each hydrogen.

[0079] Aspect 16: The compound according to Aspect 11 or 12, wherein is

[0080]

[0081]

[0082] Aspect 17: The compound according to Aspect 1 or 2, wherein is

[0083] Aspect 18: The compound according to Aspect 17, wherein R7is halo.

[0084] Aspect 19: The compound according to Aspect 18, wherein R7is F.

[0085] Aspect 20: The compound according to Aspect 1 or 2, wherein R6is hydrogen, -CN, halo, morpholino, -CONR a R b , -OR a , -NR a R b , -C 3-5 cycloalkyl, phenyl, or -C 1-8 alkyl, said -C 1-8 alkyl or -C 3-5 cycloalkyl or phenyl is optionally substituted with at least one R d ; R a and R b are each hydrogen, -C 3-6cycloalkyl or -C 1-8 alkyl; R d independently at each occurrence is -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -NH2, -SH, -CN, -CONH2, -H, -CH3, -C2H5, -C3H7, -CH2OH, -OCH3, -OC2H5, morpholino, or cyclopropyl.

[0086] Aspect 21 : The compound according to Aspect 1 or 2, wherein R6 is -CONR a R b , -NR a R b , -NR a CO-R b , -NRa-SO2-R b or -OR a ; R a and R b are each hydrogen, -C 3-6 cycloalkyl, -C 1-8 alkyl, 5- or 6-membered heterocyclyl, aryl, or heteroaryl; each of said -C 1-8 alkyl, -C 3-6 cycloalkyl, 5- or 6-membered heterocyclyl, aryl, or heteroaryl is optionally substituted with 1-3 R d ; or

[0087] R a and R b , together with the atom or atoms to which they are attached, form a 3- to 8-membered ring comprising 0, 1, or 2 additional heteroatoms as a ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring is optionally substituted with 1-3 R d ;

[0088] R d independently at each occurrence is hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR e , -SR a , -SO2R e , -SO2NR e R f , -COR e , -CO2R e , -CONR e R f , -C(=NRe )NR f R g 、-NR e R f 、-NR e COR f 、-NR e CONR f R g 、-NR e CO2R f 、-NR e SONR f R g 、-NR e SO2NR f R g or –NR e SO2R f , the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -C 3-8 Cycloalkyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with at least one substituent selected from halogen, -C 1-8 Alkyl, -OR h 、-NR h R i , cycloalkyl, heterocyclyl, aryl or heteroaryl; and

[0089] R e 、R f 、R g 、R h and R i are independently hydrogen, -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.

[0090] Aspect 22: The compound according to Aspect 21, wherein R6 is -CONR a R b or -NR a CO-R b , R a and R b Each is hydrogen, -C 1-3 Alkyl, -C 3-6 Cycloalkyl, phenyl, 5- or 6-membered heterocyclic group (eg, azetidine, pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran or tetrahydrofuran); the -C1-3 alkyl, -C 3-6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl (e.g., azetidine, pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, or tetrahydrofuran) optionally substituted with at least one substituent selected from halogen, -C 1-3 alkyl, morpholine, OR e or -NR e R f ; R e and R f are independently hydrogen, halogen, -C 1-8 alkyl or C 1-8 alkoxy-C 1-8 alkyl-.

[0091] Aspect 23: The compound according to Aspect 21, wherein R6is -CONR a R b , R a and R b together with the nitrogen atom to which they are attached form a 4- to 6-membered ring comprising 0, 1, or 2 additional heteroatoms as a ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring being optionally substituted with 1-3 R d ; R d are independently halogen, -C 1-3 alkyl or OR e ; R e are independently hydrogen, halogen, or -C 1-8 alkyl.

[0092] Aspect 24: The compound according to Aspect 21, wherein R6is -NH2, -CONH2, -CONHCH3, -CONHC2H5, -CON(CH3)2, -CONHCH2CF3, -CONHC2H4OCH3, -CONHC2H4OC2H4OCH3, -CONHCH(CH3)2, -CONHC2H4OH, -CONHC2H4N(CH3)2, -O-(CH2)2-OCH3, -O-(CH2)2-OH, -NH-(CH2)2-OCH3, -NH-(CH2)2-OH, -NH-CO-CH3, -NH-CO-C2H5, -NH-CO-CH(CH3)2, -NHC2H5, -NH-CH2-CF3, CH3CH2SO2NH-, or cyclopropylSO2NH-.

[0093] Aspect 25: The compound according to aspect 20, wherein R6 is hydrogen, halogen, -CN, -CONH2, Cyclopropyl, -CH2OH, -CF3, -OH, -CH3 or -OC2H5.

[0094] Aspect 26: The compound according to aspect 1 or 2, wherein R 12 and R 13 are each independently hydrogen or -C 1-8 alkyl.

[0095] Aspect 27: The compound according to Aspect 26, wherein R 12 is hydrogen or -CH3; R 13 It is hydrogen or -CH3.

[0096] Aspect 28: The compound according to aspect 1 or 2, wherein

[0097] R 10 and R 11 are independently hydrogen, -C 1-8 Alkyl, -C 3-8 Cycloalkyl, -C 5-6 Aryl, 5- to 6-membered heteroaryl, or -CONR a R b , wherein the-C 1-8 Alkyl, -C 3-8 Cycloalkyl, -C 5-6 Aryl or 5- to 6-membered heteroaryl are each optionally substituted with 1-3 R d ;

[0098] R a and R b are each independently hydrogen or -C 1-8 Alkyl; or

[0099] (R a and R b ) together with the nitrogen atom to which they are attached form a 3 to 6 membered ring containing 0 or 1 additional oxygen atom; said ring is optionally substituted with one R d ;

[0100] R d -C independently at each occurrence 1-8 Alkyl, halogen, aryl or -OR e , where R e are each independently hydrogen or -C 1-8 alkyl, phenethyl, benzyl or phenyl.

[0101] Aspect 29: The compound according to Aspect 28, wherein R 10 is hydrogen; R11 -CONR a R b , phenyl, benzyl, pyridyl, or furanyl, wherein each of said phenyl, benzyl, pyridyl, or furanyl is optionally substituted with 1-3 R d ; R a and R b are each independently hydrogen or methyl, or (R a and R b ), together with the nitrogen atom to which they are attached, form a 5- to 6- membered ring comprising 0 or 1 additional oxygen atoms.

[0102] Aspect 30: The compound according to Aspect 29, wherein R 10 is hydrogen; and R 11 is hydrogen, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, tert-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-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -CH2OCH3, -CH2OCH(CH3)2, -CH2OC2H5, -CH2F, -CHF2, -CF3, -H, -F, -Cl, -Br, -I, -OH, -NH2, -SH, -CONH2, -CONHCH3, -CON(CH3)2, -CH2O-Ph, -CH2-Ph, -CH2O-CH2-Ph, phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-F-phenyl, benzyl, pyridyl (4-pyridyl, 3-pyridyl, or 2-pyridyl), or furanyl (2-furanyl or 3-furanyl).

[0103] Aspect 31 : The compound according to Aspect 30, wherein R 10 is hydrogen; and R 11 is hydrogen, methyl, ethyl, 2-propyl, -CF3, -CHF2, -CH2CH2OCH3, -CH2OH, -CH2OCH3, -CH2OCH(CH3)2, -CH2OC2H5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CONH2, -CONHCH3, -CON(CH3)2, -CH2O-Ph, -CH2O-CH2-Ph, phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-F-phenyl, benzyl, 4-pyridyl, 3-pyridyl, 2-pyridyl, 2-furyl, or 3-furyl.

[0104] Aspect 32: The compound according to any one of aspects 1-31, wherein R 10 and R 11 are in the (S) configuration. 10 and R 11 are in the (S) configuration.

[0105] Aspect 33: The compound according to aspect 1 or 2, wherein R 10 and R 11 together form a 3-membered carbocyclic ring.

[0106] Aspect 34: The compound according to aspect 1 or 2, which is

[0107]

[0108] wherein 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 as defined for formula (II).

[0109] Aspect 35: The compound according to aspect 1 or 2, wherein R 14 and R 15 are each independently selected from hydrogen or -C 1-8 alkyl (methyl or ethyl).

[0110] Aspect 36: The compound according to aspect 1, which is

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122] or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer or prodrug thereof.

[0123] In one embodiment, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a stereoisomer, tautomer or prodrug thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0124] In one embodiment, disclosed herein is a method of treating a disease responsive to inhibition of cIAP, comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt disclosed herein, or a stereoisomer, tautomer, or prodrug thereof.

[0125] In one embodiment, disclosed herein is a method of treating a cancer modulated by cIAP, comprising administering to a subject in need thereof a compound or pharmaceutically acceptable salt disclosed herein, or a stereoisomer, tautomer, or prodrug thereof. DETAILED DESCRIPTION

[0126] The following terms have the indicated meanings throughout this specification:

[0127] As used herein (including the appended aspects), singular forms such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0128] Unless the context clearly indicates otherwise, the term "or" is used to mean, and is used interchangeably with, the term "and / or."

[0129] The term "alkyl" refers to a hydrocarbon group selected from a straight chain saturated hydrocarbon group and a branched chain saturated hydrocarbon group, which contains 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8 or 1 to 6 or 1 to 4) carbon atoms. 1-6Examples of (C1-C6alkyl) groups include, but are not limited to, methyl, ethyl, 1 -propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1 -butyl or n-butyl (“n-Bu”), 2-methyl-l -propyl or isobutyl (“i-Bu”), 1 -methylpropyl or sec-butyl (“s-Bu”), 1,1 -dimethylethyl or tert-butyl (“t-Bu”), 1 -pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-l -butyl, 2-methyl-l -butyl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0130] The term “cycloalkyl” refers to a hydrocarbyl group selected from saturated cyclic hydrocarbyl groups, which include monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocyclic cycloalkyl groups.

[0131] The term “aryl” used alone or in combination with other terminology, refers to a group selected from:

[0132] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0133] - bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, at least one of which is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0134] - tricyclic ring systems, such as 10- to 15-membered tricyclic ring systems, at least one of which is carbocyclic and aromatic, such as fluorenyl.

[0135] The terms “aromatic hydrocarbon ring” and “aryl” are used interchangeably in the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-l-yl, naphth-2-yl, anthryl, phenanthryl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-l-yl or naphth-2-yl) or a benzene ring. In some embodiments, the aromatic hydrocarbon ring is a benzene ring.

[0136] The term “aryl-alkyl-” refers to an alkyl group as defined above further substituted with an aryl group. Examples of arylalkyl groups include aryl-C 1-8 alkyl, such as phenethyl or phenylmethyl (benzyl).

[0137] The term “heteroaryl” refers to a group selected from:

[0138] - 5-, 6-, or 7-membered aromatic monocyclic ring comprising at least one heteroatom, for example, 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms, and in some embodiments, 1 to 2 heteroatoms, the heteroatoms being selected from nitrogen (N), sulfur (S), and oxygen (O), the remaining ring atoms being carbon;

[0139] - 7- to 12-membered bicyclic ring comprising at least one heteroatom, for example, 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms, or in other embodiments, 1 or 2 heteroatoms, the heteroatoms being selected from N, O, and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0140] - 11- to 14-membered tricyclic ring comprising at least one heteroatom, for example, 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms, or in other embodiments, 1 or 2 heteroatoms, the heteroatoms being selected from N, O, and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0141] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is not greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. A nitrogen atom in one or more rings of a heteroaryl group can be oxidized to form an N-oxide. As used herein, the term “C-linked heteroaryl” refers to a heteroaryl group connected to the core molecule through a bond from a C atom of the heteroaryl ring.

[0142] The terms “aromatic heterocycle” and “heteroaryl” are used interchangeably in the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, wherein 1, 2, 3, or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), the remaining ring members being carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring that is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0143] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to non-aromatic heterocyclic groups that include one or more heteroatoms as ring members selected from nitrogen, oxygen, or optionally oxidized sulfur, the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclyl groups. The term "optionally oxidized sulfur" as used herein refers to S, SO, or S02.

[0144] The compounds disclosed herein can contain asymmetric centers and therefore can exist in enantiomeric forms. "Enantiomorphs" refer to the two stereoisomers of a compound that are non-superimposable mirror images of one another. When a compound disclosed herein has two or more asymmetric centers, they can additionally occur as diastereomeric mixtures. Enantiomorphs and diastereomorphs belong to the broader category of stereoisomers. All such possible stereoisomers, as substantially pure resolved individual enantiomorphs, racemic mixtures thereof, and diastereomeric mixtures are intended to be included within the scope of the compounds disclosed herein. All stereoisomers and / or pharmaceutically acceptable salts of the compounds disclosed herein are intended to be within the scope of the disclosure. Unless otherwise specifically mentioned, a reference to one enantiomorph is intended to apply also to any possible enantiomorph. Whenever an enantiomeric composition is not specified, then all possible enantiomorphs are included.

[0145] The term "substantially pure" as used herein means that the target stereoisomer contains no more than 35% (such as no more than 30%, further such as no more than 25%, even further such as no more than 20%) by weight of any other stereoisomer. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10% (e.g., no more than 5%, such as no more than 1%) by weight of any other stereoisomer.

[0146] When a compound disclosed herein contains an olefinic double bond, such double bond is intended to encompass both E and Z geometry, unless otherwise indicated.

[0147] When a compound disclosed herein contains a disubstituted cyclohexyl or cyclobutyl group, the substituents found on the cyclohexyl or cyclobutyl ring can adopt a cis and trans configuration. Cis configuration means that the two substituents are found on the same side of the carbon at the 2 substituent positions, while trans means that they are found on opposite sides.

[0148] It can be advantageous to separate and / or isolate the reaction products from one another and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter isolated) to the desired degree of homogeneity using techniques generally known in the art. Typically, such isolation will involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include many methods including, for example: reverse and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography and devices; small scale analytical; simulated moving bed (“SMB”), and preparative thin or thick layer chromatography, and small scale thin and flash chromatography techniques. The skilled artisan will apply the technique most likely to achieve the desired separation.

[0149] “Diastereomers” refer to stereoisomers of a compound having two or more chiral centers that are not mirror images of one another. Diastereomers can be separated into their individual components by physical separation processes, which do not rely on chemical changes to the structured compounds. Methods of separating diastereomers include, but are not limited to, chromatography and fractional crystallization. Diastereomers can be isolated by methods well known in the art such as by chromatography and / or fractional crystallization based on the physico-chemical differences between the diastereomeric mixtures. Enantiomers can be separated by converting the enantiomeric mixture into a mixture of diastereomers by reaction with an appropriate optically active compound (e.g., a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers back to the corresponding pure enantiomers. Chiral HPLC columns can also be used to separate enantiomers.

[0150] “Pharmaceutically acceptable salt” refers to salts of the compounds disclosed herein that are within the scope of sound medical judgment, that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid, or by reacting the acid function with a suitable base.

[0151] Further, if the compounds disclosed herein are obtained as acid addition salts, the free bases can be obtained by basifying these solutions of acid salts. Conversely, if the products are the free bases, the addition salts can be prepared according to conventional procedures for preparing acid addition salts from basic compounds, by dissolving the free base in a suitable organic solvent and treating the solution with an acid, such as a pharmaceutically acceptable acid. Those of skill in the art will recognize a variety of synthetic methodologies that can be used to prepare nontoxic pharmaceutically acceptable addition salts without undue experimentation.

[0152] As defined herein, "pharmaceutically acceptable salts" of a compound of Formula (I) include at least one salt of a compound of Formula (I) and a salt of a stereoisomer of a compound of Formula (I), such as a salt of an enantiomer and / or a salt of a diastereomer.

[0153] The terms "administration" and "administering" when applied to an animal, human, test subject, cell, tissue, organ or biological fluid mean the contact of an exogenous agent, therapeutic agent, diagnostic agent or composition with the animal, human, test subject, cell, tissue, organ or biological fluid. Treatment of a cell encompasses contact of the agent with the cell, as well as contact of the agent with a fluid with which the cell is in contact. The terms "administration" and "treatment" also mean in vitro and ex vivo treatment of, for example, a cell by an agent, diagnostic agent, binding compound or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human.

[0154] The term "effective amount" or "therapeutically effective amount" refers to that amount of an active ingredient (such as a compound) which is sufficient to effect treatment, as described herein, of a disease or at least one clinical symptom of a disease or disorder when administered to a subject. The "therapeutically effective amount" can vary depending on the compound, the disease, disorder and / or symptom of the disease or disorder, the severity of the disease, disorder and / or symptom of the disease or disorder, the age of the subject to be treated, and / or the body weight of the subject to be treated. In any given instance, the appropriate amount will be readily apparent or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer thereof and / or at least one pharmaceutically acceptable salt thereof effective to "treat" (as defined above) a disease or disorder in a subject. In the case of combination therapy, "therapeutically effective amount" refers to the total amount of the combination that is effective for the treatment of the disease, disorder or condition.

[0155] The pharmaceutical composition comprising the compound disclosed herein can be administered to a subject in need thereof via oral, inhalation, rectal, parenteral, or topical administration. For oral administration, the pharmaceutical composition can be a conventional solid formulation such as a tablet, powder, granule, capsule, etc., a liquid formulation such as an aqueous or oily suspension, or other liquid formulation such as a syrup, solution, suspension, etc.; for parenteral administration, the pharmaceutical composition can be a solution, aqueous solution, oily suspension concentrate, lyophilized powder, etc. Preferably, the formulation of the pharmaceutical composition is selected from a tablet, a coated tablet, a capsule, a suppository, a nasal spray, or an injection, more preferably a tablet or a capsule. The pharmaceutical composition can be a single unit administration with an accurate dose. In addition, the pharmaceutical composition can further comprise an additional active ingredient.

[0156] All formulations of the pharmaceutical composition disclosed herein can be prepared by conventional methods in the pharmaceutical field. For example, the active ingredient can be mixed with one or more excipients, and then the desired formulation is prepared. The "pharmaceutically acceptable excipient" refers to a conventional pharmaceutical carrier suitable for the desired pharmaceutical formulation, for example: diluents, vehicles (such as water, various organic solvents, etc.), fillers (such as starch, sucrose, etc.), binders (such as cellulose derivatives, alginate, gelatin, and polyvinylpyrrolidone (PVP)); wetting agents such as glycerol; disintegrants such as agar, calcium carbonate, and sodium bicarbonate; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol; absorption carriers such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol, etc. In addition, the pharmaceutical composition further comprises other pharmaceutically acceptable excipients, such as dispersants, stabilizers, thickeners, complexing agents, buffers, penetration enhancers, polymers, fragrances, sweeteners, and dyes.

[0157] The term "disease" refers to any illness, ailment, sickness, symptom, or indication, and can be used interchangeably with the terms "disorder" or "condition."

[0158] Throughout the specification and the following aspects, unless the context requires otherwise, the terms "comprise" and variations such as "comprises" and "comprising" are intended to indicate the presence of the features stated after the term, but not the exclusion of one or more other features. When used in this document, the term "comprise" can be replaced by the terms "contain", "include", or sometimes by "have".

[0159] Throughout the specification and the following aspects, the term "C n-m " indicates a range including the endpoints, wherein n and m are integers and represent the number of carbons. Examples include C 1-8 , C 1-6 , etc.

[0160] Unless otherwise defined, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this application belongs.

[0161] General Synthesis

[0162] The compounds disclosed herein, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0163] The reactions for preparing the compounds disclosed herein can be performed in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials, intermediates, or products at the temperatures at which the reactions are carried out, e.g., room temperature or the temperature of a thermal cycle used to carry out the reactions. Given the broad scope of rationally designed reactions that can be carried out, the reactions can be performed in a wide variety of solvents.

[0164] The selection of appropriate protecting groups can be readily determined by one skilled in the art.

[0165] Reactions can be monitored by any suitable method known in the art, e.g., NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified by any suitable method known in the art, including HPLC and normal phase silica gel chromatography.

[0166] Scheme I

[0167]

[0168] Compounds of formula (I) can be prepared as shown in Scheme I. Nucleophilic substitution between an alcohol and compound (i) gives compound (ii), followed by iron mediated reductive cyclization to give compound (iii). Compound (iii) is converted to compound (iv) via borane mediated reduction. The three step procedure gives compound (vi). Subsequent Negishi or Suzuki coupling gives compound (vii). Deprotection and subsequent acylation gives compound (ix). Reaction of compound (ix) with key intermediate (x) gives compound (xi). Final deprotection gives the compound (xii) described in formula (I).

[0169] Scheme II

[0170]

[0171] The compounds of formula (I) can also be synthesized as shown in Scheme II. Nucleophilic substitution between compound (i) and Boc protected amino alcohol gives compound (ii). Subsequent Cu or Pd mediated C-N coupling gives compound (iii), followed by Negishi or Suzuki coupling to give compound (iv). Deprotection gives compound (v). Reaction of compound (v) with 2-chloroacetyl chloride gives compound (vi). Reaction of compound (vi) with key intermediate (vii) gives compound (viii). Final deprotection gives compound (ix) as described in formula (I).

[0172] Abbreviations

[0173]

[0174]

[0175] Representative Examples

[0176] Example 1: 7-(4-fluorobenzyl)-l-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l- yl)acetyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-6-carbonitrile formate salt (Compound 1)

[0177]

[0178] Step 1: Ethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate

[0179]

[0180] To 5-bromo-2-chloro-3-nitropyridine (20 g, 84.2 mmol) and ethyl 2-hydroxyacetate (9.6 g, 92.6 mmol) in anhydrous THF (100 mL) was added NaH (4.4 g, 60% dispersion in mineral oil, 109.5 mmol) slowly at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were dried over Na2S04, filtered and evaporated in vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 10: 1) to give the product (13 g, 51% yield). LC-MS (M+H) + = 305.0, 307.0.

[0181] Step 2: 7-Bromo-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one

[0182]

[0183] To ethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate (13 g, 42.6 mmol) in AcOH (300 mL) was added Fe powder (13 g, 232 mmol) slowly at 70 °C, the resulting mixture was stirred at 70 °C for 1 h. AcOH was removed in vacuo, the resulting solid was washed with MeOH (200 mL) and filtered. This was repeated 5 times. The MeOH phase was concentrated in vacuo to give the crude product (9.6 g, 98% yield), which was used directly in the next step. LC-MS (M+H) + = 228.9, 230.9.

[0184] Step 3: 7-Bromo-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin

[0185]

[0186] To 7-bromo-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one (9 g, 39.3 mmol) in anhydrous THF (150 mL) was added BH3(98.3 mL, 1 N in THF) dropwise at room temperature, the resulting solution was stirred at 60 °C for 1 h. The reaction was cooled to room temperature, quenched with MeOH (10 mL), pH was adjusted to 1-2 by adding 1 N HC1, and stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature, water (100 mL) was added, and pH was adjusted to 8-9. The mixture was extracted with EtOAc (100 mL*3), the combined organic layers were dried over Na2S04, filtered and evaporated in vacuo to give the crude product (7.46 g, 88% yield), which was used directly in the next step. LC-MS (M+H) + = 215.1, 217.1.

[0187] Step 4: 7-Bromo-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylic acid tert-butyl ester

[0188]

[0189] 7-Bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (6.9 g, 32 mmol), (Boc)2O (10.5 g, 48 mmol), DMAP (3.9 g, 32 mmol) and Et3N (6.46 g, 64 mmol) were stirred in THF (200 mL) at room temperature for 12 h. The reaction was washed with water (100 mL) and extracted with EtOAc (100 mL*3). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give the product (9 g, 90% yield). LC-MS (M+H) + =315.2,317.2.

[0190] Step 5: 7-Bromo-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine 5-oxide

[0191]

[0192] To tert-butyl 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (7g, 22.2mmol) in DCM (200mL) was added 3-chlorobenzoperoxy acid (11.5g, 66.67mmol) at room temperature, and the resulting mixture was stirred at 50°C for 18h. The reaction mixture was cooled to room temperature and filtered to remove the solid, washed with saturated aqueous NaHCO3 solution (100mL), extracted with DCM (100mL*3), and the combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give the product (5.8g, 78.8% yield). LC-MS (M+H) + =331.1,333.1.

[0193] Step 6: tert-Butyl 7-bromo-6-cyano-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0194]

[0195] To a solution of 7-bromo-l-(tert-butoxycarbonyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine 5-oxide (2.9 g, 8.8 mmol) in MeCN (100 mL) was added TMSCN (13.04 g, 131.4 mmol) at room temperature under N2, the resulting solution was stirred at 80 °C for 12 h. The reaction was concentrated in vacuo, the residue was purified by silica gel chromatography (DCM:MeOH = 50: 1) to give the product (715 mg, 24% yield). LC-MS (M+H) + = 340.2, 342.2.

[0196] Step 7: 6-cyano-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l- carboxylic acid tert-butyl ester

[0197]

[0198] To a solution of 7-bromo-6-cyano-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l- carboxylic acid tert-butyl ester (715 mg, 2.1 mmol) and bis(triphenylphosphine)palladium (54 mg, 0.11 mmol) in anhydrous THF (100 mL) was added dropwise (4- fluorobenzyl)zinc(II) chloride (8.4 mL, 4.2 mmol, 0.5 M in THF), the resulting solution was stirred at 60 °C for 2 h. The reaction was quenched with MeOH (5 mL) and concentrated in vacuo, the residue was purified by silica gel chromatography (PE:EtOAc = 5: 1) to give the product (470 mg, 61% yield). LC-MS (M+H) + = 370.4.

[0199] Step 8: 7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-6-carbonitrile

[0200]

[0201] To a solution of 6-cyano-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine- l-carboxylic acid tert-butyl ester (360 mg, 0.98 mmol) in DCM (10 mL) was added a solution of HC1 in 1,4-dioxane (4 N, 2.5 mL, 10 mmol), the resulting solution was stirred at room temperature for 12 h. The solution was concentrated in vacuo. The mixture was neutralized with aqueous NaHC03solution and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated to give the title compound (260 mg, 99% yield). LC-MS (M+H) + = 270.4.

[0202] Step 9: l-(2-chloroacetyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-6-carbonitrile

[0203]

[0204] To a solution of 7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-6- carbonitrile (100 mg, 0.37 mmol) and Et3N (99 mg, 0.98 mmol) in MeCN (10 mL) was added 2-chloroacetyl chloride (111 mg, 0.98 mmol) at room temperature and the resulting solution was stirred at room temperature for 12 h. The solution was concentrated in vacuo and the residue was purified by Prep-TLC (DCM:MeOH = 20: 1) to give the title product (68 mg, 53% yield). LC-MS (M+H) + = 346.3.

[0205] Step 10: ((Benzoyloxy)carbonyl)-L-serine-D-alanine methyl ester

[0206]

[0207] To a solution of (R)-2-amino-propionic acid methyl ester hydrochloride (20 g, 143.2 mmol), EDC (33 g, 171.8 mmol), ((benzyloxy)carbonyl)-L-serine (34.3 g, 143.2 mmol) and DCM (700 mL) was added DIEA (36.9 g, 286.4 mmol) dropwise. The resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for 16 h. The mixture was concentrated, the residue was diluted with saturated sodium carbonate solution, water and extracted with EtOAc. The combined organic layers were washed with 2M HC1 solution, saturated brine solution, dried over Na2S04and concentrated to give the product (20 g, 43% yield). LC-MS (M+H) + = 325.1.

[0208] Step 11: (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione

[0209]

[0210] To ((benzyloxy)carbonyl)-L-serine-D-alanine methyl ester (10 g, 30.8 mmol) was added 10% Pd / C (500 mg), MeOH (100 mL), and cyclohexene (65 mL) under nitrogen. The mixture was heated to reflux and stirred at this temperature overnight. The hot reaction mixture was filtered through celite and the filter cake was washed with hot MeOH. The combined filtrates were concentrated. The resulting solid was slurried in 2-butanone and petroleum ether was added gradually over 10 min. After stirring for 30 min, the solid was filtered and further washed with a mixture of PE / 2-butanone (v / v = 2 / 1). The filter cake was dried thoroughly to give the product (2.5 g, 51% yield). LC-MS (M+H) + = 159.1.

[0211] Step 12: ((2R,5R)-5-methylpiperazin-2-yl)methanol hydrochloride

[0212]

[0213] To (3S,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione (2.5 g, 15.8 mmol) was added borane in THF (1 M, 126 mL, 126.4 mmol) and the mixture was heated to 70 °C for 18 h. The solution was cooled in ice and then MeOH (30 mL) was added gradually followed by 5 N HC1 (8 mL). The mixture was warmed to 70 °C for 2 h and then cooled to room temperature. The resulting solid was filtered, washed with THF and dried to give the product (2.0 g, 77% yield). LC-MS (M+H) + = 131.1.

[0214] Step 13: tert-butyl (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylate

[0215]

[0216] To ((2R,5R)-5-methylpiperazin-2-yl)methanol hydrochloride (2 g, 12.0 mmol) in MeOH (20 mL) was added TEA (3.6 g, 36.0 mmol) at 0 °C. Then (Boc)20 (6.3 g, 28.8 mmol) was added dropwise. The resulting mixture was slowly warmed to room temperature and heated to 50 °C overnight. The resulting mixture was concentrated and the residue was dissolved in ethanol (40 mL). A solution of NaOH (2.4 g, 60 mmol) in water (40 mL) was added and the reaction was heated to 100 °C for 18 h and then cooled to ambient temperature. The mixture was neutralized to pH 7 with 1 N HC1 and the resulting solid was filtered and washed with water. The filter cake was dried thoroughly to give the product (2.5 g, 95% yield). LC-MS (M+H) The mixture was partitioned between saturated NaHC03solution and DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give the title product (2.0 g, 90% yield). LC-MS (M+H) + = 231.1.

[0217] Step 14: (2R,5R)-4-benzyl-5-(hydroxymethyl)-2-methylpiperazine-1 -carboxylic acid tert-butyl ester

[0218]

[0219] (2R,5R)-5-(hydroxymethyl)-2-methylpiperazine-1 -carboxylic acid tert-butyl ester (1.6 g, 6.9 mmol), benzaldehyde (805 mg, 7.6 mmol), sodium triacetoxyborohydride (1.8 g, 8.5 mmol) and DCM (30 mL) were stirred at room temperature overnight. The mixture was then partitioned between saturated NaHC03solution and DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20: 1) to give the title product (2.0 g, 90% yield). LC-MS (M+H) + = 321.2.

[0220] Step 15: (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1 -carboxylic acid tert-butyl ester

[0221]

[0222] Methanesulfonyl chloride (0.6 mL, 7.4 mmol) was added to a solution of (2R,5R)-4-benzyl-5-(hydroxymethyl)-2-methylpiperazine-1 -carboxylic acid tert-butyl ester (2.0 g, 6.2 mmol) in DCM (30 mL) containing TEA (2.6 mL, 18.4 mmol) at 0 °C. The mixture was stirred at room temperature overnight. The reaction was partitioned between NH4CI solution and DCM. The combined organic layers were dried, filtered and concentrated. The crude material was purified by silica gel column chromatography (PE:EtOAc = 3: 1) to give the title product (1.4 g, 67% yield). LC-MS (M+H) + = 339.2.

[0223] Step 16: (2R,5S)-4-benzyl-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1 - carboxylic acid tert-butyl ester

[0224]

[0225] To (2R,5R)-tert-butyl 4-benzyl-5-(chloromethyl)-2-methylpiperazine-l-carboxylate (1.4 g, 4.1 mmol) in MeCN (20 mL) was added K2CO3 (1.7 g, 12.3 mmol), KI (1.4 g, 8.4 mmol) and (R)-3-methylmorpholine (630 mg, 6.2 mmol). The mixture was stirred at 70 °C overnight. The solids were filtered off and the solvent was concentrated. The residue was partitioned between water and DCM. The combined organic layers were dried, filtered and evaporated. The crude residue was purified by silica gel column chromatography (DCM:MeOH = 40: 1) to give the product (1.3 g, 78% yield). LC-MS (M+H) + = 404.3.

[0226] Step 17: (2R,5S)-tert-butyl 2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylate

[0227]

[0228] To (2R,5S)-tert-butyl 4-benzyl-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylate (1.3 g, 3.2 mmol) in EtOH (20 mL) was carefully added Pd / C (130 mg) and a few drops of AcOH. The mixture was stirred at ambient temperature under H2atmosphere for 3 h. The mixture was concentrated and extracted with DCM. The combined organic layers were washed with saturated NaHC03solution, dried, filtered and concentrated. The resulting title compound (1.0 g) was used in the next step without purification. LC-MS (M+H) + = 314.2.

[0229] Step 18: (2R,5S)-tert-butyl 4-(2-(6-cyano-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylate

[0230]

[0231] A solution of 1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carbonitrile (68 mg, 0.196 mmol), (2R,5S)-tert-butyl 2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate (62 mg, 0.196 mmol), KI (65 mg, 0.392 mmol), and KCO (81 mg, 0.588 mmol) in MeCN (10 mL) was stirred at room temperature for 2 h. The reaction solution was concentrated in vacuo to remove the solvent, and the residue was washed with H0 (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were concentrated and purified by Prep-TLC (DCM:MeOH=20:1) to give the title compound (80 mg, 65.5% yield). LC-MS (M+H) + =623.7.

[0232] Step 19: 7-(4-Fluorobenzyl)-1-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carbonitrile formate (Compound 1)

[0233] To tert-butyl (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)piperazine-1-carboxylate (80 mg, 0.128 mmol) in DCM (10 mL) was added a solution of hydrochloric acid in 1,4-dioxane (4 N, 2.5 mL) and the resulting solution was stirred at room temperature for 4 h. The solution was concentrated in vacuo, dissolved in MeOH (10 mL), the pH was adjusted to 8-9 by adding aqueous NaHCO3, and then concentrated in vacuo to remove the solvent. The residue was purified by Prep-HPLC (gradient eluent: CH3CN / H2O from 10% to 25%, each containing 0.1% FA) to give compound 1 (30 mg, 41% yield) as a formate salt. 1H NMR (400 MHz, DMSO-d6) δ 11.31 - 9.78 (m, 1H), 8.63 (s, 1H), 8.26 (s, 2H), 7.31 - 7.22 (m, 2H), 7.22 - 7.11 (m, 2H), 4.53 - 4.34 (m, 2H), 4.17 - 3.79 (m, 6H), 3.52 - 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.

[0234] 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)piperazin-1-yl)ethan-1-one formate salt (Compound 2)

[0235]

[0236] Step 1: 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazole-1,1-dicarboxylate

[0237]

[0238] The title compound of Step 1 (1.56 g) was prepared in a similar manner as described in Example 1, Step 7 from 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazole-1-carboxylate and (4-fluorobenzyl)zinc(II) chloride. LCMS (M+H) + = 345.2.

[0239] Step 2: 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazole

[0240]

[0241] The title compound of Step 2 (100 mg) was prepared in a similar manner as described in Example 1, Step 8 from 7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazole-1-carboxylate. LC-MS (M+H) + = 245.2.

[0242] Step 3: 2-chloro-l-(7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)ethan-l-one

[0243]

[0244] The title compound of Step 3 (80 mg) was prepared from 7-(4-fluorobenzyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazine and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 321.1.

[0245] Step 4: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylic acid tert-butyl ester

[0246]

[0247] The title compound of Step 4 (80 mg) was prepared from 2-chloro-l-(7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)- 2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 598.6.

[0248] Step 5: l-(7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-((2R,5R)- 5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l-one formate salt (Compound 2)

[0249] Compound 2 (20 mg) as its formate salt was prepared from (2R,5S)-4-(2-(7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5- (((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. 1H NMR (400MHz, DMSO-d6) δ8.64-8.11(s,3H),7.85(s,1H),7.30-7.19(m,2H),7.18-7.04(m,2H),4.45-4.26(m,2H),4.07 -3.71(m,6H),3.52-3.33(m,2H),3.22-3.04(m,2H),3.03-2.59(m,7H),2.47-2.37(m,1H),2.2 1-2.07(m,1H),2.04-1.91(m,1H),1.89-1.74(m,1H),1.02(d,J=5.8Hz,3H),0.91-0.74(m,3H). LC-MS (M+H) + =498.6.

[0250] Example 3: 7-(4-fluorobenzyl)-1-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carboxamide formate (Compound 3)

[0251]

[0252] Step 1: 7-(4-Fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carboxamide

[0253]

[0254] To tert-butyl 6-cyano-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (680 mg, 1.84 mmol) in DMSO (6 mL) and H2O (10 mL) was added KOH (1.55 g, 27.6 mmol), and the resulting solution was stirred at 120°C for 12 h. The solvent was removed in vacuo, and the residue was purified by Prep-TLC (DCM:MeOH=30:1) to give the title product (40 mg, 7.5% yield). LC-MS (M+H) + =288.1.

[0255] Step 2: 7-(4-Fluorobenzyl)-1-(2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)acetyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-6-carboxamide formate (Compound 3)

[0256] Compound 3 (30 mg) was prepared from 7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazole-6-carboxamide and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l -carboxylic acid tert-butyl ester as its formate salt in a similar manner as described in Example 1, step 9 and steps 18-19. 1 H NMR (400 MHz, DMSO-d6) δ 10.26 - 8.03 (m, 4H), 7.79 (s, 1H), 7.44 (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.

[0257] Example 4: l-(6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- l-yl)ethan-l-one (Compound 4)

[0258]

[0259] Step 1: 6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole

[0260]

[0261] To 7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole (612 mg, 2.51 mmol) in DMF (15 mL) was added NBS (446 mg, 2.51 mmol) portion wise at 0 °C and the resulting solution was stirred at room temperature for 2 h. Water (30 mL) was added and the mixture was extracted with EtOAc (15 mL*3). The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH = 50: 1) to give the title product (350 mg, 43.2% yield). LC-MS (M+H) += 323.0, 325.0.

[0262] Step 2: tert-Butyl 6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine- 1 -carboxylate

[0263]

[0264] To 6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine (350 mg, 1.1 mmol) in THF (10 mL) was added TEA (330 mg, 3.3 mmol). The mixture was cooled to 0 °C. Then (Boc)20 (480 mg, 2.2 mmol) was added dropwise. The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting residue was purified by silica gel column chromatography (PE:EtOAc = 3: 1) to give the title product (300 mg, 64% yield). LC-MS (M+H) + = 423.1, 425.1.

[0265] Step 3: l-(6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l- yl)ethan-l-one (Compound 4)

[0266] Compound 4 as formate salt was prepared from tert-butyl 6-bromo-7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylate and tert-butyl (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylate in a similar manner as described in Example 1, Steps 8-9 and Steps 18-19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined EtOAc layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 4 as free base (27 mg). 1H 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), 2.16 (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.

[0267] Example 5: l-(7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 5)

[0268]

[0269] Step 1: 7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l- carboxylic acid tert-butyl ester

[0270]

[0271] To a solution of tert-butyl 6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine-l-carboxylate (300 mg, 0.709 mmol) and methylboronic acid (128 mg, 2.13 mmol) in 1,4-dioxane (20 mL) and H2O (5 mL) was added Pd(PPh3)4 (82 mg, 0.071 mmol) and Cs2CO3 (699 mg, 2.15 mmol), the resulting solution was stirred at 100 °C for 12 h. The reaction solution was cooled to room temperature and washed with H2O (25 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were dried over Na2SO4, concentrated in vacuo and purified by silica gel chromatography (PE:EtOAc = 5: 1) to give the title product (250 mg, 98% yield). LC-MS (M+H) + = 359.2.

[0272] Step 2: 1-(7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-1-one (Compound 5)

[0273] Compound 5 as formate salt was prepared from 7-(4-fluorobenzyl)-6-methyl-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester and (2R,5S)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1 Step 8-9 and Step 18-19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined EtOAc layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 5 as free base (12.6 mg). 1 H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.06 (m, 1H), 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) + = 512.3.

[0274] Example 6: 1-(6-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)piperazin- 1-yl)ethan-1-one (Compound 6)

[0275]

[0276] Step 1: 6-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1- carboxylic acid tert-butyl ester

[0277]

[0278] To a solution of 6-bromo-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl formate (73 mg, 0.173 mmol) and cyclopropylboronic acid (22 mg, 0.258 mmol) in toluene (10 mL) and H20 (5 mL) was added Pd(OAc)2(2 mg, 0.009 mmol) and tricyclohexylphosphine (5 mg, 0.018 mmol) and K3PO4(109 mg, 0.518 mmol) and the resulting solution was stirred at 80 °C under N2for 12 h. The reaction solution was concentrated in vacuo to remove toluene, washed with water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product (78 mg) which was used in the next step without further purification. LC-MS (M+H) + = 385.3.

[0279] Step 2: l-(6-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l- yl)ethan-l-one (Compound 6)

[0280] Compound 6 as formate salt was prepared from 6-cyclopropyl-7-(4-fluorobenzyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-carboxylic acid tert-butyl ester and (2R,5S)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Steps 8-9 and Steps 18-19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 6 as free base (10 mg). 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), 2.31 - 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.

[0281] Example 7: l-(7-(4-fluorobenzyl)-6-(trifluoromethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 7)

[0282]

[0283] Step 1: tert-Butyl 7-(4-fluorobenzyl)-6-(trifluoromethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine-l-carboxylate

[0284]

[0285] To a solution of tert-butyl 7-(4-fluorobenzyl)-6-(trifluoromethyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine-l-carboxylate (110 mg, 0.26 mmol) and methyl 2,2-difluoro-2- (fluorosulfonyl)acetate (200 mg, 1.04 mmol) in DMF (5 mL) was added Cul (99 mg, 0.52 mmol), the resulting solution was stirred at 120 °C for 1 h. The reaction solution was cooled to room temperature, washed with H2O (10 mL), and extracted with EtOAc (10 mL*3). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo, the residue was purified by silica gel column chromatography (PE:EtOAc = 5: 1) to give the title product (73 mg, 68% yield). LC-MS (M+H) + = 413.2.

[0286] Step 2: l-(7-(4-fluorobenzyl)-6-(trifluoromethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin- l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l- one (Compound 7)

[0287] Compound 7 as formate salt was prepared from 7-(4-fluorobenzyl)-6-(trifluoromethyl)- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-carboxylic acid tert-butyl ester and (2R,5S)- 2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, steps 8-9 and steps 18-19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give compound 7 as free base (26.4 mg). 1 H NMR (400 MHz, 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, 1H), 0.97 - 0.89 (m, 3H), 0.89 - 0.80 (m, 3H). LCMS (M+H) + = 566.3.

[0288] Example 8: l-(7-(4-fluorobenzyl)-6-(hydroxymethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 8)

[0289]

[0290] Step 1: l-(tert-Butoxycarbonyl)-7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine 5-oxide

[0291]

[0292] The title compound of step 1 (1.2 g) was prepared from 7-(4-fluorobenzyl)-6- methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, step 5. LC-MS (M+H) + = 375.2.

[0293] Step 2: 6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl butylate

[0294]

[0295] A solution of l-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-6-methyl-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazine 5-oxide (1.2 g, 3.2 mmol) in Ac2O (20 mL) was stirred at 130 °C for 3 h. The reaction solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (5 mL*3). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to give the crude product (1.0 g), which was used directly in the next step without purification. LC-MS (M+H) + = 417.2.

[0296] Step 3: (2R,5S)-4-(2-(6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0297]

[0298] The title compound of Step 3 (40 mg) was prepared in a similar manner as described in Example 1, Steps 8-9 and Step 18 from 6-(acetyloxymethyl)-7-(4-fluorobenzyl)- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylic acid tert-butyl ester and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 670.4.

[0299] Step 4: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-6-(hydroxymethyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0300]

[0301] To a solution of (2R,5S)-4-(2-(6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2,3- dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-1 -carboxylic acid tert-butyl ester (40 mg, 0.06 mmol) in MeOH (5 mL) and H2O (5 mL) was added NaOH (12 mg, 0.3 mmol) and the resulting solution was stirred at room temperature for 3 h. The reaction solution was extracted with EtOAc (10 mL*3). The combined organic layers were dried, filtered and concentrated. The residue was purified by Prep-TLC (DCM:MeOH=20:1 ) to give the title compound (20 mg, 53% yield). LC-MS (M+H) + = 628.3.

[0302] Step 5: 1 -(7-(4-fluorobenzyl)-6-(hydroxymethyl)-2,3-dihydro-1 H-pyrido[2,3- b][1,4]oxazin-1 -yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1 -yl)ethan-1 -one (Compound 8)

[0303] Compound 8 as formate salt was prepared from (2R,5S)-4-(2-(7-(4-fluorobenzyl)-6- (hydroxymethyl)-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-2-methyl-5- (((R)-3-methylmorpholino)methyl)piperazine-1 -carboxylic acid tert-butyl ester in a similar manner as described in Example 1 Step 19. The salt was neutralized with aqueous NaHC03 and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 8 as free base (5.7 mg). 1 H NMR (400 MHz, DMSO-d6) d 8.34 (s, 1 H), 7.26-7.16 (m, 2H), 7.16-7.06 (m, 2H), 5.11 (s, 1 H), 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, 1 H), 2.05-1.94 (m, 1 H), 1.91 -1.80 (m, 1 H), 1.10-1.01 (m, 3H), 0.95-0.76 (m, 3H). LC-MS (M+H) + = 528.3.

[0304] Example 9: l-(7-(4-fluorobenzyl)-6-hydroxy-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 9)

[0305]

[0306] Step 1: l-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine 5-oxide

[0307]

[0308] The title compound of Step 1 (166 mg) was prepared from tert-butyl 7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylate in a similar manner as described in Example 1, Step 5. LC-MS (M+H) + = 361.3.

[0309] Step 2: tert-butyl 6-acetyloxy-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine-l-carboxylate

[0310]

[0311] A solution of l-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine 5-oxide (166 mg, 0.461 mmol) in Ac2O (2 mL) was stirred at 130 °C for 3 h. The reaction solution was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with EtOAc (5 mL*3). The combined organic layers were dried over Na2S04, filtered, and concentrated in vacuo to give the title product (160 mg), which was used directly in the next step without purification. LC-MS (M+H) + = 403.2.

[0312] Step 3: 7-(4-Fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxolan-6-ol

[0313]

[0314] To a solution of tert-butyl 6-acetyloxy-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l -carboxylate (160 mg, 0.398 mmol) in DCM (5 mL) was added TFA (1 mL) and the resulting solution was stirred at room temperature for 2 h. The reaction solution was concentrated in vacuo and the resulting residue was purified by Prep-TLC (DCM:MeOH = 15: 1) to give the title product (38 mg, 37% yield). LC-MS (M+H) + = 261.2.

[0315] Step 4: 2-Chloro-l-(7-(4-fluorobenzyl)-6-hydroxy-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)ethan-l-one

[0316]

[0317] The title compound of Step 4 (60 mg) was prepared in a similar manner as described in Example 1, Step 9 from 7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazol-6-ol and 2-chloroacetyl chloride. LC-MS (M+H) + = 337.2.

[0318] Step 5: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-6-hydroxy-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1 -carboxylic acid tert-butyl ester

[0319]

[0320] The title compound of Step 5 (20 mg) was prepared in a similar manner as described in Example 1, Step 18 from 2-chloro-l-(7-(4-fluorobenzyl)-6-hydroxy-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 614.5.

[0321] Step 6: l-(7-(4-Fluorobenzyl)-6-hydroxy-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)- 2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 9)

[0322] Compound 9 as formate salt was prepared from (2R,5S)-4-(2-(7-(4- fluorobenzyl)-6-hydroxy-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylate tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 9 as a free base (5.2 mg). 1 H NMR (400 MHz, DMSO-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, 2H), 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.

[0323] Example 10: l-(7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- l-yl)ethan-l-one (Compound 10)

[0324]

[0325] Step 1: 2-((5-Bromo-3-nitropyridin-2-yl)oxy)propionic acid ethyl ester

[0326]

[0327] To 5-bromo-2-chloro-3-nitropyridine (11.87 g, 50 mmol) and ethyl 2- hydroxypropanoate (8.85 g, 75 mmol) in anhydrous THF (100 mL) was added NaH (4 g, 60% dispersion in mineral oil, 100 mmol) slowly at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (100 mL*3), the combined EtOAc phases were dried over Na2SO4, filtered and evaporated in vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 10:1) to give the title product (8.5 g, 53% yield). LC-MS (M+H) + = 319.0, 321.0.

[0328] Step 2: 7-Bromo-3-methyl-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one

[0329]

[0330] To ethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)propanoate (8.5 g, 26.7 mmol) in AcOH (100 mL) was added Fe powder (17.3 g, 310 mmol) slowly at 70 °C, the resulting mixture was stirred at 70 °C for 1 h. The AcOH was removed in vacuum, the resulting solid was washed with MeOH (200 mL), filtered. This procedure was repeated 5 times. The MeOH phase was concentrated in vacuum to give the crude product (2.2 g), which was used directly in the next step without purification. LC-MS (M+H) + = 243.0, 245.0.

[0331] Step 3: 7-Bromo-3-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine

[0332]

[0333] To 7-bromo-3-methyl-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one (2.2 g, 9.05 mmol) in anhydrous THF (50 mL) was added borane in THF (1 N, 23 mL) dropwise at room temperature, the resulting solution was stirred at 60 °C for 1 h. The reaction was cooled to room temperature, quenched with MeOH (10 mL), pH was adjusted to 1-2 by adding 1 N HC1, and stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature, water (100 mL) was added, and pH was adjusted to 8-9, extracted with EtOAc (100 mL*3). The combined EtOAc layer was dried over Na2S04, filtered and evaporated in vacuum to give the title product (1.2 g), which was used in the next step without purification. LC-MS (M+H) + = 229.0, 231.0.

[0334] Step 4: 7-Bromo-3-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-tert-butyl ester

[0335]

[0336] To 7-bromo-3-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine (1 g, 4.37 mmol), DMAP (0.8 g, 6.55 mmol) and Et3N (0.882 g, 8.72 mmol) in THF (30 mL) was added (Boc)20 (1.42 g, 6.55 mmol) dropwise at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction was washed with water (50 mL), extracted with EtOAc (50 mL*3). The combined EtOAc layer was dried over Na2S04, filtered and evaporated in vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 5: 1) to give the title product (0.99 g, 69% yield). LC-MS (M+H) + = 329.2, 331.2.

[0337] Step 5: 7-(4-Fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-tert-butyl ester

[0338]

[0339] To a solution of 7-bromo-3-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methylate tert-butyl (990 mg, 3 mmol) and bis(triphenylphosphine) palladium (77 mg, 0.15 mmol) in anhydrous THF (20 mL) was added dropwise a solution of (4-fluorobenzyl)zinc(II) (0.5 N, 12 mL, 6 mmol), the resulting solution was stirred at 60 °C for 2 h. The reaction was quenched with MeOH (5 mL) and concentrated in vacuo, the residue was purified by silica gel chromatography (PE:EtOAc = 5: 1) to give the title product (850 mg, 79% yield). LC-MS (M+H) + = 359.4.

[0340] Step 6: 7-(4-Fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine

[0341]

[0342] To a solution of 7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methylate tert-butyl (850 mg, 2.37 mmol) in DCM (10 mL) was added a solution of hydrochloric acid in 1,4-dioxane (4 N, 2.5 mL, 10 mmol), the resulting solution was stirred at room temperature for 12 h. The solution was concentrated in vacuo. A solution of NaHC03(saturated, 20 mL) was added, extracted with DCM (20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04, concentrated to give the title product (550 mg, 90% yield). LC-MS (M+H) + = 259.1.

[0343] Step 7: 2-Chloro-l-(7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)ethan-l-one

[0344]

[0345] The title compound of Step 7 (110 mg) was prepared in a similar manner as described in Example 1, Step 9 from 7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine and 2-chloroacetyl chloride. LC-MS (M+H) + = 334.9.

[0346] Step 8: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0347]

[0348] The title compound of Step 8 (45 mg) was prepared in a similar manner as described in Example 1, Step 18 from 2-chloro-l-(7-(4-fluorobenzyl)-3-methyl-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 612.3.

[0349] Step 9: l-(7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)- 2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l- one (Compound 10)

[0350] Compound 10 as formate salt was prepared in a similar manner as described in Example 1, Step 19 from (2R,5S)-4-(2-(7-(4-fluorobenzyl)-3-methyl-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 10 as free base (8 mg). 1H NMR(400MHz,DMSO-d6)δ8.28(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,1H),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,1H),1.34-1.28(m,3H),0.91-0.82(m,6H). LC-MS(M+H) + =512.0.

[0351] Example 11: 1-(6-Bromo-7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (Compound 11)

[0352]

[0353] Step 1: 6-Bromo-7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0354]

[0355] To 7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (620 mg, 2.4 mmol) in DMF (15 mL) was added NBS (428 mg, 2.4 mmol) at 0°C, and the resulting solution was stirred at room temperature for 2 h. Water (30 mL) was added and extracted with EtOAc (15 mL*3). The combined organic layers were concentrated and purified by silica gel chromatography (PE:EtOAc=3:1) to give the title product (350 mg, 43% yield). LC-MS (M+H) + =337.0,339.0

[0356] Step 2: 1-(6-bromo-7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-chloroethan-1-one

[0357]

[0358] The title compound of Step 2 (140 mg) was prepared from 6-bromo-7-(4- fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin and 2- chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 413.3, 415.3.

[0359] Step 3: (2R,5S)-4-(2-(6-bromo-7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0360]

[0361] The title compound of Step 3 (80 mg) was prepared from l-(6-bromo-7-(4- fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- chloroethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl) piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 690.3, 692.3.

[0362] Step 4: l-(6-bromo-7-(4-fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl) piperazin-l-yl)ethan-l-one (Compound 11)

[0363] Compound 11 as formic acid salt was prepared from (2R,5S)-4-(2-(6-bromo-7- (4-fluorobenzyl)-3-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 11 as free base (10 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.23 (s, 2H), 7.23-7.14 (m, 2H), 4.55 (s, 1H), 4.13-4.09 (m, 2H), 3.97 (s, 2H), 3.59 (br s, 1H), 3.55-3.42 (m, 3H), 3.27-3.21 (m, 1H), 2.95 (br s, 1H), 2.77-2.74 (m, 3H), 2.65-2.59 (m, 3H), 2.30-2.23 (m, 1H), 2.16 (br s, 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 Hz, 6H). LC-MS (M+H) + = 590.0, 592.0.

[0364] Example 12: l-(6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 12)

[0365]

[0366] Step 1: 2-bromo-N-(5-bromo-2-hydroxypyridin-3-yl)-2-methylpropanamide

[0367]

[0368] To a solution of 3-amino-5-bromopyridin-2-ol (4 g, 21.2 mmol) in THF (40 mL) was added TEA (6.4 g, 63.5 mmol). The mixture was cooled to 0 °C. 2-bromo-2-methyl- propanoyl bromide (5.3 g, 23.3 mmol) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 2 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 1:1) to give the title product (4.2 g, 60% yield). LC-MS (M+H) + = 336.9.

[0369] Step 2: 7-bromo-3,3-dimethyl-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one

[0370]

[0371] To a solution of 2-bromo-N-(5-bromo-2-hydroxypyridin-3-yl)-2-methylpropanamide (4.2 g, 12.5 mmol) in DMF (100 mL) was added K2CO3(5.2 g, 37.5 mmol). The mixture was warmed to 70 °C and stirred for 8 h. After cooling, the mixture was concentrated, diluted with H2O, and extracted with EtOAc. The combined organic layers were dried, filtered, and evaporated. The residue was purified by silica gel column chromatography (DCM:MeOH = 30:1) to give the title product (1.6 g, 50% yield). LC-MS (M+H) + = 257.0, 259.0.

[0372] Step 3: 7-Bromo-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine

[0373]

[0374] The title compound of Step 3 (830 mg) was prepared in a similar manner as described in Example 1, Step 3 from 7-bromo-3,3-dimethyl-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one. LC-MS (M+H) + = 243.0, 245.0.

[0375] Step 4: 7-Bromo-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-tert-butyl ester

[0376]

[0377] The title compound of Step 4 (830 mg) was prepared in a similar manner as described in Example 10, Step 4 from 7-bromo-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine. LC-MS (M+H) + = 342.9, 344.9.

[0378] Step 5: 7-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-tert-butyl ester

[0379]

[0380] The title compound of Step 5 (500 mg) was prepared in a similar manner as described in Example 10, Step 5 from 7-bromo-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-tert-butyl ester. LC-MS (M+H) + = 373.0.

[0381] Step 6: 7-(4-Fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl formate

[0382]

[0383] The title compound of Step 6 (280 mg) was prepared in a similar manner as described in Example 10, Step 6 from 7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l -methyl formate. LC-MS (M+H) + = 273.0.

[0384] Step 7: 6-Bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl formate

[0385]

[0386] The title compound of Step 7 (230 mg) was prepared in a similar manner as described in Example 11, Step 1 from 7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl formate. LC-MS (M+H) + = 351.0, 353.0.

[0387] Step 8: l-(6-Bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-chloroethan-l-one

[0388]

[0389] The title compound of Step 8 (100 mg) was prepared in a similar manner as described in Example 1, Step 9 from 6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l -methyl formate and 2-chloroacetyl chloride. LC-MS (M+H) + = 427.0, 429.0.

[0390] Step 9: (2R,5S)-4-(2-(6-Bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylate

[0391]

[0392] The title compound of Step 9 (85 mg) was prepared in a similar manner as described in Example 1, Step 18 from l-(6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-chloroethan-l-one and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylate tert-butyl ester. LC-MS (M+H) + = 704.0, 706.0.

[0393] Step 10: l-(6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 12)

[0394] Compound 12 as a formate salt was prepared in a similar manner as described in Example 1, Step 19 from (2R,5S)-4-(2-(6-bromo-7-(4-fluorobenzyl)-3,3-dimethyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylate tert-butyl ester. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 12 as a free base (15 mg). 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 (br s, 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.

[0395] Example 13: 2-((2R,5R)-2-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-5- methylpiperazin-1-yl)-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1- yl)ethan-1-one (Compound 13)

[0396]

[0397] Step 1: (2R,5S)-5-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-4-benzyl-2- methylpiperazine-1-carboxylic acid tert-butyl ester

[0398]

[0399] The title compound of Step 1 (110 mg) was prepared in a similar manner as described in Example 1, Step 16 from (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 402.0.

[0400] 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 ester

[0401]

[0402] The title compound of Step 2 (60 mg) was prepared in a similar manner as described in Example 1, Step 17 from (2R,5S)-5-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-4-benzyl-2- methylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 312.0.

[0403] Step 3: (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-pyrrolo[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester

[0404]

[0405] The title compound of Step 3 (30 mg) was prepared from (2R,5S)-5-(((1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)-2-methylpiperazine-1 -carboxylate and 2-chloro-1 -(7-(4- fluorobenzyl)-2,3-dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-1 -yl)ethan-1 -one in a similar manner as described in Example 1 Step 18. LC-MS (M+H) + = 596.0.

[0406] Step 4: 2-((2R,5R)-2-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-5- methylpiperazin-1-yl)-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1- yl)ethan-1-one (Compound 13)

[0407] Compound 13 as formate salt was prepared from (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-pyrrolo[2,3-b][1,4]oxazin-1-yl)-2- oxoethyl)-2-methylpiperazine-1-carboxylate in a similar manner as described in Example 1 Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 13 as free base (8 mg). 1 H NMR (400 MHz, 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 (br s, 3H), 3.79 (br s, 1H), 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 = 9.2 Hz, 1H), 1.54 (d, J = 9.3 Hz, 1H), 1.03 (s, 3H). LC-MS (M+H) + = 496.3.

[0408] Example 14: 2-((2R,5R)-2-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-5- methylpiperazin-1-yl)-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1- yl)ethan-1-one (Compound 14)

[0409]

[0410] Step 1: (2R,5S)-5-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-4-benzyl-2- methylpiperazine-1-carboxylic acid tert-butyl ester

[0411]

[0412] The title compound of Step 1 (100 mg) was prepared from (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 16. LC-MS (M+H) + = 402.0.

[0413] 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 ester

[0414]

[0415] The title compound of Step 2 (60 mg) was prepared from (2R,5S)-5-(((1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)-4-benzyl-2-methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 17. LC-MS (M+H) + = 312.0.

[0416] Step 3: (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-pyrrolo[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester

[0417]

[0418] The title compound of Step 3 (30 mg) was prepared from (2R,5S)-5-(((1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)methyl)-2-methylpiperazine-1 -carboxylate and 2-chloro-1 -(7-(4- fluorobenzyl)-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 -yl)ethan-1 -one in a similar manner as described in Example 1 Step 18. LC-MS (M+H) + = 596.0.

[0419] Step 4: 2-((2R,5R)-2-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-5- methylpiperazin-1-yl)-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- yl)ethan-1-one (Compound 14)

[0420] Compound 14 as formate salt was prepared from (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]oxazin-1-yl)-2- oxoethyl)-2-methylpiperazine-1-carboxylate in a similar manner as described in Example 1 Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 14 as free base (5 mg). 1 H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 7.80 (s, 1H), 7.22 (s, 2H), 7.04-7.02 (m, 2H), 4.42 (br s, 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 = 12.2 Hz, 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, 1H), 2.31 (d, J = 9.4 Hz, 1H), 1.51 (s, 2H), 1.10-1.05 (m, 3H). LC-MS (M+H) + = 496.3.

[0421] 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-methylpiperazin-2-yl)methyl)oxazolidin- 2-one (Compound 15)

[0422]

[0423] Step 1: (2R,5R)-4-Benzyl-5-(((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)methyl)-2- methylpiperazine-1-carboxylic acid tert-butyl ester

[0424]

[0425] The title compound of Step 1 (120 mg) was prepared in a similar manner as described in Example 1, Step 16 from (S)-4-(difluoromethyl)oxazolidin-2-one and (2R,5R)-4-benzyl-5- (chloromethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 440.0.

[0426] Step 2: (2R,5R)-5-(((S)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)methyl)-2- methylpiperazine-1-carboxylic acid tert-butyl ester

[0427]

[0428] The title compound of Step 2 (45 mg) was prepared in a similar manner as described in Example 1, Step 17 from (2R,5R)-4-benzyl-5-(((S)-4-(difluoromethyl)-2-oxooxazolidin-3- yl)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 350.0.

[0429] Step 3: (2R,5R)-5-(((S)-4-(difluoromethyl)-2-oxooxazolidin-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-carboxylic acid tert-butyl ester

[0430]

[0431] The title compound of Step 3 (15 mg) was prepared from (2R,5R)-5-(((S)-4- (difluoromethyl)-2-oxooxazolidin-3-yl)methyl)-2-methylpiperazine-1 -carboxylate and 2-chloro-1 -(7-(4-fluorobenzyl)-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 -yl)ethan-1 - one in a similar manner as described in Example 1 Step 18. LC-MS (M+H) + = 634.3.

[0432] Step 4: (S)-4-(difluoromethyl)-3-(((2R,5R)-1 -(2-(7-(4-fluorobenzyl)-2,3-dihydro-1 H- pyrido[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-5-methylpiperazin-2-yl)methyl)oxazolidin-2- one (Compound 15)

[0433] Compound 15 as formate salt was prepared from (2R,5R)-5-(((S)-4-(difluoromethyl)- 2-oxooxazolidin-3-yl)methyl)-4-(2-(7-(4-fluorobenzyl)-2,3-dihydro-1 H-pyrido[2,3-b][1,4] oxazin-1 -yl)-2-oxoethyl)-2-methylpiperazine-1 -carboxylate tert-butyl in a similar manner as described in Example 1 Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 15 as free base (5 mg). 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.

[0434] Example 16: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1 -yl)-1 -(7-(4-fluorobenzyl)-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 - yl)ethan-1 -one (Compound 16)

[0435]

[0436] Step 1: (2R,5S)-4-benzyl-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2- methylpiperazine-1 -carboxylate

[0437]

[0438] The title compound of Step 1 (80 mg) was prepared from (3R,5R)-3,5- dimethylmorpholine hydrochloride and (2R,5R)-4-benzyl-5-(chloromethyl)-2- methylpiperazine-1 -carboxylate in a similar manner as described in Example 1, Step 16. LC-MS (M+H) + = 418.3.

[0439] Step 2: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1 - carboxylate

[0440]

[0441] The title compound of Step 2 (40 mg) was prepared from (2R,5S)-4-benzyl-5- (((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1 -carboxylate in a similar manner as described in Example 1, Step 17. LC-MS (M+H) + = 328.5.

[0442] Step 3: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-(7-(4- fluorobenzyl)-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-2- methylpiperazine-1 -carboxylate

[0443]

[0444] The title compound of Step 3 (20 mg) was prepared from (2R,5S)-5-(((3R,5R)- 3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1 -carboxylate and 2-chloro-1 -(7- (4-fluorobenzyl)-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 -yl)ethan-1 -one in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 612.3.

[0445] Step 4: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrrolo[2,3- b][1,4]oxazin-1 -yl)ethan-1 -one (Compound 16)

[0446] Compound 16 as formate salt was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-(7-(4-fluorobenzyl)-2,3-dihydro-1H- pyrrolo[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-2-methylpiperazine-1 -carboxylic acid tert-butyl ester in a similar manner as described in Example 1 Step 19. The salt was neutralized with NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 16 as free base (4 mg). 1 H NMR (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 (br s, 1H), 4.30 (br s, 1H), 4.04-3.96 (m, 2H), 3.85 (br s, 2H), 3.83-3.73 (m, 1H), 3.50-3.41 (m, 1H), 3.41-3.34 (m, 2H), 3.04 (br s, 2H), 2.90-2.82 (m, 1H), 2.73 (br s, 1H), 2.65 (br s, 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 (br s, 1H), 0.89-0.75 (m, 9H). LC-MS (M+H) + = 512.3.

[0447] Example 17: 1-(6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (Compound 17)

[0448]

[0449] Step 1: 6-ethoxy-3-nitropyridin-2-amine

[0450]

[0451] NaH (1.2 g, 60% dispersion in mineral oil, 30 mmol) was added slowly to 100 mL of ethanol and stirred at room temperature for 10 min. 2-Amino-6-chloro-3-nitropyridine (5 g, 28.9 mmol) was added in portions and the mixture was stirred at ambient temperature for 30 min. After concentration, water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the title product (3.0 g, 56% yield). LC-MS (M+H) + = 184.1.

[0452] Step 2: 5-Bromo-6-ethoxy-3-nitropyridin-2-amine

[0453]

[0454] To 6-ethoxy-3-nitropyridin-2-amine (3.0 g, 16.4 mmol) was added 30 mL of DMF. The mixture was cooled to 0 °C. NBS (3.2 g, 18.04 mmol) was added to the above cooled mixture in portions. The new mixture was slowly warmed to room temperature and stirred for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with aqueous Na2S2O3, dried, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the title product (3.4 g, 80% yield). LC-MS (M+H) + = 262.0, 264.0.

[0455] Step 3: 3-Bromo-6-chloro-2-ethoxy-5-nitropyridine

[0456]

[0457] To a solution of 5-bromo-6-ethoxy-3-nitropyridin-2-amine (3.4 g, 13.02 mmol) in CH3CN (60 mL) was added CuCl (2.57 g, 26.0 mmol) and t-BuONO (2.68 g, 26.0 mmol). The mixture was warmed to 65 °C and stirred for 1.5 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give the title product (2 g, 55% yield). LC-MS (M+H) + = 280.9.

[0458] Step 4: Ethyl 2-((5-bromo-6-ethoxy-3-nitropyridin-2-yl)oxy)acetate

[0459]

[0460] To a solution of 3-bromo-6-chloro-2-ethoxy-5-nitropyridine (2 g, 7.14 mmol) and ethyl 2-hydroxyacetate (880 mg, 8.5 mmol) was added 60% NaH (340 mg, 8.5 mmol) portion wise at 0 °C. The resulting mixture was slowly warmed to room temperature and stirred overnight. The mixture was carefully quenched, diluted and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give the title product (2 g, 80% yield). LC-MS (M+H) + = 349.0.

[0461] Step 5: 7-Bromo-6-ethoxy-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one

[0462]

[0463] The title compound of Step 5 (1 g, crude) was prepared from ethyl 2-((5-bromo-6- ethoxy-3-nitropyridin-2-yl)oxy)acetate in a similar manner as described in Example 1, Step 2. This crude material was used in the next step without purification. LC-MS (M+H) + = 273.0, 275.0.

[0464] Step 6: 7-Bromo-6-ethoxy-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine

[0465]

[0466] 7-Bromo-6-ethoxy-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine (500 mg, crude) was prepared from 7-bromo-6-ethoxy-lH-pyrido[2,3-b][l,4]oxazin-2(3H)-one in a similar manner as described in Example 1, Step 3. This crude material was used in the next step without purification. LC-MS (M+H) + = 259.0, 261.0.

[0467] Step 7: 7-Bromo-6-ethoxy-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylic acid tert-butyl ester

[0468]

[0469] The title compound of Step 7 (400 mg) was prepared in a similar manner as described in Example 1, Step 4 from 7-bromo-6-ethoxy-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-1-one. LC-MS (M+H) + = 359.1, 361.1.

[0470] Step 8: 6-Ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin- 1 -carboxylic acid tert-butyl ester

[0471]

[0472] The title compound of Step 8 (300 mg) was prepared in a similar manner as described in Example 1, Step 7 from 7-bromo-6-ethoxy-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-1-carboxylic acid tert-butyl ester and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 389.2.

[0473] Step 9: 6-Ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin

[0474]

[0475] The title compound of Step 9 (210 mg) was prepared in a similar manner as described in Example 1, Step 8 from 6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 289.1.

[0476] Step 10: 2-Chloro-l-(6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one

[0477]

[0478] The title compound of Step 10 (120 mg) was prepared in a similar manner as described in Example 1, Step 9 from 6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin and 2-chloroacetyl chloride. LC-MS (M+H) + = 365.1.

[0479] Step 11: (2R,5S)-4-(2-(6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0480]

[0481] The title compound of Step 11 (100 mg) was prepared from 2-chloro-l-(6- ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l- one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 642.4.

[0482] Step 12: l-(6-ethoxy-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)- piperazin-l-yl)ethan-l-one (Compound 17)

[0483] Compound 17 as a formate salt was prepared from (2R,5S)-4-(2-(6-ethoxy-7- (4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert- butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 17 as a free base (53 mg). 1H NMR (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, 2H), 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 = 8.0 Hz, 3H), 1.14 (d, J = 8.0 Hz, 3H), 0.92-0.86 (m, 3H). LC-MS (M+H) + = 542.3.

[0484] Example 18: l-(8-(4-fluorobenzyl)-3,4-dihydropyrido[2,3-b][l,4]oxazepin-l(2H)-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 18)

[0485]

[0486] Step 1: N-(3-((3,5-dibromopyridin-2-yl)oxy)propyl)-4-methylbenzenesulfonamide

[0487]

[0488] To a solution of N-(3-hydroxypropyl)-4-methylbenzenesulfonamide (7.6 g, 33 mmol) in THF (150 mL) was added NaH (1.44 g, 60%, 36 mmol) at 0 °C under nitrogen and stirred for 30 min. Then 3,5-dibromo-2-fluoropyridine (7.65 g, 30 mmol) was added portionwise and stirred at 70 °C overnight. The reaction was quenched with water and the resulting mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and evaporated. The residue was purified by silica gel column chromatography (PE:EtOAc = 2: 1) to give the title product (2.4 g, 17% yield). LC-MS (M+H) + = 464.9.

[0489] Step 2: 8-bromo-l-tosyl-l,2,3,4-tetrahydropyrido[2,3-b][l,4]oxazepine

[0490]

[0491] To a mixture of N-(3-((3,5-dibromopyridin-2-yl)oxy)propyl)-4-methylbenzenesulfonamide (2.2 g, 4.74 mmol), picolinic acid (466 mg, 3.79 mmol), CuI (1.08 g, 5.69 mmol) and K2CO3 (1.96 g, 14.2 mmol) was added DMSO (20 mL). The mixture was stirred at 140 °C under nitrogen atmosphere for 3 h. The mixture was cooled, diluted with water and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give the title product (1.03 g, 57% yield). LC-MS (M+H) + = 383.0, 385.0.

[0492] Step 3: 8-(4-Fluorobenzyl)-l-tosyl-l,2,3,4-tetrahydropyrido[2,3- b][l,4]oxazepine

[0493]

[0494] The title compound of Step 3 (630 mg) was prepared in a similar manner as described in Example 1, Step 7 from 8-bromo-l-tosyl-l,2,3,4-tetrahydropyrido[2,3- b][l,4]oxazepine and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 413.1.

[0495] Step 4: 8-(4-Fluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b][l,4]oxazepine

[0496]

[0497] To a solution of 8-(4-fluorobenzyl)-l-tosyl-l,2,3,4-tetrahydropyrido[2,3- b][l,4]oxazepine (350 mg, 0.85 mmol) in methanol (10 mL) was added Mg (204 mg, 8.5 mmol) portion wise at 80 °C. The mixture was stirred at 80 °C overnight. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to give the title product (80 mg, 36% yield). LC-MS (M+H) + = 259.1.

[0498] Step 5: 2-Chloro-l-(8-(4-fluorobenzyl)-3,4-dihydropyrido[2,3- b][l,4]oxazepin-l(2H)-yl)ethan-l-one

[0499]

[0500] The title compound of Step 5 (50 mg, crude) was prepared from 8-(4- fluorobenzyl)-l,2,3,4-tetrahydropyrido[2,3-b][l,4]oxazepine and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. The crude material was used in the next step without purification. LC-MS (M+H) + = 335.1.

[0501] Step 6: (2R,5S)-4-(2-(8-(4-fluorobenzyl)-3,4-dihydropyrido[2,3- b][l,4]oxazepin-l(2H)-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0502]

[0503] The title compound of Step 6 (70 mg) was prepared from 2-chloro-l-(8-(4- fluorobenzyl)-3,4-dihydropyrido[2,3-b][l,4]oxazepin-l(2H)-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 612.4.

[0504] Step 7: l-(8-(4-fluorobenzyl)-3,4-dihydropyrido[2,3-b][l,4]oxazepin-l(2H)- yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l- yl)ethan-l-one (Compound 18)

[0505] Compound 18 as a formate salt was prepared from (2R,5S)-4-(2-(8-(4- fluorobenzyl)-3,4-dihydropyrido[2,3-b][l,4]oxazepin-l(2H)-yl)-2-oxoethyl)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert- butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 18 as a free base (25 mg). 1H NMR (400 MHz, CD3OD) 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, 9H), 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.

[0506] Example 19: 1-(7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-1 -yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1 -yl)ethan-1 -one (Compound 19)

[0507]

[0508] Step 1: tert-Butyl (1-((3,5-dibromopyridin-2-yl)oxy)propan-2-yl)carbamate

[0509]

[0510] To a mixture of tert-butyl (1-hydroxypropan-2-yl)carbamate (2 g, 11.4 mmol) and 3,5-dibromo-2-fluoropyridine (2.6 g, 10.3 mmol) was added THF (40 mL). The mixture was cooled to 0 °C. NaH (456 mg, 60% dispersion in mineral oil, 11.4 mmol) was added portionwise. The new mixture was slowly warmed to room temperature and stirred overnight. The mixture was carefully quenched, diluted and extracted with EtOAc. The combined organic layers were dried, filtered and evaporated. The crude was purified by silica gel column chromatography (PE:EtOAc = 8:1) to give the title product (4 g, 95% yield). LC-MS (M+H) + = 409.0.

[0511] Step 2: tert-Butyl 7-bromo-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1- carboxylate

[0512]

[0513] The title compound of Step 2 (300 mg) was prepared in a similar manner as described in Example 18, Step 2 from tert-butyl (l-((3,5-dibromopyridin-2-yl)oxy)propan-2-yl)carbamate. LC-MS (M+H) + = 329.0.

[0514] Step 3: tert-Butyl 7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine-l-carboxylate

[0515]

[0516] The title compound of Step 3 (260 mg) was prepared in a similar manner as described in Example 1, Step 7 from tert-butyl 7-bromo-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine-l-carboxylate and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 359.2.

[0517] Step 4: 7-(4-Fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine

[0518]

[0519] The title compound of Step 4 (200 mg) was prepared in a similar manner as described in Example 1, Step 8 from tert-butyl 7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine-l-carboxylate. The crude material was used directly in the next step without purification. LC-MS (M+H) + = 259.1.

[0520] Step 5: 2-Chloro-l-(7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)ethan-l-one

[0521]

[0522] The title compound of Step 5 (150 mg) was prepared in a similar manner as described in Example 1, Step 9 from 7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine and 2-chloroacetyl chloride. LC-MS (M+H) + = 335.1.

[0523] Step 6: (2R,5S)-4-(2-(7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0524]

[0525] The title compound of Step 6 (100 mg, mixture of diastereomers, 1 / 1 ratio) was prepared in a similar manner as described in Example 1, Step 18 from 2-chloro-l-(7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 612.3.

[0526] Step 7: l-(7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- ((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 19)

[0527] Compound 19 as formate salt (mixture of diastereomers, 1 / 1 ratio) was prepared in a similar manner as described in Example 1, Step 19 from (2R,5S)-4-(2-(7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 19 as free base (20 mg, mixture of diastereomers, 1 / 1 ratio). 1H NMR (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 - 2.17 (m, 3H), 2.06 - 1.89 (m, 2H), 1.76 (t, J = 12.0 Hz, 1H), 1.19 - 1.12 (m, 3H), 0.91 - 0.82 (m, 6H). LC-MS (M+H) + = 512.3.

[0528] Example 19A: l-((S)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1 -yl) ethan- 1 -one (Compound 19A)

[0529]

[0530] Compound 19A as a formate salt was prepared from chiral starting material (S)-(l- hydroxypropan-2-yl)carbamic acid tert-butyl ester and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in Step 1 in a similar manner as described in Example 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 19A as a free base (23 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 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.

[0531] Example 19B: l-((R)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 19B)

[0532]

[0533] Compound 19B as a formate salt was prepared from chiral starting material (R)-(l- hydroxypropan-2-yl)carbamic acid tert-butyl ester and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in Step 1 in a similar manner as described in Example 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 19B as a free base (15 mg). 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 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.

[0534] Example 20: l-(7'-(4-fluorobenzyl)-l'H,3'H-spiro[cyclopropane-l,2'-pyrido[2,3- b][l,4]oxazol]-l'-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one hydrochloride (Compound 20)

[0535]

[0536] Step 1: tert-Butyl (l-(((3,5-dibromopyridin-2-yl)oxy)methyl)cyclopropyl)carbamate

[0537]

[0538] The title compound of Step 1 (3.9 g) was prepared in a similar manner as described in Example 19, Step 1 from tert-butyl (l-(hydroxymethyl)cyclopropyl)carbamate and 3,5-dibromo-2- fluoropyridine. LC-MS (M+H) + = 423.0.

[0539] Step 2: tert-Butyl 7'-bromo-l'H,3'H-spiro[cyclopropane-l,2'-pyrido[2,3-b][l,4]oxazol]-l'- carboxylate

[0540]

[0541] To a mixture of tert-butyl (l-(((3,5-dibromopyridin-2-yl)oxy)methyl)cyclopropyl)carbamate (1.69 g, 4 mmol), Cul (762 mg, 4 mmol), picolinic acid (492 mg, 4 mmol) and Cs2CO3(2.6 g, 8 mmol) was added DMSO (15 mL). The mixture was stirred at 120 °C under nitrogen atmosphere for 2 h. After cooling to room temperature, the mixture was treated with water and the resulting mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography (PE / EtOAc = 5: 1) to give the title product (360 mg, 27% yield). LC-MS (M+H) + = 341.0, 343.0.

[0542] Step 3: tert-Butyl 7'-(4-fluorobenzyl)-l'H,3'H-spiro[cyclopropane-l,2'- pyrido[2,3-b][l,4]oxazin]-l'-carboxylate

[0543]

[0544] The title compound of Step 3 (230 mg) was prepared in a similar manner as described in Example 1, Step 7 from tert-butyl 7'-bromo-l'H,3'H-spiro[cyclopropane-l,2'- pyrido[2,3-b][l,4]oxazin]-l'-carboxylate and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 371.1.

[0545] Step 4: 7'-(4-Fluorobenzyl)-l'H,3'H-spiro[cyclopropane-l,2'-pyrido[2,3-b][l,4]oxazine]

[0546]

[0547] The title compound of Step 4 (45 mg) was prepared in a similar manner as described in Example 1, Step 8 from tert-butyl 7'-(4-fluorobenzyl)-l'H,3'H-spiro[cyclopropane-l,2'- pyrido[2,3-b][l,4]oxazin]-l'-carboxylate. LC-MS (M+H) + = 271.1.

[0548] Step 5: 2-Chloro-l-(7'-(4-fluorobenzyl)-l'H,3'H-spiro[cyclopropane-l,2'- pyrido[2,3-b][l,4]oxazin]-l'-yl)ethan-l-one

[0549]

[0550] The title compound of Step 5 (60 mg, crude) was prepared from 7'-(4- fluorobenzyl)-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[2,3-b][1,4]oxazine] and 2- chloroacetyl chloride in a similar manner as described in Example 1, Step 9. The crude material was used in the next step without purification. LC-MS (M+H) + = 347.1.

[0551] Step 6: (2R,5S)-4-(2-(7'-(4-fluorobenzyl)-1'H,3'H-spiro[cyclopropane-1,2'- pyrido[2,3-b][1,4]oxazin]-1'-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl ester

[0552]

[0553] The title compound of Step 6 (100 mg) was prepared from 2-chloro-1-(7'-(4- fluorobenzyl)-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[2,3-b][1,4]oxazin]-1'-yl)ethan-1- one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 624.4.

[0554] Step 7: 1-(7'-(4-fluorobenzyl)-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[2,3-b][1,4]oxazin]- 1'-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1- one hydrochloride (Compound 20)

[0555] Compound 20 as a formate salt was prepared from (2R,5S)-4-(2-(7'-(4- fluorobenzyl)-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[2,3-b][1,4]oxazin]-1'-yl)-2- oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was acidified with 1 N HC1 and lyophilized to give Compound 20 as its hydrochloride salt (23 mg). 1H 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 - 7.06 (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 Hz, 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.

[0556] Example 21: l-(7-(4-fluorobenzyl)-6-(l-hydroxycyclopropyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 21)

[0557]

[0558] Step 1: 7-(4-fluorobenzyl)-6-(hydroxymethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine- 1 -carboxylic acid tert-butyl ester

[0559]

[0560] To a solution of tert-butyl 6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine-l-carboxylate (5 g, 12 mmol) was added THF / H20 (60 mL, v / v = 1 / 1). The mixture was cooled to 0 °C. LiOH H20 (1.0 g, 24 mmol) was added portionwise. The mixture was stirred at room temperature for 2 h. The mixture was concentrated and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated to give the crude title product (4.5 g), which was used directly in the next step without further purification. LC-MS (M+H) + = 375.2.

[0561] Step 2: 1-(tert-Butoxy carbonyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-6-carboxylic acid

[0562]

[0563] To a solution of tert-butyl 7-(4-fluorobenzyl)-6-(hydroxymethyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazine-1 -carboxylate (1.2 g, 3.2 mmol) and TEMPO (64 mg, 0.41 mmol) in MeCN (20 mL) was added phosphate buffer (20 mL, pH = 7.4). Then an aqueous solution of NaC102(1.8 g, 15.9 mmol, 10 mL) and NaCIO (1.2 g, 15.9 mmol, 10 mL) was added. The mixture was stirred at room temperature overnight. The pH of the mixture was adjusted to 8 by the addition of 1 M NaOH. The mixture was poured into ice-cooled saturated aqueous Na2S203and stirring was continued for 30 min. The pH was adjusted to pH = 3 by the addition of 1 N HC1 and the aqueous phase was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and evaporated to give the crude title product (1.3 g) which was used directly in the next step without further purification. LC-MS (M+H) + = 389.2.

[0564] Step 3: tert-Butyl 7-(4-fluorobenzyl)-6-(methoxy(methyl)carbamoyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazine-1 -carboxylate

[0565]

[0566] A reaction mixture of 1-(tert-butoxy carbonyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazine-6-carboxylic acid (600 mg, 1.55 mmol), N,O-dimethylhydroxylamine hydrochloride (252 mg, 2.58 mmol), DIPEA (333 mg, 2.58 mmol) and HATU (589 mg, 1.55 mmol) in DMF (10 mL) was stirred at room temperature overnight. The mixture was treated with water and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and evaporated. The resulting residue was purified by column chromatography (PE:EtOAc = 2:1 ) to give the title product (640 mg, 98% yield). LC-MS (M+H) + = 432.2.

[0567] Step 4: 6-acetyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl carboxylate

[0568]

[0569] To a solution of 7-(4-fluorobenzyl)-6-(methoxy(methyl)carbamoyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l -methyl carboxylate (640 mg, 1.53 mmol) in THF (20 mL) was added MeLi (1.4 mL, 1.6 M in hexanes, 2.24 mmol) under nitrogen at -78 °C and stirred at the same temperature for 2 h. The reaction was quenched with saturated aqueous NH4Cl and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine, dried over Na2S04, filtered and evaporated. The resulting residue was purified by column chromatography (PE:EtOAc = 2: 1) to give the title product (380 mg, 64% yield). 1 H NMR (400 MHz, 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.

[0570] Step 5: 6-(l-((tert-butyldimethylsilyl)oxy)vinyl)-7-(4-fluorobenzyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l -methyl carboxylate

[0571]

[0572] To a solution of 6-acetyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl carboxylate (380 mg, 0.98 mmol) and Et3N (298 mg, 2.95 mmol) in DCM (20 mL) was added tert-butyldimethylsilyl triflate (390 mg, 1.48 mmol) at 0 °C and stirred at room temperature overnight. The mixture was diluted with DCM, washed with water and brine, dried over Na2S04, filtered and evaporated. The resulting residue was purified by column chromatography (PE:EtOAc = 1:2) to give the title product (415 mg, 84% yield). 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.

[0573] Step 6: 6-(l-((tert-butyldimethylsilyl)oxy)cyclopropyl)-7-(4-fluorobenzyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazine

[0574]

[0575] To a solution of Et2Zn (3.32 mL, 1 M in hexanes, 3.32 mmol) in hexanes was added CH2I2 (1.8 g, 6.64 mmol) at 0 °C under nitrogen and stirred for 30 min. Then a solution of 6-(l-((tert-butyldimethylsilyl)oxy)vinyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine- 1 -carboxylic acid tert-butyl ester (415 mg, 0.83 mmol) in DCM (15 mL) was added dropwise and the mixture was stirred at 0 °C for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography (DCM:MeOH = 20: 1) to give the title product (180 mg, 52% yield). 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.

[0576] Step 7: l-(6-(l-((tert-butyldimethylsilyl)oxy)cyclopropyl)-7-(4-fluorobenzyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-chloroethan-l-one

[0577]

[0578] The title compound of Step 7 (230 mg, 69% yield) was prepared in a similar manner as described in Example 1, Step 18 from l-(6-(l-((tert-butyldimethylsilyl)oxy)cyclopropyl)-7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-chloroethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylate. LC-MS (M+H) + = 491.1.

[0579] Step 8: (2R,5S)-4-(2-(6-(l-((tert-butyldimethylsilyl)oxy)cyclopropyl)-7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylate

[0580]

[0581] The title compound of Step 8 (230 mg, 69% yield) was prepared in a similar manner as described in Example 1, Step 18 from l-(6-(l-((tert-butyldimethylsilyl)oxy)cyclopropyl)-7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-chloroethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylate. LC-MS (M+H) + = 768.4.

[0582] Step 9: l-(7-(4-Fluorobenzyl)-6-(l-hydroxycyclopropyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3- methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 21)

[0583] To a solution of (2R,5S)-4-(2-(6-(1-((tert-butyldimethylsilyl)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-carboxylic acid tert-butyl ester (230 mg, 0.3 mmol) in methanol (3 mL) at 0 °C was added a solution of HC1 in 1,4-dioxane (3 mL, 4 M). The mixture was stirred at room temperature for 4 h. The solvent was evaporated and the residue was washed with aqueous NaHC03solution, extracted with EA. The combined organic layers were dried, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title product (60 mg, 36% yield). 1 H NMR (400 MHz, 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, 1H), 3.61 (d, J = 15.7 Hz, 1H), 3.45 (d, J = 10.1 Hz, 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.

[0584] Example 22: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-1-yl)ethan-1-one (Compound 22)

[0585]

[0586] The compound as formate salt was prepared from the corresponding chiral starting material (S)-(1-hydroxypropan-2-yl) carbamate and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester in Step 1 in a similar manner as described in Example 19. The salt was neutralized with aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give compound 22 as a free base (224 mg, 41% yield). 1 H NMR (400 MHz, DMSO-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 = 10.8 Hz, 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.

[0587] Example 23: 1-((S)-2-((benzyloxy)methyl)-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- methylpiperazin-1-yl)ethan-1-one (Compound 23)

[0588]

[0589] Step 1: (S)-(1-(benzyloxy)-3-((3,5-dibromopyridin-2-yl)oxy)propan-2-yl) carbamic acid tert-butyl ester

[0590]

[0591] The title compound of Step 1 (19 g, 95% yield) was prepared in a similar manner as described in Example 19, Step 1 from (R)-(l-(benzyloxy)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester and 3,5-dibromo-2-fluoropyridine. LC-MS (M+H) + = 515.0.

[0592] Step 2: (S)-2-((benzyloxy)methyl)-7-bromo-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -ium chloride

[0593]

[0594] The title compound of Step 2 (2.5 g, 38% yield) was prepared in a similar manner as described in Example 18, Step 2 from (S)-(l-(benzyloxy)-3-((3,5- dibromopyridin-2-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester. LC-MS (M+H) + = 435.0.

[0595] Step 3: (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -ium chloride

[0596]

[0597] The title compound of Step 3 (1.5 g, 56% yield) was prepared in a similar manner as described in Example 1, Step 7 from (S)-2-((benzyloxy)methyl)-7-bromo-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-carboxylate and (4-fluorobenzyl)zinc(ll) chloride. LC-MS (M+H) + = 465.2.

[0598] Step 4: (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine

[0599]

[0600] The title compound of Step 4 (1.1 g, 94% yield) was prepared in a similar manner as described in Example 1, Step 8 from (S)-2-((benzyloxy)methyl)-7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-carboxylate. LC-MS (M+H) + = 365.2.

[0601] Step 5: (S)-l-(2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-chloroethan-l-one

[0602]

[0603] The title compound of Step 5 (750 mg, 56% yield) was prepared from (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 441.1.

[0604] Step 6: (2R,5S)-4-(2-((S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[0605]

[0606] The title compound of Step 6 (520 mg, 86% yield) was prepared from (S)-l-(2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-chloroethan-l-one and (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 732.4.

[0607] Step 7: l-((S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-l-yl)ethan-l-one (Compound 23)

[0608] Compound 23 as formate salt was prepared from (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-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 23 as free base (210 mg, 47% yield). 1 H 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, 2H), 4.97 (br s, 1H), 4.58 - 4.52 (m, 1H), 4.51 - 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, 1H), 3.48 - 3.41 (m, 3H), 3.31 - 3.24 (m, 2H), 3.11 (br s, 2H), 3.05 - 2.98 (m, 1H), 2.83 - 2.72 (m, 1H), 2.68 - 2.53 (m, 4H), 2.38 (br s, 1H), 2.27 - 2.17 (m, 1H), 2.08 - 1.98 (m, 1H), 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.

[0609] Example 24: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 24)

[0610]

[0611] Step 1: tert-Butyl (S)-(1-((3,5-dibromo-6-methylpyridin-2-yl)oxy)propan-2-yl)carbamate

[0612]

[0613] The title compound of Step 1 (4.2 g, 75% yield) was prepared in a similar manner as described in Example 19, Step 1 from (S)-(1-hydroxypropan-2-yl)carbamic acid tert-butyl ester and 3,5-dibromo-2-fluoro-6-methylpyridine. LC-MS (M+H) + = 423.0.

[0614] Step 2: (S)-7-bromo-2,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester

[0615]

[0616] The title compound of Step 2 (890 mg, 15% yield) was prepared in a similar manner as described in Example 18, Step 2 from (S)-(1-((3,5-dibromo-6-methylpyridin-2- yl)oxy)propan-2-yl)carbamic acid tert-butyl ester. LC-MS (M+H) + = 343.1.

[0617] Step 3: (S)-7-(4-fluorobenzyl)-2,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester

[0618]

[0619] The title compound of Step 3 (1.0 g, 90% yield) was prepared in a similar manner as described in Example 1, Step 7 from (S)-7-bromo-2,6-dimethyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazine-1-carboxylic acid tert-butyl ester and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 373.2.

[0620] Step 4: (S)-1-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-2,6-dimethyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazine 5-oxide

[0621]

[0622] The title compound of Step 4 (900 mg, 65% yield) was prepared in a similar manner as described in Example 1, Step 5 from (S)-7-(4-fluorobenzyl)-2,6-dimethyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester and 3-chlorobenzoic acid peroxide. LC-MS (M+H) + = 389.2.

[0623] Step 5: (S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l -methyl butylate

[0624]

[0625] The title compound of Step 5 (855 mg, 86% yield) was prepared in a similar manner as described in Example 8, Step 2 from (S)-l-(tert-butoxycarbonyl)-7-(4- fluorobenzyl)-2,6-dimethyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine 5-oxide and Ac20. LC-MS (M+H) + = 431.2.

[0626] Step 6: (S)-(7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazol-6- yl)acetic acid methyl ester

[0627]

[0628] The title compound of Step 6 (462 mg, 70% yield) was prepared in a similar manner as described in Example 1, Step 8 from (S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 331.1.

[0629] Step 7: (S)-(l-(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazol-6-yl)acetic acid methyl ester

[0630]

[0631] The title compound of Step 7 (570 mg, 90% yield) was prepared in a similar manner as described in Example 1, Step 9 from (S)-(7-(4-fluorobenzyl)-2-methyl-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazol-6-yl)acetic acid methyl ester and 2-chloroacetyl chloride. LC-MS (M+H) + = 407.1.

[0632] Step 8: (2R, 5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[0633]

[0634] The title compound of Step 8 (252 mg, 51% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-(l-(2-chloroacetyl)-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-6-yl)acetic acid methyl ester and (2R, 5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2- methylpiperazine- 1 -carboxylic acid tert-butyl ester. LC-MS (M+H) + = 698.5.

[0635] Step 9: (2R, 5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[0636]

[0637] The title compound of Step 9 (240 mg, 100% yield) was prepared in a similar manner as described in Example 8, Step 4 from (2R, 5S)-4-(2-((S)-6-(acetyloxymethyl)-7- (4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)- 5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 656.5.

[0638] Step 10: 2-((2R, 5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-l-yl)-l-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one (Compound 24)

[0639] Compound 24 as formate salt was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methylpiperazine-l- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 24 as free base (97 mg, 48% yield). 1 H NMR (400 MHz, DMSO-d6) 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 = 10.6 Hz, 1H), 4.20 (d, J = 10.9 Hz, 1H), 3.97 (s, 2H), 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.

[0640] Example 25: l-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 25)

[0641]

[0642] Step 1: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0643]

[0644] The title compound in Step 1 (259 mg, 54% yield) was prepared from (S)-(l-(2- chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrano[2,3-b][l,4]oxazin-6- yl)acetic acid methyl ester and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 684.5.

[0645] Step 2: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro- lH-pyrano[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1-carboxylic acid tert-butyl ester

[0646]

[0647] The title compound in Step 2 (240 mg, 90% yield) was prepared from (2R,5S)-4-(2- ((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrano[l,4]oxazin-l- yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 8, Step 4. LC-MS (M+H) + = 642.5.

[0648] Step 3: l-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrano[l,4]oxazin- 1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan- 1-one (Compound 25)

[0649] Compound 25 as formate salt was prepared from (2R,5S)-4-(2-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrano[2,3-b][l,4]oxazin-l- yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 25 as a free base (103 mg, 51% yield). 1 H NMR (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, 1H), 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-MS (M+H) + = 542.5.

[0650] Example 26: l-((S)-2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrano[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 26)

[0651]

[0652] Step 1: (S)-2-amino-2-cyclopropylethan-l-ol

[0653]

[0654] To a solution of (S)-2-amino-2-cyclopropylacetic acid (6.9 g, 60 mmol) in anhydrous THF (190 mL) was added slowly LiAlH4(4.56 g, 120 mmol) at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (100 mL*3). The combined EtOAc phases were dried over Na2SO4, filtered and evaporated in vacuum to give the crude product (6.4 g) which was used in the next step without further purification. LC-MS (M+H) + = 102.0.

[0655] Step 2: (S)-1-cyclopropyl-2-((3,5-dibromopyridin-2-yl)oxy)ethan-1-amine

[0656]

[0657] To a solution of 3,5-dibromo-2-fluoropyridine (5 g, 20 mmol) and (S)-2-amino-2- cyclopropyl-ethan-1-ol (2.5 g, 25 mmol) in anhydrous THF (100 mL) was added slowly NaH (2 g, 60%, 50 mmol) at 0 °C. The resulting solution was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (100 mL*3). The combined EtOAc phases were dried over Na2SO4, filtered and evaporated in vacuum. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1) to give the product (6.5 g, 97% yield for 2 steps). LC-MS (M+H) + = 334.9, 336.9.

[0658] Step 3: (S)-(1-cyclopropyl-2-((3,5-dibromopyridin-2-yl)oxy)ethyl)carbamic acid tert-butyl ester

[0659]

[0660] (S)-1-cyclopropyl-2-((3,5-dibromopyridin-2-yl)oxy)ethan-1-amine (6.5 g, 19.3 mmol), (Boc)2O (6.3 g, 29 mmol), DMAP (0.1 g, 0.82 mmol) and Et3N (5.8 g, 58 mmol) in DCM (100 mL) was stirred at room temperature for 12 h. The reaction was washed with water (50 mL), extracted with DCM (50 mL*3), the combined DCM phases were dried over Na2SO4, filtered and evaporated in vacuum. The residue was purified by silica gel chromatography (PE:EtOAc = 5:1) to give the product (6.5 g, 77% yield). LC-MS (M+H) += 434.9, 436.9.

[0661] Step 4: (S)-7-bromo-2-cyclopropyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l- carboxylic acid tert-butyl ester

[0662]

[0663] The title compound of Step 4 (1.2 g, 26% yield) was prepared from (S)-(l- cyclopropyl-2-((3,5-dibromopyridin-2-yl)oxy)ethyl)carbamic acid tert-butyl ester in a similar manner as described in Example 18, Step 2. LC-MS (M+H) + = 355.0, 357.0.

[0664] Step 5: (S)-2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l- carboxylic acid tert-butyl ester

[0665]

[0666] The title compound of Step 5 (0.8 g, 62% yield) was prepared from (S)-7-bromo-2- cyclopropyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylic acid tert-butyl ester and (4-fluorobenzyl)zinc(II) chloride in a similar manner as described in Example 1, Step 7. LC-MS (M+H) + = 385.2.

[0667] Step 6: (S)-2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine

[0668]

[0669] The title compound of Step 6 (0.6 g, 100% yield) was prepared from (S)-2- cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 8. LC-MS (M+H) + = 285.0.

[0670] Step 7: (S)-2-chloro-l-(2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)ethan-l-one

[0671]

[0672] The title compound of Step 7 (520 mg, 68% yield) was prepared from (S)-2- cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin and 2- chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 361.1.

[0673] Step 8: (2R,5S)-4-(2-((S)-2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0674]

[0675] The title compound of Step 8 (300 mg, 66% yield) was prepared from (S)-2- chloro-l-(2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 638.9.

[0676] Step 9: l-((S)-2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 26)

[0677] Compound 26 as formate salt was prepared from (2R,5S)-4-(2-((S)-2- cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 26 as free base (190 mg, 75% yield).1H NMR (400 MHz, 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), 3.89 (s, 2H), 3.56 - 5.48 (m, 2H), 3.40 - 3.37 (m, 2H), 3.02 (br s, 1H), 2.85 - 2.82 (m, 1H), 2.71 (br s, 2H), 2.58 - 2.54 (m, 3H), 2.35 - 2.09 (m, 3H), 2.04 (br s, 1H), 1.77 (s, 1H), 0.85 (d, J = 6.1 Hz, 3H), 0.80 (br s, 4H), 0.52 (d, J = 5.9 Hz, 1H), 0.44 (s, 3H). LC-MS (M+H) + = 538.9.

[0678] Example 27: l-((S)-2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-l-yl)ethan-l-one (Compound 27)

[0679]

[0680] Step 1: (2R,5S)-4-(2-((S)-2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)- 2-methylpiperazine-l-carboxylic acid tert-butyl ester

[0681]

[0682] The title compound of Step 1 (300 mg, 64% yield) was prepared from (S)-2-chloro-1-(2-cyclopropyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 652.9.

[0683] 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-methylpiperazin-1-yl)ethan-1-one (Compound 27)

[0684] Compound 27 as formate salt was prepared from (2R,5S)-4-(2-((S)-2-cyclopropyl-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-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHCO3 and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 27 as free base (210 mg, 83% yield). 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 (br s, 2H), 3.04-3.01 (m, 1H), 2.76-2.68 (m, 3H), 2.52 (br s, 2H), 2.40 (br s, 1H), 2.22-2.19 (m, 1H), 2.07-2.02 (m, 1H), 1.96-1.91 (m, 1H), 0.84 (br s, 10H), 0.53-0.51 (m, 2H), 0.45 (s, 2H). LC-MS (M+H) + = 552.9.

[0685] Example 28: l-((S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 28)

[0686]

[0687] Step 1: (S)-(l-((3,5-dibromopyridin-2-yl)oxy)butan-2-yl)carbamic acid tert-butyl ester

[0688]

[0689] The title compound of Step 1 (12 g, 94% yield) was prepared in a similar manner as described in Example 19, Step 1 from (S)-(l-hydroxybutan-2-yl)carbamic acid tert-butyl ester and 3,5-dibromo-2-fluoropyridine. LC-MS (M+H) + = 423.0.

[0690] Step 2: (S)-7-bromo-2-ethyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-carboxylic acid tert-butyl ester

[0691]

[0692] The title compound of Step 2 (1.1 g, 11% yield) was prepared in a similar manner as described in Example 19, Step 2 from (S)-(l-((3,5-dibromopyridin-2-yl)oxy)butan-2-yl)carbamic acid tert-butyl ester. LC-MS (M+H) + = 343.1.

[0693] Step 3: (S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- carboxylic acid tert-butyl ester

[0694]

[0695] The title compound of Step 3 (1 g, 82% yield) was prepared in a similar manner as described in Example 1, Step 7 from (S)-7-bromo-2-ethyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-carboxylic acid tert-butyl ester and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 373.2.

[0696] Step 4: (S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -carboxylate

[0697]

[0698] The title compound of Step 4 (700 mg, 95% yield) was prepared in a similar manner as described in Example 1, Step 8 from (S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 273.2.

[0699] Step 5: (S)-2-chloro-l-(2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)ethan-l-one

[0700]

[0701] The title compound of Step 5 (550 mg, 61% yield) was prepared in a similar manner as described in Example 1, Step 9 from (S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-carboxylic acid tert-butyl ester and 2-chloroacetyl chloride. LC-MS (M+H) + = 349.2.

[0702] Step 6: (2R,5S)-4-(2-((S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1-carboxylic acid tert-butyl ester

[0703]

[0704] The title compound of Step 6 (760 mg, 77% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-l-(2-ethyl-7-(4-fluorobenzyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 626.4.

[0705] Step 7: l-((S)-2-ethyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 28)

[0706] Compound 28 as formate salt was prepared from (2R,5S)-4-(2-((S)-2-ethyl-7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5- (((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 28 as a free base (290 mg, 45% yield). 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.

[0707] Example 29: l-((S)-2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 29)

[0708]

[0709] Step 1: (S)-(l-((3,5-dibromopyridin-2-yl)oxy)-3-phenylpropan-2-yl)carbamic acid tert-butyl ester

[0710]

[0711] To a solution of tert-butyl N-[(2S)-1-hydroxy-3-phenylpropan-2-yl]carbamate (4.7 g, 18.9 mmol) and 3,5-dibromo-2-fluoropyridine (4.4 g, 17.1 mmol) in THF (80 mL) was added NaH (865 mg, 21.6 mmol, 60%) portion wise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 5 h. When the reaction was complete, the reaction was then quenched by the addition of water (60 mL). The resulting solution was extracted with ethyl acetate (60 mL x 3). The organic phase was combined, washed with brine and dried over Na2S04. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography (DCM:EtOAc = 3:1) to afford the title product (9.9 g, 73% yield). LC-MS (M+H) + = 485.0.

[0712] Step 2: (S)-tert-butyl 2-benzyl-7-bromo-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazine-1 -carboxylate

[0713]

[0714] To a solution of tert-butyl (S)-(1-((3,5-dibromopyridin-2-yl)oxy)-3-phenylpropan-2- yl)carbamate (1.5 g, 3.1 mmol) in THF (10 mL) was added CuI (190 mg, 1.0 mmol), Cs2C03(2.1 g, 6.4 mmol) and DMEDA (105 mg, 1.3 mmol) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. After the reaction was complete, the resulting mixture was filtered, the filter cake was washed with DCM (2 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 5:1) to afford the title product (260 mg, 20% yield). LC-MS (M+H) + = 405.1.

[0715] Step 3: (S)-tert-butyl 2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazine-1 -carboxylate

[0716]

[0717] A solution of (S)-tert-butyl 2-benzyl-7-bromo-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine-l-carboxylate (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) was stirred at 60 °C under nitrogen atmosphere for 2 h. When the reaction was complete, the reaction was then quenched by the addition of 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 the filter cake was washed with DCM (2 x 10 mL). The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 3: 1) to give the title product (200 mg, 81% yield). LC-MS (M+H) + = 435.2.

[0718] Step 4: (S)-2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine

[0719]

[0720] To a solution of (S)-tert-butyl 2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine-l-carboxylate (200 mg, 0.5 mmol) in DCM (5 mL) at 0 °C was added HCl (g) (1.2 mL, 4.8 mmol, 4 M) in 1,4-dioxane dropwise. The resulting mixture was stirred at room temperature for 3 h. When the reaction was complete, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with saturated NaHC03(15 mL) and extracted with EtOAc (2 x 20 mL). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 1: 1) to give the title product (120 mg, 78% yield). LC-MS (M+H) + = 335.0.

[0721] Step 5: (S)-l-(2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)-2-chloroethan-l-one

[0722]

[0723] The title compound of Step 5 (83 mg, crude) was prepared from (S)-2-benzyl-7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. The crude material was used in the next step without purification. LC-MS (M+H) + = 411.0.

[0724] Step 6: (2R,5S)-4-(2-((S)-2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0725]

[0726] The title compound of Step 6 (90 mg, 64% yield) was prepared from (S)-l-(2-benzyl-7- (4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-chloroethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 688.4.

[0727] Step 7: l-((S)-2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)- 2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 29)

[0728] To a solution of (2R,5S)-4-(2-((S)-2-benzyl-7-(4-fluorobenzyl)-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l -carboxylate (90 mg, 0.13 mmol) in DCM (3 mL) at 0 °C was added HC1 (g) in 1,4-dioxane (0.5 mL, 2 mmol, 4 M) dropwise. The resulting mixture was stirred at room temperature for 3 h. When the reaction was complete, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with saturated NaHC03solution (10 mL). The resulting mixture was extracted with EtOAc (2 x 15 mL). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: Column, XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 um; mobile phase, Acetonitrile in water (containing 10 mmol / L NH4HC03and 0.1% NH3.H20), gradient of 25% to 55% over 8 min; Detector, UV 254 nm. The title compound was obtained (29 mg, 38% yield). 1 H 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, 1H), 4.28 - 4.20 (m, 1H), 3.93 (d, J = 2.2 Hz, 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, 1H), 0.82 (d, J = 6.2 Hz, 6H). LC-MS (M+H) + = 588.2.

[0729] Example 30: l-((S)-7-(4-fluorobenzyl)-2-(p-tolyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- l-yl)ethan-l-one (Compound 30)

[0730]

[0731] Step 1: (S)-2-amino-2-(p-tolyl)ethan-1-ol

[0732]

[0733] To a solution of (S)-amino(4-methylphenyl)acetic acid (1.9 g, 11.5 mmol) in THF (30 mL) was added dropwise LiAlH4(17.5 mL, 17.5 mmol, 1 M) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 16 h under nitrogen atmosphere. When the reaction was complete, the reaction was then quenched by the addition of NaOH (2 M) at 0 °C. The resulting mixture was filtered, and the filter cake was washed with THF (2 x 10 mL). The filtrate was concentrated under reduced pressure. The aqueous layer was extracted with CH2Cl2(2 x 30 mL). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure to give the title compound (800 mg, 46% yield). LC-MS (M+H) + = 152.2.

[0734] Step 2: (S)-(2-hydroxy-1-(p-tolyl)ethyl)carbamic acid tert-butyl ester

[0735]

[0736] To a solution of (S)-2-amino-2-(p-tolyl)ethan-1-ol (800 mg, 5.3 mmol) and TEA (1.4 g, 13.2 mmol) in THF (20 mL) was added Boc20 (1.7 g, 7.9 mmol) portion-wise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h under nitrogen atmosphere. When the reaction was complete, the reaction was then quenched by the addition of saturated NaHCO3(20 mL) at room temperature. The resulting solution was extracted with CH2Cl2(2 x 30 mL). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography (DCM:MeOH = 10:1) to give the title compound (850 mg, 64% yield). LC-MS (M+H) + = 252.1.

[0737] Step 3: (S)-(2-((3,5-dibromopyridin-2-yl)oxy)-1-(p-tolyl)ethyl)carbamic acid tert-butyl ester

[0738]

[0739] The title compound of Step 3 (1.3 g, 86% yield) was prepared in a similar manner as described in Example 29, Step 1 from (S)-(2-hydroxy-l-(p-tolyl)ethyl)carbamic acid tert-butyl ester and 3,5-dibromo-2-fluoropyridine. LC-MS (M+H) + = 485.0.

[0740] Step 4: (S)-7-bromo-2-(p-tolyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-l- carboxylic acid tert-butyl ester

[0741]

[0742] The title compound of Step 4 (350 mg, 31% yield) was prepared in a similar manner as described in Example 29, Step 2 from (S)-(2-((3,5-dibromopyridin-2-yl)oxy)-l-(p-tolyl)ethyl)carbamic acid tert-butyl ester. LC-MS (M+H) + = 405.2.

[0743] Step 5: (S)-7-(4-fluorobenzyl)-2-(p-tolyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-l- carboxylic acid tert-butyl ester

[0744]

[0745] The title compound of Step 5 (275 mg, 73% yield) was prepared in a similar manner as described in Example 29, Step 3 from (S)-7-bromo-2-(p-tolyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazole-l-carboxylic acid tert-butyl ester and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 435.3.

[0746] Step 6: (S)-7-(4-fluorobenzyl)-2-(p-tolyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole

[0747]

[0748] The title compound of Step 6 (180 mg, 84% yield) was prepared in a similar manner as described in Example 29, Step 4 from (S)-7-(4-fluorobenzyl)-2-(p-tolyl)-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazole-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 335.1.

[0749] Step 7: (S)-2-chloro-l-(7-(4-fluorobenzyl)-2-(p-tolyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one

[0750]

[0751] The title compound of Step 7 (162 mg, 73% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-(p-tolyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine and 2- chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 411.2.

[0752] Step 8: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-(p-tolyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0753]

[0754] The title compound of Step 8 (90 mg, 64% yield) was prepared from (S)-2- chloro-l-(7-(4-fluorobenzyl)-2-(p-tolyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 688.4.

[0755] Step 9: l-((S)-7-(4-fluorobenzyl)-2-(p-tolyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin- l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l- yl)ethan-l-one (Compound 30)

[0756] To a solution of (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-(p-tolyl)-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylic acid tert-butyl ester (90 mg, 0.13 mmol) in DCM (3 mL) at 0 °C was added HC1 (g) in 1,4-dioxane (0.5 mL, 2 mmol, 4 M). The resulting mixture was stirred at room temperature for 3 h. When the reaction was complete, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with saturated NaHC03solution (10 mL). The resulting mixture was extracted with EtOAc (2 x 15 mL). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was concentrated under reduced pressure and the residue was purified by prep-HPLC under the following conditions: Column, XBridge Shield RP18 OBD Column, 30 x 150 mm, 5 um; mobile phase, Acetonitrile in water (containing 10 mmol / L NH4HC03and 0.1% NH3.H20), gradient of 25% to 55% over 8 min; Detector, UV 254 nm. The title compound was obtained (29 mg, 38% yield). 1 H NMR (400 MHz, DMSO-d6) d 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, 1H), 4.28 - 4.20 (m, 1H), 3.93 (d, J = 2.2 Hz, 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, 1H), 0.82 (d, J = 6.2 Hz, 6H). LC-MS (M+H) + = 588.2.

[0757] Example 31: (S)-7-(4-fluorobenzyl)-2-methyl-l-(2-((2R,5R)-5-methyl-2-(((R)-3- methylmorpholino)methyl)piperazin-l-yl)acetyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-6-carboxamide (Compound 31)

[0758]

[0759] Step 1: (S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l -methyl butylate

[0760]

[0761] The title compound of Step 1 (3g, 90% yield) was prepared in a similar manner as described in Example 21, Step 1 from (S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l -methyl butylate. LC-MS (M+H) + = 389.2.

[0762] Step 2: (S)-l-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-6-carboxylic acid

[0763]

[0764] The title compound of Step 2 (2g, crude) was prepared in a similar manner as described in Example 21, Step 2 from (S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l -methyl butylate. LC-MS (M+H) + = 403.2.

[0765] Step 3: (S)-6-carbamoyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl butylate

[0766]

[0767] A reaction mixture of (S)-l-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-6-carboxylic acid (430 mg, 1.1 mmol), NH4CI (289 mg, 5.3 mmol), DIPEA (276 mg, 2.1 mmol) and HATU (407 mg, 1.1 mmol) in DMF (8 mL) was stirred at room temperature overnight. The mixture was treated with water and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2S04, filtered and evaporated. The resulting residue was purified by column chromatography (PE:EtOAc = 2: 1) to give the title product (340 mg, 79% yield). LC-MS (M+H) + = 402.1.

[0768] Step 4: (S)-7-(4-Fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-6- carboxamide

[0769]

[0770] The title compound of Step 4 (255 mg, 100% yield) was prepared from (S)-6- carbamoyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-l- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 8. LC-MS (M+H) + = 302.1.

[0771] Step 5: (S)-l-(2-Chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazole-6-carboxamide

[0772]

[0773] The title compound of Step 5 (200 mg, 62% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-6-carboxamide and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 378.1.

[0774] Step 6: (2R,5S)-4-(2-((S)-6-carbamoyl-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-lH-pyrano[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0775]

[0776] The title compound of Step 6 (150 mg, 88% yield) was prepared from (S)-l-(2- chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrano[2,3-b][l,4]oxazine-6- carboxamide and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 655.3.

[0777] Step 7: (S)-7-(4-fluorobenzyl)-2-methyl-l-(2-((2R,5R)-5-methyl-2-(((R)-3- methylmorpholino)methyl)piperazin-l-yl)acetyl)-2,3-dihydro-lH-pyrano[2,3-b][l,4]oxazine- 6-carboxamide (Compound 31)

[0778] Compound 31 as formate salt was prepared from (2R,5S)-4-(2-((S)-6- carbamoyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrano[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 31 as a free base (53 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.30 - 7.17 (m, 2H), 7.08 (t, J = 8.8 Hz, 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, 1H), 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.

[0779] Example 32: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazole-6-carboxamide (Compound 32)

[0780]

[0781] Step 1: (2R,5S)-4-(2-((S)-6-carbamoyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazol-1-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)- 2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0782]

[0783] The title compound of Step 1 (100 mg, 60% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazole-6-carboxamide and (2R,5S)-5- (((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 669.3.

[0784] Step 2: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-6-carboxamide (Compound 32)

[0785] Compound 32 as formate salt was prepared from (2R,5S)-4-(2-((S)-6- carbamoyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazol-1- yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2- methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated. The residue was further lyophilized to give Compound 32 as a free base (15 mg, 17% yield). 1 H NMR (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 = 8.8 Hz, 2H), 4.75 (s, 1H), 4.43 - 4.21 (m, 4H), 3.96 (d, J = 15.4 Hz, 1H), 3.52 (d, J = 15.3 Hz, 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 = 8.4 Hz, 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.

[0786] Example 33: 1-((S)-7-(4-fluorobenzyl)-2-isobutyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazol-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)- piperazin-1-yl)ethan-1-one (Compound 33)

[0787]

[0788] Step 1: (S)-(1-((3,5-dibromopyridin-2-yl)oxy)-4-methylpentan-2-yl) carbamic acid tert-butyl ester

[0789]

[0790] The title compound of Step 1 (6 g, 83% yield) was prepared in a similar manner as described in Example 29, Step 1 from (S)-(1-hydroxy-4-methylpentan-2-yl)carbamic acid tert-butyl ester and 3,5-dibromo-2-fluoropyridine. LC-MS (M+H) + = 451.0.

[0791] Step 2: (S)-7-bromo-2-isobutyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- carboxylic acid tert-butyl ester

[0792]

[0793] The title compound of Step 2 (760 mg, 15% yield) was prepared in a similar manner as described in Example 29, Step 2 from (S)-(1-((3,5-dibromopyridin-2-yl)oxy)-4-methylpentan-2-yl)carbamic acid tert-butyl ester. LC-MS (M+H) + = 371.1.

[0794] Step 3: (S)-7-(4-fluorobenzyl)-2-isobutyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- carboxylic acid tert-butyl ester

[0795]

[0796] The title compound of Step 3 (600 mg, 69% yield) was prepared in a similar manner as described in Example 29, Step 3 from (S)-7-bromo-2-isobutyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- carboxylic acid tert-butyl ester and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 401.2.

[0797] Step 4: (S)-7-(4-fluorobenzyl)-2-isobutyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0798]

[0799] The title compound of Step 4 (350 mg, 91% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-isobutyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole- 1 -carboxylic acid tert-butyl ester in a similar manner as described in Example 29, Step 4. LC-MS (M+H) + = 301.1.

[0800] Step 5: (S)-2-chloro-l-(7-(4-fluorobenzyl)-2-isobutyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazol-l-yl)ethan-l-one

[0801]

[0802] The title compound of Step 5 (330 mg, 90% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-isobutyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole and 2- chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 377.1.

[0803] Step 6: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-isobutyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazol-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0804]

[0805] The title compound of Step 6 (300 mg, 57% yield) was prepared from (S)-2- chloro-l-(7-(4-fluorobenzyl)-2-isobutyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazol-l- yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1 -carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 654.5.

[0806] Step 7: l-((S)-7-(4-fluorobenzyl)-2-isobutyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazol- l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan- l-one (Compound 33)

[0807] Compound 33 (13 mg, 6% yield) was prepared from (2R,5S)-4-(2-((S)-7-(4- fluorobenzyl)-2-isobutyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as in Example 29, Step 7. 1 H NMR (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, 3H), 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.

[0808] Example 34: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-l-yl)-l-((S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro- lH-pyrrolo[2,3-b][l,4]oxazin-l-yl)ethan-l-one (Compound 34)

[0809]

[0810] Step 1: (S)-(l-(benyloxy)-3-((3-bromo-5-chloropyridin-2-yl)oxy)propan-2-yl) carbamic acid tert-butyl ester

[0811]

[0812] The title compound of Step 1 (19.5 g, 78% yield) was prepared from (R)-(l- (benyloxy)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester and 3-bromo-5- chloro-2-fluoropyridine in a similar manner as described in Example 29, Step 1. LC-MS (M+H) + = 471.0.

[0813] Step 2: (S)-2-((benyloxy)methyl)-7-chloro-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazine- 1-carboxylic acid tert-butyl ester

[0814]

[0815] To a solution of (S)-(l-(benzyloxy)-3-((3-bromo-5-chloropyridin-2-yl)oxy)propan-2- yl)carbamic acid tert-butyl ester (19.5 g, 41.9 mmol) in dioxane (200 mL) was added XantPhos (4.9 g, 8.4 mmol), Cs2CO3(41.0 g, 125.9 mmol) and Pd2(dba)3(3.8 g, 4.2 mmol). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 4 h. When the reaction was complete, the reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (250 mL x 2). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 5: 1) to afford the title compound (14.3 g, 87% yield). LC-MS (M+H) + = 391.1.

[0816] Step 3: (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-carboxylic acid tert-butyl ester

[0817]

[0818] To a solution of (S)-2-((benzyloxy)methyl)-7-chloro-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-carboxylic acid tert-butyl ester (14.3 g, 36.6 mmol), [l,3-bis[2,6-bis(propan-2-yl)phenyl]-2,3-dihydro-lH-imidazol-2-yl]dichloropalladium(l- chloropyridin-l-ium-l-yl) (1.2 g, 1.8 mmol) and LiBr (9.5 g, 109.7 mmol) in THF (200 mL) and NMP (300 mL) was added chloro[(4-fluorophenyl)methyl]zinc (15.4 g, 73.2 mmol) under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 h. When the reaction was complete, the reaction was then quenched by the addition of 2.5% w / w citric acid (600 mL). The resulting solution was extracted with ethyl acetate (600 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 1: 1) to afford the title compound (15 g, 74% yield). LC-MS (M+H) + = 465.2.

[0819] Step 4: (S)-tert-Butyl 7-(4-fluorobenzyl)-2-(hydroxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0820]

[0821] To a solution of (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (15 g, 32.3 mmol) in MeOH (150 mL) and AcOH (30 mL) was added Pd / C (8.6 g, 8.0 mmol, 10%). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 18 h. When the reaction was complete, the mixture was filtered through a celite pad and concentrated under reduced pressure. The residue was basified to pH = 8 with saturated NaHCO3 solution. The resulting mixture was extracted with CH2Cl2 (200 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with (DCM:MeOH=10:1) to give the title compound (11.0 g, 90% yield). LC-MS (M+H) + =375.1.

[0822] Step 5: (R)-tert-Butyl 7-(4-fluorobenzyl)-2-(((methylsulfonyl)oxy)methyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0823]

[0824] To a solution of (S)-7-(4-fluorobenzyl)-2-(hydroxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester (2.5 g, 6.7 mmol) and TEA (1.3 g, 13.3 mmol) in DCM (40 mL) was added MsCl (1.2 g, 10.0 mmol) at 0°C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 6 h. When the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EtOAc=4:1) to give the title compound (3 g, 92% yield). LC-MS (M+H) + =453.0.

[0825] Step 6: (R)-(7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-2-yl)methanesulfonic acid methyl ester

[0826]

[0827] The title compound of Step 6 (2g, 85% yield) was prepared from (R)-7-(4- fluorobenzyl)-2-(((methylsulfonyl)oxy)methyl)-2,3-dihydro-lH-pyrrolo[2,3- b][l,4]oxazin-l -carboxylate in a similar manner as described in Example 29, Step 4. LC-MS (M+H) + = 353.1.

[0828] Step 7: (S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrrolo[2,3- b][l,4]oxazin-2-ol

[0829]

[0830] A solution of (R)-(7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazol- 2-yl)methyl methanesulfonate (280 mg, 0.8 mmol) and NaOMe (430 mg, 7.9 mmol) in MeOH (15 mL) was stirred at 80 °C under nitrogen atmosphere for 16 h. When the reaction was complete, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography (DCM:EtOAc = 2:3) to afford the title compound (170 mg, 74% yield). LC-MS (M+H) + = 289.1.

[0831] Step 8: (S)-2-chloro-l-(7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH- pyrrolo[2,3-b][l,4]oxazol-l-yl)ethan-l-one

[0832]

[0833] The title compound of Step 8 (110 mg, 81% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazol and 2- chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 365.0.

[0834] Step 9: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methylpiperazine-l -carboxylate

[0835]

[0836] The title compound of Step 9 (42 mg, 45% yield) was prepared from (S)-2-chloro-l-(7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)ethan-l-one and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2- methylpiperazine- 1 -carboxylate in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 656.4.

[0837] Step 10: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin- 1 -yl)- 1 -((S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro- 1H-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one (Compound 34)

[0838] Compound 34 (30 mg, 85% yield) was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3- dihydro- lH-pyrido[2,3-b][ 1,4]oxazin- 1 -yl)-2-oxoethyl)-2-methylpiperazine- 1 - carboxylate in a similar manner as described in Example 29, Step 7. 1HNMR (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, 2.7 Hz, 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, 1H), 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.

[0839] Example 35: l-((S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 35)

[0840]

[0841] Step 1: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0842]

[0843] The title compound of Step 1 (115 mg, 59% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-l-(7-(4-fluorobenzyl)-2- (methoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 642.5.

[0844] 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)piperazin-1-yl)ethan-1-one (Compound 35)

[0845] Compound 35 (57 mg, 59% yield) was prepared from (2R,5S)-4-(2-((S)-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-butyl ester in a similar manner as described in Example 29, Step 7. 1 H NMR (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, 2.8 Hz, 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, 1H), 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.

[0846] Example 36: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-2-(ethoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 36)

[0847]

[0848] Step 1: (S)-2-(Ethoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin

[0849]

[0850] The title compound of step 1 (140 mg, 66% yield) was prepared from (R)-(7-(4- fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-2-yl)methyl methanesulfonate and sodium ethoxide in a similar manner as described in Example 34, step 7. LC-MS (M+H) + = 303.3.

[0851] Step 2: (S)-2-chloro-1-(2-(ethoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one

[0852]

[0853] The title compound of step 2 (95 mg, 54% yield) was prepared from (S)-2- (ethoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and 2- chloroacetyl chloride in a similar manner as described in Example 1, step 9. LC-MS (M+H) + = 379.1.

[0854] 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]oxazol-1-yl)-2- oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0855]

[0856] The title compound of step 3 (155 mg, 77% yield) was prepared from (S)-2- chloro-1-(2-(ethoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazol-1- yl)ethan-1-one and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2- methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, step 18. LC-MS (M+H) + = 670.4.

[0857] Step 4: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-2-(ethoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 36)

[0858] Compound 36 (21 mg, 15% yield) was prepared from (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-carboxylic acid tert-butyl ester in a similar manner as in Example 29, Step 7. 1 HNMR (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, 2H), 3.63 (d, J = 10.9, 3.0 Hz, 2H), 3.56-3.46 (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 = 13.7 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.

[0859] 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)piperazin-1-yl)ethan-1-one (Compound 37)

[0860]

[0861] Step 1: (2R,5S)-4-(2-((S)-2-(ethoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine- 1 -carboxylic acid tert-butyl ester

[0862]

[0863] The title compound of Step 1 (150 mg, 85% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-l-(2-(ethoxymethyl)-7-(4- fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 656.4.

[0864] Step 2: l-((S)-2-(ethoxymethyl)-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1 -yl)ethan- 1 -one (Compound 37)

[0865] Compound 37 (40 mg, 47% yield) was prepared in a similar manner as described in Example 29, Step 7 from (2R,5S)-4-(2-((S)-2-(ethoxymethyl)-7-(4-fluorobenzyl)-2,3- dihydro- 1 H-pyrido [2,3 -b] [ 1,4]oxazin- 1 -yl)-2-oxoethyl)-2-methyl-5 -(((R)-3- methylmorpholino)methyl)piperazine- 1 -carboxylic acid tert-butyl ester. 1H NMR (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, 2H), 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.

[0866] Example 38: l-((S)-7-(4-fluorobenzyl)-2-(isopropoxymethyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 38)

[0867]

[0868] Step 1: (S)-7-(4-fluorobenzyl)-2-(isopropoxymethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine

[0869]

[0870] The title compound of Step 1 (240 mg, 87% yield) was prepared in a similar manner as described in Example 34, Step 7 from (R)-(7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-2-yl)methanesulfonic acid methyl ester and sodium isopropoxide. LC-MS (M+H) + = 317.1.

[0871] Step 2: (S)-2-chloro-l-(7-(4-fluorobenzyl)-2-(isopropoxymethyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one

[0872]

[0873] The title compound of Step 2 (225 mg, 90% yield) was prepared in a similar manner as described in Example 1, Step 9 from (S)-7-(4-fluorobenzyl)-2- (isopropoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin and 2-chloroacetyl chloride. LC-MS (M+H) + = 393.0.

[0874] Step 3: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-(isopropoxymethyl)-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0875]

[0876] The title compound of Step 3 (150 mg, 86% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-l-(7-(4-fluorobenzyl)-2- (isopropoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 670.4.

[0877] Step 4: l-((S)-7-(4-fluorobenzyl)-2-(isopropoxymethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- l-yl)ethan-l-one (Compound 38)

[0878] Compound 38 (63 mg, 73% yield) was prepared in a similar manner as described in Example 29, Step 7 from (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2- (isopropoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. 1HNMR (300 MHz, chloroform-d) δ 8.50 (s, 1H), 7.83 (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.

[0879] Example 39: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-2-(isopropoxymethyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 39)

[0880]

[0881] Step 1: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-2-(isopropoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2- oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[0882]

[0883] The title compound of Step 1 (150 mg, 86% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-1-(7-(4-fluorobenzyl)-2- (isopropoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 684.4.

[0884] Step 2: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-2-(isopropoxymethyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 39)

[0885] Compound 39 (60 mg, 72% yield) was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-(isopropoxymethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as in Example 29, Step 7. 1 H 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 = 9.8 Hz, 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.

[0886] Example 40: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-2-(phenoxymethyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 40)

[0887]

[0888] Step 1: (S)-7-(4-fluorobenzyl)-2-(phenoxymethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin

[0889]

[0890] The title compound of Step 1 (240 mg, 80% yield) was prepared in a similar manner as described in Example 34, Step 7 from (R)-(7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-2-yl)methyl methanesulfonate and sodium phenolate. LC-MS (M+H) + = 351.0.

[0891] Step 2: (S)-2-chloro-l-(7-(4-fluorobenzyl)-2-(phenoxymethyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one

[0892]

[0893] The title compound of Step 2 (160 mg, 80% yield) was prepared in a similar manner as described in Example 1, Step 9 from (S)-7-(4-fluorobenzyl)-2-(phenoxymethyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazine and 2-chloroacetyl chloride. LC-MS (M+H) + = 427.2.

[0894] Step 3: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-2-(phenoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[0895]

[0896] The title compound of Step 3 (100 mg, 46% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-l-(7-(4-fluorobenzyl)-2- (phenoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)- 5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 718.5.

[0897] Step 4: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-2-(phenoxymethyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 40)

[0898] Compound 40 (48 mg, 56% yield) was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-(phenoxymethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as in Example 29, Step 7. 1 HNMR (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, 2H), 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.

[0899] Example 41: 1-((S)-7-(4-fluorobenzyl)-2-(phenoxymethyl)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (Compound 41)

[0900]

[0901] Step 1: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-(phenoxymethyl)-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 ester

[0902]

[0903] The title compound of Step 1 (97 mg, 46% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-l-(7-(4-fluorobenzyl)-2- (phenoxyrnethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylate. LC-MS (M+H) + = 704.5.

[0904] Step 2: l-((S)-7-(4-fluorobenzyl)-2-(phenoxyrnethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 41)

[0905] Compound 41 (45 mg, 49% yield) was prepared in a similar manner as described in Example 29, Step 7 from (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2- (phenoxyrnethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-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, 2H), 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.

[0906] Example 42: l-((S)-2-cyclohexyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 42)

[0907]

[0908] Step 1: 3-bromo-2-fluoro-5-(4-fluorobenzyl)pyridine

[0909]

[0910] To a solution of 3,5-dibromo-2-fluoropyridine (9.5 g, 37.2 mmol), XantPhos (650 mg, 1.1 mmol) and Pd2(dba)3(70 mg, 0.07 mmol) in THF (75 mL) was added dropwise chloro[(4-fluorophenyl)methyl]zinc (74.6 mL, 37.3 mmol, 0.5 M in THF) at rt over 5 min. The resulting mixture was stirred at 40 °C under nitrogen atmosphere for 6 h. When the reaction was complete, the resulting mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 20: 1) to afford the title compound (2.8 g, 31% yield). LC-MS (M+H) + = 284.0.

[0911] Step 2: (S)-(2-((3-bromo-5-(4-fluorobenzyl)pyridin-2-yl)oxy)-l-cyclohexylethyl)carbamic acid tert-butyl ester

[0912]

[0913] The title compound of Step 2 (270 mg, 63% yield) was prepared in a similar manner as described in Example 29, Step 1 from 3-bromo-2-fluoro-5-(4-fluorobenzyl)pyridine and (S)-(l-cyclohexyl-2- hydroxyethyl)carbamic acid tert-butyl ester. LC-MS (M+H) + = 507.1.

[0914] Step 3: (S)-2-cyclohexyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l- carboxylic acid tert-butyl ester

[0915]

[0916] The title compound of Step 3 (195 mg, 86% yield) was prepared from (S)-(2-((3-bromo-5-(4-fluorobenzyl)pyridin-2-yl)oxy)-l-cyclohexylethyl) carbamic acid tert-butyl ester in a similar manner as described in Example 34, Step 2. LC-MS (M+H) + = 427.3.

[0917] Step 4: (S)-2-cyclohexyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-1 -carboxylic acid tert-butyl ester

[0918]

[0919] The title compound of Step 4 (130 mg, 89% yield) was prepared from (S)-2- cyclohexyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l -carboxylic acid tert-butyl ester in a similar manner as described in Example 29, Step 4. LC-MS (M+H) + = 327.1.

[0920] Step 5: (S)-2-chloro-l-(2-cyclohexyl-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one

[0921]

[0922] The title compound of Step 5 (105 mg, 88% yield) was prepared from (S)-2- cyclohexyl-7-(4-fluorobenzyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin and 2- chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 403.2.

[0923] Step 6: (2R,5S)-4-(2-((S)-2-cyclohexyl-7-(4-fluorobenzyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[0924]

[0925] The title compound of Step 6 (40 mg, 30% yield) was prepared from (S)-2-chloro- 1-(2-cyclohexyl-7-(4-fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1- one and (2R,5S)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-1-carboxylate tert-butyl in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 680.5.

[0926] 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)piperazin-1-yl)ethan-1-one (Compound 42)

[0927] Compound 42 (12 mg, 24% yield) was prepared from (2R,5S)-4-(2-((S)-2-cyclohexyl-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-carboxylate tert-butyl in a similar manner as described in Example 29, Step 7. 1 H NMR (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, 2H), 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), 1.39 (s, 1H), 1.26 - 0.63 (m, 12H). LC-MS (M+H) + = 680.5.

[0928] 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-methylpiperazin-1-yl)ethan-1-one (Compound 43)

[0929]

[0930] Step 1: (2R,5S)-4-(2-((S)-2-cyclohexyl-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-butyl ester

[0931]

[0932] The title compound of Step 1 (61 mg, 41% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-1-(2-cyclohexyl-7-(4- fluorobenzyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one and (2R,5S)-5- (((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1-carboxylic acid tert- butyl ester. LC-MS (M+H) + = 694.4.

[0933] 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-methylpiperazin-1-yl)ethan- 1-one (Compound 43)

[0934] Compound 43 (15 mg, 27% yield) was prepared in a similar manner as in Example 29, Step 7 from (2R,5S)-4-(2-((S)-2-cyclohexyl-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-butyl ester. 1H NMR (300 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.84 (s, 1H), 7.14 (t, J = 7.1 Hz, 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, 2H), 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), 1.49 - 1.36 (m, 1H), 1.15 - 1.11 (m, 2H), 1.06 - 0.86 (m, 13H). LC-MS (M+H) + = 594.3.

[0935] Example 44: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-2-phenyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 44)

[0936]

[0937] Step 1: (S)-(2-((3-bromo-5-chloropyridin-2-yl)oxy)-1-phenylethyl) tert- butylcarbamate

[0938]

[0939] The title compound of Step 1 (2.1 g, 38% yield) was prepared in a similar manner as described in Example 34, Step 1 from (S)-(tert-butoxy-(2-hydroxy-1- phenylethyl)carbamate and 3-bromo-5-chloro-2-fluoropyridine. LC-MS (M+H) + = 427.0.

[0940] Step 2: (S)-7-chloro-2-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester

[0941]

[0942] The title compound of Step 2 (1.5 g, 88% yield) was prepared from (S)-(2-((3-bromo-5-chloropyridin-2-yl)oxy)-l-phenylethyl) carbamic acid tert-butyl ester in a similar manner as described in Example 34, Step 2. LC-MS (M+H) + = 347.1.

[0943] Step 3: (S)-7-(4-Fluorobenzyl)-2-phenyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl butyrate

[0944]

[0945] The title compound of Step 3 (750 mg, 41% yield) was prepared from (S)-7-chloro-2-phenyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l -methyl butyrate in a similar manner as described in Example 34, Step 3. LC-MS (M+H) + = 421.1.

[0946] Step 4: (S)-7-(4-Fluorobenzyl)-2-phenyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin

[0947]

[0948] The title compound of Step 4 (550 mg, 96% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-phenyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l -methyl butyrate in a similar manner as described in Example 29, Step 4. LC-MS (M+H) + = 321.1.

[0949] Step 5: (S)-2-Chloro-l-(7-(4-fluorobenzyl)-2-phenyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one

[0950]

[0951] The title compound of Step 5 (350 mg, 51% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-phenyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 397.1.

[0952] Step 6: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-2-phenyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[0953]

[0954] The title compound of Step 6 (150 mg, 57% yield) was prepared from (S)-2- chloro-l-(7-(4-fluorobenzyl)-2-phenyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)ethan-l-one and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2- methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 688.4.

[0955] Step 7: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-l-yl)-l-((S)-7-(4-fluorobenzyl)-2-phenyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one (Compound 44)

[0956] Compound 44 (51 mg, 66% yield) was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-phenyl-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 29, Step 7. 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.39 - 7.27 (m, 3H), 7.24 - 7.11 (m, 4H), 7.08 - 6.94 (m, 2H), 6.01 (s, 1H), 4.86 (d, J = 11.7, 1.9 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.29 (d, J = 14.4 Hz, 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), 2.96 (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, 3H), 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.

[0957] Example 45: l-((S)-7-(4-fluorobenzyl)-2-phenyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- l-yl)ethan-l-one (Compound 45)

[0958]

[0959] Step 1: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-phenyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1-carboxylic acid tert-butyl ester

[0960]

[0961] The title compound of Step 1 (150 mg, 58% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-l-(7-(4-fluorobenzyl)-2-phenyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) +=674.4.

[0962] Step 2: 1-((S)-7-(4-Fluorobenzyl)-2-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (Compound 45)

[0963] Compound 45 as the free base (44 mg, 35% yield) was prepared in a similar manner to that in Example 29, Step 7 from tert-butyl (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-phenyl-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. 1 HNMR(300MHz, chloroform-d)δ8.63(s,1H),7.80(s,1H),7.35-7.11(m,7H),7.06-6.95(m,2H),6.23(s,1H),4.94(d,J=11.5,1.9Hz,1H), 4.54(d,J=11.6,3.0Hz,2H),3.92(s,2H),3.60(d,J=11.5Hz,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=11.4,2.3Hz,1H),2.89-2.76(m,2H),2.76-2.67(m,2H),2.55(t,J=10.9Hz,1H),2.50(s,1H),2.22-2. 17(m,1H),2.09(t,J=10.9Hz,1H),2.01-1.91(m,1H),1.83(dd,J=13.4,3.1Hz,1H),1.04(d,J=6.2Hz,3H),0.58(d,J=6.3Hz,3H). LC-MS(M+H) + =574.3.

[0964] Example 46: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5-methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 46)

[0965]

[0966] Step 1: (S)-(1-((3-bromo-5-(4-fluorobenzyl)pyridin-2-yl)oxy)-3-methylbutan-2-yl) carbamic acid tert-butyl ester

[0967]

[0968] The title compound of Step 1 (2.4 g, 75% yield) was prepared in a similar manner as described in Example 29, Step 1 from 3-bromo-2-fluoro-5-(4-fluorobenzyl)pyridine and (S)-(1- hydroxy-3-methylbutan-2-yl)carbamic acid tert-butyl ester. LC-MS (M+H) + = 467.1.

[0969] Step 2: (S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1- carboxylic acid tert-butyl ester

[0970]

[0971] The title compound of Step 2 (370 mg, 95% yield) was prepared in a similar manner as described in Example 34, Step 2 from (S)-(1-((3-bromo-5-(4-fluorobenzyl)pyridin-2- yl)oxy)-3-methylbutan-2-yl)carbamic acid tert-butyl ester. LC-MS (M+H) + = 387.2.

[0972] Step 3: (S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

[0973]

[0974] The title compound of Step 3 (240 mg, 92% yield) was prepared in a similar manner as described in Example 29, Step 4 from (S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 287.1.

[0975] Step 4: (S)-2-chloro-1-(7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin- 1-yl)ethan-1-one

[0976]

[0977] The title compound of Step 4 (250 mg, 83% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-isopropyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole and 2- chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 363.1.

[0978] Step 5: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-2-isopropyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[0979]

[0980] The title compound of Step 5 (95 mg, 45% yield) was prepared from (S)-2- chloro-l-(7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)ethan-l-one and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2- methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 654.3.

[0981] Step 6: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-l-yl)-l-((S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one (Compound 46)

[0982] Compound 46 (30 mg, 31% yield) was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-isopropyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methylpiperazine-l- carboxylic acid tert-butyl ester in a similar manner as described in Example 29, Step 7. 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 = 11.2 Hz, 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.

[0983] Example 47: l-((S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1-yl)ethan-l-one (Compound 47)

[0984]

[0985] Step 1: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine- 1-carboxylic acid tert-butyl ester

[0986]

[0987] The title compound of Step 1 (95 mg, 45% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-2-chloro-l-(7-(4-fluorobenzyl)-2-isopropyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 640.3.

[0988] Step 2: 1-((S)-7-(4-fluorobenzyl)-2-isopropyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-1 -yl)-2-((2R,5R)-5-methyl-2-(((R)-3-methylmorpholino)methyl)piperazin- 1 -yl)ethan-1 -one (Compound 47)

[0989] Compound 47 (36 mg, 44% yield) was prepared from (2R,5S)-4-(2-((S)-7-(4- fluorobenzyl)-2-isopropyl-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 ester in a similar manner as described in Example 29, Step 7. 1 H NMR (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, 2H), 4.65 (dd, J = 11.4, 1.4 Hz, 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, 1H), 2.15 (s, 1H), 2.05-1.76 (m, 4H), 1.02 (dd, J = 19.5, 6.4 Hz, 6H), 0.90 (s, 6H). LC-MS (M+H) + = 540.5.

[0990] Example 48: 2-((2R,5R)-2-((3,3-dimethylmorpholino)methyl)-5-methylpiperazin-1-yl)-1- ((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin- 1 -yl)ethan-1 -one (Compound 48)

[0991]

[0992] Step 1: (2R,5S)-4-benzyl-5-((3,3-dimethylmorpholino)methyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester

[0993]

[0994] The title compound of Step 1 (500 mg, 81% yield) was prepared in a similar manner as described in Example 1, Step 16 from 3,3-dimethylmorpholine and (2R,5R)-4-benzyl-5- (chloromethyl)-2-methylpiperazine-1 -carboxylate. LC-MS (M+H) + = 418.4.

[0995] Step 2: (2R,5S)-5-((3,3-dimethylmorpholino)methyl)-2-methylpiperazine-1 - carboxylate

[0996]

[0997] The title compound of Step 2 (350 mg, crude) was prepared in a similar manner as described in Example 1, Step 17 from (2R,5S)-4-benzyl-5-((3,3-dimethylmorpholino)methyl)-2- methylpiperazine-1 -carboxylate. LC-MS (M+H) + = 328.3.

[0998] Step 3: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-5-((3,3-dimethylmorpholino)methyl)- 2-methylpiperazine-1 -carboxylate

[0999]

[1000] The title compound of Step 3 (550 mg, 59% yield over 2 steps) was prepared in a similar manner as described in Example 1, Step 18 from (S)-methyl (1 -(2-chloroacetyl)-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-6-yl)acetate and (2R,5S)-5- ((3,3-dimethylmorpholino)methyl)-2-methylpiperazine-1 -carboxylate. LC-MS (M+H) + = 698.4.

[1001] Step 4: ((S)-1 -(2-((2R,5R)-2-((3,3-dimethylmorpholino)methyl)-5-methylpiperazin-1 -yl)acetyl)- 7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-6-yl)methyl acetate

[1002]

[1003] The title compound of Step 4 (120 mg, 70% yield) was prepared from (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5-((3,3-dimethylmorpholino)methyl)-2- methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 8. LC-MS (M+H) + = 598.4.

[1004] Step 5: 2-((2R,5R)-2-((3,3-dimethylmorpholino)methyl)-5-methylpiperazin-l-yl)-l-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan- 1-one (Compound 48)

[1005] To a solution of ((S)-l-(2-((2R,5R)-2-((3,3-dimethylmorpholino)methyl)-5- methylpiperazin-l-yl)acetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-6-yl)methyl acetate (120 mg, 0.2 mmol) in THF (5 mL) was added LiOH (10 mg, 0.4 mmol) in H2O (5 mL). The resulting mixture was stirred at room temperature for 1 h. When the reaction was complete, the resulting mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 30x150mm, 5um; Mobile Phase, Acetonitrile in Water (containing 10 mmol / L NH4HCO3 and 0.1% NH3.H2O), 23% to 53% gradient over 8 min; Detector, UV 254 nm. The title compound (47 mg, 42% yield) was obtained. 1H NMR (300 MHz, Chloroform-d) δ 8.39 (br s, 1H), 7.14-7.03 (m, 2H), 7.03-6.91 (m, 2H), 4.95 (s, 1H), 4.64-4.47 (m, 2H), 4.45-4.35 (m, 1H), 4.35-4.24 (m, 1H), 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, 1H), 2.57-2.40 (m, 4H), 2.44-2.36 (m, 1H), 2.23-2.01 (m, 2H), 1.36-1.28 (m, 3H), 1.05-0.98 (m, 3H), 0.98-0.89 (m, 6H). LC-MS (M+H) + = 556.3.

[1006] Example 49: 2-((2R,5R)-2-(((2S,5R)-2,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 49)

[1007]

[1008] Step 1: (2R,5S)-4-benzyl-5-(((2S,5R)-2,5-dimethylmorpholino)methyl)-2- methylpiperazine-1-carboxylic acid tert-butyl ester

[1009]

[1010] The title compound of Step 1 (460 mg, 51% yield) was prepared in a similar manner as described in Example 1, Step 16 from (2S,5R)-dimethylmorpholine and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 418.3.

[1011] Step 2: (2R,5S)-5-(((2S,5R)-2,5-dimethylmorpholino)methyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester

[1012]

[1013] The title compound of Step 2 (280 mg, 78% yield) was prepared from (2R,5S)-4-benzyl-5-(((2S,5R)-2,5-dimethylmorpholino)methyl)-2-methylpiperazine-1 -carboxylate in a similar manner as described in Example 1 Step 17. LC-MS (M+H) + = 328.3.

[1014] Step 3: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-1 H-pyrano[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-5-(((2S,5R)-2,5- dimethylmorpholino)methyl)-2-methylpiperazine-1 -carboxylate

[1015]

[1016] The title compound of Step 3 (150 mg, 62% yield) was prepared from (S)-methyl (1 -(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrano[2,3- b][1,4]oxazin-6-yl)acetate and (2R,5S)-5-(((2S,5R)-2,5-dimethylmorpholino)methyl)- 2-methylpiperazine-1 -carboxylate in a similar manner as described in Example 1 Step 18. LC-MS (M+H) + = 698.3.

[1017] Step 4: (2R,5S)-5-(((2S,5R)-2,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1 H-pyrano[2,3-b][1,4]oxazin-1 - yl)-2-oxoethyl)-2-methylpiperazine-1 -carboxylate

[1018]

[1019] The title compound of Step 4 (130 mg, 92% yield) was prepared from (2R,5S)-4-(2- ((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrano[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-5-(((2S,5R)-2,5-dimethylmorpholino)methyl)-2- methylpiperazine-1 -carboxylate in a similar manner as described in Example 8 Step 4. LC-MS (M+H) + = 656.3.

[1020] Step 5: 2-((2R,5R)-2-(((2S,5R)-2,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 49)

[1021] Compound 49 as formate salt was prepared from (2R,5S)-5-(((2S,5R)-2,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2- methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated. The residue was further lyophilized to give Compound 49 as a free base (15 mg, 14% yield). 1 H NMR (400 MHz, DMSO-d6) 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), 4.79 (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 (br s, 2H), 2.60 (br s, 1H), 2.55 (br s, 1H), 2.32-2.27 (m, 1H), 2.21-2.18 (m, 1H), 1.96 (br s, 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.

[1022] Example 50: 2-((2R,5R)-2-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 50)

[1023]

[1024] Step 1: (2R,5S)-5-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)-4-benzyl-2- methylpiperazine-1-carboxylic acid tert-butyl ester

[1025]

[1026] The title compound of Step 1 (500 mg, 81% yield) was prepared in a similar manner as described in Example 1, Step 16 from (2R,5R)-4-benzyl-5-(chloromethyl)-2- methylpiperazine-1-carboxylic acid tert-butyl ester and 7-oxa-4-azaspiro[2.5]octane. LC-MS (M+H) + = 416.3.

[1027] Step 2: (2R,5S)-5-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester

[1028]

[1029] The title compound of Step 2 (320 mg, crude) was prepared in a similar manner as described in Example 1, Step 17 from (2R,5S)-5-((7-oxa-4-azaspiro[2.5]octan-4- yl)methyl)-4-benzyl-2-methylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 326.2.

[1030] Step 3: (2R,5S)-5-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)-4-(2-((S)-6- (acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1- yl)-2-oxoethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[1031]

[1032] The title compound of Step 3 (448 mg, 53% yield over 2 steps) was prepared from (S)-(l-(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrrolo[2,3- b][l,4]oxazin-6-yl)acetic acid methyl ester and (2R,5S)-5-((7-oxa-4- azaspiro[2.5]octan-4-yl)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 696.4.

[1033] Step 4: (2R,5S)-5-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazin-l- yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[1034]

[1035] The title compound of Step 4 (240 mg, crude) was prepared from (2R,5S)-5-((7-oxa-4- azaspiro[2.5]octan-4-yl)methyl)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methylpiperazine- 1-carboxylic acid tert-butyl ester in a similar manner as described in Example 8, Step 4. LC-MS (M+H) + = 654.4.

[1036] Step 5: 2-((2R,5R)-2-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)-5-methylpiperazin-l- yl)-l-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrrolo[2,3- b][l,4]oxazin-l-yl)ethan-l-one (Compound 50)

[1037] Compound 50 (25 mg, 11% yield) was prepared from (2R,5S)-5-((7-oxa-4- azaspiro[2.5]octan-4-yl)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methylpiperazine- 1-carboxylic acid tert-butyl ester in a similar manner as described in Example 29, Step 7. 1H NMR (300 MHz, Chloroform-d) δ 8.40 (br s, 1H), 7.15-7.04 (m, 2H), 7.04-6.92 (m, 2H), 4.91 (s, 1H), 4.66-4.47 (m, 2H), 4.44-4.24 (m, 2H), 4.18-4.07 (m, 1H), 3.83 (s, 2H), 3.69-3.63 (m, 2H), 3.43-3.30 (m, 2H), 3.20-2.98 (m, 2H), 2.89-2.76 (m, 4H), 2.76-2.66 (m, 1H), 2.55-2.34 (m, 3H), 2.18-2.05 (m, 1H), 1.36-1.27 (m, 3H), 1.05-0.97 (m, 3H), 0.64-0.41 (m, 4H). LC-MS (M+H) + = 554.4.

[1038] Example 51: 2-((2R,5R)-2-(((R)-3-ethylmorpholino)methyl)-5-methylpiperazin-1-yl)-1- ((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1- yl)ethan-1-one (Compound 51)

[1039]

[1040] Step 1: (2R,5S)-4-benzyl-5-(((R)-3-ethylmorpholino)methyl)-2-methylpiperazine-1- carboxylate

[1041]

[1042] The title compound of Step 1 (550 mg, 89% yield) was prepared from (R)-3- ethylmorpholine and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1-carboxylate in a similar manner as described in Example 1, Step 16. LC-MS (M+H) + = 418.3.

[1043] Step 2: (2R,5S)-5-(((R)-3-ethylmorpholino)methyl)-2-methylpiperazine-1-carboxylate

[1044]

[1045] The title compound of Step 2 (350 mg, crude) was prepared from (2R,5S)-4-benzyl-5-(((R)-3-ethylmorpholino)methyl)-2-methylpiperazine-1 -carboxylate in a similar manner as described in Example 1 Step 17. LC-MS (M+H) + = 328.3.

[1046] Step 3: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-1 H-pyrano[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-5-(((R)-3- ethylmorpholino)methyl)-2-methylpiperazine-1 -carboxylate

[1047]

[1048] The title compound of Step 3 (534 mg, 58% yield over 2 steps) was prepared from (2R,5S)-5-(((R)-3-ethylmorpholino)methyl)-2-methylpiperazine-1 -carboxylate and (S)-(1 -(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrano[2,3-b][1,4]oxazin-6- yl)acetic acid methyl ester in a similar manner as described in Example 1 Step 18. LC-MS (M+H) + = 698.4.

[1049] Step 4: (2R,5S)-5-(((R)-3-ethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6- (hydroxymethyl)-2-methyl-2,3-dihydro-1 H-pyrano[2,3-b][1,4]oxazin-1 -yl)-2- oxoethyl)-2-methylpiperazine-1 -carboxylate

[1050]

[1051] The title compound of Step 4 (250 mg, 88% yield) was prepared from (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrano[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-5-(((R)-3- ethylmorpholino)methyl)-2-methylpiperazine-1 -carboxylate in a similar manner as described in Example 8 Step 4. LC-MS (M+H) + = 656.4.

[1052] Step 5: 2-((2R,5R)-2-(((R)-3-ethylmorpholino)methyl)-5-methylpiperazin-l-yl)-l-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazin-l-yl)ethan- 1 -one (Compound 51)

[1053] Compound 51 (52 mg, 24% yield) was prepared from (2R,5S)-5-(((R)-3-ethylmorpholino)methyl)- 4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazin-l- yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as in Example 29, Step 7. 1 HNMR (400 MHz, Chloroform-d) δ 8.49 (br s, 1H), 7.16 - 7.08 (m, 2H), 7.05 - 6.95 (m, 2H), 5.01 (s, 1H), 4.67 - 4.52 (m, 2H), 4.52 - 4.36 (m, 2H), 4.36 - 4.26 (m, 1H), 3.85 (s, 2H), 3.79 - 3.65 (m, 2H), 3.59 - 3.50 (m, 1H), 3.37 - 3.21 (m, 2H), 3.05 - 2.99 (m, 1H), 2.98 - 2.89 (m, 1H), 2.88 - 2.83 (m, 2H), 2.79 - 2.70 (m, 1H), 2.68 - 2.54 (m, 2H), 2.21 - 2.12 (m, 3H), 2.02 - 1.94 (m, 1H), 1.70 - 1.54 (m, 1H), 1.36 - 1.29 (m, 4H), 1.07 - 1.00 (m, 3H), 0.92 - 0.84 (m, 3H). LC-MS (M+H) + = 556.4.

[1054] Example 52: l-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH- pyrrolo[2,3-b][l,4]oxazin-l-yl)-2-((2R,5R)-2-(((R)-3-(methoxymethyl)morpholino)methyl)-5- methylpiperazin-l-yl)ethan-l-one (Compound 52)

[1055]

[1056] Step 1: (2R,5S)-4-benzyl-5-(((R)-3-(methoxymethyl)morpholino)methyl)-2- methylpiperazine- 1 -carboxylic acid tert-butyl ester

[1057]

[1058] The title compound of Step 1 (500 mg, 78% yield) was prepared from (R)-3- (methoxymethyl)morpholine and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine- 1 -carboxylate tert-butyl ester in a similar manner as described in Example 1, Step 16. LC-MS (M+H) + = 434.3.

[1059] Step 2: (2R,5S)-5-(((R)-3-(methoxymethyl)morpholino)methyl)-2- methylpiperazine-1-carboxylate tert-butyl ester

[1060]

[1061] The title compound of Step 2 (300 mg, crude) was prepared from (2R,5S)-4- benzyl-5-(((R)-3-(methoxymethyl)morpholino)methyl)-2-methylpiperazine-1- carboxylate tert-butyl ester in a similar manner as described in Example 1, Step 17. LC-MS (M+H) + = 344.2.

[1062] Step 3: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-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-carboxylate tert-butyl ester

[1063]

[1064] The title compound of Step 3 (425 mg, 51% yield over 2 steps) was prepared from (2R,5S)-5-(((R)-3-(methoxymethyl)morpholino)methyl)-2-methylpiperazine-1- carboxylate tert-butyl ester and (S)-(1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)acetic acid methyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 714.4.

[1065] Step 4: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5-(((R)-3- (methoxymethyl)morpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[1066]

[1067] The title compound of Step 4 (170 mg, 60% yield) was prepared in a similar manner as described in Example 8, Step 4 from (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5- (((R)-3-(methoxymethyl)morpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 672.4.

[1068] Step 5: l-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-((2R,5R)-2-(((R)-3-(methoxymethyl)morpholino)methyl)- 5-methylpiperazin-l-yl)ethan-l-one (Compound 52)

[1069] Compound 52 as a free base (45 mg, 26% yield) was prepared in a similar manner as described in Example 29, Step 7 from (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-6- (hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5- (((R)-3-(methoxymethyl)morpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, Chloroform-d) δ 8.41 (br s, 1H), 7.17-7.06 (m, 2H), 7.06-6.94 (m, 2H), 4.97 (s, 1H), 4.68-4.46 (m, 3H), 4.45-4.27 (m, 2H), 3.86 (s, 2H), 3.77-3.60 (m, 2H), 3.58-3.42 (m, 3H), 3.39-3.33 (m, 2H), 3.26 (s, 3H), 3.14-2.83 (m, 4H), 2.83-2.51 (m, 3H), 2.41 (s, 1H), 2.32-1.91 (m, 3H), 1.36-1.28 (m, 3H), 1.07-0.99 (m, 3H). LC-MS (M+H) + = 572.4.

[1070] Example 53: 2-((2R,5R)-2-(((R)-3-(ethoxymethyl)morpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 53)

[1071]

[1072] Step 1: (R)-4-benzyl-3-(ethoxymethyl)morpholine

[1073]

[1074] To a solution of [(3R)-4-benzylmorpholin-3-yl]methanol (395 mg, 1.9 mmol) and iodoethane (740 mg, 4.7 mmol) in DMF (6 mL) was added NaH (96 mg, 4 mmol) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 4 h under nitrogen atmosphere. When the reaction was complete, the reaction was quenched with H2O at room temperature. The resulting mixture was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 4:1) to afford the title compound (342 mg, 76% yield). LC-MS (M+H) + = 236.0.

[1075] Step 2: (R)-3-(ethoxymethyl)morpholine

[1076]

[1077] To a solution of (R)-4-benzyl-3-(ethoxymethyl)morpholine (342 mg, 1.4 mmol) in MeOH (12 mL) was added Pd / C (300 mg, 0.3 mmol, 10%) under nitrogen atmosphere. The mixture was hydrogenated under hydrogen atmosphere using a hydrogen balloon at room temperature for 16 h. When the reaction was complete, the mixture was filtered through a pad of celite and concentrated under reduced pressure to afford the title compound (210 mg, crude). LC-MS (M+H) + = 146.3.

[1078] Step 3: (2R,5S)-4-benzyl-5-(((R)-3-(ethoxymethyl)morpholino)methyl)-2- methylpiperazine-1 -carboxylate

[1079]

[1080] The title compound of Step 3 (338 mg, 51% yield over 2 steps) was prepared from (R)-3-(ethoxymethyl)morpholine and (2R,5R)-4-benzyl-5-(chloromethyl)-2- methylpiperazine-1 -carboxylate in a similar manner as described in Example 1, Step 16. LC-MS (M+H) + = 448.3.

[1081] Step 4: (2R,5S)-5-(((R)-3-(ethoxymethyl)morpholino)methyl)-2-methylpiperazine-1 - carboxylate

[1082]

[1083] The title compound of Step 4 (280 mg, crude) was prepared from (2R,5S)-4-benzyl-5- (((R)-3-(ethoxymethyl)morpholino)methyl)-2-methylpiperazine-1 -carboxylate in a similar manner as described in Example 1, Step 17. LC-MS (M+H) + = 358.3.

[1084] Step 5: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-5-(((R)-3- (ethoxymethyl)morpholino)methyl)-2-methylpiperazine-1 -carboxylate

[1085]

[1086] The title compound of Step 5 (307 mg, 55% yield over 2 steps) was prepared from (2R,5S)-5-(((R)-3-(ethoxymethyl)morpholino)methyl)-2-methylpiperazine-1 -carboxylate and (S)-(1 -(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-6- yl)methyl acetate in a similar manner as described in Example 1 Step 18. LC-MS (M+H) + = 728.4.

[1087] Step 6: (2R,5S)-5-(((R)-3-(ethoxymethyl)morpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-1 -yl)-2- oxoethyl)-2-methylpiperazine-1 -carboxylate

[1088]

[1089] The title compound of Step 6 (101 mg, 87% yield) was prepared from (2R,5S)-4-(2- ((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin- 1 -yl)-2-oxoethyl)-5-(((R)-3-(ethoxymethyl)morpholino)methyl)-2-methylpiperazine-1 - carboxylate in a similar manner as described in Example 8 Step 4. LC-MS (M+H) + = 686.5.

[1090] Step 7: 2-((2R,5R)-2-(((R)-3-(ethoxymethyl)morpholino)methyl)-5-methylpiperazin-1 -yl)-1 - ((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-1 - yl)ethan-1 -one (Compound 53)

[1091] Compound 53 (54 mg, 42% yield) was prepared from (2R,5S)-5-(((R)-3-(ethoxymethyl)morpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-2-methylpiperazine-1 -carboxylate in a similar manner as described in Example 29 Step 7. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (br s, 1H), 7.26-7.17 (m, 2H), 7.17-7.07 (m, 2H), 5.12-5.04 (m, 1H), 4.75 (s, 1H), 4.49-4.30 (m, 3H), 4.25-4.17 (m, 1H), 4.02-3.93 (m, 3H), 3.68-3.53 (m, 2H), 3.46-3.33 (m, 4H), 3.32-3.23 (m, 2H), 2.90-2.81 (m, 1H), 2.81-2.73 (m, 3H), 2.66-2.53 (m, 2H), 2.34-2.18 (m, 3H), 2.08-1.98 (m, 1H), 1.96-1.87 (m, 1H), 1.21-1.15 (m, 3H), 1.10-1.02 (m, 3H), 0.89-0.83 (m, 3H). LC-MS (M+H) + = 586.4.

[1092] Example 54: 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)-2-(((R)-3-(hydroxymethyl)morpholino)methyl)- 5-methylpiperazin-1-yl)ethan-1-one (Compound 54)

[1093]

[1094] Step 1: (S)-4-benzyl-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine

[1095]

[1096] To a solution of [(3R)-4-benzylmorpholin-3-yl]methanol (425 mg, 2.1 mmol) and imidazole (350 mg, 5.2 mmol) in DMF (10 mL) was added TBDMSCl (375 mg, 2.5 mmol) portion wise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 16 h. When the reaction was complete, the reaction was quenched with H2O at room temperature. The resulting mixture was extracted with EtOAc (2 x 30 mL). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 4:1) to afford the title compound (342 mg, 76% yield). LC-MS (M+H) + = 322.2.

[1097] Step 2: (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholine

[1098]

[1099] The title compound of Step 2 (200 mg, crude) was prepared from (S)-4-benzyl-3- (((tert-butyldimethylsilyl)oxy)methyl)morpholine in a similar manner as described in Example 53, Step 2. LC-MS (M+H) + = 232.2.

[1100] Step 3: (2R,5S)-4-benzyl-5-(((S)-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)methyl)- 2-methylpiperazine-1-carboxylic acid tert-butyl ester

[1101]

[1102] The title compound of Step 3 (281 mg, 49% yield over 2 steps) was prepared from (S)-3- (((tert-butyldimethylsilyl)oxy)methyl)morpholine and (2R,5R)-4-benzyl-5-(chloromethyl)-2- methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 16. LC-MS (M+H) + = 534.4.

[1103] Step 4: (2R,5S)-5-(((S)-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)methyl)-2- methylpiperazine-1-carboxylic acid tert-butyl ester

[1104]

[1105] The title compound of Step 4 (220 mg, crude) was prepared from (2R,5S)-4-benzyl-5- (((S)-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)methyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 17. LC-MS (M+H) + = 444.3.

[1106] Step 5: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-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-methylpiperazine-1-carboxylic acid tert-butyl ester

[1107]

[1108] The title compound of Step 5 (250 mg, 58% yield over 2 steps) was prepared from (2R,5S)-5-(((S)-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)methyl)-2- methylpiperazine-1 -carboxylate and (S)-(1 -(2-chloroacetyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin-6-yl)methyl acetate in a similar manner as described in Example 1 Step 18. LC-MS (M+H) + = 814.5.

[1109] Step 6: (2R,5S)-5-(((S)-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)methyl)- 4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3- b][1,4]oxazin-1 -yl)-2-oxoethyl)-2-methylpiperazine-1 -carboxylate

[1110]

[1111] The title compound of Step 6 (162 mg, 68% yield) was prepared from (2R,5S)-4-(2- ((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b][1,4]oxazin- 1 -yl)-2-oxoethyl)-5-(((S)-3-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)methyl)- 2-methylpiperazine-1 -carboxylate in a similar manner as described in Example 8 Step 4. LC-MS (M+H) + = 772.4.

[1112] Step 7: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1 H- pyrrolo[2,3-b][1,4]oxazin-1 -yl)-2-((2R,5R)-2-(((R)-3-(hydroxymethyl)morpholino)methyl)- 5-methylpiperazin-1 -yl)ethan-1 -one (Compound 54)

[1113] Compound 54 (70 mg, 59% yield) was prepared from (2R,5S)-5-(((S)-3-(((tert- butyldimethylsilyl)oxy)methyl)morpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6- (hydroxymethyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)- 2-methylpiperazin-l-ium tert-butyldimethylsilylate in a similar manner as described in Step 7 of Example 29. 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (br s, 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 - 1.02 (m, 3H). LC-MS (M+H) + = 558.3.

[1114] Example 55: 2-((2R,5R)-2-(((S)-3-(difluoromethyl)morpholino)methyl)-5- methylpiperazin-l-yl)-l-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)ethan-l-one (Compound 55)

[1115]

[1116] Step 1: (S)-4-benzylmorpholine-3-carbaldehyde

[1117]

[1118] To a solution of DMSO (1.95 mL, 27.5 mmol) in DCM (10 mL) was added dropwise oxalyl chloride (1.16 mL, 13.6 mmol) in DCM (5 mL) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 15 min under nitrogen atmosphere. To the above mixture was added dropwise [(3R)-4-benzylmorpholin-3-yl]methanol (950 mg, 4.6 mmol) in DCM (5 mL) at -78 °C over 30 min. The resulting mixture was stirred at -78 °C for another 30 min. To the above mixture was added dropwise TEA (7.60 mL, 54.7 mmol) at -78 °C over 10 min. The reaction mixture was stirred at -78 °C for 1 h. When the reaction was complete, the reaction was quenched with saturated NaHC03at room temperature. The resulting mixture was extracted with DCM (2 x 50 mL). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 3:1) to give the title compound (455 mg, 48% yield). LC-MS (M+H) + = 206.2.

[1119] Step 2: (S)-4-benzyl-3-(difluoromethyl)morpholine

[1120]

[1121] To a solution of (S)-4-benzylmorpholine-3-carbaldehyde (455 mg, 2.2 mmol) in DCM was added dropwise diethylaminosulfur trifluoride (345 mg, 2.2 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. When the reaction was complete, the reaction was quenched with saturated NaHC03at room temperature. The resulting mixture was extracted with DCM (2 x 30 mL). The organic phases were combined, washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (PE:EtOAc = 2:1) to give the title compound (260 mg, 51% yield). LC-MS (M+H) + = 228.1.

[1122] Step 3: (S)-3-(difluoromethyl)morpholine hydrochloride

[1123]

[1124] To a solution of (S)-4-benzyl-3-(difluoromethyl)morpholine (260 mg, 1.1 mmol) in MeOH (12 mL) was added Pd / C (250 mg, 0.2 mmol, 10%) under nitrogen atmosphere. The mixture was hydrogenated under hydrogen atmosphere using a hydrogen balloon at room temperature for 16 h. When the reaction was complete, the mixture was filtered through a pad of celite. To the above mixture was added dropwise HC1 (2 mL, 8 mmol, 4 M) in dioxane at room temperature. The resulting mixture was stirred at room temperature for another 30 min. The resulting mixture was concentrated under reduced pressure to afford the title compound (200 mg, crude), which was used in the next step without purification. LC-MS (M+H) + = 138.1.

[1125] Step 4: (2R,5S)-4-benzyl-5-(((S)-3-(difluoromethyl)morpholino)methyl)-2- methylpiperazine-1 -carboxylic acid tert-butyl ester

[1126]

[1127] The title compound of Step 4 (225 mg, 44% yield over 2 steps) was prepared from (S)-3-(difluoromethyl)morpholine hydrochloride and (2R,5R)-4-benzyl-5- (chloromethyl)-2-methylpiperazine-1 -carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 16. LC-MS (M+H) + = 440.3.

[1128] Step 5: (2R,5S)-5-(((S)-3-(difluoromethyl)morpholino)methyl)-2-methylpiperazine-1 - carboxylic acid tert-butyl ester

[1129]

[1130] The title compound of Step 5 (180 mg, crude) was prepared from (2R,5S)-4-benzyl- 5-(((S)-3-(difluoromethyl)morpholino)methyl)-2-methylpiperazine-1 -carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 17. LC-MS (M+H) + = 350.2.

[1131] Step 6: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-5-(((S)-3- (difluoromethyl)morpholino)methyl)-2-methylpiperazine-1 -carboxylic acid tert-butyl ester

[1132]

[1133] The title compound of Step 6 (220 mg, 59% yield over 2 steps) was prepared from (2R,5S)-5-(((S)-3-(difluoromethyl)morpholino)methyl)-2-methylpiperazine-1 - carboxylate and (S)-(1 -(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H- pyrido[2,3-b][1,4]oxazin-6-yl)methyl acetate in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 720.4.

[1134] Step 7: (2R,5S)-5-(((S)-3-(difluoromethyl)morpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 -yl)-2- oxoethyl)-2-methylpiperazine-1 -carboxylate

[1135]

[1136] The title compound of Step 7 (134 mg, 65% yield) was prepared from (2R,5S)-4-(2- ((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin- 1 -yl)-2-oxoethyl)-5-(((S)-3-(difluoromethyl)morpholino)methyl)-2-methylpiperazine-1 - carboxylate in a similar manner as described in Example 8, Step 4. LC-MS (M+H) + = 678.3.

[1137] Step 8: 2-((2R,5R)-2-(((S)-3-(difluoromethyl)morpholino)methyl)-5-methylpiperazin-1 - yl)-1 -((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin- 1 -yl)ethan-1 -one (Compound 55)

[1138] Compound 55 (53 mg, 46% yield) was prepared from (2R,5S)-5-(((S)-3- (difluoromethyl)morpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- methyl-2,3-dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-2-methylpiperazine-1 - carboxylate in a similar manner as described in Example 29, Step 7. 1H NMR (400 MHz, Chloroform-d) δ 8.41 (br s, 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.

[1139] Example 56: 2-((2R,5R)-2-((8-oxa-5-azaspiro[3.5]non-5-yl)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 56)

[1140]

[1141] Step 1: (2R,5S)-5-((8-oxa-5-azaspiro[3.5]non-5-yl)methyl)-4-benzyl-2- methylpiperazine-1-carboxylic acid tert-butyl ester

[1142]

[1143] The title compound of Step 1 (500 mg, 78% yield) was prepared from 8-oxa-5- azaspiro[3.5]nonane and (2R,5R)-4-benzyl-5-(chloromethyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 16. LC-MS (M+H) + = 430.3.

[1144] Step 2: (2R,5S)-5-((8-oxa-5-azaspiro[3.5]non-5-yl)methyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester

[1145]

[1146] The title compound of Step 2 (300 mg, crude) was prepared from (2R,5S)-5-((8-oxa- 5-azaspiro[3.5]non-5-yl)methyl)-4-benzyl-2-methylpiperazine-1 -carboxylate in a similar manner as described in Example 1 Step 17. LC-MS (M+H) + = 340.3.

[1147] Step 3: (2R,5S)-5-((8-Oxa-5-azaspiro[3.5]non-5-yl)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1 H-pyrano[2,3-b][1,4]oxazin-1 - yl)-2-oxoethyl)-2-methylpiperazine-1 -carboxylate

[1148]

[1149] The title compound of Step 3 (350 mg, 42% yield over 2 steps) was prepared from (2R,5S)-5-((8-oxa-5-azaspiro[3.5]non-5-yl)methyl)-2-methylpiperazine-1 -carboxylate and (S)-(1 -(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1 H- pyrano[2,3-b][1,4]oxazin-6-yl)acetic acid methyl ester in a similar manner as described in Example 1 Step 18. LC-MS (M+H) + = 710.4.

[1150] Step 4: (2R,5S)-5-((8-Oxa-5-azaspiro[3.5]non-5-yl)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1 H-pyrano[2,3-b][1,4]oxazin-1 - yl)-2-oxoethyl)-2-methylpiperazine-1 -carboxylate

[1151]

[1152] The title compound of Step 4 (250 mg, 75% yield) was prepared from (2R,5S)-5-((8-oxa- 5-azaspiro[3.5]non-5-yl)methyl)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-1 H-pyrano[2,3-b][1,4]oxazin-1 -yl)-2-oxoethyl)-2-methylpiperazine-1 - carboxylate in a similar manner as described in Example 8 Step 4. LC-MS (M+H) + = 668.4.

[1153] Step 5: 2-((2R,5R)-2-((8-oxa-5-azaspiro[3.5]non-5-yl)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 56)

[1154] Compound 56 (59 mg, 28% yield) was prepared from (2R,5S)-5-((8-oxa-5- azaspiro[3.5]non-5-yl)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-2-methylpiperazine- 1-carboxylic acid tert-butyl ester in a similar manner as described in Example 29, Step 7. 1 H NMR (300 MHz, Chloroform-d) δ 8.45 (br s, 1H), 7.17-7.06 (m, 2H), 7.06-6.93 (m, 2H), 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.

[1155] Example 57: 1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- (methoxymethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)-2-((2R,5R)-5- methyl-2-(((R)-3-methylmorpholino)methyl)piperazin-1-yl)ethan-1-one (Compound 57)

[1156]

[1157] Step 1: tert-Butyl (S)-(1-(benzyloxy)-3-((3,5-dibromo-6-methylpyridin-2-yl)oxy)propan- 2-yl)carbamate

[1158]

[1159] The title compound of Step 1 (9.8 g, 99% yield) was prepared in a similar manner as described in Example 19, Step 1 from (R)-(l-(benzyloxy)-3-hydroxypropan-2-yl)carbamic acid tert-butyl ester and 3,5-dibromo-2-chloro-6-methylpyridine. LC-MS (M+H) + = 529.0.

[1160] Step 2: (S)-2-((benzyloxy)methyl)-7-bromo-6-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -ium chloride

[1161]

[1162] The title compound of Step 2 (4 g, 74% yield) was prepared in a similar manner as described in Example 34, Step 2 from (S)-(l-(benzyloxy)-3-((3,5-dibromo-6- methylpyridin-2-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester. LC-MS (M+H) + = 449.1.

[1163] Step 3: (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l -ium chloride

[1164]

[1165] The title compound of Step 3 (2.9 g, 91% yield) was prepared in a similar manner as described in Example 1, Step 7 from (S)-2-((benzyloxy)methyl)-7-bromo-6-methyl- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l -ium chloride and (4-fluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 479.2.

[1166] Step 4: (S)-7-(4-fluorobenzyl)-2-(hydroxymethyl)-6-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l -ium chloride

[1167]

[1168] The title compound of Step 4 (2 g, 84% yield) was prepared in a similar manner as described in Example 34, Step 4 from (S)-2-((benzyloxy)methyl)-7-(4-fluorobenzyl)-6- methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l -ium chloride. LC-MS (M+H) += 389.2.

[1169] Step 5: (R)-7-(4-fluorobenzyl)-6-methyl-2-(((methylsulfonyl)oxy)methyl)-2,3- dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-l-carboxylate

[1170]

[1171] The title compound of Step 5 (2.3 g, 99% yield) was prepared in a similar manner as described in Example 34, Step 5 from (S)-7-(4-fluorobenzyl)-2- (hydroxymethyl)-6-methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-l-tert-butyl ester and MsCl. LC-MS (M+H) + = 467.2.

[1172] Step 6: (R)-(7-(4-fluorobenzyl)-6-methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazol-2- yl)methanesulfonic acid methyl ester

[1173]

[1174] The title compound of Step 6 (1.4 g, 75% yield) was prepared in a similar manner as described in Example 34, Step 6 from (R)-7-(4-fluorobenzyl)-6-methyl-2- (((methylsulfonyl)oxy)methyl)-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-l-tert-butyl ester. LC-MS (M+H) + = 367.1.

[1175] Step 7: (S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-6-methyl-2,3-dihydro-lH- pyrrolo[2,3-b][l,4]oxazole

[1176]

[1177] The title compound of Step 7 (665 mg, 58% yield) was prepared in a similar manner as described in Example 34, Step 7 from (R)-(7-(4-fluorobenzyl)-6-methyl-2,3- dihydro-lH-pyrrolo[2,3-b][l,4]oxazol-2-yl)methanesulfonic acid methyl ester and sodium methoxide. LC-MS (M+H) + = 303.1.

[1178] Step 8: (S)-7-(4-fluorobenzyl)-2-(methoxymethyl)-6-methyl-2,3-dihydro-lH- pyrrolo[2,3-b][l,4]oxazole-l-tert-butyl ester

[1179]

[1180] The title compound of Step 8 (590 mg, 79% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-(methoxymethyl)-6-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole in a similar manner as described in Example 1, Step 4. LC-MS (M+H) + = 403.2.

[1181] Step 9: (S)-l-(tert-Butoxycarbonyl)-7-(4-fluorobenzyl)-2-(methoxymethyl)-6- methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole 5-oxide

[1182]

[1183] The title compound of Step 9 (457 mg, 74% yield) was prepared from (S)-7-(4- fluorobenzyl)-2-(methoxymethyl)-6-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole- 1 - carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 5. LC-MS (M+H) + = 419.2.

[1184] Step 10: (S)-6-(Acetyloxymethyl)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazole-l-carboxylic acid tert-butyl ester

[1185]

[1186] The title compound of Step 10 (409 mg, 93% yield) was prepared from (S)-l-(tert- butoxycarbonyl)-7-(4-fluorobenzyl)-2-(methoxymethyl)-6-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazole 5-oxide in a similar manner as described in Example 8, Step 2. LC-MS (M+H) + = 461.2.

[1187] Step 11: (S)-(7-(4-Fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazol-6-yl)acetic acid methyl ester

[1188]

[1189] The title compound of Step 11 (298 mg, 98% yield) was prepared from (S)-6- (acetyloxymethyl)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l -methyl butyrate in a similar manner as described in Example 1, Step 8. LC-MS (M+H) + = 361.1.

[1190] Step 12: (S)-(l-(2-chloroacetyl)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-6-yl)methyl acetate

[1191]

[1192] The title compound of Step 12 (400 mg, crude) was prepared from (S)-(7-(4- fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-6-yl)methyl acetate and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 437.1.

[1193] Step 13: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2- (methoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[1194]

[1195] The title compound of Step 13 (400 mg, crude) was prepared from (S)-(l-(2- chloroacetyl)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-6-yl)methyl acetate and (2R,5S)-2-methyl-5-(((R)-3- methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 714.4.

[1196] Step 14: (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- (methoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2- methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester

[1197]

[1198] The title compound of Step 14 (110 mg, 61% yield) was prepared in a similar manner as described in Example 8, Step 4 from (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4- fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 672.4.

[1199] Step 15: l-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-(methoxymethyl)-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-((2R,5R)-5-methyl-2-(((R)-3- methylmorpholino)methyl)piperazin-l-yl)ethan-l-one (Compound 57)

[1200] Compound 57 (20 mg, 15% yield) was prepared in a similar manner as described in Example 29, Step 7 from (2R,5S)-4-(2-((S)-7-(4-fluorobenzyl)-6- (hydroxymethyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methyl-5-(((R)-3-methylmorpholino)methyl)piperazine-l-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, DMSO-d6) δ 8.22 (br s, 1H), 7.25 - 7.14 (m, 2H), 7.17 - 7.04 (m, 2H), 5.14 - 5.04 (m, 1H), 4.85 (s, 1H), 4.54 - 4.45 (m, 1H), 4.45 - 4.33 (m, 2H), 4.25 - 4.09 (m, 2H), 3.96 (s, 2H), 3.54 - 3.45 (m, 2H), 3.49 - 3.33 (m, 1H), 3.30 - 3.24 (m, 2H), 3.21 (s, 3H), 3.07 - 2.95 (m, 1H), 2.93 - 2.74 (m, 2H), 2.73 - 2.53 (m, 4H), 2.39 - 2.12 (m, 3H), 2.10 - 1.96 (m, 1H), 1.82 - 1.71 (m, 1H), 1.22 (s, 1H), 0.92 - 0.85 (m, 3H), 0.85 - 0.79 (m, 3H). LC-MS (M+H) + = 572.0.

[1201] Example 58: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)-1-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- (methoxymethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)ethan-1-one (Compound 58)

[1202]

[1203] Step 1: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2- (methoxymethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5- (((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[1204]

[1205] The title compound of Step 1 (400 mg, crude) was prepared in a similar manner as described in Example 1, Step 18 from (S)-(1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2- (methoxymethyl)-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazin-6-yl)acetic acid methyl ester and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester. LC-MS (M+H) += 728.4.

[1206] Step 2: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-(hydroxymethyl)-2-(methoxymethyl)-2,3-dihydro-lH-pyrano[2,3- b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[1207]

[1208] The title compound of Step 2 (109 mg, 59% yield) was prepared from (2R,5S)-4-(2- ((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-(methoxymethyl)-2,3-dihydro-lH- pyrano[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)- 2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 8, Step 4. LC-MS (M+H) + = 686.4.

[1209] Step 3: 2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5-methylpiperazin-l- yl)-l-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2-(methoxymethyl)-2,3-dihydro-lH- pyrano[2,3-b][l,4]oxazin-l-yl)ethan-l-one (Compound 58)

[1210] Compound 58 (29 mg, 32% yield) was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-(hydroxymethyl)-2- (methoxymethyl)-2,3-dihydro-lH-pyrano[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2- methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 29, Step 7. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (br s, 1H), 7.25-7.17 (m, 2H), 7.21-7.07 (m, 2H), 5.13-5.06 (m, 1H), 4.86 (s, 1H), 4.55-4.36 (m, 3H), 4.26-4.18 (m, 1H), 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, 5H), 2.50-2.44 (m, 1H), 2.30-2.20 (m, 1H), 2.19-2.10 (m, 1H), 2.00-1.90 (m, 1H), 0.90-0.80 (m, 9H). LC-MS (M+H) + = 586.3.

[1211] Example 59: 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)-2-(((S)-3-(isopropoxymethyl)morpholino)methyl)- 5-methylpiperazin-1-yl)ethan-1-one (Compound 59)

[1212]

[1213] Step 1: (S)-(4-benzylmorpholin-3-yl)methyl methanesulfonate

[1214]

[1215] The title compound of Step 1 (335 mg, 61% yield) was prepared in a similar manner as described in Example 34, Step 5 from (R)-(4-benzylmorpholin-3-yl)methanol and MsCl. LC-MS (M+H) + = 286.1.

[1216] Step 2: (S)-4-benzyl-3-(isopropoxymethyl)morpholine

[1217]

[1218] The title compound of Step 2 (230 mg, 78% yield) was prepared in a similar manner as described in Example 34, Step 7 from (S)-(4-benzylmorpholin-3-yl)methyl methanesulfonate and sodium isopropoxide. LC-MS (M+H) + = 250.2.

[1219] Step 3: (S)-3-(isopropoxymethyl)morpholine

[1220]

[1221] The title compound of Step 3 (160 mg, crude) was prepared from (S)-4-benzyl-3- (isopropoxymethyl)morpholine in a similar manner as described in Example 53, Step 2. LC-MS (M+H) + = 160.1.

[1222] Step 4: (2R,5S)-4-benzyl-5-(((S)-3-(isopropoxymethyl)morpholino)methyl)-2- methylpiperazine-1 -carboxylate

[1223]

[1224] The title compound of Step 4 (310 mg, 46% yield over 2 steps) was prepared from (S)-3-(isopropoxymethyl)morpholine and (2R,5R)-4-benzyl-5-(chloromethyl)-2- methylpiperazine-1 -carboxylate in a similar manner as described in Example 1, Step 16. LC-MS (M+H) + = 462.3.

[1225] Step 5: (2R,5S)-5-(((S)-3-(isopropoxymethyl)morpholino)methyl)-2-methylpiperazine-1- carboxylate

[1226]

[1227] The title compound of Step 5 (250 mg, crude) was prepared from (2R,5S)-4-benzyl-5- (((S)-3-(isopropoxymethyl)morpholino)methyl)-2-methylpiperazine-1-carboxylate in a similar manner as described in Example 1, Step 17. LC-MS (M+H) + = 372.3.

[1228] Step 6: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-1 H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethyl)-5-(((S)-3-(isopropoxymethyl)- morpholino)methyl)-2-methylpiperazine-1-carboxylate

[1229]

[1230] The title compound of Step 6 (130 mg, 52% yield over 2 steps) was prepared from (2R,5S)-5-(((S)-3-(isopropoxymethyl)morpholino)methyl)-2-methylpiperazine-1- carboxylate and (S)-(1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-6-yl)methyl acetate in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 742.4.

[1231] Step 7: (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-(((S)-3-(isopropoxymethyl)morpholino) methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

[1232]

[1233] The title compound of Step 7 (90 mg, 74% yield) was prepared from (2R,5S)-4-(2- ((S)-6-(acetyloxymethyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin- 1-yl)-2-oxoethyl)-5-(((S)-3-(isopropoxymethyl)morpholino)methyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester in a similar manner as described in Example 8, Step 4. LC-MS (M+H) + = 700.5.

[1234] Step 8: 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)-2-(((S)-3-(isopropoxymethyl)morpholino)methyl)-5- methylpiperazin-1-yl)ethan-1-one (Compound 59)

[1235] Compound 59 (54 mg, 70% yield) was prepared from (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-(((S)-3-(isopropoxymethyl)morpholino)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester in a similar manner as described in Example 29, Step 7. 1H NMR (400 MHz, Chloroform-d) δ 8.40 (br s, 1H), 7.13-7.05 (m, 2H), 7.03-6.93 (m, 2H), 5.03 (s, 1H), 4.63-4.47 (m, 2H), 4.42-4.21 (m, 3H), 3.84 (s, 2H), 3.75-3.67 (m, 1H), 3.66-3.59 (m, 1H), 3.56-3.37 (m, 6H), 3.02-2.92 (m, 2H), 2.92-2.82 (m, 2H), 2.78-2.67 (m, 2H), 2.64-2.54 (m, 1H), 2.43 (s, 1H), 2.19-2.15 (m, 3H), 1.93–1.81 (m, 1H), 1.33-1.23 (m, 3H), 1.13-1.07 (m, 6H), 1.04-0.98 (m, 3H). LC-MS (M+H) + = 600.3.

[1236] Example 60: 1-((S)-7-(2,4-difluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)ethan-1-one (Compound 60)

[1237]

[1238] Step 1: (S)-7-(2,4-difluorobenzyl)-2,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1- carboxylic acid tert-butyl ester

[1239]

[1240] The title compound of Step 1 (1.5 g, 94% yield) was prepared in a similar manner as described in Example 1, Step 7 from (S)-7-bromo-2,6-dimethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1- carboxylic acid tert-butyl ester and (2,4-difluorobenzyl)zinc(II) chloride. LC-MS (M+H) + = 391.2.

[1241] Step 2: (S)-1-(tert-butoxycarbonyl)-7-(2,4-difluorobenzyl)-2,6-dimethyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazine 5-oxide

[1242]

[1243] The title compound of Step 2 (590 mg, 47% yield) was prepared from (S)-7-(2,4- difluorobenzyl)-2,6-dimethyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 5. LC-MS (M+H) + = 407.2.

[1244] Step 3: (S)-6-(acetyloxymethyl)-7-(2,4-difluorobenzyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine-l-carboxylic acid tert-butyl ester

[1245]

[1246] The title compound of Step 3 (540 mg, 75% yield) was prepared from (S)-l-(tert- butyloxycarbonyl)-7-(2,4-difluorobenzyl)-2,6-dimethyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine 5-oxide in a similar manner as described in Example 8, Step 2. LC-MS (M+H) + = 449.2.

[1247] Step 4: (S)-(7-(2,4-difluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin- 6-yl)acetic acid methyl ester

[1248]

[1249] The title compound of Step 4 (150 mg, 96% yield) was prepared from (S)-6- (acetyloxymethyl)-7-(2,4-difluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 8. LC-MS (M+H) + = 349.2.

[1250] Step 5: (S)-(l-(2-chloroacetyl)-7-(2,4-difluorobenzyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-6-yl)acetic acid methyl ester

[1251]

[1252] The title compound of Step 5 (180 mg, crude) was prepared from (S)-(7-(2,4- difluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-6-yl)acetic acid methyl ester and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 425.1.

[1253] Step 6: (2R,5S)-4-(2-((S)-6-(acetyloxymethyl)-7-(2,4-difluorobenzyl)-2-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[1254]

[1255] The title compound of Step 6 (274 mg, 91% yield) was prepared from (S)-(l-(2- chloroacetyl)-7-(2,4-difluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-6- yl)acetic acid methyl ester and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2- methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 716.4.

[1256] Step 7: (2R,5S)-4-(2-((S)-7-(2,4-difluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester.

[1257]

[1258] The title compound of Step 7 (218 mg, 84% yield) was prepared from (2R,5S)-4-(2- ((S)-6-(acetyloxymethyl)-7-(2,4-difluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazin-l-yl)-2-oxoethyl)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2- methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 8, Step 4. LC-MS (M+H) + = 674.4.

[1259] Step 8: 1-((S)-7-(2,4-difluorobenzyl)-6-(hydroxymethyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-1-yl)-2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)- 5-methylpiperazin-1-yl)ethan-1-one (Compound 60)

[1260] Compound 60 (88 mg, 47% yield) was prepared from (2R,5S)-4-(2-((S)-7-(2,4- difluorobenzyl)-6-(hydroxymethyl)-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 tert-butyl ester in a similar manner as described in Example 29, Step 7. 1 H NMR (400 MHz, Chloroform-d) δ 8.41 (br s, 1H), 7.11 - 7.01 (m, 1H), 6.89 - 6.78 (m, 2H), 5.06 - 5.00 (m, 1H), 4.69 - 4.57 (m, 2H), 4.51 - 4.26 (m, 3H), 3.91 - 3.77 (m, 2H), 3.67 - 3.59 (m, 2H), 3.37 - 3.23 (m, 3H), 3.15 - 3.08 (m, 1H), 2.94 - 2.77 (m, 4H), 2.76 - 2.68 (m, 1H), 2.66 - 2.51 (m, 2H), 2.23 - 2.11 (m, 2H), 1.37 - 1.30 (m, 3H), 1.06 - 1.02 (m, 3H), 1.00 - 0.94 (m, 6H). LC-MS (M+H) + = 574.3.

[1261] Example 61: (S)-1-(2-((2R,5R)-2-((3,3-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazine-6-carboxamide (Compound 61)

[1262]

[1263] Step 1: (2R,5S)-4-(2-((S)-6-carbamoyl-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-butyl ester

[1264]

[1265] The title compound of Step 1 (400 mg, 65% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-1-(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazole-6-carboxamide and (2R,5S)-5-((3,3-dimethylmorpholino)methyl)- 2-methylpiperazine-1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 669.4.

[1266] Step 2: (S)-1-(2-((2R,5R)-2-((3,3-dimethylmorpholino)methyl)-5-methylpiperazin-1- yl)acetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazole-6- carboxamide (Compound 61)

[1267] Compound 61 (64 mg, 18% yield) was prepared in a similar manner as described in Example 29, Step 7 from (2R,5S)-4-(2-((S)-6-carbamoyl-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazol-1-yl)-2-oxoethyl)-5-((3,3-dimethylmorpholino)methyl)- 2-methylpiperazine-1-carboxylic acid tert-butyl ester. 1 HNMR (300 MHz, chloroform-d) δ 8.44 (br s, 1H), 7.63 (s, 1H), 7.28-7.16 (m, 2H), 7.02-6.89 (m, 2H), 5.44 (d, J = 4.3 Hz, 1H), 5.01-4.92 (m, 1H), 4.58-4.45 (m, 2H), 4.42-4.25 (m, 2H), 4.20-4.09 (m, 1H), 3.68-3.59 (m, 2H), 3.33-3.08 (m, 4H), 2.89-2.76 (m, 1H), 2.75-2.66 (m, 1H), 2.60-2.34 (m, 5H), 2.22-1.99 (m, 2H), 1.37-1.28 (m, 3H), 1.06-0.98 (m, 3H), 1.06-0.86 (m, 9H). LC-MS (M+H) + = 569.3.

[1268] Example 62: (S)-7-(4-fluorobenzyl)-l-(2-((2R,5R)-2-(((S)-3- (isopropoxymethyl)morpholino)methyl)-5-methylpiperazin-l-yl)acetyl)-2-methyl- 2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-6-carboxamide (Compound 62)

[1269]

[1270] Step 1: (2R,5S)-4-(2-((S)-6-carbamoyl-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-lH-pyrrolo[2,3-b][l,4]oxazol-l-yl)-2-oxoethyl)-5-(((S)-3- (isopropoxymethyl)morpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[1271]

[1272] The title compound of Step 1 (60 mg, 63% yield) was prepared in a similar manner as described in Example 1, Step 18 from (S)-l-(2-chloroacetyl)-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-6-carboxamide and (2R,5S)-5-(((S)-3-(isopropoxymethyl)morpholino)methyl)-2-methylpiperazine- 1-carboxylic acid tert-butyl ester. LC-MS (M+H) + = 713.4.

[1273] Step 2: (S)-7-(4-fluorobenzyl)-l-(2-((2R,5R)-2-(((S)-3- (isopropoxymethyl)morpholino)methyl)-5-methylpiperazin-l-yl)acetyl)-2-methyl- 2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-6-carboxamide (Compound 62)

[1274] Compound 62 (11 mg, 22% yield) was prepared in a similar manner as described in Example 29, Step 7 from (2R,5S)-4-(2-((S)-6-carbamoyl-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazol-l-yl)-2-oxoethyl)-5-(((S)-3- (isopropoxymethyl)morpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (br s, 1H), 7.80 (s, 1H), 7.42 (s, 1H), 7.28-7.18 (m, 2H), 7.13-7.01 (m, 2H), 4.81-4.74 (m, 1H), 4.45-4.31 (m, 3H), 4.31-4.21 (m, 1H), 4.04-3.95 (m, 1H), 3.78-3.69 (m, 1H), 3.58-3.51 (m, 1H), 3.49-3.35 (m, 3H), 3.29-3.18 (m, 3H), 2.91-2.72 (m, 4H), 2.67-2.59 (m, 1H), 2.59-2.52 (m, 1H), 2.33-2.28 (m, 2H), 2.28-2.21 (m, 1H), 2.07-1.98 (m, 1H), 1.97-1.90 (m, 1H), 1.26-1.17 (m, 3H), 1.07-1.00 (m, 6H), 0.92-0.84 (m, 3H). LC-MS (M+H) + = 613.4.

[1275] Example 63: (S)-N-cyclopropyl-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazole- 6-carboxamide (Compound 63)

[1276]

[1277] Step 1: (S)-6-(cyclopropylcarbamoyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrrolo[2,3-b][1,4]oxazole-1-carboxylic acid tert-butyl ester

[1278]

[1279] The title compound of Step 1 (5.1 g, 95% yield) was prepared in a similar manner as described in Example 31, Step 3 from (S)-1-(tert-butoxycarbonyl)-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-1H-pyrrolo[2,3-b][1,4]oxazole-6-carboxylic acid and cyclopropylamine. LC-MS (M+H) + = 442.4.

[1280] Step 2: (S)-N-cyclopropyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazole- 6-carboxamide

[1281]

[1282] The title compound of Step 2 (3.3 g, 84% yield) was prepared from (S)-6- (cyclopropylcarbamoyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazole-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 8. LC-MS (M+H) + = 342.5.

[1283] Step 3: (S)-l-(2-chloroacetyl)-N-cyclopropyl-7-(4-fluorobenzyl)-2-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazole-6-carboxamide

[1284]

[1285] The title compound of Step 3 (3.2 g, 79% yield) was prepared from (S)-N- cyclopropyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-6- carboxamide and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 418.4.

[1286] Step 4: (2R,5S)-4-(2-((S)-6-(cyclopropylcarbamoyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazol-l-yl)-2-oxoethyl)-5-(((3R,5R)-3,5- dimorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[1287]

[1288] The title compound of Step 4 (220 mg, 65% yield) was prepared from (S)-l-(2- chloroacetyl)-N-cyclopropyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazole-6-carboxamide and (2R,5S)-5-(((3R,5R)-3,5-dimorpholino)methyl)-2- methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 709.5.

[1289] Step 5: (S)-N-cyclopropyl-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazole-6-carboxamide (Compound 63)

[1290] Compound 63 as formate salt was prepared from (2R,5S)-4-(2-((S)-6-(cyclopropylcarbamoyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazol-1-yl)-2- oxoethyl)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined EtOAc layers were dried, filtered, and concentrated. The residue was further lyophilized to give Compound 63 as a free base (68 mg, 36% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.32 (s, 1H), 7.26 - 7.19 (m, 2H), 7.11 - 7.06 (m, 2H), 4.73 (s, 1H), 4.36 (d, J = 8.0 Hz, 1H), 4.25 (s, 3H), 3.94 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 16.0 Hz, 1H), 3.41 (d, J = 12.0 Hz, 2H), 3.07 (s, 2H), 2.94 (d, J = 12.0 Hz, 2H), 2.81 - 2.57 (m, 7H), 2.33 - 2.22 (m, 2H), 1.98 - 1.94 (m, 1H), 1.23 - 1.16 (m, 3H), 0.89 - 0.79 (m, 9H), 0.69 - 0.63 (m, 2H), 0.59 - 0.53 (m, 2H). LC-MS (M+H) + = 609.6.

[1291] Example 64: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-7-(4-fluorobenzyl)-2-methyl-N-(2,2,2-trifluoroethyl)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazole-6-carboxamide (Compound 64)

[1292]

[1293] Step 1: (S)-7-(4-fluorobenzyl)-2-methyl-6-((2,2,2-trifluoroethyl)carbamoyl)- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-l-carboxylic acid tert-butyl ester

[1294]

[1295] The title compound of Step 1 (220 mg, 98% yield) was prepared in a similar manner as described in Example 31, Step 3 from (S)-l-(tert-butoxycarbonyl)-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-6-carboxylic acid and 2,2,2-trifluoroethan-l-amine. LC-MS (M+H) + = 484.2.

[1296] Step 2: (S)-7-(4-fluorobenzyl)-2-methyl-N-(2,2,2-trifluoroethyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazole-6-carboxamide

[1297]

[1298] The title compound of Step 2 (130 mg, 80% yield) was prepared in a similar manner as described in Example 1, Step 8 from (S)-7-(4-fluorobenzyl)-2-methyl-6-((2,2,2- trifluoroethyl)carbamoyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-l-carboxylic acid tert- butyl ester. LC-MS (M+H) + = 384.1.

[1299] Step 3: (S)-l-(2-chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-N-(2,2,2-trifluoroethyl)- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-6-carboxamide

[1300]

[1301] The title compound of Step 3 (120 mg, 70% yield) was prepared in a similar manner as described in Example 1, Step 9 from (S)-7-(4-fluorobenzyl)-2-methyl-N-(2,2,2- trifluoroethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-6-carboxamide and 2- chloroacetyl chloride. LC-MS (M+H) + = 460.2.

[1302] Step 4: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-2-methyl-6-((2,2,2-trifluoroethyl)carbamoyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[1303]

[1304] The title compound of Step 4 (130 mg, 61% yield) was prepared from (S)-l-(2- chloroacetyl)-7-(4-fluorobenzyl)-2-methyl-N-(2,2,2-trifluoroethyl)-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine-6-carboxamide and (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 751.4.

[1305] Step 5: (S)-l-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-l-yl)acetyl)-7-(4-fluorobenzyl)-2-methyl-N-(2,2,2- trifluoroethyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-6-carboxamide (Compound 64)

[1306] Compound 64 as formate salt was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-2-methyl-6-((2,2,2- trifluoroethyl)carbamoyl)-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l-yl)-2- oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 64 as free base (30 mg, 43% yield). 1HNMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.38 (s, 1H), 7.25 - 7.18 (m, 2H), 7.10 - 7.07 (m, 2H), 4.73 (s, 1H), 4.40 - 4.31 (m, 4H), 4.02 (d, J = 12.0 Hz, 1H), 3.65 (d, J = 16.0 Hz, 1H), 3.42 (d, J = 8.0 Hz, 1H), 3.08 (d, J = 8.0 Hz, 3H), 2.85 - 2.78 (m, 3H), 2.67 (d, J = 8.0 Hz, 3H), 2.43 (d, J = 8.0 Hz, 2H), 2.01 (d, J = 12.0 Hz, 1H), 1.22 - 1.17 (m, 3H), 1.00 - 0.94 (m, 3H), 0.88 - 0.81 (m, 6H). LC-MS (M+H) + = 651.4.

[1307] Example 65: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-N-ethyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazole-6-carboxamide (Compound 65)

[1308]

[1309] Step 1: (S)-6-(ethylcarbamoyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazole-1-carboxylic acid tert-butyl ester

[1310]

[1311] The title compound of Step 1 (200 mg, 98% yield) was prepared in a similar manner as described in Example 31, Step 3 from (S)-1-(tert-butoxycarbonyl)-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazole-6-carboxylic acid and ethylamine. LC-MS (M+H) + = 430.2.

[1312] Step 2: (S)-N-ethyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazole- 6-carboxamide

[1313]

[1314] The title compound of Step 2 (130 mg, 85% yield) was prepared from (S)-6- (ethylcarbamoyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazole-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 8. LC-MS (M+H) + = 330.2.

[1315] Step 3: (S)-l-(2-chloroacetyl)-N-ethyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro- lH-pyrido[2,3-b][l,4]oxazole-6-carboxamide

[1316]

[1317] The title compound (110 mg, 69% yield) was prepared from (S)-N-ethyl-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-6-carboxamide and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 406.2.

[1318] Step 4: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-6- (ethylcarbamoyl)-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazol-l-yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[1319]

[1320] The title compound of Step 4 (120 mg, 63% yield) was prepared from (S)-l- (2-chloroacetyl)-N-ethyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazole-6-carboxamide and (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino) methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 697.4.

[1321] Step 5: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-N-ethyl-7-(4-fluorobenzyl)-2-methyl-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazole-6-carboxamide (Compound 65)

[1322] Compound 65 as formate salt was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-6-(ethylcarbamoyl)-7-(4-fluorobenzyl)-2- methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazol-1-yl)-2-oxoethyl)-2-methylpiperazine-1- carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 65 as a free base (33 mg, 32% yield). 1 H NMR (400 MHz, DMSO-d6) d 8.43 (s, 1H), 8.34 (s, 1H), 7.26 - 7.20 (m, 2H), 7.10 - 7.06 (m, 2H), 4.73 (s, 1H), 4.38 - 4.27 (m, 4H), 3.96 (d, J = 16.0 Hz, 1H), 3.58 (d, J = 16.0 Hz, 1H), 3.42 (d, J = 12.0 Hz, 2H), 3.25 (s, 2H), 3.08 (s, 2H), 2.99 (d, J = 8.0 Hz, 1H), 2.79 - 2.60 (m, 6H), 2.35 - 2.26 (m, 2H), 1.98 (d, J = 12.0 Hz, 1H), 1.26 - 1.18 (m, 4H), 1.10 - 1.07 (m, 3H), 0.91 (s, 3H), 0.87 - 0.80 (m, 6H). LC-MS (M+H) + = 597.4.

[1323] Example 66: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-7-(4-fluorobenzyl)-N-(2-methoxyethyl)-2-methyl-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazole-6-carboxamide (Compound 66)

[1324]

[1325] Step 1: (S)-7-(4-fluorobenzyl)-6-((2-methoxyethyl)carbamoyl)-2-methyl-2,3- dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-l-carboxylic acid tert-butyl ester

[1326]

[1327] The title compound of Step 1 (170 mg, 97% yield) was prepared in a similar manner as described in Example 31, Step 3 from (S)-l-(tert-butoxycarbonyl)-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-6-carboxylic acid and 2-methoxyethan-l -amine. LC-MS (M+H) + = 460.2.

[1328] Step 2: (S)-7-(4-fluorobenzyl)-N-(2-methoxyethyl)-2-methyl-2,3-dihydro-lH- pyrrolo[2,3-b][l,4]oxazole-6-carboxamide

[1329]

[1330] The title compound of Step 2 (110 mg, 83% yield) was prepared in a similar manner as described in Example 1, Step 8 from (S)-7-(4-fluorobenzyl)-6-((2- methoxyethyl)carbamoyl)-2-methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-l- carboxylic acid tert-butyl ester. LC-MS (M+H) + = 360.2.

[1331] Step 3: (S)-l-(2-chloroacetyl)-7-(4-fluorobenzyl)-N-(2-methoxyethyl)-2-methyl-2,3- dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-6-carboxamide

[1332]

[1333] The title compound of Step 3 (140 mg, 75% yield) was prepared in a similar manner as described in Example 1, Step 9 from (S)-7-(4-fluorobenzyl)-N-(2- methoxyethyl)-2-methyl-2,3-dihydro-lH-pyrrolo[2,3-b][l,4]oxazole-6-carboxamide and 2-chloroacetyl chloride. LC-MS (M+H) + = 436.2.

[1334] Step 4: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-((2-methoxyethyl)carbamoyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-l-yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester

[1335]

[1336] The title compound of Step 4 (160 mg, 67% yield) was prepared from (S)-l-(2- chloroacetyl)-7-(4-fluorobenzyl)-N-(2-methoxyethyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazine-6-carboxamide and (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 727.4.

[1337] Step 5: (S)-l-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-l-yl)acetyl)-7-(4-fluorobenzyl)-N-(2-methoxyethyl)-2-methyl- 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazine-6-carboxamide (Compound 66)

[1338] Compound 66 as formate salt was prepared from (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-4-(2-((S)-7-(4-fluorobenzyl)-6-((2- methoxyethyl)carbamoyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-l- yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 19. The salt was neutralized with aqueous NaHC03and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was further lyophilized to give Compound 66 as free base (56 mg, 48% yield). 1HNMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.35 (s, 1H), 7.27 - 7.19 (m, 2H), 7.10 - 7.07 (m, 2H), 4.77 (s, 1H), 4.45 - 4.23 (m, 4H), 3.97 (d, J = 16.0 Hz, 1H), 3.52 (d, J = 16.0 Hz, 1H), 3.42 (s, 6H), 3.27 (s, 3H), 3.09 (s, 2H), 2.92 (d, J = 12.0 Hz, 1H), 2.78 - 2.56 (m, 6H), 2.27 (t, J = 12.0 Hz, 1H), 2.17 (t, J = 12.0 Hz, 1H), 1.96 (d, J = 12.0 Hz, 1H), 1.26 - 1.17 (m, 4H), 0.91 - 0.80 (m, 9H). LC-MS (M+H) + = 627.4.

[1339] Example 67: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-7-(4-fluorobenzyl)-N-(2-(2-methoxyethoxy)ethyl)-2- methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazole-6-carboxamide (Compound 67)

[1340]

[1341] Step 1: (S)-7-(4-fluorobenzyl)-6-((2-(2-methoxyethoxy)ethyl)carbamoyl)-2- methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazole-1-carboxylic acid tert-butyl ester

[1342]

[1343] The title compound of Step 1 (230 mg, 98% yield) was prepared in a similar manner as described in Example 31, Step 3 from (S)-1-(tert-butoxycarbonyl)-7-(4- fluorobenzyl)-2-methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]oxazole-6-carboxylic acid and 2-(2-methoxyethoxy)ethan-1-amine. LC-MS (M+H) + = 504.2.

[1344] Step 2: (S)-7-(4-fluorobenzyl)-N-(2-(2-methoxyethoxy)ethyl)-2-methyl-2,3- dihydro-1H-pyrrolo[2,3-b][1,4]oxazole-6-carboxamide

[1345]

[1346] The title compound of Step 2 (160 mg, 88% yield) was prepared from (S)-7-(4- fluorobenzyl)-6-((2-(2-methoxyethoxy)ethyl)carbamoyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazole-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 8. LC-MS (M+H) + = 404.2.

[1347] Step 3: (S)-l-(2-chloroacetyl)-7-(4-fluorobenzyl)-N-(2-(2- methoxyethoxy)ethyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazole-6-carboxamide

[1348]

[1349] The title compound of Step 3 (150 mg, 71% yield) was prepared from (S)-7-(4- fluorobenzyl)-N-(2-(2-methoxyethoxy)ethyl)-2-methyl-2,3-dihydro-lH-pyrido[2,3- b][l,4]oxazole-6-carboxamide and 2-chloroacetyl chloride in a similar manner as described in Example 1, Step 9. LC-MS (M+H) + = 480.2.

[1350] Step 4: (2R,5S)-5-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-(2-((S)-7-(4- fluorobenzyl)-6-((2-(2-methoxyethoxy)ethyl)carbamoyl)-2-methyl-2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazol-l-yl)-2-oxoethyl)-2-methylpiperazine-l-carboxylic acid tert- butyl ester

[1351]

[1352] The title compound of Step 4 (180 mg, 66% yield) was prepared from (S)-l-(2- chloroacetyl)-7-(4-fluorobenzyl)-N-(2-(2-methoxyethoxy)ethyl)-2-methyl-2,3- dihydro-lH-pyrido[2,3-b][l,4]oxazole-6-carboxamide and (2R,5S)-5-(((3R,5R)-3,5- dimethylmorpholino)methyl)-2-methylpiperazine-l-carboxylic acid tert-butyl ester in a similar manner as described in Example 1, Step 18. LC-MS (M+H) + = 771.4.

[1353] Step 5: (S)-1-(2-((2R,5R)-2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-5- methylpiperazin-1-yl)acetyl)-7-(4-fluorobenzyl)-N-(2-(2-methoxyethoxy)ethyl)-2- methyl-2,3-dihydro-1H-pyrrolo[2,3-b][1,4]o...

Claims

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein X1is -CH2-; X2is -0-, -N hydrogen-, -N methyl-, or -N ethyl-; m1is 0; m2and m3are each independently 0, 1, or 2; n is 0, 1, 2, 3, or 4; R 1a , R 1b , R 1c , and R 1d are each independently hydrogen, halogen, -C 1-8 alkyl, or oxo, wherein said -C 1-8 alkyl is optionally substituted with at least one halogen; R4and R5together with the same carbon atom to which they are attached form a 3- to 5- membered spiro carbocyclic ring; or R3and R5are each independently hydrogen, halogen, -C 3-8 cycloalkyl or -C 1-8 alkyl, said -C 1-8 alkyl or -C 3-8 cycloalkyl optionally substituted with at least one halogen or -OR a wherein R a is hydrogen or -C 1-8 alkyl; R2and R4are each independently hydrogen or -C 1-8 alkyl; or R2at one occurrence and R4at one occurrence together form a bridge comprising zero, one, or two -CH2- moieties in the bridge; or R7is halogen; or R 1b and R4at one occurrence together form a 3- to 6-membered carbocyclic ring; or R 1d and R4at one occurrence together form a bridge comprising one or two -CH2- moieties in the bridge; R6is hydrogen, -CN, halogen, morpholine, -CONR a R b , -NR a COR b , -NR a SO2R b , -OR a , -NR a R b , -C 3-5 cycloalkyl, phenyl or -C 1-8 alkyl, each of which is optionally substituted with 1-3 R 3-5 cycloalkyl, phenyl or -C 1-8 alkyl, each of which is optionally substituted with 1-3 R d ; 2. A compound of Formula (II): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, R8and R9are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl or C 3-8 cycloalkyl; R 10 and R 11 each independently is hydrogen, -C 1-8 alkyl, -C 3-8 cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl comprising 1 to 2 heteroatoms selected from N, O, or S, or -CONR a R b wherein the -C 1-8 alkyl, -C 3-8 cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl is each optionally substituted with 1-3 R d ; or R 10 and R 11 together form a 3- to 5-membered spiro carbocyclic ring, optionally substituted with 1-3 R d ; R 12 and R 13 each independently is hydrogen or -C 1-8 alkyl; R 14 and R 15 are each independently selected from hydrogen or -C 1-8 alkyl; R6and R 10 and R 11 in R a , R b are each independently hydrogen, -C 3-6 cycloalkyl, -C 1-8 alkyl, -5 or 6-membered heterocyclyl, or phenyl; each of said -C 1-8 alkyl, -C 3-6 cycloalkyl, -5 or 6-membered heterocyclyl, or phenyl is optionally substituted with 1-3 R d ; said -5 or 6-membered heterocyclyl is selected from pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, or tetrahydrofuran; or R6and R 10 and R 11 in R a and R b together with the atom or atoms to which they are attached form a 3- to 8-membered ring comprising 0, 1, or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring being optionally substituted with 1-3 R d ; R d independently at each occurrence hydrogen, halogen, -C 1-8 alkyl, -C 3-8 cycloalkyl, heterocyclyl, phenyl, or -OR e , said -C 1-8 alkyl, -C 3-8 cycloalkyl, heterocyclyl, or phenyl is each optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, or -OR h ; said heterocyclyl is selected from azetidine, pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, and tetrahydrofuran; and R e , R h each independently is hydrogen, -C 1-8 alkyl or C 1-8 alkoxy-C 1-8 alkyl-. wherein X1is -CH2-; X2is -0-, -N hydrogen-, -N methyl-, or -N ethyl-; m1is 0; m2and m3are each independently 0, 1, or 2; n is 0, 1, 2, 3, or 4; R4and R5together with the same carbon atom to which they are attached form a 3- to 5- membered spiro carbocyclic ring; or R 1a , R 1b , R 1c , and R 1d are each independently hydrogen, halogen, -C 1-8 alkyl, or oxo, wherein said -C 1-8 alkyl is optionally substituted with at least one halogen; R2at one occurrence and R4at one occurrence together form a bridge comprising zero, one, or two -CH2- moieties in the bridge; or R3and R5are each independently hydrogen, halogen, -C 3-8 cycloalkyl or -C 1-8 alkyl, said -C 1-8 alkyl or -C 3-8 cycloalkyl is optionally substituted with at least one halogen or -OR a wherein R a is hydrogen or -C 1-8 alkyl; R2and R4are each independently hydrogen or -C 1-8 alkyl; or R7is halogen; 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein m2is 1; and m3is 0 or 1. R 1b and R4at one occurrence thereof together form a 3- to 6-membered carbocyclic ring; or R 1d and R4 together at one occurrence thereof form a bridge comprising one or two -CH2- moieties in the bridge; R6 is hydrogen, -CN, halogen, morpholine, -CONR a R b 、-NR a COR b 、-NR a SO2R b 、-OR a 、-NR a R b 、-C 3-5 Cycloalkyl, phenyl or -C 1-8 Alkyl, the -C 3-5 Cycloalkyl, phenyl or -C 1-8 Each alkyl group is optionally substituted with 1-3 R d ; 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R3and R5are each hydrogen, methyl or ethyl, -CH2OH, -CH2OCH3, -CH2OC2H5, -CHF2, -CH2OCH(CH3)2, cyclopropyl, or CF3. R8and R9are each independently hydrogen, -C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, -C 2-8 alkenyl, -C 2-8 alkynyl or C 3-8 cycloalkyl; R 10 and R 11 each independently is hydrogen, -C 1-8 alkyl, -C 3-8 cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl comprising 1 to 2 heteroatoms selected from N, O, or S, or -CONR a R b wherein the -C 1-8 alkyl, -C 3-8 cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl is each optionally substituted with 1-3 R d ; or R 10 and R 11 together form a 3- to 5-membered spiro carbocyclic ring, optionally substituted with 1-3 R d ; R 12 and R 13 each independently is hydrogen or -C 1-8 alkyl; R6and R 10 and R 11 in R a , R b are each independently hydrogen, -C 3-6 cycloalkyl, -C 1-8 alkyl, -5 or 6-membered heterocyclyl, or phenyl; each of said -C 1-8 alkyl, -C 3-6 cycloalkyl, -5 or 6-membered heterocyclyl, or phenyl is optionally substituted with 1-3 R d ; said -5 or 6-membered heterocyclyl is selected from pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, and tetrahydrofuran; or R6and R 10 and R 11 in R a and R b together with the atom(s) to which they are attached form a 3- to 8-membered ring comprising 0, 1, or 2 additional heteroatoms as ring members independently selected from nitrogen, oxygen, or optionally oxidized sulfur, which ring is optionally substituted with 1-3 R d ; R d independently at each occurrence is hydrogen, halogen, -C 1-8 alkyl, -C 3-8 cycloalkyl, heterocyclyl, phenyl, or -OR e , said -C 1-8 alkyl, -C 3-8 cycloalkyl, heterocyclyl, or phenyl is each optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, or -OR h ; said heterocyclyl is selected from azetidine, pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, and tetrahydrofuran; and R e and R h each independently is hydrogen, -C 1-8 alkyl or C 1-8 alkoxy-C 1-8 alkyl-.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R4and R5together with the same carbon atom to which they are attached form a 3- to 5- membered spiro carbocyclic ring.

16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R7is F.

23. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein 6. The compound or pharmaceutically acceptable salt or stereoisomer thereof of claim 1 or 2, wherein is wherein R 1a , R 1b , R 1c , R 1d , R2, R3, R4, R5and R a are as defined for formula (I).

7. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer of claim 6, wherein is wherein R 1c , R 1d , R4 and R5 are independently hydrogen or -C 1-8 alkyl.

8. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer of claim 7, wherein R 1c and R4 is hydrogen, R 1d and R5 are independently hydrogen or -C 1-8 alkyl.

9. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer of claim 7, wherein R 1c and R4 is hydrogen, R 1d and R5 is methyl.

10. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer of claim 6, wherein R 1a , R 1b , R 1c , R 1d each independently is hydrogen, halogen, -C 1-8 alkyl or oxo, wherein the -C 1-8 alkyl is optionally substituted with 1-3 halogens.

11. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer of claim 6, wherein R 1a , R 1b , R 1c , R 1d each independently is hydrogen, halogen, -CH3, -C2H5, or oxo, wherein the -C 1-8 alkyl is optionally substituted with 1-3 halogens.

12. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof of claim 6, wherein R5 is halogen, -C2H5, -CH3, cyclopropyl, CHF2, -CH2F, -CF3, -CH2OH, -CH2OCH3, -CH2OC2H5, -CH2OCH(CH3)2; and R4 is hydrogen or -CH3; or R5 and R4 together with the carbon atom to which they are attached form a 3- to 5-membered carbocyclic ring; or R2 and R4 together form a bridge comprising one -CH2- moiety in the bridge, and R3 and R5 are each hydrogen; or R 1b and R4 together form a 3-membered carbocyclic ring, and R 1a and R5 are each hydrogen; or R 1d and R4 together form a bridge comprising two -CH2- moieties in the bridge, and R 1c and R5 are each hydrogen.

13. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer of claim 6, wherein is 14. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer of claim 6, wherein is 15. The compound or pharmaceutically acceptable salt or stereoisomer thereof of claim 1 or 2, wherein is 24. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein 17. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R6 is hydrogen, -CN, halogen, morpholine, -CONR a R b a b a b a a R b 3-5 1-8 1-8 3-5 d ; R a and R b are each hydrogen, -C 3-6 cycloalkyl, or -C 1-8 alkyl; R d is independently at each occurrence -CH2F, -CHF2, -CF3, -F, -Cl, -Br, -I, -OH, -H, -CH3, -C2H5, -C3H7, -CH2OH, -OCH3, -OC2H5, morpholino, or cyclopropyl.​​​​​​​​​​​ 18. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R6is -CONR a R b , -NR a R b , -NR a CO-R b , -NR a -SO2-R b , or -OR a ; R a and R b are each hydrogen, -C 3-6 cycloalkyl, -C 1-8 alkyl, -5 or 6 membered heterocyclyl, or phenyl; each of said -C 1-8 alkyl, -C 3-6 cycloalkyl, -5 or 6 membered heterocyclyl, or phenyl is optionally substituted with 1-3 R d ; said -5 or 6 membered heterocyclyl is selected from pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, and tetrahydrofuran; or 18. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R6is -CONR a R b , -NR a R b , -NR a CO-R b , -NR a -SO2-R b , or -OR a ; R a and R b are each hydrogen, -C 3-6 cycloalkyl, -C 1-8 alkyl, -5 or 6 membered heterocyclyl, or phenyl; each of said -C 1-8 alkyl, -C 3-6 cycloalkyl, -5 or 6 membered heterocyclyl, or phenyl is optionally substituted with 1-3 R d ; said -5 or 6 membered heterocyclyl is selected from pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, and tetrahydrofuran; or R a and R b one or more atoms to which they are attached form a 3- to 8-membered ring, which ring contains 0, 1, or 2 additional heteroatoms as ring members, which heteroatoms are independently selected from nitrogen, oxygen, or optionally oxidized sulfur, which ring is optionally substituted with 1-3 R d .

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R6 is -CONR a R b or -NR a CO-R b , R a and R b are each hydrogen, -C 1-3 alkyl, -C 3-6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl; said -C 1-3 alkyl, -C 3-6 cycloalkyl, phenyl, 5- or 6-membered heterocyclyl is optionally substituted with 1-3 R d substituents selected from halo, -C 1-3 alkyl, morpholine, or OR e ; R e is independently hydrogen, halo, -C 1-8 alkyl, or C 1-8 alkoxy-C 1-8 alkyl-, said 5- or 6-membered heterocyclyl is selected from pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, and tetrahydrofuran.

20. The compound of claim 18, or a pharmaceutically acceptable salt thereof or stereoisomer thereof, wherein R6is -CONR a R b or -NR a CO-R b , R a and R b are each hydrogen, -C 1-3 alkyl, -C 3-6 cycloalkyl, phenyl, azetidine, pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, or tetrahydrofuran; said -C 1-3 alkyl, -C 3-6 cycloalkyl, phenyl, azetidine, pyrrolidine, piperidine, oxazolidine, isoxazolidine, oxazinane, morpholine, piperazine, tetrahydropyran, or tetrahydrofuran is optionally substituted with 1-3 R d , said substituents selected from halo, -C 1-3 alkyl, morpholine, or OR e ; R e is independently hydrogen, halo, -C 1-8 alkyl, or C 1-8 alkoxy-C 1-8 alkyl-.

21. The compound of claim 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R6is -CONR a R b , R a and R b together with the nitrogen atom to which they are attached form a 4- to 6-membered ring comprising 0, 1, or 2 additional heteroatoms as a ring member(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring is optionally substituted with 1-3 R d ; R d is independently halogen, -C 1-3 alkyl, or OR e ; R e is independently hydrogen, halogen, or -C 1-8 alkyl.

22. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer of claim 18, wherein R6 is -NH2, -CONH2, -CONHCH3, -CONHC2H5, -CON(CH3)2, -CONHCH2CF3, -CONHC2H4OCH3, -CONHC2H4OC2H4OCH3, -CONHCH(CH3)2, -CONHC2H4OH, -CONHC2H4N(CH3)2, -O-(CH2)2-OCH3, -O-(CH2)2-OH, -NH-(CH2)2-OCH3, -NH-(CH2)2-OH, -NH-CO-CH3, -NH-CO-C2H5, -NH-CO-CH(CH3)2, -NHC2H5, -NH-CH2-CF3, CH3CH2SO2NH-, or cyclopropylSO2NH-.

26. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R6 is 27. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R6is hydrogen, halogen, -CN, -CONH2, cyclopropyl, -CH2OH, -CF3, -OH, -CH3, or -OC2H5.

25. The compound or pharmaceutically acceptable salt or stereoisomer thereof of claim 1 or 2, wherein R 12 is hydrogen or -CH3; R 13 is hydrogen or -CH3. -2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -CH2OCH3, -CH2OCH(CH3)2, R 10 and R 11 each independently is hydrogen, -C 1-8 alkyl, -C 3-8 cycloalkyl, phenyl, 5- to 6-membered monocyclic heteroaryl comprising 1 to 2 heteroatoms selected from N, O, or S, or -CONR a R b wherein the -C 1-8 alkyl, -C 3-8 cycloalkyl, phenyl, or 5- to 6-membered monocyclic heteroaryl is each optionally substituted with 1-3 R d ; R a and R b each independently is hydrogen or -C 1-8 alkyl; or R a and R b together with the nitrogen atom to which they are attached form a 3- to 6-membered ring comprising 0 or 1 additional oxygen atom; said ring is optionally substituted with one R d ; R d independently at each occurrence -C 1-8 alkyl, halogen, phenyl or -OR e wherein R e each independently hydrogen or -C 1-8 alkyl. -CH2OC2H5, -CH2F, -CHF2, -CF3, -H, -F, -Cl, -Br, -I, -OH, -NH2, -SH, R 10 is hydrogen; R 11 is -CONR a R b , phenyl, benzyl, pyridyl or furanyl, wherein each of said phenyl, benzyl, pyridyl or furanyl is optionally substituted with 1-3 R d ; R a and R b are each independently hydrogen or methyl, or R a and R b together with the nitrogen atom to which they are attached form a 5- to 6- membered ring comprising 0 or 1 additional oxygen atoms.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 10 is hydrogen; and R 11 is hydrogen, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, tert-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- ​ ​ -CONH2, -CONHCH3, -CON(CH3)2, -CH2O-Ph, -CH2-Ph, -CH2O-CH2-Ph, phenyl, 4-methyl-phenyl, 4-methoxy- phenyl, 4-F-phenyl, benzyl, pyridyl or furanyl.

29. The compound of claim 27, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 10 is hydrogen; and R 11 is hydrogen, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, tert-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-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, -CH2OH, -CH2CH2OH, -CH2CH2OCH3, -CH2OCH3, -CH2OCH(CH3)2, -CH2OC2H5, -CH2F, -CHF2, -CF3, -H, -F, -Cl, -Br, -I, -OH, -NH2, -SH, -CONH2, -CONHCH3, -CON(CH3)2, -CH2O-Ph, -CH2-Ph, -CH2O-CH2-Ph, phenyl, 4-methyl-phenyl, 4-methoxy- phenyl, 4-F-phenyl, benzyl, 4-pyridyl, 3-pyridyl, 2-pyridyl, 2-furyl or 3-furyl.

30. The compound or a pharmaceutically acceptable salt thereof or a stereoisomer of claim 29, wherein R 10 is hydrogen; and R 11 is hydrogen, methyl, ethyl, 2-propyl, -CF3, -CHF2, -CH2CH2OCH3, -CH2OH, -CH2OCH3, -CH2OCH(CH3)2, -CH2OC2H5, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CONH2, -CONHCH3, -CON(CH3)2, -CH2O-Ph, -CH2O-CH2-Ph, phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-F-phenyl, benzyl, 4-pyridyl, 3-pyridyl, 2-pyridyl, 2-furyl, or 3-furyl.

31. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein in R 10 and R 11 the carbon atom to which R 10 and R 11 are attached is in the S configuration in the case of a chiral center.

32. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 10 and R 11 together form a 3-membered carbocyclic ring.

33. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which is wherein R 1a , R 1b , R 1c , R 1d , R2, R3, R4, R5, R6, R7, R 10 , R 11 , R 12 , R 13 and X1are as defined for formula (II).

34. The compound of claim 1, wherein R 14 and R 15 are each independently selected from hydrogen, methyl or ethyl.

35. A compound which is or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

36. A pharmaceutical composition comprising a compound according to any one of claims 1-35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

37. Use of a compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the manufacture of a medicament for the treatment of a cancer modulated by cIAPs.

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