A condensed heterocycle as a RIPK1 inhibitor

Abstract

The present invention provides novel substituted heterocycles represented by formula I, or pharma- ceutically acceptable salts, solvates, polymorphs, esters, tautomers or prodrugs thereof, and compositions comprising such compounds. The provided compounds can be used as inhibitors and methods of treatment of RIPK1. [Formula 1] JPEG2024545552000127.jpg3587

Description

[Technical Field]

[0001] The present invention relates to a series of substituted heterocyclic compounds used as inhibitors and therapeutic agents for receptor-interaction protein-1 (RIP1) kinase-mediated diseases or disorders. [Background technology]

[0002] Receptor-interacting protein-1 (RIP1) kinase is a serine / threonine protein kinase called RIPK1, RIP1, or RIP. RIP1 kinase plays a vital role in cell survival. RIP1 is involved in apoptotic and non-apoptotic cell death; cellular necroptosis[1]. The intracellular domains of TNF receptor 1 (TNFR1), FAS, and TRAIL receptor 2 (TRAILR2) together contain death domains (DDs), which are stimulated by ligands tumor necrosis factor alpha (TNFα), Fas ligand (FASL), and TRAIL to recruit RIP1 and bind its DDs to RIP1. Stimulation of TNFR1 by TNFα induces the formation of complex I, which induces NF-κB activation, playing a crucial role in regulating RIP1 activation and activating important cell survival programs[2]. RIP1 activation can lead to a cell death pathway through the formation of the RIP1-TNF receptor-binding death domain protein (TRADD)-FAS-binding DD protein (FADD)-caspase-8 complex (complex IIa), which stimulates caspase activation and leads to RIPK1-dependent apoptosis (RDA) [3-9]. When caspase-8 activity is blocked, recruited protein receptor-interacting serine / threonine-protein kinase 3 (RIPK3) kinase induces the formation of the RIP1-RIP3-mixed kinase domain-like (MLKL) complex (complex IIb), inducing necroptosis, which leads to cell lysis and cell membrane disruption [10-11].

[0003] Necroptosis and RIP1 have played important checkpoint roles during embryonic development. Activation of necroptosis and RIP1 exhibits significant pathological mechanisms and can be involved in most human diseases by mediating cell death and inflammation. Necroptosis may also be associated with central nervous system (CNS) diseases, atherosclerosis, Huntington's disease, colitis, fatty liver disease, acute hepatitis, stroke, myocardial infarction, and pathogenesis disorders of the intestinal epithelium and skin. Therefore, necroptosis inhibitors play an important role in clinical drug development. [12-14]

[0004] Necroptosis can be inhibited by deactivating RIP1 kinase or RIP3 kinase. The first and most commonly used inhibitor of necroptosis is the RIP1 inhibitor necrostatin-1 (Nec-1). Nec-1 has demonstrated efficacy in vitro and in vivo. Nec-1 mitigates renal and cerebral ischemia / reperfusion injury, ConA-induced hepatitis, and DSS-induced colitis, and reduced symptoms of Huntington's disease in mouse (murine) studies [15-19].

[0005] The novel compounds of the present invention inhibit RIP1 kinase activity and are therefore expected to be useful in treating diseases and / or conditions associated with inflammatory and / or necroptotic cell death

[20] . Recently, RIP1 kinase inhibitors have been found to be structurally different from necrostatin compounds [21-22]. Each of the aforementioned cited references is incorporated herein by reference in its entirety:

[0006] 1. Literature [Degterev, A., Hitomi, J., Germscheid, M., Ch’en, I., Korkina, O., Teng, X., Abbott, D., Cuny, G., Yuan, C., Wagner, G., Hedrick, S., Gerber, S., Lugovskoy, A. and Yuan, J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 4, 313-321(2008)].

[0007] 2. Literature [Ofengeim, D. and Yuan, J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14, 727-736(2013)].

[0008] 3. Literature [Shan, B., Pan, H., Najafov, A. and Yuan, J. Necroptosis in development and diseases. Genes Dev. 32, 327-340(2018)].

[0009] 4. Literature [Vanden Berghe, T., Linkermann, A., Jouan-Lanhouet, S., Walczak, H. and Vandenabeele, P. Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nature reviews. Molecular cell biology. 15, 135-147(2014)].

[0010] 5. Reference [Newton, K. RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends in cell biology. 25, 347-353(2015)].[]

[0011] 6. de Almagro, M.C. and Vucic, D. Necroptosis: Pathway diversity and characteristics. Semin Cell Dev Biol. 39, 56-62(2015).

[0012] 7. Reference [O’Donnell, M.A., Legarda-Addison, D., Skountzos, P., Yeh, W.C. and Ting, A.T. Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol. 17, 418-424(2007)].[]

[0013] 8. Reference [Feoktistova, M., Geserick, P., Kellert, B., Dimitrova, D.P., Langlais, C., Hupe, M., Cain, K., MacFarlane, M., Hacker, G. and Leverkus, M. cIAPs block Ripoptosome formation, a RIP1 / caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Molecular cell. 43, 449-463(2011)].[]

[0014] 9. Reference [Bertrand, M.J., Milutinovic, S., Dickson, K.M., Ho, W.C, Boudreault, A., Durkin, J., Gillard, J.W., Jaquith, J.B., Morris, S.J. and Barker, P.A. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 30, 689-700(2008)].

[0015] 10. Reference [Cho, Y.S., Challa, S., Moquin, D., Genga, R., Ray, T.D., Guildford, M. and Chan, F.K. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 137, 1112-1123(2009)].

[0016] 11. Reference [Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X. and Wang, X. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 148, 213-227 (2012)].

[0017] 12. Literature [Zhao,J.,Jitkaew,S.,Cai,Z.,Choksi,S.,Li,Q.,Luo,J.and Liu,Z.G.Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis.Proceedings of the National Academy of Sciences of the United States of America.109,5322-5327 (2012)].

[0018] 13. Literature [Sun,L.,Wang,H.,Wang,Z.,He,S.,Chen,S.,Liao,D.,Wang,L.,Yan,J.,Liu,W.,Lei,X.and Wang,X.Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase.Cell.148,213-227(2012)].

[0019] 14. Literature [Linkermann,A.and Green,D.R.Necroptosis.The New England journal of medicine.370,455-465(2014)].

[0020] 15. Literature [Degterev,A.,Huang,Z.,Boyce,M.,Li,Y.,Jagtap,P.,Mizushima,N.Cuny,G.D.,Mitchison,T.J.,Moskowitz,M.A.and Yuan,J.Chemical Inhibitor of Nonapoptotic Cell Death with Therapeutic Potential for Ischemic Brain Injury.Nat.Chem.Biol.1,112-119(2005)].

[0021] 16. Journal[Linkermann,A.,Brasen,JH,Himmerkus,N.,Liu,S.,Huber,TB,Kunzendorf,U.and Krautwald,S.Rip1(Receptor-Interacting Protein Kinase 1)Mediates Necroptosis and Contributes to Renal Ischemia / Reperfusion Injury.Kidney Int.81,751–761(2012)].

[0022] 17th [Jouan-Lanhouet,S.,Arshad,MI,Piquet-Pellorce,C.,Martin-Chouly,C.,Le Moigne-Muller,G.,Van Herreweghe,F.,Takahashi,N.,Sergent,O.,Lagadic-Gossmann,D.and Vandenabeele,P.TRAIL Induces Necroptosis Involving RIPK1 / RIPK3-Dependent PARP-1 Activation.Cell Death Differ.19,2003-2014(2012)].

[0023] 18. Journal[Gunther,C.,Martini,E.,Wittkopf,N.,Amann,K.,Weigmann,B.,Neumann,H.,Waldner,MJ,Hedrick,SM,Tenzer,S.and Neurath,MFCaspase-8 Regulates TNF-Alpha-Induced Epithelial Necroptosis and Terminal Ileitis.Nature.477,335–339(2011)].

[0024] 19. Literature [Zhu, S., Zhang, Y., Bai, G. and Li, H. Necrostatin-1 Ameliorates Symptoms in R6 / 2 Transgenic Mouse Model of Huntington’s Disease. Cell. Death Dis. 2, e115(2011)].

[0025] 20. Literature [Newton, K., Dugger, D.L., Wickliffe, K.E., Kapoor, N., de Almagro, M.C, Vucic, D., Komuves, L., Ferrando, R.E., French, D.M., Webster, J., Roose-Girma, M., Warming, S. and Dixit, V.M. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science. 343, 1357-1360(2014)].

[0026] 21. Literature [Harris, P.A., Bandyopadhyay, D., Berger, S.B., Campobasso, N., Capriotti, C.A., Cox, J.A., Dare, L., Finger, J.N., Hoffman, S.J., Kahler, K.M., Lehr, R., Lich, J.D., Nagilla, R., Nolte, R.T., Ouellette, M.T., Pao, C.S., Schaeffer, M.C , Smallwood, A., Sun, H.H., Swift, B.A., Totoritis, R.D., Ward, P., Marquis, R.W., Bertin, J. and Gough, P.J. Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS medicinal chemistry letters. 4, 1238-1243(2013)].

[0027] 22. Literature [Najjar, M., Suebsuwong, C, Ray, SS, Thapa, RJ, Maki, JL, Nogusa, S., Shah, S., Saleh, D., Gough, PJ, Bertin, J., Yuan, J., Balachandran, S., Cuny, GDand Degterev, A. Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1.Cell Rep.24,1850-1860(2015)]. [Overview of the project] [Means for solving the problem]

[0028] The present invention provides compounds of chemical formula I, or pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers, or prodrugs thereof. [Chemical formula I]

[0029] [ka] During the ceremony,

[0030] R 1 -O[(C1-C6)alkyl]NR 4 R 5 -O(C1-C6)alkyl, -O[gem-dimethylhydroxy(C1-C6)alkyl], -O(C1-C6)alkyl[(C1-C6)alkoxy], -O(C1-C6)alkyl[(C3-C6)cycloalkyl], -O(C1-C6)alkyl[(C3-C6)cycloalkyl]hydroxy, -O(C3-C6)cycloalkyl, -O(C3-C6)hydroxycycloalkyl, -O(C1-C6)alkyl-(hetAr 2 or hetAr 3 ), -O(C1-C6)alkyl-(hetCyc 1 or hetCyc 2 ), -C(O)NR 4R 5 , -OC(O)NR 4 R 5 , -O[(C1-C3)alkyl]C(O)NR 4 R 5 , or

[0031] [[Chemical formula]] ; R 2 is H, CD3, or is optionally substituted by C1-C6 alkyl; each R 3 is independently H, methyl, CF3, halogen or cyano; n is 1, 2 or 3; Z is CH2, NR 2 , O or S; R 4 is H or C1-C6 alkyl;

[0032] R 5 is H, -(C1-C6)alkyl, -(C1-C6)fluoroalkyl, -(C1-C6)difluoroalkyl, -(C1-C6)trifluoroalkyl, -gem-dimethyl(C1-C6)hydroxy, -(C1-C6)hydroxyalkyl, -(C2-C6)dihydroxyalkyl, [(C1-C6)alkoxy](C1-C6)alkyl-, [(C1-C6)alkoxy]-[(C1-C6)alkoxy]-(C1-C6)alkyl-, -O(C1-C6)alkyl, -O(C1-C6)hydroxyalkyl, -O(C1-C6)alkyl[(C1-C6)alkoxy], -O(C1-C3)alkyl[(C3-C6)cycloalkyl], Cyc 1 , Ar 1 , -CH2Ar 1 , hetCyc 1 , hetAr 2 , hetAr 3 , hetCyc 2 (C1-C2)alkyl- or hetCyc 3 (C1-C2)alkyl-; or

[0033] Or, NR 4 R 5 It forms a 4-6 membered heterocycle having a ring nitrogen atom and a second ring heteroatom selectively selected from N and O, where the ring is selectively substituted with at least one substituent independently selected from (C1-C6)alkyl, OH, alkoxy and (C1-C6)hydroxyalkyl;

[0034] R 6 H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -gem-dimethylhydroxy(C1-C6)alkyl, -(C3-C6)hydroxycycloalkyl, hetAr 2 and;

[0035] hetAr 1 This is a 5-membered heteroaryl ring having 2-3 ring heteroatoms, where at least one of the ring heteroatoms is N, and the ring is (C1-C6)alkyl, NH2, (C1-C6 hydroxyalkyl)NH-, (HO)2P(=O)OCH2-, (C1-C6)hydroxyalkyl, Cyc 1 and selectively substituted with substituents selected from (C1-C6 alkyl)COOH;

[0036] Cyc 1 is a 3- to 6-membered cycloalkyl ring selectively substituted with at least one substituent independently selected from -(C1-C4 alkyl), OH,OCH3, COOH, -(C1-C4 alkyl)OH, halogen, and CF3; hetCyc 1 It is a carbon-linked 4- to 6-membered heterocycle that is selectively substituted with substituents selected from (C1-C6) alkyl groups;

[0037] hetCyc 2 This is a 5-6 membered heterocycle having a ring nitrogen atom and a second ring heteroatom selectively selected from N and O, where the ring is selectively substituted with substituents selected from (C1-C6)alkyl, OH, (C1-C6)alkoxy, halogen, and oxo; hetCyc3 It is a bridged 8-membered heterocycle having a ring nitrogen atom and selectively a ring oxygen atom;

[0038] Ar 1 is a phenyl molecule selectively substituted with at least one substituent independently selected from (C1-C6)alkoxy, halogen, (C1-C6)alkyl, and CF3;

[0039] hetAr 2 This is a pyridyl selectively substituted with at least one substituent independently selected from halogens, CF3, (C1-C6)alkyls, and (C1-C6)alkoxys;

[0040] hetAr 3 It is a 5-membered heteroaryl having 2-3 ring heteroatoms independently selected from N, O, and S, and selectively substituted with (C1-C6) alkyl and OH groups.

[0041] Compounds of chemical formula I further include absolute sequence compounds of chemical formulas IIa and IIb, or pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers, or prodrugs thereof: [Chemical formula IIa]

[0042] [ka] [Formula IIb]

[0043] [ka] During the ceremony,

[0044] R 1 -O[(C1-C6)alkyl]NR 4 R 5-O(C1-C6)alkyl, -O[gem-dimethylhydroxy(C1-C6)alkyl], -O(C1-C6)alkyl[(C1-C6)alkoxy], -O(C1-C6)alkyl[(C3-C6)cycloalkyl], -O(C1-C6)alkyl[(C3-C6)cycloalkyl]hydroxy, -O(C3-C6)cycloalkyl, -O(C3-C6)hydroxycycloalkyl, -O(C1-C6)alkyl-(hetAr 2 or hetAr 3 ), -O(C1-C6)alkyl-(hetCyc 1 or hetCyc 2 ), -C(O)NR 4 R 5 -OC(O)NR 4 R 5 -O[(C1-C3)alkyl]C(O)NR 4 R 5 ,or

[0045] [ka] and; R 2 is either H, CD3, or selectively substituted with a C1-C6 alkyl group; Each R 3 These are independently H, methyl, CF3, halogen, or cyano; n is 1, 2, or 3; Z is CH2, NR 2 , O or S; R 4 is H or C1-C6 alkyl;

[0046] R 5H, -(C1-C6)alkyl, -(C1-C6)fluoroalkyl, -(C1-C6)difluoroalkyl, -(C1-C6)trifluoroalkyl, -gem-dimethyl(C1-C6)hydroxy, -(C1-C6)hydroxyalkyl, -(C2-C6)dihydroxyalkyl, [(C1-C6)alkoxy](C1-C6)alkyl-, [(C1-C6)alkoxy]-[(C1-C6)alkoxy]-(C1-C6)alkyl-, -O(C1-C6)alkyl, -O(C1-C6)hydroxyalkyl, -O(C1-C6)alkyl[(C1-C6)alkoxy], -O(C1-C3)alkyl[(C3-C6)cycloalkyl], Cyc 1 Ar 1 -CH2Ar 1 hetCyc 1 hetAr 2 hetAr 3 hetCyc 2 (C1-C2) alkyl- or hetCyc 3 (C1-C2)alkyl-;

[0047] Or, NR 4 R 5 It forms a 4-6 membered heterocycle having a ring nitrogen atom and a second ring heteroatom selectively selected from N and O, where the ring is selectively substituted with at least one substituent independently selected from (C1-C6)alkyl, OH, alkoxy and (C1-C6)hydroxyalkyl;

[0048] R 6 H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -gem-dimethylhydroxy(C1-C6)alkyl, -(C3-C6)hydroxycycloalkyl, hetAr 2 That is the case.

[0049] In certain embodiments, the present invention provides compounds of chemical formula III, or pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers, or prodrugs thereof: [Chemical formula III]

[0050] [ka] During the ceremony,

[0051] R 1 -O[(C1-C6)alkyl]NR 4 R 5 -O(C1-C6)alkyl, -O[gem-dimethylhydroxy(C1-C6)alkyl], -O(C1-C6)alkyl[(C1-C6)alkoxy], -O(C1-C6)alkyl[(C3-C6)cycloalkyl], -O(C1-C6)alkyl[(C3-C6)cycloalkyl]hydroxy, -O(C3-C6)cycloalkyl, -O(C3-C6)hydroxycycloalkyl, -O(C1-C6)alkyl-(hetAr 2 or hetAr 3 ), -O(C1-C6)alkyl-(hetCyc 1 or hetCyc 2 ), -C(O)NR 4 R 5 ,or

[0052] [ka] and; Each R 3 These are independently H, methyl, CF3, halogen, or cyano; n is 1, 2, or 3; R 4 is H or C1-C6 alkyl;

[0053] R 5is H, -(C1-C6)alkyl, -(C1-C6)fluoroalkyl, -(C1-C6)difluoroalkyl, -(C1-C6)trifluoroalkyl, -gem-dimethyl(C1-C6)hydroxy, -(C1-C6)hydroxyalkyl, -(C2-C6)dihydroxyalkyl, [(C1-C6)alkoxy](C1-C6)alkyl-, [(C1-C6)alkoxy]-[(C1-C6)alkoxy]-(C1-C6)alkyl-, -O(C1-C6)alkyl, -O(C1-C6)hydroxyalkyl, -O(C1-C6)alkyl[(C1-C6)alkoxy], -O(C1-C3)alkyl[(C3-C6)cycloalkyl], Cyc 1 , Ar 1 , -CH2Ar 1 , hetCyc 1 , hetAr 2 , hetAr 3 , hetCyc 2 (C1-C2)alkyl- or hetCyc 3 (C1-C2)alkyl-; or

[0054] alternatively, NR 4 R 5 forms a 4- to 6-membered heterocyclic ring having a ring nitrogen atom and optionally a second ring heteroatom selected from N and O, wherein said ring is optionally substituted with at least one substituent independently selected from (C1-C6)alkyl, OH, alkoxy and (C1-C6)hydroxyalkyl;

[0055] R 6 is H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -gem-dimethylhydroxy(C1-C6)alkyl, -(C3-C6)hydroxycycloalkyl, hetAr 2 .

[0056] In certain embodiments, the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of chemical formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, auxiliary and / or excipient.

[0057] In certain embodiments, such compositions may contain at least one of preservatives, formulations for delayed absorption, fillers, binders, adsorbents, buffers, disintegrants, solubilizers, and other carriers, as well as auxiliary and / or excipients as inactive components. The compositions can be put into dosage forms in methods well known in the art.

[0058] In certain embodiments, the present invention relates to a method for treating a disease in an individual, comprising the step of administering to the individual suffering from the disease a therapeutically effective amount of a composition comprising a compound of chemical formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof.

[0059] In certain embodiments, the present invention relates to a method for treating a disorder in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of chemical formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof.

[0060] In certain embodiments, the present invention relates to a method for treating a disorder in a human being, comprising the step of administering to a human being a therapeutically effective amount of a compound of chemical formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof.

[0061] In certain embodiments, RIP1 kinase-mediated diseases or disorders are described herein, and inflammatory or immunomodulatory diseases or disorders include inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, systemic lupus erythematosus (SLE), retinal detachment, retinitis pigmentosa, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, osteoarthritis and systemic juvenile idiopathic arthritis (SoJIA)), graft-versus-host disease due to transplantation, non-alcoholic steatohepatitis (NASH), ischemia-reperfusion, multiple sclerosis, tumor necrosis factor receptor-associated periodic syndromes, multiple organ dysfunction syndrome (MODS), thermal injury / burn, systemic inflammatory response syndrome (SIRS), radiation injury, radiotherapy, chemotherapy, pneumonia, hemorrhagic shock, trauma (including multiple trauma), traumatic brain injury, acute pancreatitis, serious illness (general), sepsis, septic Shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, stroke, heatstroke, stroke-associated pneumonia, multiple organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), intestinal obstruction, cirrhosis, surgery, major abdominal surgery, abdominal aortic aneurysm repair, colectomy, ischemia-reperfusion injury (including ischemia-reperfusion injury of solid organs (intestines, brain, liver, kidneys) and limb ischemia), intestinal ischemia (small and large intestines), cardiopulmonary This includes cardiac surgery requiring bypass surgery, autoimmune hepatitis, autoimmune hepatobiliary disease, autoimmune ITP, Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's Plus syndrome, tau disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, myotrichosis, progressive muscular atrophy, pseudobulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, demyelinating diseases, allergic diseases, asthma, atopic dermatitis, type 1 diabetes, Wegener's granulomatosis, Behçet's disease, and interleukin-1 converting enzyme-associated fever syndrome.

[0062] In certain embodiments, the present invention relates to a method for treating pancreatic cancer, metastatic adenocarcinoma of the pancreas, ductal adenocarcinoma, mesothelioma, melanoma, rectal cancer, acute myeloid leukemia, metastasis, glioblastoma, breast cancer, gallbladder cancer, clear cell renal carcinoma, non-small cell lung carcinoma, and radiation-induced necrosis, certain RIP1 kinase-mediated diseases or disorders in a mammal, including a human, comprising the step of administering a therapeutically effective amount of a compound of chemical formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, e.g., hydrate, polymorph or tautomer, thereof.

[0063] In certain embodiments, the present invention relates to a method for treating a disorder or condition regulated by RIP1 kinase in a mammal, including a human, comprising the step of administering to the mammal a certain amount of a compound of chemical formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, e.g., hydrate, polymorph, or tautomer thereof, that is effective in modulating the chain reaction. A dosage suitable for a particular patient can be determined according to methods known to those skilled in the art.

[0064] In certain embodiments, the present invention relates to the use of compounds of chemical formula I, or pharmaceutically acceptable salts, esters, prodrugs, solvates, e.g., hydrates, polymorphs, or tautomers thereof, in the preparation of pharmaceutical compositions. Pharmaceutical compositions can be used to treat disorders or conditions regulated by RIP1 kinase in mammals, including humans.

[0065] In certain embodiments, the present invention relates to pharmaceutical compositions comprising a compound of chemical formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. In further or additional embodiments, the pharmaceutical composition is in the form of tablets, capsules, powders, sustained-release formulations, solutions, and suspensions. In some embodiments, the pharmaceutical composition is in a form suitable for parenteral injection, such as a sterile solution, suspension, or emulsion; in a form suitable for topical administration as an ointment or cream; or in a form suitable for rectal administration as a suppository. In further or additional embodiments, the pharmaceutical composition is in a unit dose form suitable for single administration at a precise dose. In further or additional embodiments, the amount of the compound of chemical formula I is in the range of about 0.001 to about 1000 mg / kg body weight / day. In further or additional embodiments, the amount of the compound of chemical formula I is in the range of about 0.5 to about 50 mg / kg body weight / day.

[0066] In certain embodiments, the present invention relates to a method for producing a compound of chemical formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof. technical challenges The problem that this invention aims to solve is to provide a novel compound of chemical formula I. Another technical problem that the present invention aims to solve is to provide a novel compound of chemical formula I that has inhibitory activity against RIPK1.

[0067] Another technical problem that the present invention aims to solve is to provide a pharmaceutical composition comprising the compound, a pharmaceutically acceptable salt thereof, a solvate, a polymorph, an ester, a tautomer, or a prodrug thereof, and a salt thereof. Another technical problem that the present invention aims to solve is to provide a pharmaceutical composition for the prevention and / or treatment of diseases associated with RIPK1.

[0068] Solutions to the problem Novel features of the present invention are described in particular in the appended claims. The features and advantages of the present invention will be better understood by referring to the following detailed description, which includes exemplary embodiments in which the principles of the present invention are utilized.

[0069] Preferred embodiments of the present invention are illustrated and described herein, but such embodiments are provided only as examples. It should be understood that various alternatives to the embodiments of the present invention described herein can be used in carrying out the invention. Those skilled in the art will understand that various modifications, changes, and substitutions can be made without departing from the present invention.

[0070] The following claims define the scope of embodiments of the present invention, and methods and structures within the scope of such claims and their equivalents are intended to be included therein.

[0071] The section titles used herein are for structural purposes only and should not be construed as limiting the claims described herein. All documents or parts of documents cited herein, including but not limited to patents, patent applications, articles, books, manuals, and papers, are expressly incorporated herein by reference in whole for any purpose whatsoever. [Modes for carrying out the invention]

[0072] Specific chemical terms Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by experts in the art to which the claimed subject matter pertains. Unless otherwise stated, all patents, patent applications, and published materials referenced throughout the disclosure herein are taken as such in their entirety. If there are multiple definitions for a term herein, the definition in this section shall prevail. Where URLs or other such identifiers or addresses are referenced, such identifiers may change and certain information on the Internet may fluctuate, but it is understood that equivalent information can be found by searching the Internet or other appropriate reference sources. This reference demonstrates the availability and widespread publication of such information.

[0073] The above general description and the following detailed description are illustrative and descriptive only and should be understood not to limit any claims to be made. In this application, singular terms include plural unless otherwise specified. Note that, as used in the specification and the attached claims, singular forms include plural subjects unless otherwise specifically indicated in the context. Furthermore, unless otherwise specified, the use of “or” should be noted as meaning “and / or.” Furthermore, the use of different forms of the term such as “beginning,” “start,” and “beginning” is not restrictive. Similarly, the use of different forms of the term such as “include,” “contain,” “included,” and “included” is not restrictive.

[0074] The definitions of standard chemical terms can be found in the literature [Carey and Sundberg, "ADVANCED ORGANIC CHEMISTRY 4"]. THReferences can be found in the bibliography, including [ED. Vols. A (2000) and B (2001), Plenum Press, New York]. Unless otherwise indicated, mass spectrometry, NMR, HPLC, IR and UV / Vis spectroscopy, and conventional methods of pharmacology belonging to the art of this specification are used. Unless a specific definition is provided, the nomenclature, laboratory procedures, and techniques used in relation to analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are publicly known in the art. Standard techniques for chemical synthesis, chemical analysis, pharmaceutical manufacturing, dosage forms, and delivery and treatment to patients may be used. Reaction and purification techniques may be performed, for example, using kits according to manufacturer specifications, or as commonly practiced in the art, or as described herein. In general, the techniques and procedures described herein may be performed as commonly practiced in the art and as described in the various general and more specific references cited and discussed throughout this specification. Throughout this specification, groups and their substituents may be selected by those skilled in the art to provide stable moieties and compounds.

[0075] Unless otherwise specified, the use of general chemical terms such as "alkyl," "amine," and "aryl" is equivalent to, but not limited to, their selectively substituted forms. For example, "alkyl" as used herein includes selectively substituted alkyls.

[0076] The terms “selective” or “selectively” mean that the events or circumstances described therein may or may not occur, and that the description includes both cases where such events or circumstances occur and where they do not. For example, “selectively substituted alkyl” means “alkyl” or “substituted alkyl” as defined below. Furthermore, selectively substituted groups include unsubstituted (e.g., CH2CH3), fully substituted (e.g., CF2CF3), and monosubstituted (e.g., CH2CH3). 2)F) or substituted at any level between complete substitution and monosubstituted (e.g., CH2CHF2, CF2CH3, CFHCHF2, etc.). For any group containing one or more substituents, it will be understood that it is not intended to introduce any substitution or substitution pattern that is sterically unrealistic or synthetically unrealistic (e.g., a substituted alkyl contains a selectively substituted cycloalkyl group, which is ultimately defined as containing a selectively substituted alkyl group, and is potentially infinitely possible). Therefore, any substituents described should be understood to have a maximum molecular weight of generally about 1,000 daltons, more typically about 500 daltons or less (except when macromolecular substituents are clearly intended, e.g., polypeptides, polysaccharides, polyethylene glycol, DNA, RNA, etc.).

[0077] As used herein, C1-Cn includes C1-C2, C1-C3, ..., C1-Cn. For example, a group indicated as "C1-C4" indicates that there are 1 to 4 carbon atoms in the part, i.e., it represents the range of C1-C2 and C1-C3, as well as groups containing 1, 2, 3, or 4 carbon atoms. Thus, for example, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Numerical ranges such as "1 to 10" refer to each integer within the given range whenever they appear herein; for example, "1 to 10 carbon atoms" means that the group may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0078] As used herein, the term "heteroatom" or "hetero", alone or in combination, refers to atoms other than carbon and hydrogen. Heteroatoms are independently selected from, but not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may each be different.

[0079] As used herein, the term "alkyl", alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched-chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer chain alkyl groups such as heptyl, octyl and the like. "C1-C6 alkyl" or "C 1-6 Whenever a numerical range such as alkyl" is presented herein, it means that the alkyl group can consist of 1 carbon atom 、 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and this definition also encompasses the presence of the term "alkyl" where no numerical range is indicated.

[0080] As used herein, the term “aliphatic” refers, either alone or in combination, to selectively substituted linear or branched, acyclic, saturated, partially unsaturated, or fully unsaturated non-aromatic hydrocarbons. Therefore, the term encompasses alkyl, alkenyl, and alkynyl groups collectively.

[0081] As used herein, the terms “cycle,” “cyclic,” “ring,” and “-membered ring” refer, alone or in combination, to any covalently closed structure, including alicyclic, heterocyclic, aromatic, heteroaromatic, and polycyclic condensed or uncondensed ring systems as described herein. Rings may be selectively substituted. Rings may form part of a condensed ring system. The term “-membered” refers to the number of skeletal atoms constituting the ring. For example, cyclohexane, pyridine, pyran, and pyrimidine are 6-membered rings, and cyclopentane, pyrrole, tetrahydrofuran, and thiophene are 5-membered rings.

[0082] As used herein, the term "cycloalkyl" refers to a selectively substituted saturated hydrocarbon monoradical ring, either alone or in combination, containing 3 to about 15 ring carbon atoms or 3 to about 10 ring carbon atoms, but which may also contain additional acyclic carbon atoms as substituents (e.g., methylcyclopropyl).

[0083] Non-restrictive examples of "cycloalkyl" include azinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, quinolidinyl, and others. The aforementioned terms also include all cyclic carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides.

[0084] As used herein, the term “aromatic” refers to a non-uniformly distributed portion of a planar, cyclic, or polycyclic ring in an electronic system containing 4n+2n electrons (where n is an integer). Aromatic rings can be formed by 5, 6, 7, 8, 9, or more than 9 atoms. Aromatic rings may be selectively substituted and may be monocyclic or polycyclic fused rings. The term “aromatic” includes both rings containing all carbon atoms (e.g., phenyl) and rings containing one or more heteroatoms (e.g., pyridine).

[0085] Specific pharmaceutical terms As used herein, the term “necroptosis analysis against RIP1 activity” refers to compounds that, when measured by kinase analysis as generally described herein, exhibit an IC50 of about 100 μM or less or about 50 μM or less against RIP1 kinase activity. “IC50” is the concentration of an inhibitor that reduces the enzyme activity to half of its maximum level. The compounds described herein have been shown to exhibit inhibition against RIPK1. The compounds of the present invention, when measured by necroptosis analysis as described herein, preferably exhibit an IC50 of about 10 μM or less, more preferably about 5 μM or less, even more preferably about 1 μM or less, and most preferably about 200 nM or less against RIPK1.

[0086] As used herein, the terms “selective,” “selective,” or “selectivity” refer to the compounds of the present invention having a lower IC50 value than any other enzyme (e.g., at least 2 times, 5 times, or 10 times lower).

[0087] The terms “subject,” “patient,” or “individual” as used herein in reference to individuals suffering from disorders, conditions, etc., include mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; livestock such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0088] As used herein, the terms “to treat,” “to cure,” or “to treat” and other grammatical equivalents are intended to include, and include, the alleviation, reduction or improvement of the symptoms of a disease or condition, the prevention of further symptoms, the improvement or prevention of the basal metabolic causes of symptoms, the inhibition of a disease or condition, e.g., the prevention of the onset of a disease or condition, the alleviation of a disease or condition, the suppression or induction of a disease or condition, the alleviation of a condition induced by a disease or condition, or the interruption of the symptoms of a disease or condition. The terms further include achieving therapeutic and / or preventive benefits. Therapeutic benefit means the eradication or improvement of the basal disorder being treated. Furthermore, therapeutic benefit is achieved if, although the patient may still be suffering from a basal disorder, one or more of the physiological symptoms associated with the basal disorder are eradicated or improved and improvement is observed in the patient. For preventive benefits, the composition may be administered to patients at risk of developing a particular disease, or to patients who have reported one or more of the physiological symptoms of a disease, even if a diagnosis of the disease has not been made.

[0089] As used herein, the terms “effective dose,” “therapeutic effective dose,” or “pharmaceutically effective dose” mean a sufficient amount of at least one formulation or compound administered that alleviates, to some extent, one or more of the symptoms of the disease or condition being treated. The result may be a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable modification of the biological system. For example, an “effective dose” for therapeutic use is the amount of a composition containing a compound such as those disclosed herein that is necessary to provide a clinically significant reduction in the disease. An appropriate “effective” dose in any individual may be determined using techniques such as dose-increase studies.

[0090] As used herein, terms such as “administer,” “give,” and “give” refer to methods that may be used to enable the delivery of a compound or composition to a desired site of action. Such methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art will be familiar with administration techniques that may be used with the compounds and methods described herein, such as those discussed in the literature [Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon] and the literature [Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.]. In preferred embodiments, the compounds and compositions described herein are administered orally.

[0091] As used herein with respect to dosage forms, compositions, or ingredients, the term “acceptable” means that it does not have a sustained adverse effect on the general health of the subject being treated.

[0092] As used herein, the term “pharmaceutically acceptable” means a substance, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compounds described herein and is relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component contained in the composition.

[0093] As used herein, the term “pharmaceutical composition” refers to a biologically active compound that is selectively mixed with at least one pharmaceutically acceptable chemical component, such as, but not limited to, a carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. As used herein, the term “carrier” refers to a relatively non-toxic compound or formulation that facilitates the contamination of cells or tissues with a compound.

[0094] As used herein, the term “actionant” refers to molecules such as compounds, drugs, enzyme activators, or hormone regulators that enhance the activity of other molecules or the activity of receptor sites.

[0095] As used herein, the term “antagonist” refers to a molecule such as a compound, drug, enzyme inhibitor, or hormone regulator that reduces or prevents the action of another molecule or the activity of a receptor site.

[0096] As used herein, the term “modulate” means interacting with a target directly or indirectly to alter its activity, including, for example, enhancing its activity, inhibiting its activity, limiting its activity, or prolonging its activity.

[0097] As used herein, the term “modulator” refers to a molecule that interacts with a target, either directly or indirectly. Interactions include, but are not limited to, agonist-antagonist interactions.

[0098] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a particular compound that maintains the biological efficacy of the free acid and base and is not biologically or otherwise undesirable. The compounds described herein may have acidic or basic groups and can therefore react with any number of inorganic or organic salts, as well as inorganic and organic acids, to form pharmaceutically acceptable salts. Such salts may be produced in the same system during the final isolation and purification of the compounds of the present invention, or by separately reacting a suitable organic or inorganic acid with a purified compound in the form of a free base and isolating the salt formed thereby.Examples of pharmaceutically acceptable salts include salts produced by the reaction of minerals or organic acids or inorganic bases with the compounds described herein, e.g., acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, buty-1,4-dioate, camphorate, camphorsulfonate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyn-1,6-dioate, hydroxybenzoate, hydroxybutyrate, hydrochloride, hydroxy This includes salts containing drobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, sverate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoenate, and xylenesulfonate. Other acids, such as oxalic acid, are not pharmaceutically acceptable in themselves, but can be used as useful intermediates in the production of salts in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts (see, for example, reference [Berge et al., J. Pharm. Sci. 1977, 66, 1-19]).Furthermore, compounds described herein, which may contain free acid groups, can be reacted with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, with ammonia or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Typical alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, and sodium carbonate. Typical organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, and piperazine. The compounds described herein should also be understood to include quaternary modification of any basic nitrogen-containing group that may be present. Water-soluble, lipophilic, or dispersible products can be obtained by such quaternary modification. See, for example, the literature by Berge et al.

[0099] As used herein, the term “solvate” refers to the combination of the compound of the present invention and a solvent molecule formed by solvation. In some contexts, the solvate refers to a hydrate, i.e., the solvent molecule is a water molecule, and the combination of the compound of the present invention and water forms a hydrate. As used herein, the terms "polymorph" or "polymorphic" refer to the compounds of the present invention that exist in various crystal lattice forms.

[0100] As used herein, the term "ester" refers to derivatives of the compounds of the present invention derived from an oxoacid group and a hydroxyl group, wherein either an oxoacid group or a hydroxyl group may be present in the compounds of the present invention.

[0101] As used herein, the term "tautomer" refers to isomorphs that are immediately interconverted from the compounds of the present invention, for example, by the transfer of hydrogen atoms or protons.

[0102] As used herein, the term “pharmaceutically acceptable derivative or prodrug” refers to any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present invention that, when administered to a recipient, can directly or indirectly deliver the compound of the present invention or its pharmaceutically active metabolite or residue. Particularly advantageous derivatives or prodrugs are those that, when administered to a patient (for example, by making the orally administered compound more readily absorbable into the blood), increase the bioavailability of the compound of the present invention or improve the delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).

[0103] pharmaceutically acceptable prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts, and sulfonate esters. Various forms of prodrugs are widely known in the art. For example, see references to [Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396]; [Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191]; and [Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38], each of which is incorporated herein by reference. Prodrugs described herein include, but are not limited to, the following groups and combinations thereof; and amine-derived prodrugs. Hydroxyprodrugs include, but are not limited to, acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, and ester-containing disulfides.

[0104] As used herein, the terms “enhance” or “improve” mean to increase or extend one of the ability or duration of a desired effect. Therefore, in the context of enhancing the effect of a therapeutic agent, the term “enhance” refers to the ability to increase or extend the effect of another therapeutic agent on a system in terms of ability or duration. As used herein, “effective dose for improvement” refers to an amount suitable for improving the effect of another therapeutic agent in the desired system.

[0105] As used herein, terms such as “pharmaceutical combination,” “additional therapeutic administration,” and “administration of additional therapeutic agents” refer to pharmaceutical treatments resulting from the mixing or combination of more than one active ingredient, and include both immobilized and unimmobilized combinations of active ingredients. The term “immobilized combination” means the simultaneous administration to a patient of at least one of the compounds described herein and at least one co-formulation, either as a single agent or in a single dose. The term “unimmobilized combination” means the simultaneous, together, or sequentially administration to a patient of at least one of the compounds described herein and at least one co-formulation, with varying intervention time constraints, as separate independent agents, providing effective levels of two or more compounds in the patient’s body. Furthermore, this also applies to cocktail treatments, such as the administration of three or more active ingredients.

[0106] As used herein, terms such as “simultaneous administration,” “administered together with,” and their grammatical equivalents include administration of a selected therapeutic agent to a single patient, and include a therapeutic system in which the therapeutic agents are administered by the same or different routes of administration, or at the same or different times. In some embodiments, the compounds described herein are administered simultaneously with other formulations. These terms include administering two or more formulations to an animal, and that any of the formulations and / or their metabolites are present in the animal at the same time. These include simultaneous administration of individual compositions, administration of individual compositions at different times, and / or administration of a composition in which both formulations are present. Thus, in some embodiments, the compounds of the present invention and other formulations are administered as a single composition. As used herein, the term “metabolite” refers to derivatives of a compound that are formed when a compound is metabolized. As used herein, the term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized.

[0107] As used herein, the term “metabolized” refers to the sum total of processes by which a particular substance is transformed by an organism, including, but not limited to, hydrolysis and enzyme-catalyzed reactions. Thus, enzymes can cause specific structural changes in a compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolism can be found in the literature [The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996)].

[0108] Description of the Embodiment The NMR spectrum was recorded in a 5 mm OD tube (Norell, Inc. 507-HP) containing CDCl3 solution at 30°C. 1 Data was collected at 400 MHz with JEOL for H. Chemical transfer (δ) is relative to tetramethylsilane (TMS = 0.00 ppm) and is expressed in ppm. LC / MS was measured using an ISQ EM ion trap mass spectrometer, Thermo Fisher Vanquish Flex, operating in ESI(+) ionization mode; flow rate = 0.5 mL / min (column: hypersil Gold (C18, φ2.1 x 50 mm, 1.9 μm, 120 Å, 30°C)). Mobile phase = water or CH3CN with 0.01% heptafluorobutyric acid (HFBA) and 1.0% isopropyl alcohol (IPA).

[0109] [ka]

[0110] Intermediate 1: [ka]

[0111] Stage A: Methyl 4-fluoro-3-nitrobenzoate SOCl2 (3.55 mL, 48.6 mmol) was added dropwise to a solution of 4-fluoro-3-nitrobenzoic acid (3.00 g, 16.2 mmol) in MeOH (16 mL) at 0°C. The reaction mixture was stirred at 40°C for 5 hours. After concentration under vacuum, the residue was partitioned between RINKAN and water. The separated organic layer was washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, and concentrated under vacuum to provide methyl 4-fluoro-3-nitrobenzoate (3.20 g, 99%) as a yellowish-green oil, which was used in the next step without purification. 1 H-NMR (400MHz, CDCl3): δ8.75(1H,dd,J=7.2,2.4Hz), 8.33(1H,ddd,J=8.8,4.0,2.4Hz), 7.39(1H,dd,J=10.4,8.8Hz), 3.98(3H,s).

[0112] Stage B: N-(tert-butoxycarbonyl)-O-(4-(methoxycarbonyl)-2-nitrophenyl)-L-serine A suspension of NaH (55% by weight, 0.300 g, 7.53 mmol) in DMF (5.0 mL) was slowly added to a solution of (tert-butoxycarbonyl)-L-serine (0.773 g, 3.39 mmol) in DMF (5.0 mL) at -15°C. The mixture was stirred at -15°C for 1 hour. After adding a solution of methyl 4-fluoro-3-nitrobenzoate (0.500 g, 2.51 mmol) in DMF (2.5 mL) at -15°C, the reaction mixture was stirred for a further 1 hour at -15°C. The reaction was gently terminated with 1 M aqueous HCl until the pH reached 3-4 at -15°C, and then the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum to provide N-(tert-butoxycarbonyl)-O-(4-(methoxycarbonyl)-2-nitrophenyl)-L-serine (1.42 g, crude) as a yellow oil, which was used in the next step without further purification. 1H-NMR (400MHz, CDCl3): δ8.52(1H,d,J=2.4Hz), 8.21(1H,dd,J=8.8,2.0Hz), 7.13(1H,d,J=9.2Hz), 5.64(1H,d,J =8.0Hz), 4.75-4.73(1H,m), 4.68(1H,dd,J=9.6,2.4Hz), 4.48(1H,dd,J=8.8,2.8Hz), 3.94(3H,s), 1.46(9H,s).

[0113] Stage C:O-(2-amino-4-(methoxycarbonyl)phenyl)-N-(tert-butoxycarbonyl)-L-serine A suspension of N-(tert-butoxycarbonyl)-O-(4-(methoxycarbonyl)-2-nitrophenyl)-L-serine (965 mg, 2.51 mmol) and Pd / C (10 wt%, 91.0 mg, 0.0850 mmol) in  (8.4 mL) was stirred at room temperature for 5 hours under H2 atmosphere (1 atm). The reaction mixture was filtered through a Celite pad and washed with Â. The filtrate was concentrated under vacuum to provide O-(2-amino-4-(methoxycarbonyl)phenyl)-N-(tert-butoxycarbonyl)-L-serine (1.32 g, crude) as a red oil, which was used in the next step without purification. LC-MS: m / z = 355.1 [M + H] + .

[0114] Stage D: Methyl(S)-3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate

[0115] HATU (0.118 g, 0.310 mmol) was added to a solution of O-(2-amino-4-(methoxycarbonyl)phenyl)-N-(tert-butoxycarbonyl)-L-serine (0.100 g, 0.282 mmol) and DiPEA (0.0540 mL, 0.310 mmol) in DMSO (1.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. After adding water, the mixture was stirred at room temperature for a further 30 minutes. The precipitated solid was collected by filtration, washed with water, and dried under vacuum to provide methyl(S)-3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate (47.0 mg, 49% between the three steps) as a beige solid. 1 H-NMR (400MHz, CDCl3): δ7.81(2H,dd,J=8.5,2.1Hz), 7.70(1H,d,J=1.6Hz), 7.15(1H,d,J=8.4Hz), 5.58(1H,d,J=5.2Hz), 4.69-4.63(2H,m), 4.28(1H,dd,J=12.0,11.2Hz), 3.92(3H,s), 1.43(9H,s).

[0116] Stage E: Methyl(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate

[0117] At room temperature, a solution of methyl(S)-3-((tert-butoxycarbonyl)amino)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate (570 mg, 1.69 mmol) and Cs2CO3 (880 mg, 2.70 mmol) was added dropwise to DMF (5.6 mL) to which MeI (0.148 mL, 2.36 mmol). The reaction mixture was stirred at room temperature for 2 hours. After terminating the reaction with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to obtain methyl(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate (380 mg, 64%) as a yellow oil. 1 H-NMR (400MHz, CDCl3): δ7.90-7.87(2H,m), 7.20(1H,d,J=8.4Hz), 5.61(1H,d,J=6.4Hz), 4.66(1H,dt,J =10.8,6.8Hz), 4.62-4.58(1H,m), 4.25(1H,dd,J=10.8,9.6Hz), 3.93(3H,s), 3.44(3H,s), 1.40(9H,s).

[0118] Stage F: (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid

[0119] A solution of methyl(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate (380 mg, 1.09 mmol) in THF (12 mL) and water (3.8 mL) at room temperature was mixed with a solution of LiOH-H2O (68.0 mg, 1.63 mmol) in water (0.76 mL). The reaction mixture was stirred at room temperature for 2 hours. After dilution with ice water, the mixture was washed with ELISA. The separated aqueous layer was acidified to pH 3 with a 1 M aqueous HCl solution and then extracted twice with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to provide (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]-oxazepine-7-carboxylic acid (360 mg, 99%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ7.91(1H,d,J=1.2Hz), 7.89(1H,dd,J=8.4,2.0Hz), 7.23(1H,s), 5.73(1H,d,J=7.2Hz), 4.73(1 H,dt,J=11.6,7.2Hz), 4.63(1H,dd,J=9.6,7.2Hz), 4.29(1H,dd,J=11.2,9.6Hz), 3.45(3H,s), 2.35(2H,s), 1.41(9H,s).

[0120] [ka]

[0121] Intermediate 2: tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0122] [ka]

[0123] Stage A: (S)-2-(tert-butoxycarbonylamino)-3-(4-methoxy-2-nitrophenoxy)propanoic acid A suspension of NaH (55% by weight, 460 mg, 10.5 mmol) in 20 mL of dry DMF at 0°C was slowly added to a solution of N-Boc-L-serine (1.00 g, 4.87 mmol) in 5.0 mL of dry DMF. The mixture was stirred at room temperature for 30 minutes and then cooled to 0°C. After adding a solution of 1-fluoro-4-methoxy-2-nitrobenzene (900 mg, 5.26 mmol) in 5.0 mL of dry DMF at 0°C, the reaction mixture was stirred at 0°C for 2 hours. After terminating the reaction with a 0.5 M aqueous HCl solution, the mixture was extracted with ethyl acetate, washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:siRNA = 4:1 to 1:1) to obtain (S)-2-(tert-butoxycarbonylamino)-3-(4-methoxy-2-nitrophenoxy)propanoic acid (900 mg, 48%) as a yellow oil. LC-MS: m / z = 257.01 [M+H] + .

[0124] Stage B: (S)-3-(2-amino-4-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid A suspension of (S)-2-(tert-butoxycarbonylamino)-3-(4-methoxy-2-nitrophenoxy)propanoic acid (350 mg, 0.982 mmol) and Pd / C (5% by weight, 50 mg) in MeOH (10 mL) was stirred at room temperature for 2 hours under H2 atmosphere (1 atm). After filtration through a Celite pad while washing with MeOH, the filtrate was concentrated under vacuum to provide (S)-3-(2-amino-4-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (200 mg, 62%) as a black solid. LC-MS: m / z = 326.89 [M + H] + .

[0125] Stage C: (S)-tert-butyl7-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-ylcarbamate At 0°C, a solution of (S)-3-(2-amino-4-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (320 mg, 0.981 mmol) in DMSO (3.0 mL) was added, followed by DIPEA (514 μL, 2.94 mmol) and then HATU (373 mg, 0.981 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After terminating the reaction with ice water, the mixture was extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography over SiO2 (hexane:ethyl acetate = 2:1) to provide (S)-tert-butyl 7-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-ylcarbamate (200 mg, 66%) as a white solid. 1 H-NMR (400MHz, CDCl3): 7.17 (1H, brs), 6.90 (1H, d, J=8.8Hz), 6.68-6.64 (2H, m), 5 .48(1H,brs), 4.69-4.61(2H,m), 4.21(1H,t,J=9.6Hz), 3.79(3H,s), 1.42(9H,s).

[0126] Stage D: tert-butyl(S)-(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0127] At 0°C, a solution of (S)-tert-butyl 7-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-ylcarbamate (200 mg, 0.649 mmol) in DMF (5.0 mL) was added, followed by Cs2CO3 (254 mg, 0.778 mmol), and then a solution of MeI (48.7 μL, 0.778 mmol) in DMF (1.0 mL). The reaction mixture was stirred at 0°C for 4 hours, and then stirred at room temperature for another hour. After terminating the reaction with ice water, the mixture was extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:SiO=3:1) to obtain tert-butyl(S)-(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (150 mg, 72%) as a colorless oil. LC-MS: m / z = 266.87 [M-tBu+H] + .

[0128] Stage E: (S)-3-amino-7-hydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one A solution of tert-butyl(S)-(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (1.90 g, 5.89 mmol) in DCM (19 mL) at 0°C was mixed with BBr3 (18.0 mL, 17.7 mmol). The reaction mixture was stirred at room temperature for 4 hours. The precipitated solid was collected by filtration, washed with EtO2, and dried under vacuum to provide (S)-3-amino-7-hydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one (1.70 g, 100%) as a white solid. 1¹H-NMR (400 MHz, DMSO-d₆): δ 9.49 (1H, s), 6.90 (1H, d, J=8.4 Hz), 6.68 (1H, d, J=2.8 Hz), 6.54 (1H, dd, J=9.0, 2.6 Hz), 4.13 (1H, dd, J=9.8, 7.3 Hz), 3.85-3.80 (1H, m), 3.51 (1H, dd, J=11.6, 8.0 Hz), 3.19 (3H, s).

[0129] Step F: tert-butyl (S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate

[0130] To a solution of (S)-3-amino-7-hydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (300 mg, 1.44 mmol) in DMF (4.8 mL) at room temperature was added (Boc)₂O (629 mg, 2.88 mmol) and DMAP (35.0 mg, 0.288 mmol). The reaction mixture was stirred at room temperature for 18 hours. After quenching the reaction with water, the mixture was extracted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on SiO₂ (hexane:EtOAc=3:1 to 1:1) to give tert-butyl (S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (205 mg, 46%) as a white solid. 1 ¹H-NMR (400 MHz, DMSO-d₆): δ 9.59 (1H, s), 7.08 (1H, d, J=8.8 Hz), 6.94 (1H, d, J=8.8 Hz), 6.74 (1H, d, J=2.8 Hz), 6.58 (1H, dd, J=8.2, 3.0 Hz), 4.33-4.27 (1H, m), 4.18-4.12 (2H, m), 3.14 (3H, s), 1.30 (9H, s).

[0131]

Chemical Formula

[0132] Intermediate 3: (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetic acid

[0133] [ka]

[0134] Stage A: Ethyl(S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetate

[0135] To a solution of tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (intermediate 2, 0.200 g, 0.649 mmol) in DMF (6.5 mL) at room temperature, ethyl bromoacetate (0.0940 mL, 0.843 mmol) and Cs2CO3 (0.634 g, 1.95 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. After terminating the reaction with water, the mixture was extracted twice with ethyl benzoate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:SiO = 2:1 to 1:1) to provide ethyl(S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetate (0.232 g, 91%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.07(1H,d,J=8.8Hz), 6.81(1H,d,J=2.8Hz), 6.70(1H,dd,J=8.8,2.2Hz), 5.54(1H,d,J=7.2Hz), 4.65(1H,dt,J=11.6,7.2H z), 4.61(2H,s), 4.53(1H,dd,J=9.6,7.6Hz), 4.29(2H,q,J=7.2Hz), 4.11( 1H,dd,J=10.8,10.0Hz), 3.38(3H,s), 1.40(9H,s), 1.32(3H,t,J=7.2Hz).

[0136] Stage B: (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetic acid

[0137] At 0°C, a solution of ethyl(S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetate (0.232 g, 0.588 mmol) was added to EtOH (4.4 mL) and water (1.5 mL). The reaction mixture was stirred at room temperature for 1 hour. After stopping the reaction with water, the mixture was washed with ELISA. The separated aqueous layer was acidified to pH 3 with 1 M aqueous HCl solution and then extracted twice with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to provide (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetic acid (0.209 g, 97%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.09(1H,d,J=8.4Hz), 6.82(1H,d,J=2.8Hz), 6.72(1H,dd,J=8.8,2.8Hz), 5.60(1H,d,J=7.2Hz), 4. 68(1H,dt,J=11.6,7.6Hz), 4.63(2H,s), 4.53(1H,dd,J=9.6,7.2Hz), 4.13(1H,dd,J=11.2,9.2Hz), 3.38(3H,s), 1.40(9H,s).

[0138] [ka]

[0139] Intermediate 4. (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetic acid

[0140] [ka]

[0141] Stage A: Ethyl(S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetate hydrochloride

[0142] At 0°C, HCl (4M solution in dioxane, 1.90 mL, 7.61 mmol) was added to a solution of ethyl(S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy) acetate (Step A in the preparation of intermediate 3, 0.100 g, 0.254 mmol) in DCM (2.5 mL). The reaction mixture was stirred at room temperature for 18 hours and concentrated under vacuum to provide ethyl(S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy) acetate hydrochloride (84.0 mg, 100%) as a yellow oil, which was used in the next step without further purification. LC-MS: m / z = 295.0 [M + H] + .

[0143] Stage B: Ethyl(S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetate

[0144] At 0°C, a solution of ethyl(S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy) acetate hydrochloride (84.0 mg, 0.254 mmol) was added to DCE (2.5 mL) followed by CDI (49.0 mg, 0.305 mmol) and then TEA (0.0880 ml, 0.635 mmol). The reaction mixture was stirred at room temperature for 1 hour. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum.

[0145] To a solution of the residue in DCE (2.5 mL) at 0°C, 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6, 65.0 mg, 0.305 mmol) was added, followed by TEA (0.0880 mL, 0.635 mmol). The reaction mixture was stirred at 45°C for 18 hours. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:HCl = 1:1) to provide ethyl(S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetate (0.101 g, 80%) as a pale yellow foam. 1 H-NMR (400MHz, CDCl3): δ8.00(1H,d,J=7.2Hz), 7.89(1H,d,J=0.8Hz), 7.47(1H,s), 7.28 -7.22(1H,m), 7.12(1H,d,J=8.4Hz), 6.96-6.85(3H,m), 6.84(1H,d,J=2.8Hz), 6.74(1H,d d,J=9.2,3.2Hz), 4.90(1H,dt,J=11.2,7.6Hz), 4.67(1H,dd,J=9.6,7.6Hz), 4.63(2H,s), 4.29(2H,q,J=7.2Hz), 4.26-4.2(1H,m), 3.81(2H,s), 3.41(3H,s), 1.32(3H,t,J=7.2Hz).

[0146] Stage C: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetic acid

[0147] To a solution of ethyl (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)oxy)acetate (0.100 g, 0.201 mmol) in THF (0.29 mL), EtOH (1.2 mL) and water (0.58 mL) at 0°C was added LiOH hydrate (42.0 mg, 1.01 mmol). The reaction mixture was stirred at 0°C for 10 minutes. After dilution with water, the mixture was washed with EtOAc. The separated aqueous layer was acidified to pH 3 using 1 M aqueous HCl, then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo to afford (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)oxy)acetic acid (37.0 mg, 39%) as a white foam. 1 H-NMR (400 MHz, CDCl₃): δ 8.02 (1H, d, J = 7.2 Hz), 7.89 (1H, s), 7.47 (1H, s), 7.26-7.22 (1H, m), 7.13 (1H, d, J = 8.8 Hz), 6.96-6.85 (4H, m), 6.76 (1H, dd, J = 8.8, 2.8 Hz), 4.92 (1H, dt, J = 11.2, 7.6 Hz), 4.65 (3H, m), 4.30 (1H, t, J = 10.4 Hz), 3.81 (2H, s), 3.41 (3H, s)

[0148] General synthetic reaction scheme for pyrazole intermediates [[Chemical diagram]]

[0149] Intermediate 5: 4-(2-fluorobenzyl)-1H-pyrazole hydrochloride [[Chemical diagram]]

[0150] Stage A: 4-(2-fluorobenzyl]-1-(oxan-2-yl)pyrazole At room temperature, 1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (3.00 g, 10.8 mmol) and 1-(bromomethyl)-2-fluorobenzene (2.65 g, 14.0 mmol) were mixed in DME (36 mL), EtOH (9.0 mL), and H2O (9.0 mL). Pd(PPh3)4 (0.250 g, 0.216 mmol) and K3PO4 (6.87 g, 32.4 mmol) were added. The reaction mixture was stirred at 60°C for 4 hours under N2 air. After dilution with water at room temperature, the mixture was extracted twice with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (petroleum ether: SiO = 5:1) to provide 4-(2-fluorobenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.73 g, 61%) as a yellow solid. LC-MS(ESI) m / z = 261.1 [M + H] +

[0151] Stage B: 4-(2-fluorobenzyl)-1H-pyrazole hydrochloride A solution of 4-(2-fluorobenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.73 g, 6.65 mmol) in HCl (4 M in 1,4-dioxane, 16.6 mL, 66.5 mmol) was added at 0°C. The reaction mixture was stirred overnight at room temperature. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried under vacuum to provide 4-(2-fluorobenzyl)-1H-pyrazole hydrochloride (0.950 g, 66%) as a grayish-white solid. 1 H-NMR (400MHz, DMSO-d6): δ7.94(1H,s), 7.75(1H,s), 7.27(2H,dddd,J=10.2,7.3,5.6,2.5Hz), 7.20-7.09(2H,m), 3.85(2H,s). LC-MS(ESI)m / z:[M+H]+=177.0

[0152] Intermediate 6: 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride [ka]

[0153] The title compound was prepared as a white solid in two steps from 1-(bromomethyl)-3-fluorobenzene in the same manner as intermediate 6 (53%). 1 H-NMR (400MHz, DMSO-d6): δ11.78(2H,brs), 7.88(2H,d,J=2.6Hz), 7.33(1H,td,J=8.0,6.2Hz), 7.12-6.92(3H,m), 3.86(2H,s). LC-MS(ESI)m / z=177.0[M+H] +

[0154] Intermediate 7: 4-(4-fluorobenzyl)-1H-pyrazole hydrochloride [ka]

[0155] The title compound was prepared as a light brown solid from 1-(bromomethyl)-4-fluorobenzene in two steps in the same manner as intermediate 6 (62%). 1 H-NMR (400MHz, DMSO-d6): δ11.52(3H,s), 7.97-7.90(2H,m), 7.31-7.24(2H,m), 7.16-7.07(2H,m), 3.84(2H,s). LC-MS(ESI)m / z=177.0[M+H] +

[0156] Intermediate 8: 4-(2,3-difluorobenzyl)-1H-pyrazole hydrochloride [ka]

[0157] The title compound was prepared as a grayish-white solid in two steps from 1-(bromomethyl)-2,3-difluorobenzene in the same manner as intermediate 6 (59%). 1 H-NMR (400MHz, DMSO-d6): δ9.16(3H,s), 7.73(2H,s), 7.28(1H,dtd,J=10.5,7.9,2.1Hz), 7.19-7.04(2H,m), 3.89(2H,d,J=1.6Hz). LC-MS(ESI)m / z=195[M+H] +

[0158] Intermediate 9: 4-(3,4-difluorobenzyl)-1H-pyrazole hydrochloride [ka]

[0159] The title compound was prepared as a grayish-white solid from 1-(bromomethyl)-3,4-difluorobenzene in two steps using the same method as for intermediate 6 (63%). 1 H-NMR (400MHz, DMSO-d6): δ7.62-7.55(2H,m), 7.37-7.21(2H,m), 7.05(1H,ddt,J=8.3,4.0,1.7Hz), 3.80(2H,s). LC-MS(ESI)m / z=195.0[M+H] + .

[0160] Intermediate 10: 4-(3,5-difluorobenzyl)-1H-pyrazole hydrochloride [ka]

[0161] The title compound was prepared as a pale yellow solid in two steps from 1-(bromomethyl)-3,5-difluorobenzene in the same manner as intermediate 6 (66%). 1H-NMR (400MHz, DMSO-d6): δ9.53(3H,s), 7.84-7.65(2H,m), 7.03(1H,tt,J=9.5,2.5Hz), 6.96(2H,qd,J=5.9,5.1,3.2Hz), 3.85(2H,d,J=1.9Hz). LC-MS(ESI)m / z=195.0[M+H] + .

[0162] Intermediate 11: 4-(2,4-difluorobenzyl)-1H-pyrazole hydrochloride [ka]

[0163] The title compound was prepared as a grayish-white solid from 1-(bromomethyl)-2,4-difluorobenzene in two steps using the same method as for intermediate 6 (52%). 1 H-NMR (400MHz, DMSO-d6): δ9.99(3H,s), 7.69-7.62(2H,m), 7.32(1H,td,J=8.8,6.6Hz ), 7.19(1H,ddd,J=10.5,9.4,2.6Hz), 7.02(1H,tdd,J=8.6,2.6,1.1Hz), 3.81(2H,s). LC-MS(ESI)m / z=195.0[M+H] + . Intermediate 12: 4-(2,6-difluorobenzyl)-1H-pyrazole hydrochloride

[0164] [ka]

[0165] The title compound was prepared as a grayish-white solid from 2-(bromomethyl)-1,3-difluorobenzene in two steps using the same method as for intermediate 6 (52%). 1H-NMR (400MHz, DMSO-d6): δ7.52(1H,ddd,J=26.2,9.3,4.8Hz), 7.33(1H,dddd,J=15.1,8.4,6.7,1.7Hz)(4H,q,J=7.0,6.4Hz), 3.81(2H,d,J=3.9Hz). LC-MS(ESI)m / z=195.4[M+H] + .

[0166] Intermediate 13: 4-(3-(trifluoromethyl)benzyl)-1H-pyrazole hydrochloride [ka]

[0167] The title compound was prepared as a pale yellow solid from 1-(bromomethyl)-3-(trifluoromethyl)benzene in two steps using the same method as for intermediate 6 (70%). 1 H-NMR (400MHz, DMSO-d6): δ12.08(2H,brs), 7.93(2H,s), 7.61(1H,d,J=2.0Hz), 7.59-7.51(3H,m), 3.96(2H,s). LC-MS(ESI)m / z=227.0[M+H] + . Intermediate 14: 4-(3-chlorobenzyl)-1H-pyrazole hydrochloride

[0168] [ka]

[0169] The title compound was prepared as a light brown solid in two steps from 1-(bromomethyl)-3-chlorobenzene in the same manner as intermediate 6 (63%). 1 H-NMR (400MHz, DMSO-d6): δ13.01 (2H, brs), 7.95-7.79 (2H, m), 7.36-7.28 (2H, m), 7.25(1H,dt,J=7.9,1.5Hz), 7.21(1H,dt,J=7.3,1.4Hz), 3.87-3.83(2H,m). LC-MS(ESI)m / z=193.0[M+H] + .

[0170] Intermediate 15: 3-((1H-pyrazole-4-yl)methyl)benzonitrile [ka]

[0171] The title compound was prepared as a light brown solid from 3-(bromomethyl)-benzonitrile in two steps in the same manner as intermediate 6 (66%). 1 H NMR (400MHz, DMSO-d6): δ12.67(2H,brs), 7.85(2H,d,J=11.8Hz), 7.72(1H,d,J=1.9Hz ), 7.67(1H,dd,J=7.6,1.5Hz), 7.63-7.56(1H,m), 7.51(1H,t,J=7.7Hz), 3.91(2H,s). LC-MS(ESI)m / z=184.1[M+H] + . General synthesis reaction equations for amide analogs

[0172] [ka]

[0173] Examples Example 1: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0174] [ka]

[0175] Stage A: tert-butyl(S)-(5-methyl-4-oxo-7-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0176] At 0°C, a solution of (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid (intermediate 1, 0.100 g, 0.297 mmol) and piperidine (0.0350 mL, 0.357 mmol) was added to DIPEA (0.156 mL, 0.892 mmol) followed by HATU (0.170 g, 0.446 mmol). The reaction mixture was stirred at 0°C for 30 minutes. After terminating the reaction with water, the reaction mixture was extracted twice with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (DCM:SiO=1:1) to obtain tert-butyl(S)-(5-methyl-4-oxo-7-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[b]-[1,4]oxazepine-3-yl)carbamate (32.0 mg, 27%) as a white solid. 1 H-NMR (400MHz,MeOH-d4): δ7.45(1H,d,J=2.0Hz), 7.32-7.25(2H,m), 4.57(1H,dd,J=11.6,7.6Hz), 4.44(1H,dd,J=9.6,7.6 Hz), 4.30(1H,dd,J=11.6,9.6Hz), 3.79-3.61(2H,brs), 3.53-3.41(2H,brs), 3.39(3H,s), 1.78-1.51(6H,m), 1.40(9H,s).

[0177] Stage B: (S)-3-amino-5-methyl-7-(piperidine-1-carbonyl)-2,3-dihydrobenzo[b]-[1,4]oxazepine-4(5H)-onehydrochloride

[0178] At 0°C, a solution of tert-butyl(S)-(5-methyl-4-oxo-7-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (32.0 mg, 0.0790 mmol) in DCM (0.80 mL) was mixed with HCl (4 M solution in dioxane, 0.198 mL, 0.793 mmol). The reaction mixture was stirred at room temperature for 20 hours and concentrated under vacuum to provide (S)-3-amino-5-methyl-7-(piperidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one HCl (28.0 mg) as a colorless oil, which was used in the next reaction without further purification. 1 H-NMR (400MHz,MeOH-d4): δ7.49(1H,s), 7.33(2H,s), 4.67(1H,dd,J=9.6,7.6Hz), 4.52(1H,dd,J=11.2,9. 6Hz), 4.43(1H,dd,J=10.8,7.2Hz), 3.75-3.64(2H,m), 3.50-3.37(2H,m), 3.44(3H,s), 1.73-1.57(6H,m).

[0179] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0180] At 0°C, a solution of (S)-3-amino-5-methyl-7-(piperidine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (27.0 mg, 0.0790 mmol) in DCE (0.80 mL) was mixed with CDI (26.0 mg, 0.159 mmol) followed by TEA (0.0280 mL, 0.199 mmol). The reaction mixture was stirred at 0°C for 1 hour. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum.

[0181] To the residue solution in DCE (0.80 mL) at 0°C, 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6, 20.0 mg, 0.0950 mmol) was added, followed by TEA (0.0280 mL, 0.199 mmol). The reaction mixture was stirred at 40°C for 3 hours. After terminating the reaction with water, the reaction mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC on SiO2 (DCM:siRNA=1:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (17.0 mg, 42%) as a yellow form. 1 H-NMR (400MHz, CDCl3): δ8.02(1H,d,J=7.2Hz), 7.88(1H,d,J=0.8Hz), 7.48(1H ,s), 7.33(1H,d,J=1.6Hz), 7.28-7.19(3H,m), 6.96-6.85(3H,m), 4.94(1H,dt, J=11.2,7.2Hz), 4.73(1H,dd,J=9.6,7.6Hz), 4.34(1H,dd,J=11.2,9.6Hz), 3.8 1(2H,s), 3.80-3.59(2H,m), 3.51-3.36(2H,m), 3.44(3H,s), 1.75-1.58(6H,m). LC-MS:m / z=506.10[M+H] + .

[0182] Example 2: (S)-N-(7-(4,4-dimethylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0183] [ka]

[0184] Stage A: tert-butyl(S)-(7-(4,4-dimethylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0185] The title compound was prepared using intermediate 1 and 4,4-dimethylpiperidine hydrochloride in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:ELISA = 2:1 to 1:1) to provide tert-butyl(S)-(7-(4,4-dimethylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (94%) as a colorless oil. 1 H-NMR(400MHz,CDCl3)δ7.30(1H,d,J=1.6Hz), 7.21(1H,dd,J=8.0, 2.4Hz), 7.14(1H,d,J=8.4Hz), 5.53(1H,d,J=6.4Hz), 4.68(1H,dt,J=11.2,7.6Hz), 4.61(1H,dd,J=9.2,7.6Hz), 4.20(1H,dd,J=1 1.2,9.6Hz), 3.78-3.65(2H,m), 3.49-3.32(2H,m), 3.41(3H,s), 1.52-1.47(2H,m), 1.40(9H,s), 1.35-1.30(2H,m), 1.02(6H,s).

[0186] Stage B: (S)-3-amino-7-(4,4-dimethylpiperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0187] The title compound was prepared using tert-butyl(S)-(7-(4,4-dimethylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). 1H-NMR (400MHz,MeOH-d4): δ7.50(1H,d,J=1.2Hz), 7.33(2H,d,J=1.6Hz), 4.66(1H,dd,J=9.6,7.6Hz), 4.52(1H,dd,J=10.8,9. 6Hz), 4.42(1H,dd,J=10.8,7.2Hz), 3.81-3.69(2H,m), 3.52-3.38(2H,m), 3.44(3H,s), 1.48(2H,m), 1.36(2H,m), 1.03(6H,s).

[0188] Stage C: (S)-N-(7-(4,4-dimethylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0189] The title compound was prepared in the same manner as in Example 1 (Step C) using (S)-3-amino-7-(4,4-dimethylpiperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by preparative TLC on SiO2 (DCM:ELISA=5:1) to provide (S)-N-(7-(4,4-dimethylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (44% between the two steps) as a white foam. 1H-NMR (400MHz, CDCl3): δ8.01(1H,d,J=7.2Hz), 7.88(1H,s), 7.48(1H,s), 7.33(1H,d ,J=2.0Hz), 7.28-7.19(3H,m), 6.97-6.85(3H,m), 4.93(1H,dt,J=11.2,7.2Hz), 4.73 (1H,dd,J=9.6,7.6Hz), 4.34(1H,dd,J=11.2,9.6Hz), 3.82(2H,s), 3.79-3.63(2H,m) , 3.53-3.37(2H,m), 3.45(3H,s), 1.54-1.42(2H,m), 1.41-1.29(2H,m), 1.02(6H,s). LC-MS:m / z=534.20[M+H] + .

[0190] Example 3: ((S)-N-(7-(4,4-difluoropiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0191] [ka]

[0192] Stage A: tert-butyl(S)-(7-(4,4-difluoropiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0193] The title compound was prepared using intermediate 1 and 4,4-difluoropiperidine hydrochloride in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography on SiO2 (DCM:ELISA=3:1) to provide tert-butyl(S)-(7-(4,4-difluoropiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (98%) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.33(1H,d,J=1.6Hz), 7.23(1H,dd,J=8.0,1.6Hz), 7.18(1H,d,J=8.0Hz), 5.56(1H,d,J=6.8Hz), 4.69(1H,dt,J= 11.6,6.8Hz), 4.60(1H,dd,J=9.6,6.8Hz), 4.22(1H,dd,J=11.6,9.6Hz), 4.05-3.49(4H,m), 3.42(3H,s), 2.22-1.90(4H,m), 1.40(9H,s).

[0194] Stage B: (S)-3-amino-7-(4,4-difluoropiperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0195] The title compound was prepared using tert-butyl(S)-(7-(4,4-difluoropiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). 1 H-NMR (400MHz,MeOH-d4): δ7.56(1H,d,J=2.0Hz), 7.40(1H,dd,J=8.4,2.0Hz), 7.33(1H,d,J=8.4Hz), 4.66(1H,dd,J=9.6,7.2Hz), 4.52(1H,dd,J=11.2,9.6Hz), 4.42(1H,dd,J=10.8,7.2Hz), 3.95-3.76(2H,m), 3.75-3.53(2H,m), 3.45(3H,s), 2.07-1.99(4H,m).

[0196] Stage C: ((S)-N-(7-(4,4-difluoropiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0197] The title compound was prepared in the same manner as in Example 1 using (S)-3-amino-7-(4,4-difluoropiperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:ELISA=8:1) to provide (S)-N-(7-(4,4-difluoropiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (52% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.01(1H,d,J=6.8Hz), 7.88(1H,s), 7.48(1H,s), 7.37(1H,d,J=1.6Hz), 7.29-7.22, (3H,m), 6.97-6.85(3H,m), 4.94(1H ,dt,J=11.6,7.2Hz), 4.73(1H,dd,J=9.8,7.2Hz), 4.36(1H,dd,J=11.6,1 0.0Hz), 4.02-3.55(4H,m), 3.82(2H,s), 3.45(3H,s), 2.22-1.91(4H,m). LC-MS: m / z = 542.1 [M + H] + .

[0198] Example 4: (S)-4-(3-fluorobenzyl)-N-(7-(4-hydroxypiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0199] [ka]

[0200] Stage A: tert-butyl-(S)-(7-(4-hydroxypiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b]][1,4]oxazepine-3-yl)carbamate

[0201] The title compound was prepared using intermediate 1 and piperidine-4-ol in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 20:1) to provide tert-butyl-(S)-(7-(4-hydroxypiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (80%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.30(1H,d,J=1.8Hz), 7.22(1H,dd,J=8.2,1.8Hz), 7.15(1H,d,J=7.8Hz), 5.53(1H,d,J=6.9Hz), 4.71-4.65(1H,m), 4.60(1H,dd ,J=9.6,7.3Hz), 4.20(1H,dd,J=11.0,9.6Hz), 4.02(1H,td,J=7.9,3.8Hz),3 .41(3H,s), 3.35-3.20(2H,m), 2.02-1.84(2H,m), 1.48(4H,m), 1.40(9H,s).

[0202] Stage B: (S)-3-amino-7-(4-hydroxypiperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0203] The title compound was prepared using tert-butyl-(S)-(7-(4-hydroxypiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). LC-MS: m / z = 320.10 [M + H] + .

[0204] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-(4-hydroxypiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0205] The title compound was prepared in the same manner as in Example 1 (Step C) using (S)-3-amino-7-(4-hydroxypiperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:ELISA=10:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-(4-hydroxypiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (2% between the two steps) as a white form. 1 H-NMR (400MHz, CDCl3): δ8.01(1H,d,J=7.3Hz), 7.88(1H,s), 7.48(1H,s), 7.34(3H,d,J =1.8Hz), 7.24(3H,d,J=7.8Hz), 7.00-6.85(3H,m), 4.97-4.91(1H,m), 4.73(1H,dd,J=9 .6,7.3Hz), 4.35(1H,d,J=11.2,9.8Hz), 4.12-4.25(1H,m), 4.02(1H,m), 3.82(2H,s), 3 .44(3H,s), 3.37-3.39(1H,m), 2.01-1.91(2H,m), 1.34-1.28(2H,m), 0.89-0.82(2H,m). LC-MS:m / z=522.10[M+H] +

[0206] Example 5: (S)-4-(3-fluorobenzyl)-N-(7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0207] [ka]

[0208] Stage A: tert-butyl(S)-(7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0209] The title compound was prepared using intermediates 1 and 4-methylpiperidine-4-ol in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography on SiO2 (siRNA:MeOH=9:1) to provide tert-butyl(S)-(7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (89%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.31(1H,s), 7.22(1H,dd,J=8.0,2.0Hz), 7.15(1H,d,J=8.0Hz), 5.55(1H,d,J=6.8Hz), 4.71-4.65(1H,dt,11.6,6.8H z), 4.61(1H,dd,J=9.6,7.6Hz), 4.20(1H,dd,J=11.2,9.6Hz), 3.65-3.25(3H,br), 3.41(3H,s), 1.78-1.50(5H,br), 1.40(9H,s), 1.32(3H,s).

[0210] Stage B: (S)-3-amino-7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0211] The title compound was prepared using tert-butyl(S)-(7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). LC-MS: m / z = 334.10 [M + H] + .

[0212] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0213] The title compound was prepared in the same manner as in Example 1 (Step C) using (S)-3-amino-7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography over SiO2 (ELISA:MeOH=30:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (67% between the two steps) as a pale yellow form. 1H-NMR (400MHz, CDCl3): δ8.02(1H,d,J=7.2Hz), 7.88(1H,s), 7.48(1H,s), 7.34( 1H,d,J=1.6Hz), 7.28-7.24(2H,m), 7.21(1H,d,J=8.2Hz), 6.97-6.85(3H,m), 4. 94(1H,dt,11.6,7.2Hz), 4.73(1H,dd,J=9.6,7.6Hz), 4.35(1H,d,J=11.2,9.6Hz ), 3.81(2H,s), 3.68-3.27(3H,m), 3.44(3H,s), 1.80-1.48(5H,m), 1.32(3H,s). LC-MS:m / z=536.20[M+H] + .

[0214] Example 6: (S)-4-(3-fluorobenzyl)-N-(7-(4-(2-hydroxypropan-2-yl)piperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0215] [ka]

[0216] Stage A: (S)-(7-(4-(2-hydroxypropan-2-yl)piperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0217] The title compound was prepared using intermediates 1 and 2-(piperidine-4-yl)propan-2-ol in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography on SiO2 (DCM:MeOH=25:1) to provide tert-butyl(S)-(7-(4-(2-hydroxypropan-2-yl)piperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (94%) as a yellow foam. 1H-NMR (400MHz, CDCl3): δ7.31(1H,s), 7.22(1H,d,J=7.6Hz), 7.15(1H,d,J=8.4Hz), 5.53(1H,d ,J=6.8Hz), 4.91-4.73(1H,brs), 4.68(1H,dt,J=11.6,6.8Hz), 4.61(1H,dd,J=9.6,7.2Hz),4. 20(1H,dd,J=11.2,9.6Hz), 3.98-3.82(1H,brs), 3.41(3H,s), 3.13-2.93(1H,brs), 2.78-2.63 (1H,brs), 1.98-1.74(2H,brs), 1.61-1.54(1H,m), 1.40(9H,s), 1.23-1.37(2H,m), 1.22(6H,s)

[0218] Stage B: (S)-3-amino-7-(4-(2-hydroxypropan-2-yl)piperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0219] The title compound was prepared using tert-butyl(S)-(7-(4-(2-hydroxypropan-2-yl)piperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). 1 H-NMR(400MHz,MeOH-d4): δ7.51(1H,d,J=3.6Hz), 7.34(2H,d,J=2.0Hz), 4.77- 4.71(1H,brs), 4.67(1H,dd,J=9.6,7.2Hz), 4.52(1H,dd,J=11.2,9.6Hz), 4.43 (1H,dd,J=11.2,7.2Hz), 3.89-3.77(1H,brs), 3.45(3H,s), 3.20-3.07(1H,brs ), 2.80(1H,m), 2.08-1.63(3H,m), 1.58(3H,s), 1.48-1.28(2H,m), 1.17(3H,s).

[0220] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-(4-(2-hydroxypropan-2-yl)piperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0221] The title compound was prepared in the same manner as in Example 1 (Step C) using (S)-3-amino-7-(4-(2-hydroxypropan-2-yl)piperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl = 1:3~1:5) to provide (S)-4-(3-fluorobenzyl)-N-(7-(4-(2-hydroxypropan-2-yl)piperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (25% between the two steps) as a white foam. 1 H-NMR(400MHz,CDCl3)δ8.02(1H,d,J=6.8Hz), 7.89(1H,s), 7.48(1H,s), 7.35(1H,d,J=1.2Hz), 7.31-7. 20(3H,m), 6.97-6.85(3H,m), 4.94(1H,dt,J=11.2,7.2Hz), 4.88-4.80(1H,brs), 4.73(1H,dd,J=9.6,7. 2Hz), 4.35(1H,dd,J=11.2,9.6Hz), 3.97-3.85(1H,brs), 3.81(2H,s), 3.45(3H,s), 3.15-2.92(1H,brs) , 2.83-2.63(1H,brs), 2.00-1.74(2H,m), 1.58(1H,tt,J=12.0,3.2Hz), 1.40-1.24(2H,m), 1.21(6H,s). LC-MS:m / z=564.1[M+H] + .

[0222] Example 7: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(4-methylpiperazine-1-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0223] [ka]

[0224] Stage A: tert-butyl(S)-(5-methyl-7-(4-methylpiperazine-1-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0225] The title compound was prepared using intermediate 1 and 1-methylpiperazine in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography over SiO2 (petroleum ether: SiO = 1:1) to provide tert-butyl(S)-(5-methyl-7-(4-methylpiperazine-1-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (92%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.32(1H,d,J=1.6Hz), 7.23(1H,dd,J=8.4,2.0Hz), 7.16(1H,d,J=8.4Hz), 5.56(1H,d,J=6.8Hz), 4.68(1H,dt,J=11.2,7.2H z), 4.60(1H,dd,J=9.2,7.6Hz), 4.21(1H,dd,J=10.8,9.6Hz), 3.81(2H,br s), 3.50(2H,brs), 3.41(3H,s), 2.49(4H,brs), 2.37(3H,s), 1.40(9H,s).

[0226] Stage B: (S)-3-amino-5-methyl-7-(4-methylpiperazine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0227] The title compound was prepared using tert-butyl(S)-(5-methyl-7-(4-methylpiperazine-1-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). LC-MS: m / z = 319.1 [M + H] + .

[0228] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(4-methylpiperazine-1-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0229] The title compound was prepared in the same manner as in Example 1 (Step C) using (S)-3-amino-5-methyl-7-(4-methylpiperazine-1-carbonyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by preparative TLC on SiO2 (siRNA:MeOH=3:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(4-methylpiperazine-1-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (6% between the two steps) as a white solid. 1 H-NMR (400MHz, CDCl3): δ8.01(1H,d,J=7.2Hz), 7.88(1H,d,J=0.8Hz), 7.48(1 H,s), 7.35(1H,d,J=1.6Hz), 7.28-7.21(3H,m), 6.97-6.85(3H,m), 4.94(1H,d t,J=11.6,7.2Hz), 4.72(1H,dd,J=9.6,7.6), 4.35(1H,dd,J=11.6,10.0Hz),3 .82(2H,s), 3.62-3.48(4H,br), 3.45(3H,s), 2.51-2.44(4H,m), 2.34(3H,s). LC-MS: m / z = 521.2 [M + H] + .

[0230] Example 8: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(4-methylpiperazine-1-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0231] [ka]

[0232] Stage A: Benzyl(S)-4-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carbonyl)piperazine-1-carboxylate

[0233] The title compound was prepared using intermediate 1 and benzylpiperazine-1-carboxylate in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography over SiO2 (petroleum ether: SiO=1:1) to provide benzyl(S)-4-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carbonyl)piperazine-1-carboxylate (71%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.39-7.34(5H,m), 7.32(1H,d,J=1.6Hz), 7.22(1H,dd,J=8.4,2.0Hz), 7.17(1H,d,J=8.0Hz), 5.55(1H,d,J=7.2Hz), 5. 16(2H,s), 4.68(1H,dt,J=11.2,7.2Hz), 4.59(1H,dd,J=9.6,7.2Hz),4. 21(1H,dd,J=11.6,9.6Hz), 3.85-3.43(8H,m), 3.41(3H,s), 1.40(9H,s).

[0234] Stage B: tert-butyl(S)-(5-methyl-7-(4-methylpiperazine-1-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0235] The title compound was prepared using benzyl(S)-4-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carbonyl)piperazine-1-carboxylate in the same manner as in Example 1 (Step B). LC-MS: m / z = 439.10 [M + H] + .

[0236] Stage C: Benzyl(S)-4-(3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carbonyl)piperazine-1-carboxylate

[0237] The title compound was prepared in the same manner as in Example 1 (Step C) using benzyl(S)-4-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carbonyl)piperazine-1-carboxylate hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography over SiO2 (petroleum ether: ELISA = 1:3 to 1:5) to provide benzyl(S)-4-(3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carbonyl)piperazine-1-carboxylate (57% between the two steps) as a colorless oil. 1H-NMR (400MHz, CDCl3): δ8.00(1H,d,J=7.2Hz), 7.88(1H,s), 7.48(1H,s), 7.41-7.31(5H,m), 7.28-7.22(3H,m), 6.97-6.86(3H,m), 5.16(2H, s), 4.94(1H,dt,J=11.2,7.2Hz), 4.72(1H,dd,J=10.0,7.2Hz), 4.36(1H,dd,J=11.2,10.0Hz), 3.90-3.48(8H,br), 3.82(2H,s), 3.44(3H,s),

[0238] Stage D: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(4-methylpiperazine-1-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0239] A suspension of benzyl(S)-4-(3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carbonyl)piperazine-1-carboxylate (38.0 mg, 0.0590 mmol) and 10% Pd / C (6.31 mg, 5.93 μmol) was stirred at room temperature for 18 hours under H2 atmosphere (1 atm). The reaction mixture was filtered through a Celite pad and washed with MeOH. The filtrate was concentrated under vacuum. The residue was purified by column chromatography on SiO2 (DCM:MeOH = 10:1~8:1) to obtain (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(piperazine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (6.00 mg, 20%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=6.8Hz), 7.87(1H,s), 7.46(1H,s), 7.33(1H,d,J=1.6Hz), 7.26-7.19(3H,m), 6.95-6.83(3H,m), 4.92(1H,dt ,J=11.6,7.2Hz), 4.71(1H,dd,J=9.6,7.2Hz), 4.33(1H,dd,J=11.2,10.0 Hz), 3.86-3.37(4H,brs), 3.80(2H,s), 3.43(3H,s), 3.02-2.78(4H,brs). LC-MS: m / z = 507.0 [M + H] + .

[0240] Example 9: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(morpholine-4-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0241] [ka]

[0242] Stage A: (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid

[0243] The title compound was prepared using intermediate 1 and morpholine in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography over SiO2 (petroleum ether: SiO = 1:2 to 1:3) to provide tert-butyl(S)-(5-methyl-7-(morpholine-4-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (91%) as a pale yellow solid. 1H-NMR (400MHz, CDCl3): δ7.33(1H,d,J=1.6Hz), 7.22(1H,dd,J=8.4,1.6Hz), 7.16(1H,d,J=8.4Hz), 5.56(1H,d,J=7.6Hz), 4.6 8(1H,dt,J=11.2,7.2Hz), 4.59(1H,dd,J=9.6,7.2Hz), 4.21(1H,dd,J=11.2,9.6Hz), 3.73(8H,brs), 3.42(3H,s), 1.40(9H,s).

[0244] Stage B: (S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid

[0245] The title compound was prepared using tert-butyl(S)-(5-methyl-7-(morpholine-4-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). 1 H-NMR (400MHz, DMSO-d6): δ8.60(2H,s), 7.57(1H,s), 7.33(2H,s), 4.62(1H,dd,J=9.6,7.6Hz), 4.48 (1H,dd,J=10.8,10.4Hz), 4.40(1H,dd,J=10.4,7.2Hz), 3.63(4H,brs), 3.41(4H,brs), 3.36(3H,s).

[0246] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(morpholine-4-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0247] The title compound was prepared in the same manner as in Example 1 (Step C) using (S)-3-amino-5-methyl-7-(morpholine-4-carbonyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-on hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography over SiO2 (petroleum ether: ELISA = 1:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(morpholine-4-carbonyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (56% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.01(1H,d,J=7.2Hz), 7.88(1H,d,J=0.8Hz,), 7.48(1H,s), 7.37(1H,d,J=1.6Hz), 7.28-7.22(3H,m), 6.97-6.85(3H ,m), 4.94(1H,dt,J=11.6,7.2Hz), 4.72(1H,dd,J=9.6,7.2Hz), 4.36(1H,dd,J=11.6,9.6Hz), 4.00-3.49(8H,brs), 3.82(2H,s), 3.45(3H,s). LC-MS:m / z=508.1[M+H] + .

[0248] Example 10: 4-(3-fluorobenzyl)-N-((3S)-7-(3-hydroxypyrrolidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0249] [ka]

[0250] Stage A: tert-butyl((3S)-7-(3-hydroxypyrrolidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0251] The title compound was prepared using intermediate 1 and pyrrolidine-3-ol in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 10:1) to provide tert-butyl((3S)-7-(3-hydroxypyrrolidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (93%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.45-7.32(2H,m), 7.16(1H,dd,J=8.0,4.0Hz), 5.56(1H,d,J=6.4Hz), 4.69-4.63(1H,m), 4.61-4.57(1H,m), 4.46 and 4.56(1 H,s), 4.21(1H,dd,J=11.2,9.6Hz), 3.85-3.74(2H,m), 3.67-3.60(1H,m), 3 .56-3.47(1H,m), 3.42-3.40(3H,m), 2.12-1.94(2H,m), 1.37-1.43(9H,s).

[0252] Stage B: (3S)-3-amino-7-(3-hydroxypyrrolidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0253] The title compound was prepared using tert-butyl((3S)-7-(3-hydroxypyrrolidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). 1H-NMR (400MHz,MeOH-d4): δ7.63(1H,s), 7.48(1H,d,J=6.4Hz), 7.34(1H,d,J=7.2Hz), 4.72-4.68(1H,m), 4.55(1H,t,J=10.5Hz), 4.4 3-4.35(1H,m), 4.54 and 4.42(1H,brs), 3.83-3.69(2H,m), 3.61-3.50(1H,m), 3.46(3H,d,J=5.6Hz), 3.39(1H,m), 2.13-1.98(2H,m).

[0254] Stage C: 4-(3-fluorobenzyl)-N-((3S)-7-(3-hydroxypyrrolidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0255] The title compound was prepared in the same manner as in Example 1 (Step C) using (3S)-3-amino-7-(3-hydroxypyrrolidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography over SiO2 (siRNA:MeOH=30:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (67% between the two steps) as a yellow form. 1H-NMR (400MHz, CDCl3): δ8.01(1H,d,J=7.6Hz), 7.88(1H,s), 7.49-7.37(3H,m), 7. 28-7.21(2H,m), 6.97-6.85(3H,m), 4.95-4.89(1H,dt,J=11.6,7.2Hz), 4.72(1H,d d,J=9.6,7.2Hz), 4.63 and 4.52(1H,brs), 4.35(1H,dd,J=11.2,10.0Hz), 3.86-3.7 4(2H,m), 3.81(2H,s), 3.69-3.52(2H,m), 3.45(3H,d,J=6.4Hz), 2.07-2.01(2H,m). LC-MS:m / z=508.1[M+H] + .

[0256] Example 11: (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide

[0257] [ka]

[0258] Stage A: tert-butyl(S)-(5-methyl-7-(methyl(pyridine-4-ylmethyl)carbamoyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0259] The title compound was prepared using intermediate 1 and N-methyl-1-(pyridine-4-yl)methaneamine in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 30:1) to provide tert-butyl(S)-(5-methyl-7-(methyl(pyridine-4-ylmethyl)carbamoyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (92%) as a white foam. 1H-NMR (400MHz, CDCl3): δ8.64(2H,d,J=3.6Hz), 7.47-7.06(5H,m), 5.62(1H,d,J=6.8Hz), 4.84-4.59(4H,m), 4.24-4.19(1H,m), 3.43-3.32(3H,m), 3.02-2.96(3H,m), 1.40(9H,s).

[0260] Stage B: (S)-3-amino-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide hydrochloride

[0261] The title compound was prepared using tert-butyl(S)-(5-methyl-7-(methyl(pyridine-4-yl)carbamoyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1. 1 H-NMR(400MHz,MeOH-d4): δ8.86(2H,d,J=6.0Hz), 8.11(2H,d,J=4.8Hz), 7.71(1H,s), 7.55(1H,d,J=8.0Hz), 7.39 (1H,d,J=8.0Hz), 5.06(2H,s), 4.72-4.66(1H,m), 4.61-4.52(1H,m), 4.48-4.42(1H,m), 3.48(3H,s), 3.19(3H,s).

[0262] Stage C: (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide

[0263] The title compound was prepared in the same manner as in Example 1 using (S)-3-amino-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl = 1:5) to provide (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide (49% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.64(2H,d,J=5.2Hz), 7.99(1H,d,J=6.8Hz), 7.87(1H,s), 7.47(1H,s), 7.44-7.12(6H,m), 6. 96-6.85(3H,m), 4.91(1H,s), 4.75-4.72(3H,m), 4.38-4.33(1H,m), 3.81(2H,s), 3.51-3.30(3H,m), 3.13-2.99(3H,m). LC-MS:m / z=543.2[M+H] + .

[0264] Example 12: (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide

[0265] [ka]

[0266] Stage A: tert-butyl(S)-(5-methyl-7-(methyl(pyridine-4-yl)carbamoyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0267] The title compound was prepared using intermediate 1 and N-methylpyridine-4-amine in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography on SiO2 (siRNA:MeOH=20:1) to provide tert-butyl(S)-(5-methyl-7-(methyl(pyridine-4-yl)carbamoyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (99%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.52(2H,d,J=6.4Hz), 7.24(1H,d,J=2.0Hz), 7.17(1H,dd,J=8.4,2.0Hz), 7.02-6.9 6(3H,m), 5.52(1H,d,J=6.0Hz), 4.62-4.53(2H,m), 4.21-4.14(1H,m), 3.54(3H,s), 3.19(3H,s), 1.40(9H,s).

[0268] Stage B: (S)-3-amino-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide hydrochloride

[0269] The title compound was prepared using tert-butyl(S)-(5-methyl-7-(methyl(pyridine-4-yl)carbamoyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). 1 H-NMR(400MHz,MeOH-d4): δ8.66(2H,d,J=7.2Hz), 7.94(2H,d,J=7.2Hz), 7.80(1H,d,J=1.6Hz), 7.53(1H,dd,J =8.8,1.6Hz), 7.33(1H,d,J=8.0Hz), 4.74(1H,dd,J=9.2,6.8Hz), 4.61-4.50(2H,m), 3.64(3H,s), 3.43(3H,s).

[0270] Stage C: (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide

[0271] The title compound was prepared in the same manner as in Example 1 using (S)-3-amino-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl = 1:5) to provide (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-N,5-dimethyl-4-oxo-N-(pyridine-4-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide (49% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.52(2H,dd,J=4.8,2.0Hz), 7.95(1H,d,J=7.6Hz), 7.88( 1H,d,J=0.8Hz), 7.46(1H,s), 7.28-7.21(3H,m), 7.07(1H,d,J=8.0Hz), 6.99(2H,d d,J=4.8,2.0Hz), 6.96-6.84(3H,m), 4.82(1H,dt,J=11.6,7.2Hz), 4.67(1H,dd,J= 9.6,7.2Hz), 4.32(1H,dd,J=11.2,9.6Hz), 3.81(2H,s), 3.55(3H,s), 3.21(3H,s). LC-MS:m / z=529.10[M+H] + .

[0272] Example 13: (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-N-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide

[0273] [ka]

[0274] Stage A: tert-butyl(S)-(7-((2-hydroxy-2-methylpropoxy)carbamoyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0275] The title compound was prepared using intermediate 1 and 1-(aminooxy)-2-methylpropan-2-ol in the same manner as in Example 1 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=3:1) to provide tert-butyl(S)-(7-((2-hydroxy-2-methylpropoxy)carbamoyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (35%) as a white solid. 1 H-NMR (400MHz,MeOH-d4): δ7.80(1H,d,J=2.0Hz), 7.68(1H,dd,J=8.4,2.0Hz), 7.28(1H,d,J=8.4Hz), 4.55(1H,dd,J=12.0,7.6H z), 4.44(1H,dd,J=9.6,7.2Hz), 4.33(1H,dd,J=12.0,10.0Hz), 3.88(2H,s), 3.62(1H,s), 3.41(3H,s), 1.41(9H,s), 1.29(6H,s).

[0276] Stage B: ((S)-3-amino-N-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide hydrochloride

[0277] The title compound was prepared using tert-butyl(S)-(7-((2-hydroxy-2-methylpropoxy)carbamoyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 1 (Step B). LC-MS: m / z = 324.1 [M + H] + .

[0278] Stage C: (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-N-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide

[0279] The title compound was prepared in the same manner as in Example 1 (Step C) using (S)-3-amino-N-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl=1:4) to provide (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-N-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide (6% between the two steps) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=7.2Hz), 7.88(1H,d,J=0.8Hz), 7.47 (1H,s), 7.27-7.22(1H,m), 7.13(1H,dd,J=6.8,2.8Hz), 6.96-6.82(5H,m), 4.91(1H,td,J=10.8,6.0Hz), 4.74(1H,d,J=2.0Hz), 4.67(1H,dd,J=10.0,7 .6Hz), 4.25(1H,dd,J=11.2,9.6Hz), 3.81(2H,s), 3.42(3H,s), 1.53(6H,s). LC-MS: m / z = 526.10 [M + H] +

[0280] Example 14: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-6-azaspiro[3,3]heptan-6-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0281] [ka]

[0282] Stage A: Methyl(S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate hydrochloride

[0283] At 0°C, a solution of methyl(S)-3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate (intermediate 1, step D, 0.500 g, 1.43 mmol) was added to HCl (4 M solution in dioxane, 3.57 mL, 14.3 mmol). The reaction mixture was stirred at room temperature for 20 hours. The precipitated solid was collected by filtration, washed with DCM, and dried under vacuum to provide methyl(S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate hydrochloride (0.392 g, 96%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ8.06(1H,d,J=1.6Hz), 7.96(1H,dd,J=8.4,1.6Hz), 7.36(1H,d,J=8.4Hz), 4.67(1H ,dd,J=10.0,7.2Hz), 4.55(1H,dd,J=11.6,10.0Hz), 4.39(1H,dd,J=11.2,7.2Hz), 3.93(3H,s), 3.46(3H,s).

[0284] Stage B: Methyl(S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate

[0285] The title compound was prepared in the same manner as in Example 1 (Step C) using methyl(S)-3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl=1:1) to provide methyl(S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate (93%) as a white foam.1 H-NMR (400MHz, CDCl3): δ8.00(1H,d,J=7.2Hz), 7.93(2H,m), 7.88(1H,d,J=1.2Hz), 7.48(1H,s), 7.28-7.23(2H,m), 6.96-6.85(3H ,m), 4.90(1H,dt,J=11.2,7.2Hz), 4.73(1H,dd,J=9.6,7.2Hz), 4.38(1H,dd,J=11.2,9.6Hz), 3.95(3H,s), 3.81(2H,s), 3.47(3H,s)

[0286] Stage C: (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid

[0287] A solution of methyl(S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylate (50.0 mg, 0.111 mmol) in THF (1.1 mL) at 0°C was mixed with 2 M aqueous LiOH hydrate (0.276 mL, 0.553 mmol). The reaction mixture was stirred at 10°C for 20 hours. After concentration under vacuum, the residue was diluted with water and treated with 1 M aqueous HCl. The precipitated solid was collected by filtration, washed with water, and dried under vacuum to provide (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]-oxazepine-7-carboxylic acid (34.0 mg, 70%) as a white solid. LC-MS: m / z = 439.0 [M + H] + .

[0288] Stage D: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-6-azaspiro[3,3]heptan-6-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0289] At 0°C, a solution of (S)-3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxylic acid (27.0 mg, 0.0620 mmol) and 2-oxa-6-azaspiro[3.3]heptane (6.11 mg, 0.0620 mmol) was added to DMSO (0.62 mL) at 0°C, followed by DIPEA (0.0320 mL, 0.185 mmol) and then HATU (35.0 mg, 0.0920 mmol). The reaction mixture was stirred at 0°C for 30 minutes. After terminating the reaction with water, the mixture was extracted twice with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (DCM:MeOH = 30:1), and (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-6-azaspiro[3.3]heptan-6-carbonyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (21 mg, 66%) was provided as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.00(1H,d,J=6.8Hz), 7.88(1H,d,J=0.8Hz), 7.61(1H,d,J=1.6H z), 7.48(1H,s), 7.42(1H,dd,J=8.0,2.0Hz), 7.28-7.24(1H,m), 7.22(1H,d,J=8.0Hz), 6. 97-6.85(3H,m), 4.91(1H,dt,J=11.6,7.6Hz), 4.84(4H,d,J=7.6Hz), 4.72(1H,dd,J=9.6, 7.6Hz), 4.51(2H,s), 4.37(2H,s), 4.36(1H,dd,J=11.6,9.6Hz), 3.81(2H,s), 3.45(3H,s). LC-MS:m / z=520.10[M+H] + . General synthesis reaction equations for ether analogs

[0290] [ka]

[0291] Example 15: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((4-methylpentyl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0292] [ka]

[0293] Stage A: tert-butyl(S)-(5-methyl-7-((4-methylpentyl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0294] At 0°C, a solution of tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (intermediate 2, 0.150 g, 0.486 mmol) and 4-methylpentylmethanesulfonate (0.105 g, 0.584 mmol) was prepared in DMF (4.9 mL) and Cs2CO3 (0.317 g, 0.973 mmol). The reaction mixture was stirred at room temperature for 20 hours. After terminating the reaction with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:SiO=5:1) to obtain tert-butyl(S)-(5-methyl-7-((4-methylpentyl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (0.191 g, 100%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.04(1H,dd,J=7.2,0.8Hz), 6.71-6.68(2H,m), 5.51(1H,d ,J=7.6Hz), 4.65(1H,dt,J=11.2,7.2Hz), 4.52(1H,dd,J=9.6,7.2Hz), 4.22(1H,t,J= 6.4Hz), 4.09-4.07(1H,m), 3.91(2H,t,J=6.4Hz), 3.38(3H,s), 3.01(2H,s), 1.82-1 .72(2H,m), 1.67-1.55(1H,m), 1.40(9H,s), 1.28-1.38(2H,m), 0.93(6H,d,J=6.4Hz)

[0295] Stage B: (S)-3-amino-5-methyl-7-((4-methylpentyl)oxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0296] At 0°C, a solution of tert-butyl(S)-(5-methyl-7-((4-methylpentyl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b]][1,4]oxazepine-3-yl)carbamate (0.191 g, 0.487 mmol) in DCM (4.9 mL) was added to HCl (4 M solution in dioxane, 1.22 mL, 4.87 mmol). The reaction mixture was stirred at room temperature for 5 hours. After concentration under vacuum, the residue was allowed to solidify from DCM and Et2O. The solid was collected by filtration and dried under vacuum to provide (S)-3-amino-5-methyl-7-((4-methylpentyl)oxy)-2,3-dihydrobenzo[b]][1,4]oxazepine-4(5H)-onehydrochloride (0.123 g, 77%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.05(1H,d,J=8.8Hz), 6.72(1H,d,J=2.8Hz), 6.69(1H,dd,J=8.8,2.8Hz), 4.84-4.72(2H,m), 4.45(1H,dd, J=10.4,8.0Hz), 3.94-3.84(2H,m), 3.26(3H,s), 1.80-1.73(2H,m), 1.66-1.56(1H,m), 1.35-1.30(2H,m), 0.93(3H,s), 0.91(3H,s)

[0297] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((4-methylpentyl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0298] At 0°C, a solution of (S)-3-amino-5-methyl-7-((4-methylpentyl)oxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (0.123 g, 0.374 mmol) in DCE (3.7 mL) was mixed with CDI (0.121 g, 0.748 mmol) followed by TEA (0.130 ml, 0.935 mmol). The reaction mixture was stirred at 0°C for 1.5 hours. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum.

[0299] To a solution of the residue in DCE (3.7 mL) at 0°C, 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6, 0.0950 g, 0.449 mmol) was added, followed by TEA (0.130 mL, 0.935 mmol). The reaction mixture was stirred at 40°C for 16 hours. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:SiO=5:1) to obtain (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((4-methylpentyl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]-oxazepine-3-yl)-1H-pyrazole-1-carboxamide (0.127 g, 68%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.6Hz), 7.88(1H,d,J=0.8Hz), 7.47(1H,s), 7.28-7.22 (1H,m), 7.10(1H,dd,J=6.8,2.8Hz), 6.96-6.85(3H,m), 6.75(2H,m), 4.90(1H,dt,J=10.8,7.6H z), 4.66(1H,dd,J=10.0,7.6Hz), 4.24(1H,dd,J=10.8,9.6Hz), 3.93(2H,t,J=6.4Hz), 3.81(2H ,s), 3.42(3H,s), 1.83-1.76(2H,m), 1.63(1H,m), 1.38-1.32(2H,m), 0.94(3H,s), 0.92(3H,s). LC-MS:m / z=495.20[M+H] + .

[0300] Example 16: (S)-N-(7-(3-cyclohexylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0301] [ka]

[0302] Stage A: tert-butyl(S)-(7-(3-cyclohexylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0303] The title compound was prepared using intermediates 2 and 3-cyclohexylpropylmethanesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography over SiO2 (hexane:siRNA=5:1) to provide tert-butyl(S)-(7-(3-cyclohexylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]-oxazepine-3-yl)carbamate (86%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.04(1H,dd,J=7.2,2Hz), 6.70-6.68(2H,m), 5.49(1H,d,J=7.2Hz), 4.65(1H,dt,J=10.8,7.2Hz), 4.52(1H,dd,J=9.6, 7.2Hz), 4.09(1H,dd,J=10.8,9.6Hz), 3.90(2H,t,J=6.8Hz), 3.38(3H,s ), 1.82-1.67(7H,m), 1.40(9H,s), 1.36-1.18(6H,m), 0.96-0.87(2H,m)

[0304] Stage B: (S)-3-amino-7-(3-cyclohexylpropoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0305] The title compound was prepared using tert-butyl(S)-(7-(3-cyclohexylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the residue was coagulated from DCM and isopropyl ether to provide (S)-3-amino-7-(3-cyclohexylpropoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride (83%) as a pale blue solid. 1 H-NMR (400MHz, CDCl3): δ7.05(1H,d,J=8.8Hz), 6.72-6.67(2H,m), 4.84-4.70(2H,m), 4.44(1H,dd,J= 11.2,8.8Hz), 3.93-3.84(2H,m), 3.27(3H,s), 1.81-1.64(7H,m), 1.35-1.10(6H,m), 0.95-0.85(2H,m)

[0306] Stage C: (S)-N-(7-(3-cyclohexylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0307] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-(3-cyclohexylpropoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl=5:1) to provide (S)-N-(7-(3-cyclohexylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (69%) as a colorless oil. 1H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=7.6Hz), 7.88(1H,d,J=0.8Hz), 7.47(1H,s), 7.28- 7.22(1H,m), 7.10(1H,dd,J=6.4,2.8Hz), 6.96-6.85(3H,m), 6.74(2H,m), 4.90(1H,dt,J= 11.2,7.6Hz), 4.66(1H,dd,J=10.4,9.6Hz), 4.24(1H,dd,J=11.2,9.6Hz), 3.93(2H,t,J=6 .4Hz), 3.81(2H,s), 3.41(3H,s), 1.83-1.65(7H,m), 1.37-1.13(6H,m), 0.97-0.85(2H,m). LC-MS:m / z=535.20[M+H] + .

[0308] Example 17: (S)-N-(7-(2-(dimethylamino)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0309] [ka]

[0310] Stage A: tert-butyl(S)-(7-(2-(dimethylamino)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0311] At 0°C, a solution of tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (intermediate 2, 130 mg, 0.442 mmol) and 2-(dimethylamino)ethane-1-ol (0.0630 mL, 0.632 mmol) was prepared in THF (4.0 mL) at 0°C. PPh3 (221 mg, 0.843 mmol) was added, followed by DIAD (0.164 mL, 0.843 mmol). The reaction mixture was stirred at room temperature for 2 hours. After concentration under vacuum, the residue was subjected to column chromatography on SiO2 (hexane:Â1=1~Â1:MeOH=10:1~Â1:MeOH:NH4OH=100:10:1), followed by purification by column chromatography on NH2-SiO2 (hexane:Â1~1:1), yielding tert-butyl(S)-(7-(2-(dimethylamino)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (40.0 mg, 25%) as a yellow oil. 1 H-NMR (400MHz, CDCl3): δ7.03(1H,d,J=8.8Hz), 6.75-6.70(2H,m), 5.46(1H,d,J=7.2Hz), 4.67-4.60(1H,m) , 4.51(1H,dd,J=9.6,7.2Hz), 4.10-4.00(3H,m), 3.36(3H,s), 2.77-2.67(2H,m), 2.37(6H,s), 1.38(9H,s).

[0312] Stage B: (S)-3-amino-7-(2-(dimethylamino)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0313] The title compound was prepared using tert-butyl(S)-(7-(2-(dimethylamino)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 280.1 [M + H] + .

[0314] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(3-(pyrrolidine-1-yl)prop-1-in-1-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0315] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-(2-(dimethylamino)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography over SiO2 (DCM:MeOH = 50:1~20:1) to provide (S)-N-(7-(2-(dimethylamino)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (16% between the two steps) as a yellow oil. 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.2Hz), 7.86(1H,s), 7.45(1H,s), 7.2 9-7.21(1H,m), 7.09(1H,d,J=8.8Hz), 6.98-8.84(3H,m), 6.78-6.74(2H,m), 4. 92-4.85(1H,m), 4.65(1H,dd,J=9.6,7.6Hz), 4.23(1H,dd,J=10.8,10.0Hz),4. 05(2H,t,J=5.8Hz), 3.80(2H,s), 3.39(3H,s), 2.79-2.69(2H,m), 2.35(6H,s). LC-MS:m / z=482.1[M+H] + .

[0316] Example 18: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0317] [ka]

[0318] Stage A: tert-butyl-(S)-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0319] A mixture of tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (intermediate 2, 91.0 mg, 0.290 mmol), 1-(2-chloroethyl)-4-methylpiperidine-4-ol (100 mg, 0.560 mmol), NaI (4.00 mg, 0.030 mmol), and K2CO3 (123 mg, 0.890 mmol) in DMF (1.0 mL) was stirred at 80°C for 4 hours. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (DCM:MeOH = 10:1), and tert-butyl-(S)-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (50.0 mg, 59%) was provided as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.04(1H,d,J=8.7Hz), 6.74-6.70(2H,m), 5.47(1H,d,J=7.3Hz), 4.68-4.61(1H,m), 4.52(1H,dd,J=9.6,7. 3Hz), 4.09(3H,dd,J=11.2,9.8Hz), 3.37(3H,s), 2.83-2.60(4H,m), 1.82-1.73(2H,m), 1.65-1.59(4H,m), 1.39(9H,s), 1.27(3H,s).

[0320] Stage B: (S)-3-amino-7-(2-(4-hydroxy-4-methylpiperidine-1-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0321] The title compound was prepared using tert-butyl-(S)-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 350.10 [M + H] + .

[0322] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0323] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-(2-(4-hydroxy-4-methylpiperidine-1-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:MeOH=20:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (42% between the two steps) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,s), 7.47(1H,s), 7.24-7.22(1H,m), 7.10( 1H,dd,J=6.6,2.5Hz), 7.00-6.85(3H,m), 6.76(2H,dd,J=7.3,2.7Hz), 4.93-4.86(1H,m), 4.65(1H, dd,J=9.8,7.5Hz), 4.24(1H,dd,J=11.2,9.8Hz), 4.10(2H,t,J=5.9Hz), 3.81(2H,s), 3.41(3H,s), 2 .84(2H,t,J=5.7Hz), 2.71-2.69(2H,m), 2.55-2.49(2H,m), 1.73(2H,m), 1.63(2H,m), 1.26(3H,s). LC-MS:m / z=552.20[M+H] + .

[0324] Example 19: (S)-4-(3-fluorobenzyl)-N-(7-(2-(2-hydroxyethoxy)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0325] [ka]

[0326] Stage A: tert-butyl(S)-(5-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0327] The title compound was prepared using intermediate 2 and 2-(2-hydroxyethoxy)ethyl 4-methylbenzene sulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO = 1:4~1:9) to provide tert-butyl(S)-(7-(2-(2-hydroxyethoxy)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (86%) as a white solid. LC-MS: m / z = 341.1 [M-tBu+H] + .

[0328] Stage B: (S)-3-amino-7-(2-(2-hydroxyethoxy)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0329] The title compound was prepared using tert-butyl(S)-(7-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR (400MHz, CDCl3): δ7.05(1H,dd,J=8.8,2.0Hz), 6.77-6.75(1H,m), 6.72(1H,td,J=8.8,2.4Hz), 4.4 1-4.36(1H,m), 4.15-4.11(2H,m), 4.08-4.02(1H,m), 3.89-3.56(2H,m), 3.78-3.67(5H,m), 3.38(3H,s).

[0330] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-(2-(2-hydroxyethoxy)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0331] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-(2-(2-hydroxyethoxy)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:4) to provide (S)-4-(3-fluorobenzyl)-N-(7-(2-(2-hydroxyethoxy)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (17% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.6Hz), 7.88(1H,s), 7.47(1H,s), 7.27-7.22(1H, m), 7.11(1H,d,J=8.4Hz), 6.96-6.93(1H,m), 6.91-6.84(2H,m), 6.80-6.76(2H,m), 4.90( 1H,td,J=11.2,7.0Hz), 4.65(1H,dd,J=9.6,7.6Hz), 4.25(1H,dd,J=11.2,10.4Hz), 4.14( 2H,s), 3.90-3.87(2H,m), 3.81-3.77(4H,m), 3.70-3.68(2H,m), 3.41(3H,s), 2.35(6H,s). LC-MS:m / z=499.0[M+H] + .

[0332] Example 20: (S)-4-(3-fluorobenzyl)-N-(7-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0333] [ka]

[0334] Stage A: tert-butyl(S)-(7-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0335] A solution of tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (intermediate 2, 130 mg, 0.422 mmol) was added to DMF (4.0 mL) at room temperature, followed by 2,2-dimethyloxirane (3.74 mL, 4.22 mmol) and then Cs2CO3 (412 mg, 1.27 mmol). The reaction mixture was stirred at 60°C for 24 hours. After terminating the reaction with water, the mixture was extracted twice with ELISA. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to obtain tert-butyl(S)-(7-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (40.0 mg, 24%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.05(1H,d,J=7.6Hz), 6.74-6.70(2H,m), 5.45(1H,d,J=7.6Hz), 4.66-4.60(1H,m), 4. 51(1H,dd,J=9.6,7.2Hz), 4.13-4.06(1H,m), 3.75(2H,s), 3.38(3H,s), 2.13(1H,s), 1.38(9H,s), 1.36(6H,s).

[0336] Stage B: (S)-3-amino-7-(2-hydroxy-2-methylpropoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0337] The title compound was prepared using tert-butyl(S)-(7-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 281.1 [M + H] + .

[0338] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0339] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-(2-hydroxy-2-methylpropoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl=3:1~HCl only) to provide (S)-4-(3-fluorobenzyl)-N-(7-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (63% between the two steps) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.96(1H,d,J=7.2Hz), 7.86(1H,s), 7.46(1H,s), 7.25-7.23(1H,m), 7.11-7.10(1H,m), 6.95-6.82(3H,m), 6.78-6.7 5(2H,m), 4.92-4.85(1H,m), 4.65(1H,dd,J=9.6,7.2Hz), 4.24(1H,dd,J=11.6,10.4Hz), 3.80(2H,s), 3.78(2H,s), 3.41(3H,s), 1.35(6H,s). LC-MS:m / z=483.1[M+H]+ .

[0340] Example 21: (S)-4-(3-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0341] [ka]

[0342] Stage A: tert-butyl(S)-(7-(3-hydroxy-3-methylbutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0343] The title compound was prepared using intermediates 2 and 3-hydroxy-3-methylbutyl-4-methylbenzenesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO = 5:1 to 1:1) to provide tert-butyl(S)-(7-(3-hydroxy-3-methylbutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (93%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.07-7.04(1H,m), 6.74-6.71(2H,m), 5.47(1H,d,J=7.2Hz), 4.65(1H,td,J=11.6,5.6Hz), 4.52(1H ,dd,J=9.6,8.0Hz), 4.15(2H,t,J=6.4Hz), 4.12-4.07(1H,m), 3.38(3H,s), 2.00(1H,t,J=6.4Hz), 1.39(9H,s), 1.33(6H,s).

[0344] Stage B: (S)-3-amino-7-(3-hydroxy-3-methylbutoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0345] The title compound was prepared using tert-butyl(S)-(7-(3-hydroxy-3-methylbutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 295.1 [M + H] + .

[0346] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0347] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-N-(2-hydroxy-2-methylpropoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-carboxamide hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl=1:4) to provide (S)-4-(3-fluorobenzyl)-N-(7-(3-hydroxy-3-methylbutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (60% between the two steps) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=8.0Hz), 7.88(1H,s), 7.46(1H,s), 7.27-7. 22(1H,m), 7.10(1H,d,J=8.0Hz), 6.96-6.85(3H,m), 6.78-6.75(2H,m), 4.90(1H,t d,J=10.8,5.6Hz), 4.65(1H,dd,J=10.0,7.6Hz), 4.24(1H,dd,J=11.2,10.0Hz),4. 17(2H,t,J=6.4Hz), 3.80(2H,s), 3.41(3H,s), 2.00(2H,t,J=6.4Hz), 1.32(6H,s). 496.54;LC-MS:m / z=497.1[M+H] + .

[0348] Example 22: (S)-4-(3-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0349] [ka]

[0350] Stage A: tert-butyl(S)-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0351] The title compound was prepared using intermediates 2 and 5-chloro-2-methylpento-3-in-2-ol in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO = 4:1 to 1:1) to provide tert-butyl(S)-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (93%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ7.08-7.05(1H,m), 6.79-6.77(2H,m), 5.48(1H,d,J=7.2Hz), 4.72 -4.61(3H,m), 4.55-4.50(1H,m), 4.16-4.07(2H,m), 3.80(3H,s), 1.51(6H,s), 1.39(9H,s).

[0352] Stage B: (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0353] The title compound was prepared using tert-butyl(S)-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 305.1 [M + H] + .

[0354] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0355] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The residue was purified by column chromatography on SiO2 (hexane:SiO=1:4) to provide (S)-4-(3-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (67% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.2Hz), 7.87(1H,d,J=0.8Hz), 7.46(1H,s), 7.29-7.21(1H,m), 7.13-7.10(1H,m), 6.95-6.81(5H,m), 4.90( 1H,td,J=10.8,6.0Hz), 4.70(2H,d,J=2.0Hz), 4.64(1H,dd,J=10.0,8.0H z), 4.24(1H,dd,J=11.2,10.0Hz), 3.80(2H,s), 3.41(3H,s), 1.52(6H,s). LC-MS: m / z = 507.1 [M + H] + .

[0356] Example 23: (S)-4-(3-fluorobenzyl)-N-(7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0357] [ka]

[0358] Stage A: tert-butyl(S)-(7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0359] The title compound was prepared using intermediate 2 and 1-(3-chloroprop-1-in-1-yl)cyclohexane-1-ol in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide tert-butyl(S)-(7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (80%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.07(1H,dd,J=6.9,2.3Hz), 6.80(2H,dd,J=7.5,2.5Hz ), 5.47(1H,d,J=7.3Hz), 4.72(2H,d,J=2.3Hz), 4.68-4.61(1H,m), 4.53(1H,dd, J=9.6,7.3Hz), 4.10(1H,dd,J=11.4,9.6Hz), 3.38(3H,s), 1.89-1.86(2H,m), 1. 70-1.65(2H,m), 1.60-1.59(2H,m), 1.52-1.43(3H,m), 1.40(9H,s), 1.27(1H,m).

[0360] Stage B: (S)-3-amino-7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0361] The title compound was prepared using tert-butyl(S)-(7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR (400MHz, DMSO-d6): δ8.43(3H,s), 7.22-7.15(2H,m), 6.92(1H,dd,J=8.9,3.0Hz), 4.87(2H,s), 4.51(1H,dd,J=10.1,7.8Hz), 4.37( 1H,t,J=10.5Hz), 4.22(1H,dd,J=11.0,7.8Hz), 3.35(3H,s), 1.71-1.69(2H,m), 1.56-1.53(2H,m), 1.46-1.30(5H,m), 1.20-1.16(1H,m).

[0362] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0363] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl=1:2) to provide (S)-4-(3-fluorobenzyl)-N-(7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (55% between the two steps) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24 -7.22(1H,m), 7.13(1H,dd,J=6.6,2.5Hz), 6.96-6.83(5H,m), 4.93-4.86(1H,m), 4.75(2 H,d,J=1.4Hz), 4.67(1H,dd,J=9.8,7.5Hz), 4.25(1H,dd,J=11.2,9.8Hz), 3.81(2H,s), 3 .42(3H,s), 1.90-1.87(2H,m), 1.70-1.63(2H,m), 1.60-1.56(2H,m), 1.51-1.42(4H,m). LC-MS:m / z=547.10[M+H] + .

[0364] Example 24: (S)-4-(3-fluorobenzyl)-N-(7-((3-(1-hydroxycyclobutyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0365] [ka]

[0366] Stage A: tert-butyl(S)-(7-((3-(1-hydroxycyclobutyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0367] The title compound was prepared in the same manner as in Example 15 (Step A) using intermediate 2 and 1-(3-chloroprop-1-in-1-yl)cyclobutan-1-ol (117 mg, 0.811 mmol). The crude product was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to provide tert-butyl(S)-(7-((3-(1-hydroxycyclobutyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (24%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.07(1H,q,J=3.2Hz), 6.82-6.79(2H,m), 5.48(1H,d,J=7.3Hz), 4.73(2H,d,J=1.8Hz), 4.69-4.62(1H,m), 4.53 (1H,dd,J=9.6,7.3Hz), 4.11(1H,dd,J=11.2,9.8Hz), 3.38(3H,s), 2.45-2.39(2H,m), 2.30-2.21(3H,m), 1.89-1.75(2H,m), 1.40(9H,s).

[0368] Stage B: (S)-3-amino-7-((3-(1-hydroxycyclobutyl)prop-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0369] The title compound was prepared using tert-butyl(S)-(7-((3-(1-hydroxycyclobutyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR (400MHz,DMSO-d6): δ8.38(3H,s), 7.21(1H,d,J=8.7Hz), 7.15(1H,d,J=2.7Hz), 6.93(1H,dd,J=8.7,2.7Hz), 4.88(2H,s), 4. 50(1H,dd,J=9.6,7.8Hz), 4.36(1H,t,J=10.5Hz), 4.26(1H,dd,J=11.0,7.8Hz), 3.35(3H,s), 2.25-2.09(4H,m), 1.77-1.61(2H,m).

[0370] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-((3-(1-hydroxycyclobutyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0371] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:2) to provide (S)-4-(3-fluorobenzyl)-N-(7-((3-(1-hydroxycyclobutyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (48% between the two steps) as a white foam.1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24-7.22(1H,m), 7.13(1H,dt,J=8.8,1.4Hz), 6.96-6.84(5H,m), 4.94-4.87(1H,m ), 4.75(2H,d,J=1.4Hz), 4.67(1H), dd,J=9.6,7.3Hz), 4.26(1H,dd,J=11.0,10.1Hz ), 3.81(2H,s), 3.42(3H,s), 2.45-2.39(2H,m), 2.2-2.22(2H,m), 1.89-1.75(2H,m). LC-MS:m / z=519.10[M+H] + .

[0372] Example 25: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-((3-(pyridine-3-yl)prop-2-in-1-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0373] [ka]

[0374] Stage A: tert-butyl(S)-(5-methyl-4-oxo-7-((3-(pyridine-3-yl)prop-2-in-1-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0375] The title compound was prepared using intermediates 2 and 3-(pyridine-3-yl)prop-2-in-1-ylmethanesulfonate in ACN as a solvent, in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:siRNA = 4:1 to 1:1) to provide tert-butyl(S)-(5-methyl-4-oxo-7-((3-(pyridine-3-yl)prop-2-in-1-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (120 mg, 87%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ8.69(1H,d,J=1.2Hz), 8.56(1H,dd,J=4.8,1.6Hz), 7.74(1H,dt,J=8.4,1.6Hz), 7.30-7.25(1H,m), 7.10(1H,dd,J=7.2,2.0Hz ), 6.88-6.84(2H,m), 5.48(1H,d,J=7.6Hz), 4.92(2H,s), 4.70-4.63(1H,m) , 4.54(1H,dd,J=9.6,7.6Hz), 4.15-4.08(1H,m), 3.39(3H,s), 1.39(9H,s).

[0376] Stage B: (S)-3-amino-5-methyl-7-((3-(pyridine-3-yl)prop-2-in-1-yl)oxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-ondihydrochloride

[0377] The title compound was prepared using tert-butyl(S)-(5-methyl-4-oxo-7-((3-(pyridine-3-yl)prop-2-in-1-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1H-NMR(400MHz,DMSO-d6): δ8.74(1H,d,J=1.2Hz), 8.65(1H,dd,J=4.8,1.6Hz), 8.55(3H,d,J=3.6Hz), 8.02(1H,d,J=8.0Hz), 7.55(1H,dd,J=8.0,4.8Hz ), 7.25-7.21(2H,m), 7.00(1H,dd,J=8.8,3.2Hz)), 5.14(2H,s), 4.55(1H,d d,J=10.0,8.0Hz), 4.38(1H,t,J=10.4Hz), 4.25-4.23(1H,m), 3.36(3H,s).

[0378] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-((3-(pyridine-3-yl)prop-2-in-1-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0379] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-5-methyl-7-((3-(pyridine-3-yl)prop-2-in-1-yl)oxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-ondihydrochloride and 4-(3-fluorobenzyl)-1H-pyrazolehydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:ELISA=1:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-)7-((3-(pyridine-3-yl)prop-2-in-1-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (49% between the two steps) as a white foam. 1H-NMR (400MHz, CDCl3): δ8.69(1H,t,J=1.2Hz), 8.56(1H,dd,J=4.8,1.6Hz), 7.99(1H ,d,J=7.2Hz), 7.88(1H,d,J=0.8Hz), 7.74(1H,dt,J=7.6,2.0Hz), 7.47(1H,s), 7.30-7 .22(2H,m), 7.15(1H,d,J=8.8Hz), 6.96-6.84(5H,m), 4.94(2H,s), 4.93-4.88(1H,m), 4.67(1H,dd,J=9.6,7.2Hz), 4.26(1H,dd,J=10.8,10.0Hz), 3.81(2H,s), 3.42(3H,s). LC-MS:m / z=526.00[M+H] + .

[0380] Example 26: (S)-4-(3-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0381] [ka]

[0382] A suspension of (S)-4-(3-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (Example 22, 15.0 mg, 0.0300 mmol) and Pd / C (10 wt%, 1.58 mg) was stirred in 0.30 mL of ethyl alcohol at room temperature under H2 atmosphere (1 atm) for 1 hour. The reaction mixture was filtered through a Celite pad, washed with ethyl acetate, and concentrated under vacuum to provide (S)-4-(3-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (14.0 mg, 93%). 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.2Hz), 7.88(1H,s), 7.47(1H,s), 7.27-7.22 (1H,m), 7.11-7.09(1H,m), 6.96-6.85(3H,m), 6.76-6.74(2H,m), 4.90(1H,td,J=11. 2,5.6Hz), 4.66(1H,dd,J=9.6,3.6Hz), 4.24(1H,dd,J=11.2,9.6Hz), 3.98(1H,t,J=6 .0Hz), 3.81(2H,m), 3.41(3H,s), 1.94-1.86(2H,m), 1.67-1.63(2H,m), 1.28(6H,s). LC-MS:m / z=511.10[M+H] + .

[0383] Example 27: (S)-4-(3-fluorobenzyl)-N-(7-(3-(1-hydroxycyclohexyl)propoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0384] [ka]

[0385] The title compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-((3-(1-hydroxycyclohexyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (Example 23) in the same manner as in Example 26. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24-7.22 (1H,m), 7.10(1H,q,J=3.2Hz), 6.96-6.85(3H,m), 6.75(2H,dd,J=7.1,2.5Hz), 4.93-4.86(1H, m), 4.66(1H,dd,J=9.8,7.5Hz), 4.24(1H,dd,J=11.0,10.1Hz), 3.98(2H,t,J=6.4Hz), 3.81(2H ,s), 3.41(3H,s), 1.94-1.86(2H,m), 1.65-1.59(5H,m), 1.51-1.43(5H,m), 1.28-1.25(2H,m). LC-MS:m / z=551.20[M+H] + .

[0386] Example 28: (S)-4-(3-fluorobenzyl)-N-(7-(3-(1-hydroxycyclobutyl)propoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0387] [ka]

[0388] The title compound was prepared in the same manner as in Example 26 using (S)-4-(3-fluorobenzyl)-N-(7-((3-(1-hydroxycyclobutyl)prop-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (Example 24). 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24- 7.22(1H,m), 7.10(1H,dd,J=6.9,2.3Hz), 6.96-6.85(3H,m), 6.76(2H,dd,J=7.5,2.5Hz), 4 .93-4.87(1H,m), 4.6(1H,dd,J=9.8,7.5Hz), 4.24(1H,dd,J=11.2,9.8Hz), 4.01(2H,t,J=6 .2Hz), 3.81(2H,s), 3.42(3H,s), 2.14-1.99(4H,m), 1.94-1.88(2H,m), 1.83-1.75(4H,m). LC-MS:m / z=523.20[M+H] + .

[0389] Example 29: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(3-(pyridine-3-yl)propoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0390] [ka]

[0391] The title compound was prepared using (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-((3-(pyridine-3-yl)prop-2-in-1-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (Example 25) in the same manner as in Example 26. 1H-NMR (400MHz, CDCl3): δ8.51(1H,s), 8.48-8.46(1H,m), 7.98(1H,d,J=7.2Hz), 7. 88(1H,s), 7.55(1H,d,J=8.0Hz), 7.46(1H,s), 7.26-7.22(2H,m), 7.11-7.09(1H,m) , 6.96-6.85(3H,m), 6.74-6.73(2H,m), 5.13(1H,t,J=4.2Hz), 4.91-4.84(1H,m), 4 .65(1H,dd,J=7.2,9.6Hz), 4.26-4.19(3H,m), 3.801(2H,s), 3.41(3H,d,J=2.4Hz). LC-MS:m / z=530.20[M+H] + .

[0392] Example 30: (S)-N-(7-(cyclohexyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0393] [ka]

[0394] Stage A: tert-butyl(S)-(7-(cyclohexyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0395] The title compound was prepared using intermediate 2 and cyclohexylmethanesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to provide tert-butyl(S)-(7-(cyclohexyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (32%) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.03-7.00(1H,m), 6.70(2H,q,J=3.2Hz), 5.48(1H,d, J=7.3Hz), 4.73-4.63(1H,m), 4.53(1H,dd,J=9.6,7.8Hz), 4.17(1H,td,J=8.6,4 .1Hz), 4.08(1H,dd,J=11.4,9.6Hz), 3.37(3H,s), 2.01-1.96(2H,m), 1.82-1.7 6(2H,m), 1.70-1.61(2H,m), 1.53-1.48(1H,m), 1.40(9H,s), 1.38-1.25(3H,m).

[0396] Stage B: (S)-3-amino-7-(cyclohexyloxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0397] The title compound was prepared using tert-butyl(S)-(7-(cyclohexyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 291.10 [M + H] + .

[0398] Stage C: (S)-N-(7-(cyclohexyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0399] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-(cyclohexyloxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl=3:1) to provide (S)-N-(7-(cyclohexyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (15% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24 -7.22(1H,m), 7.09-7.07(1H,m), 7.00-6.85(3H,m), 6.75(2H,dd,J=8.5,2.1Hz), 4.95-4. 88(1H,m), 4.66(1H,dd,J=9.8,7.5Hz), 4.26-4.18(2H,m), 3.81(2H,s), 3.41(3H,s), 2.00 -1.95(2H,m), 1.8-1.78(2H,m), 1.61-1.57(1H,m), 1.54-1.49(1H,m), 1.43-1.28(4H,m). LC-MS:m / z=493.20[M+H] + .

[0400] Example 31: (S)-N-(7-((4,4-dimethylcyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0401] [ka]

[0402] Stage A: tert-butyl-(S)-(7-((4,4-dimethylcyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0403] The title compound was prepared using intermediate 2 and 4,4-dimethylcyclohexylmethanesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide tert-butyl(S)-(7-((4,4-dimethylcyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (68%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.00(1H,dd,J=6.6,2.5Hz), 6.68(2H,dd,J=7.3,2.7Hz), 5.47(1H,d,J=6.9Hz), 4.71-4.63(2H,m), 4.51(1H,dd,J=9.6,7.3H z), 4.11-4.04(1H,m), 3.35(3H,s), 1.90-1.73(2H,m), 1.70-1.61(1H,m), 1.54-1.45(2H,m), 1.38(9H,s), 1.29-1.22(3H,m), 0.92(6H,d,J=12.3Hz).

[0404] Stage B: (S)-3-amino-7-((4,4-dimethylcyclohexyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0405] The title compound was prepared using tert-butyl(S)-(7-((4,4-dimethylcyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 319.10 [M + H] + .

[0406] Stage C: (S)-N-(7-((4,4-dimethylcyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0407] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((4,4-dimethylcyclohexyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:ELISA=5:1) to provide (S)-N-(7-((4,4-dimethylcyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (55% between the two steps) as a white form. 1 H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24-7 .22(1H,m), 7.09-7.07(1H,m), 7.00-6.85(3H,m), 6.75(2H,dd,J=8.0,2.5Hz), 4.95-4.88( 1H,m), 4.66(1H,dd,J=9.8,7.5Hz), 4.26-4.16(1H,m), 3.81(2H,s), 3.41(3H,s), 1.90-1.8 4(2H,m), 1.73-1.64(2H,m), 1.53-1.49(1H,m), 1.31-1.24(3H,m), 0.97(6H,d,J=10.5Hz). LC-MS:m / z=521.10[M+H] + .

[0408] Example 32: 4-(3-fluorobenzyl)-N-((S)-5-methyl-4-oxo-7-(((R)-tetrahydrofuran-3-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0409] [ka]

[0410] Stage A: tert-butyl((S)-5-methyl-4-oxo-7-(((R)-tetrahydrofuran-3-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0411] At 0°C, a solution of tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (intermediate 2, 100 mg, 0.324 mmol) and (S)-tetrahydrofuran-3-ol (0.0370 mg, 0.442 mmol) was prepared in THF (3.0 mL) at 0°C. PPh3 (170 mg, 0.649 mmol) was added, followed by DIAD (0.126 mL, 0.649 mmol). The reaction mixture was stirred at 40°C for 5 hours. After concentration under vacuum, the residue was subjected to column chromatography on SiO2 (hexane:siRNA=2:1), and then purified by column chromatography on NH2-SiO2 (hexane:siRNA=1:1) to provide tert-butyl((S)-5-methyl-4-oxo-7-(((R)-tetrahydrofuran-3-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (96.0 mg, 78%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.04(1H,d,J=8.8Hz), 6.69(1H,d,J=2.8Hz), 6.64(1H,dd,J=8.8,3.2Hz), 5.47(1H,d,J=7.2Hz), 4.86-4.87(1H,m), 4.63 -4.66(1H,m), 4.51(1H,dd,J=10.0,7.6Hz), 4.08-4.11(1H,m), 3.96-3.9 9(3H,m), 3.90-3.92(1H,m), 3.36(3H,s), 2.22-2.13(2H,m), 1.39(9H,s).

[0412] Stage B: (S)-3-amino-5-methyl-7-(((R)-tetrahydrofuran-3-yl)oxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0413] The title compound was prepared using tert-butyl((S)-5-methyl-4-oxo-7-(((R)-tetrahydrofuran-3-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 279.1 [M + H] + .

[0414] Stage C: 4-(3-fluorobenzyl)-N-((S)-5-methyl-4-oxo-7-(((R)-tetrahydrofuran-3-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0415] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-5-methyl-7-(((R)-tetrahydrofuran-3-yl)oxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was subjected to column chromatography on SiO2 (hexane:siRNA = 3:1 to 1:1), followed by purification by column chromatography on NH2-SiO2 (hexane:siRNA = 1:1), yielding 4-(3-fluorobenzyl)-N-((S)-5-methyl-4-oxo-7-(((R)-tetrahydrofuran-3-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (30% between the two steps) as a white form. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.2Hz), 7.86(1H,s), 7.45(1H,s), 7.29-7.21( 1H,m), 7.10(1H,d,J=8.8Hz), 6.95-8.84(3H,m), 6.73(1H,d,J=3.5Hz), 6.69(1H,dd,J= 8.6,2.6Hz), 4.93-4.87(2H,m), 4.65(1H,dd,J=9.6,7.6Hz), 4.24(1H,dd,J=11.0,9.8H z), 3.97-4.00(3H,m), 3.91-3.93(1H,m), 3.80(2H,s), 3.39(3H,s), 2.17-2.21(2H,m). LC-MS:m / z=481.1[M+H] + .

[0416] Example 33: 4-(3-fluorobenzyl)-N-((S)-5-methyl-7-(((R)-1-methylpyrrolidine-3-yl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0417] [ka]

[0418] Stage A: tert-butyl((S)-5-methyl-7-(((R)-1-methylpyrrolidine-3-yl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0419] The title compound was prepared using intermediate 2 and (S)-1-methylpyrrolidine-3-ylmethanesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography over SiO2 (DCM:MeOH = 10:1~7:1) to provide tert-butyl((S)-5-methyl-7-(((R)-1-methylpyrrolidine-3-yl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (31%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.02(1H,d,J=8.8Hz), 6.67(1H,d,J=2.8Hz), 6.62(1H,dd ,J=8.6,2.6Hz), 5.47(1H,d,J=7.2Hz), 4.78-4.75(1H,m), 4.65-4.60(1H,m), 4.51( 1H,dd,J=9.6,7.2Hz), 4.07(1H,d,J=11.2,9.6Hz), 3.35(3H,s), 2.85-2.78(3H,m), 2.45-2.40(1H,m), 2.40(3H,s), 2.31-2.28(1H,m), 2.02-1.95(1H,m), 1.38(9H,s).

[0420] Stage B: (S)-3-amino-5-methyl-7-(((R)-1-methylpyrrolidine-3-yl)oxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0421] The title compound was prepared using tert-butyl((S)-5-methyl-7-(((R)-1-methylpyrrolidine-3-yl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 292.1 [M + H] + .

[0422] Stage C: 4-(3-fluorobenzyl)-N-((S)-5-methyl-7-(((R)-1-methylpyrrolidine-3-yl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0423] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-5-methyl-7-(((R)-1-methylpyrrolidine-3-yl)oxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl=3:1~HCl only) to provide 4-(3-fluorobenzyl)-N-((S)-5-methyl-7-(((R)-1-methylpyrrolidine-3-yl)oxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (18% between the two steps) as a colorless oil. 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.6Hz), 7.97(1H,d,J=7.6Hz), 7.87(1H,s), 7.46(1H,s), 7.2 4-7.22(1H,m), 7.08(1H,d,J=8.8Hz), 6.95-6.86(3H,m), 6.70(1H,d,J=2.8Hz), 6.67(1H,dd,J=9.2,2 .8Hz), 4.92-4.86(1H,m), 4.83-4.76(1H,m), 4.64(1H,dd,J=10.0,7.6Hz), 4.23(1H,dd,J=11.2,10.0 Hz), 3.79(2H,s), 3.39(3H,s), 2.50-2.44(3H,m), 2.41(3H,s), 2.37-2.30(1H,m), 2.05-1.99(1H,m). LC-MS:m / z=494.1[M+H] + .

[0424] Example 34: 4-(3-fluorobenzyl)-N-((S)-7-(((1s,4R)-4-hydroxycyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0425] [ka]

[0426] Stage A: tert-butyl((S)-7-(((1s,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0427] The title compound was prepared using intermediate 2 and (1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-ol in the same manner as in Example 32 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=3:1) to provide tert-butyl((S)-7-(((1s,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (54%) as a colorless oil. 1 H-NMR (400MHz, CDCl3), δ7.03(1H,d,J=8.4Hz), 6.74-6.71(2H,m), 5.49(1H,d,J=7.2Hz), 4.67(1H,dt,J=10.8,7.2Hz), 4.54(1H,dd,J=9.6,7 .2Hz), 4.25-4.21(1H,m), 4.10-4.07(1H,m), 3.84-3.80(1H,m)3.38(3 H,s), 1.89-1.82(4H,m), 1.52-1.45(4H,m), 0.91(9H,s), 0.07(6H,s).

[0428] Stage B: (S)-3-amino-7-(((1s,4R)-4-hydroxycyclohexyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0429] The title compound was prepared using tert-butyl((S)-7-(((1s,4R)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 307.10 [M + H] + .

[0430] Stage C: 4-(3-fluorobenzyl)-N-((S)-7-(((1s,4R)-4-hydroxycyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0431] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-(((1s,4R)-4-hydroxycyclohexyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl = 1:1~1:3) to provide 4-(3-fluorobenzyl)-N-((S)-7-(((1s,4R)-4-hydroxycyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (21% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3) δ7.99(1H,d,J=7.2Hz), 7.88(1H,d,J=0.8Hz), 7.47(1H,s), 7.28-7.23 (1H,m), 7.10(1H,d,J=9.6Hz), 6.97-6.85(3H,m), 6.78-6.75(2H,m), 4.92(2H,dt,J=11.6,7.6Hz), 4.66(1H,dd,J=9.6,7.6Hz), 4.38 -4.34(1H,m), 4.24(1H,dd,J=11.6,9.6Hz), 3.84-3.78(3H,m), 3.41(3H,s), 2.07-1.98(2H,m), 1.80-1.75(4H,m), 1.73-1.65(2H,m). LC-MS:m / z=509.10[M+H] + .

[0432] Example 35: 4-(3-fluorobenzyl)-N-((S)-7-(((1r,4S)-4-hydroxycyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0433] [ka]

[0434] Stage A: tert-butyl-((S)-7-(((1r,4S)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0435] The title compound was prepared using intermediate 2 and (1s,4s)-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-ol in the same manner as in Example 32 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide tert-butyl((S)-7-(((1r,4S)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (60.0 mg, 12%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.03(1H,dd,J=5.5,3.7Hz), 6.69(2H,q,J=2.7Hz), 5.48 (1H,d,J=7.3Hz), 4.69-4.63(1H,m), 4.53(1H,dd,J=9.6,7.8Hz), 4.24-4.20(1H, m), 4.09(1H,dd,J=11.2,9.8Hz), 3.81-3.77(1H,m), 3.37(3H,s), 2.10-2.04(2H, m), 1.92-1.87(2H,m), 1.40(9H,s), 1.27-1.22(4H,m), 0.87(9H,s), 0.04(6H,s).

[0436] Stage B: (S)-3-amino-7-(((1r,4S)-4-hydroxycyclohexyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0437] The title compound was prepared using tert-butyl-((S)-7-(((1r,4S)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 307.10 [M + H] + .

[0438] Stage C: 4-(3-fluorobenzyl)-N-((S)-7-(((1r,4S)-4-hydroxycyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0439] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-(((1r,4S)-4-hydroxycyclohexyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to provide 4-(3-fluorobenzyl)-N-((S)-7-(((1r,4S)-4-hydroxycyclohexyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (24% between the two steps) as a white form. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,s), 7.47(1H,s), 7.24 -7.22(1H,m), 7.09(1H,d,J=9.1Hz), 7.00-6.85(3H,m), 6.75(2H,dd,J=11.2,2 .5Hz), 4.95-4.88(1H,m), 4.66(1H,dd,J=9.6,7.8Hz), 4.27-4.21(2H,m), 3.85 -3.81(3H,m), 3.41(3H,s), 2.15-2.10(2H,m), 2.05(2H,m), 1.51-1.44(4H,m). LC-MS:m / z=509.10[M+H] + .

[0440] General synthetic reaction equations for 2-oxyacetamide analogs Route 1 [ka]

[0441] Route 2 [ka]

[0442] Example 36: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(piperidine-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0443] [ka]

[0444] At 0°C, a solution of (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetic acid (intermediate 4, 50.0 mg, 0.110 mmol) and piperidine (13.0 μL, 0.130 mmol) was prepared in DMF (1.0 mL) at 0°C. DIPEA (28.0 μL, 0.0 mmol) was added, followed by HATU (60.0 mg, 0.160 mmol). The reaction mixture was stirred at 0°C for 10 minutes. After terminating the reaction with water, the mixture was extracted twice with ELISA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:HCl = 1:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(piperidine-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (35.0 mg, 61%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24-7.22(1H,m), 7.11(1H,d,J=8.7Hz), 7.00-6.85(4H,m), 6.80(1H,dd,J=8.7,3.2 Hz), 4.93-4.87(1H,m), 4.69(2H,s), 4.66-4.64(1H,m), 4.25(1H,dd,J=11.2,9.8Hz) , 3.81(2H,s), 3.59-3.56(2H,m), 3.50-3.48(2H,m), 3.41(3H,s), 1.67-1.61(6H,m). LC-MS:m / z=536.10[M+H] + .

[0445] Example 37: (S)-N-(7-(2-(4,4-dimethylpiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0446] [ka]

[0447] The title compound was prepared in the same manner as in Example 36 using intermediates 4 and 4,4-dimethylpiperidine hydrochloride in DMSO as the solvent. The crude product was purified by column chromatography on SiO2 (hexane:ELISA=1:1) to provide (S)-N-(7-(2-(4,4-dimethylpiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (50%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24 -7.22(1H,m), 7.11(1H,d,J=8.7Hz), 7.00-6.85(4H,m), 6.80(1H,dd,J=8.9,3.0Hz), 4.93 -4.87(1H,m), 4.68(2H,s), 4.66-4.64(1H,m), 4.25(1H,dd,J=11.0,10.1Hz), 3.81(2H,s ), 3.63-3.54(2H,m), 3.49(2H,t,J=5.7Hz), 3.41(3H,s), 1.42-1.37(4H,m), 0.99(6H,s). LC-MS:m / z=564.20[M+H] + .

[0448] Example 38: (S)-N-(7-(2-(4,4-difluoropiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0449] [ka]

[0450] The title compound was prepared in the same manner as in Example 36 using intermediate 4 and 4,4-difluoropiperidine hydrochloride in DMSO as the solvent. The crude product was purified by column chromatography on SiO2 (hexane:HCl = 1:1) to provide (S)-N-(7-(2-(4,4-difluoropiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (74%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.3Hz), 7.88(1H,s), 7.47(1H,s), 7.25-7.22(1H,m), 7.13(1H,d,J=8.7Hz), 7.00-6.78(5H,m), 4.94-4.8 7(1H,m), 4.71(2H,s), 4.66(1H,dd,J=9.8,7.5Hz), 4.26(1H,dd,J=11.2, 9.8Hz), 3.81(2H,s), 3.79-3.70(4H,m), 3.41(3H,s), 2.08-1.96(4H,m). LC-MS: m / z = 572.10[M+H] + .

[0451] Example 39: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-morpholino-2-oxoethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0452] [ka]

[0453] The title compound was prepared in the same manner as in Example 36 using intermediate 4 in DMSO and morpholine as solvents. The crude product was purified by column chromatography on SiO2 (DCM:SiO=1:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2)-morpholino-2-oxoethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (71%) as a white foam. 1 H-NMR (400MHz, CDCl3) δ7.98(1H,d,J=7.2Hz), 7.88(1H,d,J=1.2Hz), 7.47(1H,s), 7.29- 7.23(1H,m), 7.13(1H,d,J=9.2Hz), 6.96-6.85(4H,m), 6.80(1H,dd,J=9.2,2.8Hz), 4.90( 1H,dt,J=11.2,7.6Hz), 4.70(2H,s), 4.66(1H,dd,J=9.6,7.6Hz), 4.26(1H,dd,J=11.2,9. 6Hz), 3.81(2H,s), 3.70-3.70(4H,m), 3.67-3.65(2H,m), 3.62-3.59(2H,m), 3.41(3H,s). LC-MS:m / z=538.20[M+H] + .

[0454] Example 40: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxypiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0455] [ka]

[0456] The title compound was prepared in the same manner as in Example 36 using intermediate 4 and piperidine-4-ol. The crude product was purified by column chromatography over SiO2 (ELISA only) to provide (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxypiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (65%) as a white form. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.2Hz), 7.87(1H,s), 7.47(1H,s), 7.26-7.22(1H,m), 7.11(1 H,d,J=8.8Hz), 6.96-6.85(4H,m), 6.80(1H,dd,J=8.8,2.8Hz), 4.90(1H,dt,J=11.6,5.6Hz), 4.71(2 H,s), 4.64(1H,t,J=9.2Hz), 4.25(1H,dd,J=11.8,10.0Hz), 4.09-4.00(1H,m), 4.00-3.94(1H,m), 3. 89-3.81(1H,m), 3.81(2H,s), 3.41(3H,s), 3.37-3.23(2H,m), 1.97-1.85(2H,m), 1.58-1.45(2H,m). LC-MS:m / z=552.1[M+H] + .

[0457] Example 41: 4-(3-fluorobenzyl)-N-((3S)-7-(3-hydroxypyrrolidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0458] [ka]

[0459] Stage A: tert-butyl(S)-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0460] At 0°C, a solution of (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)acetic acid (intermediate 3, 0.100 g, 0.273 mmol) and 4-methylpiperidine-4-ol (31.0 mg, 0.273 mmol) was added to DIPEA (0.143 mL, 0.819 mmol) followed by HATU (0.156 g, 0.409 mmol). The reaction mixture was stirred at room temperature for 1 hour. After terminating the reaction with water, the mixture was extracted twice with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (DCM:MeOH = 15:1), and tert-butyl(S)-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (86.0 mg, 68%) was provided as a white foam. 1 H-NMR (400MHz, CDCl3) δ7.06 (1H,d,J=8.8Hz), 6.84(1H,d,J=2.8Hz), 6.78-6 .74(1H,m), 5.56(1H,d,J=7.2Hz), 4.72-4.61(3H,m), 4.52(1H,dd,J=9.6,7. 6Hz), 4.20(1H,m), 4.15-4.09(1H,m), 3.72-3.60(1H,m), 3.58-3.45(1H,m), 3.38(3H,s), 3.25-3.11(1H,m), 1.68-1.50(4H,m), 1.40(9H,s), 1.28(3H,s).

[0461] Stage B: (S)-3-amino-7-(4-hydroxy-4-methylpiperidine-1-carbonyl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0462] At 0°C, a solution of tert-butyl(S)-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (86.0 mg, 0.186 mmol) was added to DCM (0.93 mL), to which HCl (4 M solution in dioxane, 1.39 mL, 5.57 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours. The precipitated solid was collected by filtration, washed with DCM and IPE, and dried under vacuum to provide (S)-3-amino-7-(2-(4-hydroxy-4-methylpiperidine-1-yl)-2-oxoethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (77.0 mg, 99%) as a yellowish-green solid. 1 H-NMR(400MHz,MeOH-d4)δ7.17(1H,d,J=8.8Hz), 7.04(1H,t,J=2.8Hz), 6.89(1H ,dd,J=8.8,2.8Hz), 4.87(2H,s), 4.58(1H,dd,J=9.6,7.6Hz), 4.41(1H,dd,J=10. 8,9.6Hz), 4.32(1H,dd,J=10.8,7.2Hz), 4.15-4.06(1H,m), 3.71-3.60(1H,m), 3. 55-3.45(1H,m), 3.41(3H,s), 3.23-3.15(1H,m), 1.66-1.48(4H,m), 1.25(3H,s).

[0463] Stage C: 4-(3-fluorobenzyl)-N-((3S)-7-(3-hydroxypyrrolidine-1-carbonyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0464] At 0°C, a solution of (S)-3-amino-7-(2-(4-hydroxy-4-methylpiperidine-1-yl)-2-oxoethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (77.0 mg, 0.193 mmol) in DCE (2.0 mL) was added, followed by CDI (62.0 mg, 0.385 mmol) and then TEA (0.0670 mL, 0.481 mmol). The mixture was stirred at room temperature for 2.5 hours. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum.

[0465] To a solution of the residue in DCE (2.0 mL) at 0°C, 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6, 0.0330 g, 0.154 mmol) was added, followed by TEA (0.0670 mL, 0.481 mmol). The reaction mixture was stirred at room temperature for 18 hours. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (DCM:MeOH = 15:1), and (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxy-4-methylpiperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (46.0 mg, 42%) was provided as a white foam. 1H-NMR (400MHz, CDCl3) δ7.99(1H,d,J=7.2Hz), 7.88(1H,s), 7.47(1H,s), 7.28-7.22(1H,m), 7.12(1H,d, J=8.8Hz), 6.97-6.85(4H,m), 6.80(1H,dt,J=8.8,2.8Hz), 4.90(1H,dt,J=10.8,7.6Hz), 4.70(2H,d,J=5. 2Hz), 4.65(1H,dd,J=9.6,7.2Hz), 4.26(1H,dd,J=10.8,9.6Hz), 4.25-4.17(1H,m), 3.81(2H,s), 3.73-3 .62(1H,m), 3.59-3.48(1H,m), 3.41(3H,s), 3.24-3.16(1H,m), 1.72-1.52(4H,m), 1.29(3H,d,J=2.0Hz). LC-MS:m / z=566.1[M+H] + .

[0466] Example 42: (S)-4-(3-fluorobenzyl)-N-(7-((1-(4-hydroxy-4-methylpiperidine-1-yl)-2-methyl-1-oxopropan-2-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0467] [ka]

[0468] Stage A: (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)-2-methylpropanoic acid

[0469] At 0°C, a solution of (S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (intermediate 2, 0.500 g, 1.62 mmol) was added in 13 mL of DMF, to which NaH (60 wt%, 0.259 mg, 6.49 mmol) was added in a fractional manner. The mixture was stirred at 0°C for 1 hour. After adding 2-bromo-2-methylpropanoic acid (0.425 mL, 8.25 mmol) at 0°C, the reaction mixture was stirred at 0°C for 20 hours and then cooled to -10°C. The reaction was stopped using 0.5N HCl aqueous solution until the pH reached 3-4, and the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography over SiO2 (SiO2 only), and (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)-2-methylpropanoic acid (0.420 g, 66%) was obtained as a yellow solid. LC-MS: m / z = 395.10 [M + H] + .

[0470] Stage B: tert-butyl(S)-(7-((1-(4-hydroxy-4-methylpiperidine-1-yl)-2-methyl-1-oxopropane-2-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0471] The title compound was prepared using (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)-2-methylpropanoic acid and 4-methylpiperidine-4-ol in the same manner as in Example 41 (Step B). The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide tert-butyl(S)-(7-((1-(4-hydroxy-4-methylpiperidine-1-yl)-2-methyl-1-oxopropan-2-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (89%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.00(1H,d,J=8.8Hz), 6.69(1H,brs), 6.65(1H,dd,J=8.8,3.2Hz), 5.46(1H,d,J=7.2Hz), 4.66-4.60(1H,m), 4.50(1H,t,J=8. 8Hz), 4.11-3.96(1H,m), 3.64-3.50(1H,m), 3.40-3.67(1H,m), 3.34(3H,s) , 1.66-1.64(6H,m), 1.57-1.46(4H,m), 1.39(9H,s), 1.19(3H,d,J=6.4Hz).

[0472] Stage C: (S)-3-amino-7-((1-(4-hydroxy-4-methylpiperidine-1-yl)-2-methyl-1-oxopropan-2-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0473] The title compound was prepared using tert-butyl(S)-(7-((1-(4-hydroxy-4-methylpiperidine-1-yl)-2-methyl-1-oxopropan-2-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 41 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification.1 H-NMR (400MHz, CDCl3): δ8.41(2H,brs), 7.18(1H,d,J=9.2Hz), 6.91(1H,brs), 6.67(1H,dd,J=8.8,2.8Hz), 4.52-4.48(1H,m), 4.40-4.33(2 H,m), 4.28-4.19(1H,m), 4.11-3.95(1H,m), 3.28(3H,s), 3.09-2.99(2 H,m), 1.55(6H,s), 1.47-1.39(1H,m), 1.35-1.20(1H,m), 1.02(3H,s).

[0474] Stage D: (S)-4-(3-fluorobenzyl)-N-(7-((1-(4-hydroxy-4-methylpiperidine-1-yl)-2-methyl-1-oxopropan-2-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0475] The title compound was prepared in the same manner as in Example 41 (Step C) using (S)-3-amino-7-((1-(4-hydroxy-4-methylpiperidine-1-yl)-2-methyl-1-oxopropan-2-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl = 1:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-((1-(4-hydroxy-4-methylpiperidine-1-yl)-2-methyl-1-oxopropan-2-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (90%) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=6.0Hz), 7.87(1H,d,J=0.8Hz), 7.46(1H,s), 7.27-7.22(1H,m), 7.04(1H, d,J=8.8Hz), 6.96-6.84(3H,m), 6.72(1H,d,J=2.8Hz), 6.69(1H,dd,J=8.8,3.2Hz), 4.89(1H,dt,J=11.2,7.6Hz), 4.64(1H,dd,J=10.0,7.2Hz), 4.27-4.21(1H,m), 4.19-4.02(2H,m), 3.80(2H,s), 3.64-3.51(1H,m), 3.37(3H,s) , 3.37-3.31(1H,m), 1.65(6H,s), 1.57-1.46(2H,m), 1.42-1.37(1H,m), 1.30-1.23(1H,m), 1.20(1H,d,J=4.4Hz). LC-MS:m / z=594.1[M+H] + .

[0476] Example 43: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0477] [ka]

[0478] The title compound was prepared in the same manner as in Example 36 using intermediates 4 and 2-(piperidine-4-yl)propan-2-ol. The crude product was purified by column chromatography over SiO2 (ELISA only) to provide (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (80%) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.97(1H,dd,J=3.2,2.0Hz), 7.87(1H,s), 7.47(1H,s), 7.28-7.22(1H,m ), 7.11(1H,d,J=8.8Hz), 6.96-6.85(4H,m), 6.80(1H,dd,J=8.8,3.2Hz), 4.89(1H,td,J=11.2,5.6 Hz), 4.71-4.62(3H,m), 4.24(1H,dd,J=11.2,10.0Hz), 4.05(1H,d,J=13.6Hz), 3.81(2H,s), 3.41 (3H,s), 2.99-3.08(1H,m), 2.59-2.53(1H,m), 1.89-1.79(2H,m), 1.58-1.49(2H,m), 1.16(6H,s). LC-MS:m / z=594.1[M+H] + .

[0479] Example 44: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyrrolidine-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0480] [ka]

[0481] The title compound was prepared in the same manner as in Example 36 using intermediate 4 and pyrrolidine. The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 20:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyrrolidine-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (45%) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,s), 7.47(1H,s), 7.24 -7.22(1H,m), 7.11(1H,d,J=8.7Hz), 7.00-6.85(4H,m), 6.81-6.78(1H,m), 4.93 -4.87(1H,m), 4.68-4.66(1H,m), 4.63(2H,s), 4.25(1H,dd,J=11.2,9.8Hz), 3.8 1(2H,s), 3.56-3.50(4H,m), 3.41(3H,s), 2.04-1.97(2H,m), 1.92-1.85(2H,m). LC-MS:m / z=522.10[M+H] + .

[0482] Example 45: (S)-N-(7-(2-(3,3-difluoropyrrolidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0483] [ka]

[0484] The title compound was prepared in the same manner as in Example 36 using intermediates 4 and 3,3-difluoropyrrolidine. The crude product was purified by column chromatography on SiO2 (hexane:HCl = 1:1) to provide (S)-N-(7-(2-(3,3-difluoropyrrolidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (34%) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=5.0Hz), 7.88(1H,s), 7.47(1H,s), 7.25-7.22(1H,m), 7.14-7.12(1H,m), 7.00-6.77(5H,m) , 4.94-4.87(1H,m), 4.68-4.63(3H,m), 4.26(1H,dd,J=11.0,10.1Hz), 3.96-3.76(6H,m), 3.41(3H,d,J=1.8Hz), 2.52-2.32(2H,m). LC-MS:m / z=558.10[M+H] + .

[0485] Example 46: 4-(3-fluorobenzyl)-N-((S)-7-(2-((S)-3-hydroxypyrrolidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0486] [ka]

[0487] The title compound was prepared in the same manner as in Example 36 using intermediate 4 and (S)-pyrrolidine-3-ol. The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 20:1) to provide 4-(3-fluorobenzyl)-N-((S)-7-(2-((S)-3-hydroxypyrrolidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (79%) as a pale yellow foam. 1H-NMR(400MHz,CDCl3)δ7.99(1H,dd,J=7.6,2.8Hz), 7.88(1H,s), 7.47(1H,s), 7.28-7.2 3(1H,m), 7.11(1H,d,J=8.8Hz), 6.97-6.85(4H,m), 6.79(1H,m), 4.89(1H,dt,J=11.6,7.2 Hz), 4.67-4.63(3H,m), 4.58 and 4.50(1H,m), 4.25(1H,dd,J=10.8,9.6Hz), 3.81(2H,s), 3.74-3.63(3H,m), 3.57-3.52(1H,m), 3.41(3H,s), 2.12-2.04(1H,m), 2.02-1.91(1H,m). LC-MS:m / z=538.1[M+H] + .

[0488] Example 47: 4-(3-fluorobenzyl)-N-((S)-7-(2-((R)-3-hydroxypyrrolidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0489] [ka]

[0490] The title compound was prepared in the same manner as in Example 36 using intermediate 4 and (R)-pyrrolidine-3-ol. The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 20:1) to provide 4-(3-fluorobenzyl)-N-((S)-7-(2-((R)-3-hydroxypyrrolidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (81%) as a white foam. 1H-NMR(400MHz,CDCl3)δ7.99(1H,d,J=7.2Hz), 7.88(1H,s), 7.47(1H,s), 7.27-7.22(1 H,m), 7.11(1H,dd,J=8.8,1.2Hz), 6.96-6.85(4H,m), 6.79(1H,dd,J=8.8,2.4Hz), 4.9 3-4.86(1H,m), 4.67-4.62(3H,m), 4.55 and 4.50(1H,m), 4.25(1H,t,J=10.8Hz), 3.81( 2H,s), 3.73-3.52(4H,m), 3.40(3H,d,J=1.6Hz), 2.10-2.05(1H,m), 2.03-1.93(1H,m). LC-MS:m / z=538.0[M+H] + .

[0491] Example 48: 4-(3-fluorobenzyl)-N-((3S)-7-(2-(3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0492] [ka]

[0493] The title compound was prepared in the same manner as in Example 36 using intermediates 4 and 2-(pyrrolidine-3-yl)propan-2-ol. The residue was purified by column chromatography on SiO2 (DCM:MeOH=20:1) to provide 4-(3-fluorobenzyl)-N-((3S)-7-(2-(3-(2-hydroxypropan-2-yl)pyrrolidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (47%) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,s), 7.47(1H,s), 7.24-7.22( 1H,m), 7.11(1H,d,J=8.7Hz), 6.96-6.77(5H,m), 4.93-4.87(1H,m), 4.68-4.59(3H,m) , 4.25(1H,t,J=10.5Hz), 3.8(2H,s), 3.77-3.64(1H,m), 3.53-3.44(2H,m), 3.41(3H,s ), 3.38-3.31(1H,m), 2.38-2.17(1H,m), 2.06-1.73(2H,m), 1.28(3H,s), 1.26(3H,s). LC-MS:m / z=580.10[M+H] + .

[0494] Example 49: (S)-4-(3-fluorobenzyl)-N-(7-(2-(3-hydroxy-3-methylazetidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0495] [ka]

[0496] The title compound was prepared in the same manner as in Example 36 using intermediate 4 and 3-methylazetidine-3-ol TFA. The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 20:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-(2-(3-hydroxy-3-methylazetidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (26%) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.8Hz), 7.87(1H,d,J=0.9Hz), 7.47( 1H,s), 7.24-7.22(1H,m), 7.14(1H,d,J=8.7Hz), 6.96-6.85(3H,m), 6.79-6. 74(2H,m), 4.93-4.86(1H,m), 4.66(1H,t,J=8.7Hz), 4.29-4.26(1H,m), 4.23 (2H,d,J=2.3Hz), 4.03-3.99(2H,m), 3.81(2H,s), 3.41(3H,s), 1.56(3H,s). LC-MS: m / z = 538.10 [M + H] + .

[0497] Example 50: (S)-4-(3-fluorobenzyl)-N-(7-(2-(3-hydroxyazetidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0498] [ka]

[0499] The title compound was prepared in the same manner as in Example 36 using intermediate 4 and azetidine-3-ol hydrochloride. The crude product was purified by column chromatography on SiO2 (siRNA:MeOH=20:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-(2-(3-hydroxyazetidine-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (83%) as a white foam. 1H-NMR(400MHz,CDCl3)δ7.99(1H,d,J=7.2Hz), 7.88(1H,s), 7.47(1H,s), 7.30-7.22(1H,m), 7. 13(1H,d,J=8.4Hz), 6.96-6.85(3H,m), 6.79(1H,t,J=2.8Hz), 6.75(1H,dt,J=8.8,2.8Hz), 4.90 (1H,dt,J=10.8,7.6Hz), 4.72-4.63(2H,m), 4.56(2H,s), 4.55-4.50(1H,m), 4.34-4.31(1H,m), 4.26(1H,dd,J=11.2,10.0Hz), 4.22-4.13(1H,m), 3.99-3.90(1H,m), 3.81(2H,s), 3.40(3H,s). LC-MS:m / z=524.1[M+H] + .

[0500] Example 51: (S)-N-(7-(2-(cyclopropylamino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0501] [ka]

[0502] Stage A: tert-butyl(S)-(7-(2-(cyclopropylamino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0503] The title compound was prepared using intermediate 3 and cyclopropanamine in the same manner as in Example 41 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1 - SiO only) to provide tert-butyl(S)-(7-(2-(cyclopropylamino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (76%) as a yellow oil. 1 H-NMR (400MHz, CDCl3): 7.73(1H,d,J=8.4Hz), 6.73-6.69(2H,m), 6.57(1H,s), 5.46(1H,d,J=7.2Hz), 4.66-4.60(1H,m), 4.51(1H,dd,J=10 .6,7.6Hz), 4.43(2H,s), 4.10(1H,dd,J=11.2,10.0Hz), 3.36(3H,s), 2.81-2.76(1H,m), 1.38(9H,s), 0.87-0.82(2H,m), 0.62-0.58(2H,m).

[0504] Stage B: (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)-N-cyclopropylacetamide hydrochloride

[0505] The title compound was prepared using tert-butyl(S)-(7-(2-(cyclopropylamino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 41 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 306.1 [M + H] + .

[0506] Stage C: (S)-N-(7-(2-(cyclopropylamino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0507] The title compound was prepared in the same manner as in Example 41 (Step C) using (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)-N-cyclopropylacetamide hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:HCl=3:1~HCl only) to provide (S)-N-(7-(2-(cyclopropylamino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (40% between the two steps) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.96(1H,d,J=7.2Hz), 7.87(1H,s), 7.46(1H,s), 7.28-7.21 (1H,m), 7.14(1H,d,J=8.0Hz), 6.95-6.84(3H,m), 6.76-6.73(2H,m), 6.58(1H,s), 4.9 0-4.85(1H,m), 4.65(1H,dd,J=9.2,8.8Hz), 4.45(2H,s), 4.25(1H,dd,J=10.4,9.6Hz ), 3.80(2H,s), 3.40(3H,s), 2.82-2.77(1H,m), 0.86-0.82(2H,m), 0.60-0.59(2H,m). LC-MS:m / z=508.1[M+H] + .

[0508] Example 52: (S)-4-(3-fluorobenzyl)-N-(7-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0509] [ka]

[0510] Stage A: tert-butyl(S)-(7-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0511] The title compound was prepared in the same manner as in Example 41 using intermediate 3 and 1-amino-2-methylpropan-2-ol. The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 20:1) to provide tert-butyl(S)-(7-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (79%) as an orange oil. 1 H-NMR (400MHz, CDCl3) δ7.10(1H,d,J=8.7Hz), 6.96(1H,t,J=5.2Hz), 6.81(1H,d,J =2.8Hz), 6.77(1H,dd,J=8.8,2.8Hz), 5.53(1H,d,J=7.6Hz), 4.62(1H,dt,J=11.2, 7.6Hz), 4.56(2H,d,J=2.8Hz), 4.47(1H,dd,J=9.6,7.2Hz), 4.12(1H,dd,J=11.2,9 .6Hz), 3.38(3H,s), 3.34(2H,t,J=5.2Hz), 1.40(9H,s), 1.21(3H,s), 1.17(3H,s).

[0512] Stage B: (3S)-3-amino-7-(2-(3-hydroxypyrrolidine-1-yl)-2-oxoethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0513] The title compound was prepared in the same manner as in Example 41 using tert-butyl(S)-(7-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate and HCl in dioxane as a solvent. After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 338.1 [M + H] + .

[0514] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0515] The title compound was prepared in the same manner as in Example 41 (Step C) using (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)-N-(2-hydroxy-2-methylpropyl)acetamide hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography over SiO2 (hexane:SiO=3:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-(2-((2-hydroxy-2-methylpropyl)amino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (13.0 mg, 10% between the two steps) as an oil. 1H-NMR(400MHz,CDCl3)δ8.00(1H,d,J=6.8Hz), 7.88(1H,s), 7.48(1H,s), 7.27-7.22(1H,m), 7.13(1H,d,J=8.8Hz), 6.97-6.82(5H,m), 4. 90(1H,dt,J=10.8,7.2Hz), 4.69(2H,s), 4.68-4.65(1H,m), 4.26(1H,t,J=10.8Hz), 3.81(2H,s), 3.65(2H,s), 3.41(3H,s), 1.42(6H,s). LC-MS:m / z=540.1[M+H] + .

[0516] Example 53: (S)-N-(7-(2-(ethyl(2-hydroxy-2-methylpropyl)amino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0517] [ka]

[0518] The title compound was prepared in the same manner as in Example 36 using intermediate 4 and 1-(ethylamino)-2-methylpropan-2-ol. The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:3) to provide (S)-N-(7-(2-(ethyl(2-hydroxy-2-methylpropyl)amino)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (93%) as a white foam. 1H-NMR (400MHz, CDCl3) δ7.98(1H,d,J=7.6Hz), 7.88(1H,d,J=1.2Hz), 7.47(1H,s), 7.30-7.2 3(1H,m), 7.12(1H,d,J=9.2Hz), 6.97-6.85(4H,m), 6.79(1H,dd,J=8.8,2.8Hz), 4.90(1H,m) , 4.78(2H,s), 4.66(1H,dd,J=9.6,7.6Hz), 4.25(1H,dd,J=10.8,10.0Hz), 3.89(1H,s), 3.81 (2H,s), 3.53(2H,q,J=7.2Hz), 3.43(2H,s), 3.41(3H,s), 1.26(4H,t,J=7.2Hz), 1.22(6H,s). LC-MS:m / z=568.3[M+H] + .

[0519] Example 54: (S)-N-(7-(2-(4-((tert-butyldimethylsilyl)oxy)-1H-pyrazole-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0520] [ka]

[0521] The title compound was prepared using intermediate 4 and 4-((tert-butyldimethylsilyl)oxy)-1H-pyrazole in the same manner as in Example 36. The crude product was purified by column chromatography on SiO2 (SiO:MeOH=20:1) to provide (S)-N-(7-(2-(4-((tert-butyldimethylsilyl)oxy)-1H-pyrazole-1-yl)-2-oxoethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (90%) as a white foam. 1H-NMR (400MHz, CDCl3) δ7.99(1H,d,J=7.2Hz), 7.88(1H,d,J=0.8Hz), 7.76(1H,s), 7.48 (1H,s), 7.47(1H,s), 7.27-7.22(1H,m), 7.13(1H,d,J=8.8Hz), 6.96-6.85(4H,m), 6.82( 1H,dd,J=8.8,2.8Hz), 5.44(2H,s), 4.90(1H,dt,J=10.8,7.2Hz), 4.67(1H,dd,J=9.6,7. 2Hz), 4.26(1H,dd,J=10.8,9.6Hz), 3.81(2H,s), 3.41(3H,s), 0.97(9H,s), 0.22(6H,s). LC-MS:m / z=649.1[M+H] + .

[0522] Example 55: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0523] [ka]

[0524] Stage A: tert-butyl(S)-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0525] The title compound was prepared in the same manner as in Example 15 (Step A) using intermediate 2 and (tetrahydro-2H-pyran-4-yl)methylmethanesulfonate. The crude product was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to provide tert-butyl(S)-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (57%) as a white foam.1 H-NMR (400MHz, CDCl3): δ7.04(1H,dd,J=7.4,2.2Hz), 6.69(2H,J=7.62.4Hz), 5.4 7(1H,d,J=7.2Hz), 4.68-4.61(1H,m), 4.52(1H,dd,J=9.6,7.6Hz), 4.12-4.07(1H, m), 4.03(2H,dd,J=11.0,3.4Hz), 3.78(2H,d,J=6.4Hz), 3.49-3.42(2H,m), 3.38( 3H,s), 2.09-2.03(1H,m), 1.76(2H,d,J=12.8Hz), 1.51-1.44(2H,m), 1.40(9H,s).

[0526] Stage B: (S)-3-amino-5-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0527] The title compound was prepared using tert-butyl(S)-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR (400MHz, DMSO-d6): δ8.45(3H,s), 7.17(1H,d,J=8.8Hz), 7.08(1H,d,J=2 .4Hz), 6.86(1H,dd,J=8.8,2.8Hz), 4.50(1H,dd,J=9.8,7.5Hz), 4.35(1H,t,J= 10.5Hz), 4.26(1H,dd,J=11.0,7.8Hz), 3.90-3.84(4H,m), 3.57-3.57(3H,s), 2 .02-1.96(1H,m), 1.68(2H,d,J=12.8Hz), 1.38-1.32(2H,m), 0.90-0.73(2H,m).

[0528] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0529] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-5-methyl-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:SiO=15:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)methoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (34% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24-7.22(1H,m), 7 .10(1H,dd,J=7.1,2.1Hz), 7.00-6.85(3H,m), 6.74(2H,dd,J=7.5,2.5Hz), 4.93-4.87(1H,m), 4.65(1H,d d,J=9.8,7.4Hz), 4.24(1H,dd,J=11.0,10.1Hz), 4.03(2H,dd,J=11.4,3.2Hz), 3.80(4H,d,J=6.9Hz), 3.4 9-3.43(2H,m), 3.42(3H,s), 2.07(1H,q,J=5.9Hz), 1.76(2H,d,J=11.0Hz), 1.47(2H,dd,J=12.8,4.6Hz). LC-MS:m / z=509.10[M+H] + .

[0530] Example 56: (S)-N-(7-(benzyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0531] [ka]

[0532] Stage A: tert-butyl(S)-(7-(benzyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0533] The title compound was prepared using intermediate 2 and benzyl bromide in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:siRNA=3:1) to provide tert-butyl(S)-(7-(benzyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (94%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.44-7.33(5H,m), 7.05(1H,dd,J=7.8,1.4Hz), 6.79-6.76(2H,m), 5.48(1H,d,J=7.2Hz), 5.04( 2H,s), 4.66(1H,dd,J=10.8,7.2Hz), 4.53(1H,dd,J=9.6,7.2Hz), 4.10(1H,dd,J=11.2,9.6Hz), 3.36(3H,s), 1.40(9H,s).

[0534] Stage B: (S)-3-amino-7-(benzyloxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0535] The title compound was prepared using tert-butyl(S)-(7-(benzyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR (400MHz,MeOH-d4): δ7.45-7.43(2H,m), 7.39-7.35(2H,m), 7.33-7.29(1H,m), 7.16(1H,d,J=9.2Hz), 7.04(1H,d,J=3.2Hz), 6.92(1 H,dd,J=8.8,2.8Hz), 5.11(2H,s), 4.61(1H,dd,J=10.0,8.0Hz), 4.42(1H,dd,J=10.8,10.0Hz), 4.31(1H,dd,J=10.8,8.0Hz), 3.39(3H,s).

[0536] Stage C: (S)-N-(7-(benzyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0537] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-(benzyloxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:SiO=15:1) to provide (S)-N-(7-(benzyloxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (67% between the two steps) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.6Hz), 7.88(1H,d,J=0.8Hz), 7.47(1 H,s), 7.45-7.33(5H,m), 7.28-7.22(1H,m), 7.11(1H,d,J=9.2Hz), 6.96-6.85 (3H,m), 6.84-6.81(2H,m), 5.07(2H,s), 4.91(1H,dt,J=11.2,7.6Hz), 4.66(1 H,dd,J=9.6,7.6Hz), 4.25(1H,dd,J=10.8,9.6Hz), 3.81(2H,s), 3.39(3H,s). LC-MS: m / z = 501.10[M+H] + .

[0538] Example 57: (S)-4-(3-fluorobenzyl)-N-(7-((4-fluorobenzyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0539] [ka]

[0540] Stage A: tert-butyl(S)-(7-((4-fluorobenzyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0541] The title compound was prepared using intermediate 2 and 1-(chloromethyl)-4-fluorobenzene in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to provide tert-butyl(S)-(7-((4-fluorobenzyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (60%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.42-7.38(2H,m), 7.12-7.04(3H,m), 6.77-6.71(2H,m), 5.47(1H,d,J=7.6Hz), 5.00(2H,s ), 4.65(1H,dt,J=11.2,7.2Hz), 4.53(1H,dd,J=9.6,7.2Hz), 4.10(1H,dd,J=11.2,9.6Hz), 3.37(3H,s), 1.40(9H,s).

[0542] Stage B: (S)-3-amino-7-((5-fluoropyridine-2-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0543] The title compound was prepared using tert-butyl(S)-(7-((4-fluorobenzyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR (400MHz,MeOH-d4): δ7.47(2H,m), 7.18-7.08(3H,m), 7.05(1H,d,J=2.8Hz), 6.93(1H,dd,J=8.8,2.8Hz), 5 .09(2H,s), 4.58(1H,dd,J=9.6,7.2Hz), 4.40(1H,dd,J=10.8,9.6Hz), 4.30(1H,dd,J=11.2,7.2Hz), 3.41(3H,s).

[0544] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-((4-fluorobenzyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0545] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((4-fluorobenzyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:ELISA=2:1) ​​to provide (S)-4-(3-fluorobenzyl)-N-(7-((4-fluorobenzyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]-oxazepine-3-yl)-1H-pyrazole-1-carboxamide (70% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=7.6Hz), 7.88(1H,d,J=0.8Hz), 7.46(1H ,s), 7.43-7.39(2H,m), 7.25(1H,td,J=8.0,6.0Hz), 7.12-7.06(3H,m), 6.96-6 .85(3H,m), 6.82-6.79(2H,m), 5.02(2H,s), 4.90(1H,dt,J=11.2,7.2Hz), 4.66 (1H,dd,J=9.6,7.2Hz), 4.25(1H,dd,J=11.2,9.6Hz), 3.80(2H,s), 3.39(3H,s). LC-MS:m / z=519.10[M+H] + .

[0546] Example 58: (S)-4-(3-fluorobenzyl)-N-(7-((5-fluoropyridine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0547] [ka]

[0548] Stage A: tert-butyl(S)-(7-((5-fluoropyridine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0549] The title compound was prepared using K2CO3 as the base, and intermediate 2 and (5-fluoropyridine-2-yl)methylmethanesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide tert-butyl(S)-(7-((5-fluoropyridine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (68%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.47(1H,d,J=2.8Hz), 7.53(1H,dd,J=8.8,4.4Hz), 7.46( 1H,td,J=8.8,2.8Hz), 7.05(1H,d,J=8.4Hz), 6.81(1H,d,J=3.2Hz), 6.77(1H,dd,J =8.8,3.2Hz), 5.48(1H,d,J=7.2Hz), 5.16(2H,s), 4.65(1H,dt,J=11.2,7.2Hz), 4. 53(1H,dd,J=9.6,7.6Hz), 4.10(1H,dd,J=11.2,9.6Hz), 3.37(3H,s), 1.40(9H,s).

[0550] Stage B: (S)-3-amino-7-((5-fluoropyridine-2-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0551] The title compound was prepared using tert-butyl(S)-(7-((5-fluoropyridine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification.1 H-NMR (400MHz,MeOH-d4): δ8.90(1H,s), 8.31(1H,td,J=8.8,2.8Hz), 8.10(1H,dd,J=8.8,4.4Hz), 7.25-7.22(2H,m), 7.04(1H,dd, J=8.8,2.8Hz), 5.45(2H,s), 4.63(1H,dd,J=9.6,7.2Hz), 4.44(1H,dd,J=10.8,9.6Hz), 4.35(1H,dd,J=10.8,7.2Hz), 3.44(3H,s).

[0552] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-((5-fluoropyridine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0553] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((5-fluoropyridine-2-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:ELISA=10:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-((5-fluoropyridine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (68% between the two steps) as a white form. 1H-NMR (400MHz, CDCl3): δ8.47(1H,d,J=3.2Hz), 8.00(1H,d,J=7.2Hz), 7.88(1H,s), 7.54( 1H,dd,J=8.8,4.4Hz), 7.49-7.44(2H,m), 7.25(1H,td,J=8.0,6.0Hz), 7.11(1H,d,J=8.8H z), 6.96-6.85(4H,m), 6.82(1H,dd,J=8.8,3.2Hz), 5.19(2H,s), 4.90(1H,dt,J=10.8,7.6 Hz), 4.66(1H,dd,J=9.6,7.6Hz), 4.25(1H,dd,J=10.8,9.6Hz), 3.81(2H,s), 3.40(3H,s). LC-MS:m / z=520.10[M+H] + .

[0554] Example 59: (S)-4-(3-fluorobenzyl)-N-(7-((6-fluoropyridine-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0555] [ka]

[0556] Stage A: tert-butyl-(S)-(7-((6-fluoropyridine-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0557] The title compound was prepared using intermediate 2 and (6-fluoropyridine-3-yl)methylmethanesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 20:1) to provide tert-butyl(S)-(7-((6-fluoropyridine-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (59%) as a white foam.1 H-NMR (400MHz, CDCl3): δ8.30(1H,d,J=1.8Hz), 7.89(1H,td,J=8.0,2.6Hz), 7.10-7.07(1H,m), 7.00(1H,dd,J=8.2,2.7Hz), 6.77(2H,dd,J=1 1.0,2.7Hz), 5.47(1H,d,J=6.9Hz), 5.03(2H,s), 4.69-4.62(1H,m), 4.53(1H,dd,J=9.6,7.3Hz), 4.15-4.08(1H,m), 3.38(3H,s), 1.40(9H,s).

[0558] Stage B: (S)-3-amino-7-((6-fluoropyridine-3-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0559] The title compound was prepared using tert-butyl-(S)-(7-((6-fluoropyridine-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 318.10 [M + H] + .

[0560] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-((6-fluoropyridine-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0561] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((6-fluoropyridine-3-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:ELISA=10:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-((6-fluoropyridine-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (21% between the two steps) as a white form. 1 H-NMR (400MHz, CDCl3): δ8.31(1H,d,J=2.3Hz), 7.98(1H,d,J=7.3Hz), 7.91(1 H,dd,J=8.0,2.5Hz), 7.88(1H,d,J=1.1Hz), 7.47(1H,s), 7.24-7.22(1H,m), 7. 14(1H,t,J=4.8Hz), 7.02-6.81(6H,m), 5.06(2H,s), 4.94-4.87(1H,m), 4.67( 1H,dd,J=9.8,7.5Hz), 4.26(1H,dd,J=11.2,9.8Hz), 3.81(2H,s), 3.42(3H,s). LC-MS: m / z = 520.10 [M + H] + .

[0562] Example 60: (S)-4-(3-fluorobenzyl)-N-(7-((2-fluoropyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0563] [ka]

[0564] Stage A: tert-butyl(S)-(7-((2-fluoropyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0565] The title compound was prepared using K2CO3 as the base, and intermediate 2 and (2-fluoropyridine-4-yl)methylmethanesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide tert-butyl(S)-(7-((2-fluoropyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (77%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ8.21(1H,d,J=4.8Hz), 7.96(1H,ddd,J=9.6,7.2,1.6Hz) , 7.29-7.25(1H,m), 7.08(1H,d,J=8.8Hz), 6.82(1H,d,J=3.2Hz), 6.79(1H,dd,J= 8.8,2.8Hz), 5.52(1H,d,J=7.6Hz), 5.11(2H,s), 4.66(1H,dt,J=10.8,7.2Hz), 4. 53(1H,dd,J=9.6,7.6Hz), 4.11(1H,dd,J=11.2,9.6Hz), 3.39(3H,s), 1.40(9H,s).

[0566] Stage B: (S)-3-amino-7-((2-fluoropyridine-4-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0567] The title compound was prepared using tert-butyl(S)-(7-((2-fluoropyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1H-NMR(400MHz,MeOH-d4): δ8.20(1H,d,J=4.8Hz), 8.09(1H,ddd,J=9.6,7.2, 2.0Hz), 7.36(1H,ddd,J=7.2,4.8,1.6Hz), 7.20(1H,d,J=8.8Hz), 7.11(1H,d ,J=2.8Hz), 6.98(1H,dd,J=8.8,2.8Hz), 5.18(2H,s), 4.58(1H,dd,J=9.6,7. 6Hz), 4.41(1H,d,11.2,10.0Hz), 4.31(1H,dd,J=11.2,7.6Hz), 3.42(3H,s).

[0568] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-((2-fluoropyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0569] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((2-fluoropyridine-4-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:SiO=15:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-((2-fluoropyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (78% between the two steps) as a white solid. 1H-NMR (400MHz, CDCl3): δ8.22(1H,d,J=5.2Hz), 7.99-7.95(2H,m), 7.88(1H,d,J=0.8Hz), 7.47(1H,s), 7.28-7.22(2H,m), 7.14(1H,dd,J=8.4,0.8Hz ), 6.97-6.82(5H,m), 5.13(2H,s), 4.91(1H,dt,J=10.8,7.6Hz), 4.67(1H, dd,J=9.6,7.6Hz), 4.26(1H,dd,J=11.2,9.6Hz), 3.81(2H,s), 3.42(3H,s). LC-MS: m / z = 520.10 [M + H] + .

[0570] Example 61: (S)-4-(3-fluorobenzyl)-N-(7-((2-methoxypyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0571] [ka]

[0572] Stage A: tert-butyl(S)-(7-((2-methoxypyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b]][1,4]oxazepine-3-yl)carbamate

[0573] The title compound was prepared using intermediate 2 and (2-methoxypyridine-4-yl)methylmethanesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide tert-butyl(S)-(7-((2-methoxypyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (80%) as a white foam. 1H-NMR (400MHz, CDCl3) δ8.18(1H,d,J=4.8Hz), 7.06(1H,d,J=8.8Hz), 6.92(1H,dd ,J=5.2,1.2Hz), 6.81(1H,s), 6.78(1H,d,J=3.2Hz), 6.73(1H,dd,J=9.2,3.2Hz), 5.48(1H,d,J=6.8Hz), 5.01(2H,s), 4.65(1H,dt,J=11.6,7.2Hz), 4.53(1H,dd,J= 9.6,7.2Hz), 4.10(1H,dd,J=11.6,9.6Hz), 3.96(3H,s), 3.37(3H,s), 1.40(9H,s).

[0574] Stage B: (S)-3-amino-7-((2-methoxypyridine-4-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0575] The title compound was prepared using tert-butyl(S)-(7-((2-methoxypyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR (400MHz,MeOH-d4): δ8.36(1H,d,J=6.0Hz), 7.68(1H,s), 7.60(1H,d,J=6.0Hz), 7.25-7.22(2H,m), 7.03(1H,dd,J=8.8,2.8H z), 5.43(2H,s), 4.63(1H,dd,J=9.6,7.2Hz), 4.44(1H,dd,J=11.2,9.6Hz), 4.35(1H,dd,J=11.2,7.2Hz), 4.27(3H,s), 3.45(3H,s).

[0576] Stage C: (S)-4-(3-fluorobenzyl)-N-(7-((2-methoxypyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0577] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((2-methoxypyridine-4-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:siRNA=3:1) to provide (S)-4-(3-fluorobenzyl)-N-(7-((2-methoxypyridine-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (60% between the two steps) as a pale yellow form. 1 H-NMR (400MHz, CDCl3): δ8.18(1H,d,J=4.8Hz), 8.00(1H,d,J=7.6Hz), 7.88(1H,d,J=0.8Hz) , 7.47(1H,s), 7.24(1H,td,J=7.6,6.0Hz), 7.11(1H,d,J=9.2Hz), 6.96-6.84(4H,m), 6.82(2H ,d,J=2.3Hz), 6.77(1H,dd,J=8.8,3.2Hz), 5.04(2H,s), 4.90(1H,dt,J=12.0,7.2Hz), 4.66( 1H,dd,J=9.6,7.2Hz), 4.26(1H,dd,J=10.8,10.0Hz), 3.95(3H,s), 3.80(2H,s), 3.40(3H,s). LC-MS:m / z=532.1[M+H] + .

[0578] Example 62: (S)-N-(7-((2-chloropyrimidine-5-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0579] [ka]

[0580] Stage A: tert-butyl-(S)-(7-((2-chloropyrimidine-5-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0581] The title compound was prepared using intermediate 2 and (2-chloropyrimidine-5-yl)methylmethanesulfonate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide tert-butyl-(S)-(7-((2-chloropyrimidine-5-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (80%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.73(2H,s), 7.11(1H,d,J=8.7Hz), 6.81-6.76(2H,m), 5.47(1H,d,J=7.3Hz), 5 .05(2H,s), 4.69-4.62(1H,m), 4.54(1H,dd,J=9.6,7.3Hz), 4.15-4.09(2H,m), 3.39(3H,s), 1.40(9H,s).

[0582] Stage B: (S)-3-amino-7-((2-chloropyrimidine-5-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0583] The title compound was prepared using tert-butyl-(S)-(7-((2-chloropyrimidine-5-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 335.10 [M + H] + .

[0584] Stage C: (S)-N-(7-((2-chloropyrimidine-5-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0585] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((2-chloropyrimidine-5-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:SiO=10:1) to provide (S)-N-(7-((2-chloropyrimidine-5-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (40% between the two steps) as a white form. 1 H-NMR (400MHz, CDCl3): δ8.74(2H,s), 7.98(1H,d,J=7.3Hz), 7.88(1H,s), 7.47(1H,s), 7.23(1H,d,J=8.2Hz), 7.17(1H,d,J=9.1Hz) , 7.00-6.81(5H,m), 5.07(2H,s), 4.94-4.88(1H,m), 4.67(1H,dd,J=9.8,7.5Hz), 4.27(1H,t,J=10.5Hz), 3.81(2H,s), 3.43(3H,s). LC-MS:m / z=537.10[M+H] + .

[0586] Example 63: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((1-methyl-1H-imidazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0587] [ka]

[0588] Stage A: tert-butyl(S)-(5-methyl-7-((1-methyl-1H-imidazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0589] The title compound was prepared using intermediate 2 and 2-(chloromethyl)-1-methyl-1H-imidazole in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (DCM:MeOH = 20:1) to provide tert-butyl(S)-(5-methyl-7-((1-methyl-1H-imidazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (61%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ7.03(1H,d,J=8.8Hz), 7.00(1H,d,J=1.2Hz), 6.90-6.84(3H,m), 5.47(1H,d,J=7.2Hz), 5.14(2H ,s), 4.68-4.57(1H,m), 4.50(1H,dd,J=9.6,8.0Hz), 4.08(1H,dd,J=11.2,9.6Hz), 3.73(3H,s), 3.35(3H,s), 1.38(9H,s).

[0590] Stage B: (S)-3-amino-5-methyl-7-((1-methyl-1H-imidazole-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0591] The title compound was prepared using tert-butyl(S)-(5-methyl-7-((1-methyl-1H-imidazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 303.10 [M + H] + .

[0592] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((1-methyl-1H-imidazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0593] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-5-methyl-7-((1-methyl-1H-imidazole-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((1-methyl-1H-imidazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (54% between the two steps) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.2Hz), 7.86(1H,d,J=1.2Hz), 7.45(1 H,m), 7.26-7.21(1H,m), 7.09(1H,d,J=8.0Hz), 7.00(1H,d,J=1.6Hz), 6.95-6 .83(6H,m), 5.16(2H,s), 4.88(1H,td,J=10.8,7.2Hz), 4.63(1H,dd,J=10.0,7 .2Hz), 4.23(1H,dd,J=11.2,10.0Hz), 3.80(2H,s), 3.74(3H,s), 3.38(3H,s). LC-MS: m / z = 505.10 [M + H] + .

[0594] Example 64: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((5-methyl-1,3,4-oxadiazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0595] [ka]

[0596] Stage A: tert-butyl-(S)-(5-methyl-7-((5-methyl-1,3,4-oxadiazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0597] The title compound was prepared using intermediate 2 and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole in the same manner as in Example 15. The crude product was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to provide tert-butyl-(S)-(5-methyl-7-((5-methyl-1,3,4-oxadiazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (66%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.08(1H,d,J=8.7Hz), 6.84(2H,td,J=8.0,2.7Hz), 5.47(1H,d,J=7.3Hz), 4.67-4. 60(1H,m), 4.52(1H,dd,J=9.6,7.3Hz), 4.11(1H,dd,J=11.0,9.6Hz), 3.38(3H,s), 2.59(3H,s), 1.40(9H,s).

[0598] Stage B: (S)-3-amino-5-methyl-7-((5-methyl-1,3,4-oxadiazole-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0599] The title compound was prepared using tert-butyl-(S)-(5-methyl-7-((5-methyl-1,3,4-oxadiazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR(400MHz,DMSO-d6): δ8.50(3H,s), 7.19(1H,d,J=8.7Hz), 7.13(1H,dd,J=11.4,3.2Hz), 6.85(1H,td,J=9.4, 2.9Hz), 4.84(2H,s), 4.52(1H,dd,J=9.6,7.8Hz), 4.37(1H,t,J=10.5Hz), 4.23(1H,s), 3.71(3H,s), 3.34(3H,s).

[0600] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((5-methyl-1,3,4-oxadiazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0601] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-5-methyl-7-((5-methyl-1,3,4-oxadiazole-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:SiO=10:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((5-methyl-1,3,4-oxadiazole-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (13% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H ,s), 7.24-7.22(1H,m), 7.12(1H,d,J=8.7Hz), 7.00-6.85(3H,m), 6.83(1H,d,J =2.7Hz), 6.73(1H,dd,J=8.7,2.7Hz), 4.93-4.87(1H,m), 4.69-4.67(1H,m), 4. 64(2H,s), 4.25(1H,dd,J=11.2,9.8Hz), 3.83(3H,s), 3.81(2H,s), 3.41(3H,s). LC-MS:m / z=507.10[M+H] + .

[0602] Example 65: Methyl(S)-2-(((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate

[0603] [ka]

[0604] Stage A: Methyl(S)-2-(((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate

[0605] The title compound was prepared using intermediate 2 and methyl 2-(chloromethyl)thiazole-4-carboxylate in the same manner as in Example 15 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to provide methyl(S)-2-(((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate (47%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ8.25(1H,s), 7.07(1H,d,J=8.7Hz), 6.84-6.78(2H,m), 5.47(1H,d,J=7.3Hz), 5.39(2H ,s), 4.67-4.61(1H,m), 4.53(1H,dd,J=9.6,7.3Hz), 4.16-4.08(1H,m), 3.98(3H,s), 3.38(3H,s), 1.39(9H,s).

[0606] Stage B: Methyl(S)-2-(((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate hydrochloride

[0607] The title compound was prepared using methyl(S)-2-(((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1H-NMR (400MHz,DMSO-d6): δ8.62(1H,s), 8.40(3H,s), 7.30(1H,d,J=2.7Hz), 7.23(1H,d,J=8.7Hz), 7.01(1H,dd,J=8.9,3.0Hz), 5 .52(2H,d,J=2.3Hz), 4.51(1H,dd,J=9.6,7.8Hz), 4.37(1H,t,J=10.3Hz), 4.28(1H,dd,J=11.0,7.8Hz), 3.84(3H,s), 3.36(3H,s).

[0608] Stage C: Methyl(S)-2-(((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate

[0609] The title compound was prepared in the same manner as in Example 15 (Step C) using methyl(S)-2-(((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide methyl(S)-2-(((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate (46% between the two steps) as a yellow solid. 1H-NMR (400MHz, CDCl3): δ8.25(1H,s), 7.97(1H,d,J=7.3Hz), 7.87(1H,d,J=0.9Hz), 7.47(1H,s), 7.24-7.22(1H,m), 7.14(1H,d,J=9.1Hz), 6.96 -6.83(5H,m), 5.42(2H,s), 4.92-4.86(1H,m), 4.66(1H,dd,J=9.8,7.5H z), 4.26(1H,dd,J=11.2,9.8Hz), 3.98(3H,s), 3.81(2H,s), 3.41(3H,s). LC-MS: m / z = 566.00 [M + H] + .

[0610] Example 66: (S)-4-(3-fluorobenzyl)-N-(7-((4-(2-hydroxypropan-2-yl)thiazole-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0611] [ka]

[0612] At 0°C, a solution of methyl(S)-2-(((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate (Example 65, 20.0 mg, 0.035 mmol) was added to 0.20 mL of THF, to which MeMgCl (3 M solution in THF, 58.0 μL, 0.177 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. After terminating the reaction with saturated NH4Cl aqueous solution at 0°C, the mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:HCl = 1:1), and (S)-4-(3-fluorobenzyl)-N-(7-((4-(2-hydroxypropan-2-yl)thiazole-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (10.0 mg, 50%) was provided as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.3Hz), 7.88(1H,d,J=0.9Hz), 7.47(1H,s), 7.24-7.22(1H,m), 7.17(1H,s), 7.13(1H,dd,J=8.0,1.1Hz), 6. 96-6.85(5H,m), 5.34(2H,s), 4.92-4.86(1H,m), 4.66(1H,dd,J=9.6,7.3 Hz), 4.25(1H,dd,J=11.0,9.6Hz), 3.81(2H,s), 3.41(3H,s), 1.63(6H,s). LC-MS: m / z = 566.20 [M + H] + .

[0613] Example 67: (S)-N-(7-((3,5-dimethylisoxazol-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0614] [ka]

[0615] Stage A: tert-butyl(S)-(7-((3,5-dimethylisoxazol-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0616] The title compound was prepared using intermediates 2 and 4-(chloromethyl)-3,5-dimethylisoxazole in the same manner as in Example 15 (Step A). ​​The residue was purified by column chromatography on SiO2 (hexane:dimethyl=1:1) to provide tert-butyl(S)-(7-((3,5-dimethylisoxazole-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (59%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.09(1H,dd,J=7.8,1.0Hz), 6.76(2H,dd,J=11.0,2.3Hz), 5.46(1H,d,J=7.3Hz), 4.75(2H,s), 4.70 -4.63(1H,m), 4.53(1H,dd,J=9.6,7.3Hz), 4.11(1H,dd,J=11.2,9.8Hz), 3.38(3H,s), 2.43(3H,s), 2.31(3H,s), 1.40(9H,s).

[0617] Stage B: (S)-3-amino-7-((3,5-dimethylisoxazol-4-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0618] The title compound was prepared using tert-butyl(S)-(7-((3,5-dimethylisoxazole-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR (400MHz, DMSO-d6): δ8.41(3H,s), 7.22-7.20(2H,m), 6.95(1H,dd,J=8.7,2.7Hz), 4.95(2H,s), 3.36(3H,s), 2.41(3H,s), 2.23(3H,s).

[0619] Stage C: (S)-N-(7-((3,5-dimethylisoxazol-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0620] The title compound was prepared in the same manner as in Example 15 (Step C) using (S)-3-amino-7-((3,5-dimethylisoxazole-4-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:siRNA=15:1) to provide (S)-N-(7-((3,5-dimethylisoxazole-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (18% between the two steps) as a white form. 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.6Hz), 7.88(1H,d,J=0.8Hz), 7.47(1H,s), 7.25-7.23(1H,m), 7.15(1H,d,J=8.4Hz), 7.00-6.78(5H,m) , 4.95-4.89(1H,m), 4.78(2H,s), 4.66(1H,dd,J=9.8,7.4Hz), 4.27(1H, dd,J=11.2,10Hz), 3.81(2H,s), 3.42(3H,s), 2.43(3H,s), 2.32(3H,s). LC-MS: m / z = 520.10 [M + H] + .

[0621] Example 68: (S)-4-(3-fluorobenzyl)-N-(7-((1-(2-hydroxy-2-methylpropyl)-1H-1,2,3-triazole-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0622] [ka]

[0623] Stage A: tert-butyl(S)-(5-methyl-4-oxo-7-(prop-2-in-1-yloxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0624] A mixture of tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (intermediate 2, 250 mg, 0.811 mmol), propargyl bromide (73.0 μL, 0.973 mmol), and Cs2CO3 (528 mg, 1.62 mmol) was stirred at room temperature for 2 hours in CH3CN (8.0 mL). After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:SiO=2:1) ​​to provide tert-butyl(S)-(5-methyl-4-oxo-7-(prop-2-in-1-yloxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (230 mg, 80%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.08(1H,dd,J=7.2,2.0Hz), 6.81(1H,s), 6.80(1H,t,J=4.2Hz), 5.48(1H,d,J=7.6Hz), 4.68(2H,d,J=2.0Hz) ), 4.67-4.62(1H,m), 4.54(1H,dd,J=9.6,7.6Hz,1H), 4.11(1H,dd,J=11.2,9.6Hz), 3.38(3H,s), 2.55(1H,t,J=2.6Hz), 1.40(9H,s).

[0625] Stage B: tert-butyl(S)-(7-((1-(2-hydroxy-2-methylpropyl)-1H-1,2,3-triazole-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0626] A mixture of tert-butyl(S)-(5-methyl-4-oxo-7-(prop-2-in-1-yloxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (200 mg, 0.577 mmol), 1-azido-2-methylpropan-2-ol (80.0 mg, 0.693 mmol), CuI (2.20 mg, 0.012 mmol), and DIPEA (0.100 mL, 0.577 mmol) in DCM (6.0 mL) was stirred at room temperature for 1 hour. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (DCM:MeOH = 20:1), and tert-butyl(S)-(7-((1-(2-hydroxy-2-methylpropyl)-1H-1,2,3-triazole-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (130 mg, 49%) was provided as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.64(1H,s), 7.02(1H,d,J=8.0Hz), 6.80-6.78(2H,m), 5.47(1H,d,J=8.0Hz), 5.28(2H,d,J=4.4Hz), 4.59-4. 53(1H,m), 4.45(1H,dd,J=9.6,8.0Hz), 4.30(2H,s), 4.08(1H,dd,J=11.4,9.8Hz), 3.36(3H,s), 1.40(9H,s), 1.20(3H,s), 1.14(3H,s).

[0627] Stage C: (S)-3-amino-7-((1-(2-hydroxy-2-methylpropyl)-1H-1,2,3-triazole-4-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0628] At 0°C, a solution of tert-butyl(S)-(7-((1-(2-hydroxy-2-methylpropyl)-1H-1,2,3-triazole-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (130 mg, 0.82 mmol) was added to DCM (2.8 mL) with HCl (4 M solution in dioxane, 0.700 mL, 2.82 mmol). The reaction mixture was stirred at room temperature for 18 hours and concentrated under vacuum to provide (S)-3-amino-7-((1-(2-hydroxy-2-methylpropyl)-1H-1,2,3-triazole-4-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (90.0 mg, 80%) as a white foam. 1 H-NMR (400MHz, DMSO-d6): δ8.48(3H,s), 8.11(1H,s), 7.21(2H,dd,J=12.2,5.8Hz), 6.99(1H,dd,J=9.0,2.6Hz), 5.18(2 H,d,J=2.0Hz), 4.52(1H,t,J=8.6Hz), 4.37(1H,t,J=10.4Hz), 4.29(2H,s), 4.27-4.20(1H,m), 3.35(3H,s), 1.07(6H,s).

[0629] Stage D: (S)-4-(3-fluorobenzyl)-N-(7-((1-(2-hydroxy-2-methylpropyl)-1H-1,2,3-triazole-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0630] At 0°C, a solution of (S)-3-amino-7-((1-(2-hydroxy-2-methylpropyl)-1H-1,2,3-triazole-4-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (90.0 mg, 0.226 mmol) was added to CDI (55.0 mg, 0.339 mmol) followed by TEA (79.0 μL, 0.566 mmol). The mixture was stirred at 0°C for 2 hours. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum.

[0631] 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6, 52.9 mg, 0.249 mmol) and TEA (79.0 μL, 0.566 mmol) were added to the residue solution in DCE (2.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 18 hours. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:siRNA=1:2) to provide (S)-4-(3-fluorobenzyl)-N-(7-((1-(2-hydroxy-2-methylpropyl)-1H-1,2,3-triazole-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (45.0 mg, 35%) as a white foam. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.2Hz), 7.87(1H,d,J=0.8Hz), 7.72(1 H,s), 7.47(1H,s), 7.25-7.22(1H,m), 7.10(1H,q,J=3.1Hz), 7.00-6.84(5H,m ), 5.26(2H,s), 4.89-4.83(1H,m), 4.62(1H,dd,J=9.8,7.6Hz), 4.33(2H,s), 4 .24(1H,dd,J=11.0,9.8Hz), 3.81(2H,s), 3.40(3H,s), 1.21(6H,d,J=3.2Hz). LC-MS: m / z = 564.20 [M + H] + . General synthetic reaction equations for hydroxyether analogs

[0632] [ka]

[0633] Example 69: 4-(3-fluorobenzyl)-N-((3S)-7-(2-hydroxy-2-(pyridine-2-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0634] [ka]

[0635] Stage A: tert-butyl(S)-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-2-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0636] At room temperature, a solution of tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (intermediate 2, 200 mg, 0.649 mmol) and 2-bromo-1-(pyridine-2-yl)ethane-1-one hydrobromide (273 mg, 0.973 mmol) was added to MeCN (2.2 mL) with Cs2CO3 (0.528 mg, 1.62 mmol). The reaction mixture was stirred at 60 °C for 3 hours and then cooled to room temperature. After terminating the reaction with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:SiO = 2:1 to 1:1) to obtain tert-butyl(S)-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-2-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (242 mg, 87%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.03(1H,d,J=8.8Hz), 6.75-6.70(2H,m), 5.46(1H,d,J=7.2Hz), 4.67-4.60(1H,m) , 4.51(1H,dd,J=9.6,7.2Hz), 4.10-4.00(3H,m), 3.36(3H,s), 2.77-2.67(2H,m), 2.37(6H,s), 1.38(9H,s).

[0637] Stage B: (S)-3-amino-5-methyl-7-(2-oxo-2-(pyridine-2-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-ondihydrochloride

[0638] At 0°C, a solution of tert-butyl(S)-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-2-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (242 mg, 0.566 mmol) in DCM (2.8 mL) was added to HCl (4 M in dioxane, 0.708 mL, 2.83 mmol). The reaction mixture was stirred overnight at room temperature and concentrated under vacuum to provide (S)-3-amino-5-methyl-7-(2-oxo-2-(pyridine-2-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-ondihydrochloride as a yellow solid, which was used in the next step without further purification. LC-MS: m / z = 280.1 [M + H] + .

[0639] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-2-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0640] At 0°C, a solution of (S)-3-amino-5-methyl-7-(2-oxo-2-(pyridine-2-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (230 mg, 0.575 mmol) in DCE (2.9 mL) was added, followed by CDI (107 mg, 0.661 mmol) and then TEA (0.200 mL, 1.44 mmol). The mixture was stirred at 0°C for 1 hour. After terminating the reaction with water, the mixture was extracted with DCM, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum.

[0641] To a solution of the residue in DCE (2.9 mL) at 0°C, 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6, 134 mg, 0.632 mmol) was added, followed by TEA (0.200 mL, 1.44 mmol). The reaction mixture was stirred at 40°C for 2 hours and then cooled to room temperature. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography over SiO2 (hexane:siRNA = 4:1 to 2:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-2-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (215 mg, 71% between the two steps) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.2Hz), 7.86(1H,s), 7.45(1H,s), 7.2 9-7.21(1H,m), 7.09(1H,d,J=8.8Hz), 6.98-8.84(3H,m), 6.78-6.74(2H,m), 4. 92-4.85(1H,m), 4.65(1H,dd,J=9.6,7.6Hz), 4.23(1H,dd,J=10.8,10.0Hz),4. 05(2H,t,J=5.8Hz), 3.80(2H,s), 3.39(3H,s), 2.79-2.69(2H,m), 2.35(6H,s). LC-MS:m / z=482.1[M+H] + .

[0642] Stage D: 4-(3-fluorobenzyl)-N-((3S)-7-(2-hydroxy-2-(pyridine-2-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0643] At 0°C, a solution of (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-2-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (16.0 mg, 0.0300 mmol) was added to MeOH (0.15 mL). The reaction mixture was stirred at 0°C for 30 minutes. After terminating the reaction with water, the mixture was extracted twice with ELISA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:HCl = 1:1 to 1:3), and 4-(3-fluorobenzyl)-N-((3S)-7-(2-hydroxy-2-(pyridine-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-2-yl)-1H-pyrazole-1-carboxamide (16 mg, 100%) was provided as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.60(1H,d,J=4.4Hz), 7.97(1H,d,J=6.8Hz), 7.87(1H,s), 7.77-7.73(1H,m), 7.52-7.46(2H,m), 7.29-7.22(2H,m), 7.09(1H,dd,J=8.8,2.4Hz ), 7.00-6.85(3H,m), 6.80-6.76(2H,m), 5.13(1H,t,J=4.2Hz), 4.91-4.84(1H,m), 4 .65(1H,dd,J=7.2,9.6Hz), 4.26-4.19(3H,m), 3.801(2H,s), 3.41(3H,d,J=2.4Hz). LC-MS:m / z=532.10[M+H] + .

[0644] Example 70: 4-(3-fluorobenzyl)-N-((3S)-7-(2-hydroxy-2-(pyridine-3-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0645] [ka]

[0646] Stage A: tert-butyl(S)-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-3-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0647] At room temperature, 2-bromo-1-(pyridine-3-yl)ethane-1-one hydrobromide (364 mg, 1.30 mmol) was added in a solution of tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (intermediate 2, 200 mg, 0.649 mmol) and Cs2CO3 (0.528 mg, 1.62 mmol) in MeCN (6.5 mL). The reaction mixture was stirred at room temperature for 30 minutes. After terminating the reaction with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (hexane:SiO = 2:1 to 1:1) to obtain tert-butyl(S)-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-3-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (125 mg, 45%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ9.22(1H,dd,J=2.8,1.2Hz), 8.83(1H,dd,J=4.8,1.6Hz), 8.28(1H,dt,J=8.0,2.0Hz), 7.49-7.46(1H,m), 7.05(1H,d,J=8.8Hz), 6.81(1H,d,J =3.2Hz), 6.72(1H,dd,J=8.4,3.2Hz), 5.46(1H,d,J=6.8Hz), 5.21(2H,s), 4.66-4.5 9(1H,m), 4.51(1H,dd,J=9.6,3.2Hz), 4.13-4.06(1H,m), 3.36(3H,s), 1.38(9H,s).

[0648] Stage B: (S)-3-amino-5-methyl-7-(2-oxo-2-(pyridine-3-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-ondihydrochloride

[0649] The title compound was prepared using tert-butyl(S)-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-3-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 69 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 328.1 [M + H] + .

[0650] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-3-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide(1300-164)

[0651] The title compound was prepared in the same manner as in Example 69 (Step C) using (S)-3-amino-5-methyl-7-(2-oxo-2-(pyridine-3-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-ondihydrochloride and 4-(3-fluorobenzyl)-1H-pyrazolehydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:ELISA=1:4) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-3-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (77% between the two steps) as a white foam. 1H-NMR (400MHz, CDCl3): δ9.24(1H,dd,J=2.0,1.2Hz), 8.85(1H,dd,J=4.4,2.0Hz), 8.30(1H,dt,J=8.4, 1.6Hz), 7.98(1H,d,J=7.2Hz), 7.87(1H,s), 7.49(1H,td,J=8.4,0.8Hz), 7.47(1H,s), 7.27-7.22(1H,m) , 7.12(1H,d,J=7.2Hz), 6.96-6.90(2H,m), 6.89-6.84(2H,m), 6.76(1H,dd,J=8.4,3.2Hz), 5.25(2H,s), 4.92-4.86(1H,m), 4.66(1H,dd,J=9.6,7.2Hz), 4.25(1H,dd,J=10.8,9.6Hz), 3.81(2H,s), 3.41(3H,s). LC-MS:m / z=530.1[M+H] + .

[0652] Stage D: 4-(3-fluorobenzyl)-N-((3S)-7-(2-hydroxy-2-(pyridine-3-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0653] The title compound was prepared using (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-3-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide in the same manner as in Example 69 (Step D). The crude product was purified by column chromatography over SiO2 (ELISA only) to provide 4-(3-fluorobenzyl)-N-((3S)-7-(2-hydroxy-2-(pyridine-3-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (80%) as a white foam. 1H-NMR (400MHz, CDCl3): δ8.71(1H,d,J=2.4Hz), 8.61(1H,dd,J=4.4,0.8Hz), 7.97(1H,d,J=7.6Hz), 7.88(1H ,d,J=1.2Hz), 7.83(1H,dt,J=8.0,2.0Hz), 7.47(1H,s), 7.36(1H,dd,J=8.0,4.8Hz), 7.28-7.22(1H,m), 7.13 -7.11(1H,m), 6.96-6.85(3H,m), 6.79-6.75(2H,m), 5.20(1H,dd,J=8.4,3.2Hz), 4.90(1H,dt,J=10.8,7.6Hz ), 4.66(1H,dd,J=10.0,8.0Hz), 4.25(1H,dd,J=10.8,10.0Hz), 4.15-4.11(2H,m), 3.81(2H,s), 3.41(3H,s). LC-MS:m / z=532.1[M+H] + .

[0654] Example 71: 4-(3-fluorobenzyl)-N-((3S)-7-(2-hydroxy-2-(pyridine-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0655] [ka]

[0656] Stage A: tert-butyl(S)-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate(4)

[0657] The title compound was prepared using intermediate 2 and 2-bromo-1-(pyridine-4-yl)ethane-1-one hydrobromide in the same manner as in Example 70 (Step A). ​​The crude product was purified by column chromatography on SiO2 (hexane:SiO = 1:1~1:3) to provide tert-butyl(S)-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (40%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ8.87(2H,dd,J=4.4,1.6Hz), 7.77(2H,dd,J=4.4,1.6Hz), 7.06(1H,d,J=8.8Hz), 6.82(1H,d,J=2.8Hz), 6.70(1H,dd,J =8.8,2.8Hz), 5.47(1H,d,J=7.2Hz), 5.21(2H,s), 4.67-4.60(1H,m), 4.51(1H,dd,J=9.6,7.2Hz), 4.10-4.00(1H,m), 3.37(3H,s), 1.39(9H,s).

[0658] Stage B: (S)-3-amino-5-methyl-7-(2-oxo-2-(pyridine-4-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-ondihydrochloride

[0659] The title compound was prepared using tert-butyl(S)-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 69 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. LC-MS: m / z = 328.0 [M + H] + .

[0660] Stage C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0661] The title compound was prepared in the same manner as in Example 69 (Step C) using (S)-3-amino-5-methyl-7-(2-oxo-2-(pyridine-4-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-ondihydrochloride and 4-(3-fluorobenzyl)-1H-pyrazolehydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (hexane:SiO=1:1) to provide methyl(S)-2-(((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-yl)oxy)methyl)thiazole-4-carboxylate (70% between the two steps) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.87(2H,dd,J=4.4,1.6Hz), 7.96(1H,d,J=7.2Hz), 7.86(1H, d,J=0.8Hz), 7.77(2H,dd,J=4.4,0.8Hz), 7.46(1H,s), 7.26-7.21(1H,m), 7.12(1H,d,J =8.8Hz), 6.98-6.84(4H,m), 6.75(1H,dd,J=8.8,3.2Hz), 5.24(2H,s), 4.92-4.85(1H,m ), 4.65(1H,dd,J=9.6,7.6Hz), 4.25(1H,dd,J=10.0,9.6Hz), 3.80(2H,s), 3.39(3H,s). LC-MS:m / z=530.1[M+H] + .

[0662] Stage D: 4-(3-fluorobenzyl)-N-((3S)-7-(2-hydroxy-2-(pyridine-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0663] The title compound was prepared using (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxo-2-(pyridine-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide in the same manner as in Example 69 (Step D). The crude product was purified by column chromatography on SiO2 (hexane:HCl = 1:1~1:3) to provide 4-(3-fluorobenzyl)-N-((3S)-7-(2-hydroxy-2-(pyridine-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (100%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.65(2H,d,J=5.6Hz), 7.97(1H,d,J=7.6Hz), 7.87(1H,d,J=1.2Hz), 7 .47(1H,s), 7.40-7.41(2H,m), 7.28-7.22(1H,m), 7.13-7.11(1H,m), 6.96-6.85(3H,m), 6.79-6 .74(2H,m), 5.15(1H,dd,J=8.0,3.2Hz), 4.92-4.86(1H,m)4.65(1H,dd,J=9.6,7.2Hz), 4.25(1H ,dd,J=11.2,9.6Hz), 4.16-4.09(1H,m), 4.01(1H,dd,J=8.4,9.6Hz), 3.80(2H,s), 3.41(3H,s). LC-MS:m / z=532.10[M+H] + .

[0664] Example 72: (S)-4-(2-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0665] [ka]

[0666] Stage A: (S)-4-(2-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0667] At 0°C, a solution of (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (Step B in Example 22, 50.0 mg, 0.147 mmol) was added to CDI (36.0 mg, 0.240 mmol) followed by TEA (0.0500 mL, 0.367 mmol). The mixture was stirred at room temperature for 1 hour. After terminating the reaction with water, the mixture was extracted with DCM, washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum.

[0668] At 0°C, 4-(2-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 5, 34.0 mg, 0.161 mmol) was added to the residue solution in DCE (1.5 mL), followed by TEA (0.0500 mL, 0.367 mmol). The reaction mixture was stirred at room temperature for 2.5 hours and then cooled to 0°C. After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (DCM:SiO=10:1) to provide (S)-4-(2-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (18.0 mg, 24%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.3Hz), 7.89(1H,s), 7.51(1H,s), 7.24-7.11(3H,m), 7.08-7.00(2H,m), 6.83(2H,dd,J=7.1,2. 5Hz), 4.93-4.87(1H,m), 4.71(2H,d,J=2.3Hz), 4.68-4.64(1H,m), 4.25(1H,dd,J=11.2,9.8Hz), 3.83(2H,s), 3.42(3H,s), 1.53(6H,s).

[0669] Stage B: (S)-4-(3-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0670] A suspension of (S)-4-(2-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (15.0 mg, 0.0300 mmol) and Pd / C (10 wt%, 0.400 mg, 2.96 μmol) was stirred in 0.30 mL of ethyl acetate under H2 atmosphere (1 atm) for 1 hour. The reaction mixture was filtered through a Celite pad and washed with ethyl acetate. The filtrate was concentrated under vacuum to provide (S)-4-(3-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (15.0 mg, 99%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.3Hz), 7.89(1H,s), 7.50(1H,s), 7.24 -7.13(2H,m), 7.11-7.01(3H,m), 6.75(2H,dd,J=7.1,2.5Hz), 4.92-4.86(1H,m) , 4.65(1H,dd,J=9.8,7.5Hz), 4.23(1H,dd,J=11.2,9.8Hz), 3.98(2H,t,J=6.2Hz ), 3.83(2H,s), 3.41(3H,s), 1.94-1.87(2H,m), 1.68-1.64(2H,m), 1.28(6H,s). LC-MS:m / z=511.10[M+H] + .

[0671] Example 73: (S)-4-(4-fluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0672] [ka]

[0673] The title compound was prepared in two steps using (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride (step B in Example 22) and 4-(4-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 7) in the same manner as in Example 72 (8.5%). 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.3Hz), 7.85(1H,s), 7.38(1H,s), 7. 18-7.09(3H,m), 7.00-6.98(2H,m), 6.76-6.73(2H,m), 4.93-4.86(1H,m), 4.6 5(1H,dd,J=9.6,7.3Hz), 4.24(1H,dd,J=11.2,9.8Hz), 3.98(2H,t,J=6.4Hz), 3.84(2H,s), 3.41(3H,s), 1.94-1.87(2H,m), 1.68-1.64(2H,m), 1.28(6H,s). LC-MS: m / z = 511.20 [M + H] + .

[0674] Example 74: (S)-4-(2,3-difluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0675] [ka]

[0676] The title compound was prepared in two steps using (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride (step B in Example 22) and 4-(2,3-difluorobenzyl)-1H-pyrazole hydrochloride (intermediate 8) in the same manner as in Example 72 (21%). 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.2Hz), 7.90(1H,s), 7.50(1H,s), 7.11- 6.96(3H,m), 6.91-6.88(1H,m), 6.76-6.74(2H,m), 4.89(1H,dt,J=10.9,7.5Hz) , 4.65(1H,dd,J=9.6,7.6Hz), 4.23(1H,dd,J=11.4,9.8Hz), 3.98(2H,t,J=6.4Hz ), 3.85(2H,s), 3.41(3H,s), 1.94-1.86(2H,m), 1.68-1.63(2H,m), 1.28(6H,s). LC-MS:m / z=529.2[M+H] + .

[0677] Example 75: (S)-4-(3,4-difluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0678] [ka]

[0679] The title compound was prepared in two steps using (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride (step B in Example 22) and 4-(3,4-difluorobenzyl)-1H-pyrazole hydrochloride (intermediate 9) in the same manner as in Example 72 (8%). 1H-NMR (400MHz, CDCl3): 7.98δ(1H,d,J=7.2Hz), 7.87(1H,s), 7.45(1H,s), 7.11-7.04 (2H,m), 6.98-6.93(1H,m), 6.89-6.86(1H,m), 6.76-6.74(2H,m), 4.89(1H,dt,J=11. 1,7.5Hz), 4.65(1H,dd,J=9.8,7.4Hz), 4.24(1H,dd,J=11.0,10.2Hz), 3.98(2H,t,J= 6.4Hz), 3.77(2H,s), 3.41(3H,s), 1.94-1.86(2H,m), 1.68-1.63(2H,m), 1.28(6H,s). LC-MS:m / z=529.2[M+H] + .

[0680] Example 76: (S)-4-(3,5-difluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0681] [ka]

[0682] The title compound was prepared in two steps using (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride (step B in Example 22) and 4-(3,5-difluorobenzyl)-1H-pyrazole hydrochloride (intermediate 10) in the same manner as in Example 72 (2%). 1H-NMR (400MHz, CDCl3): 7.99(1H,d,J=7.2Hz), 7.90(1H,s), 7.47(1H,s), 7. 12-7.09(1H,m), 6.76-6.63(5H,m), 4.90(1H,dt,J=11.2,7.5Hz), 4.66(1H, dd,J=9.8,7.4Hz), 4.25(1H,dd,J=11.0,10.2Hz), 3.98(2H,t,J=6.4Hz),3. 79(2H,s), 3.41(3H,s), 1.94-1.87(2H,m), 1.68-1.64(2H,m), 1.28(6H,s). LC-MS: m / z = 529.2 [M + H] + .

[0683] Example 77: (S)-4-(2,4-difluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0684] [ka]

[0685] The title compound was prepared in two steps using (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride (step B in Example 22) and 4-(2,4-difluorobenzyl)-1H-pyrazole hydrochloride (intermediate 11) in the same manner as in Example 72 (1%). 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.3Hz), 7.88(1H,s), 7.48(1H,s), 7.13-7.08(3H,m), 6.82-6.74(3H,m), 4.92-4.86(1H,m), 4.65(1H,d d,J=9.8,7.5Hz), 4.23(1H,t,J=10.5Hz), 3.98(2H,t,J=6.4Hz), 3.79( 2H,s), 3.41(3H,s), 1.94-1.88(2H,m), 1.68-1.62(2H,m), 1.28(6H,s). LC-MS:m / z=529.2[M+H] + .

[0686] Example 78: (S)-4-(2,6-difluorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0687] [ka]

[0688] The title compound was prepared in two steps using (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride (step B in Example 22) and 4-(2,6-difluorobenzyl)-1H-pyrazole hydrochloride (intermediate 12) in the same manner as in Example 72 (2%). 1H-NMR (400MHz, CDCl3): δ7.96(1H,d,J=7.3Hz), 7.91(1H,s), 7.53(1H,s), 7.21-7.14 (1H,m), 7.12-7.09(1H,m), 6.89-6.86(2H,m), 6.75(2H,dd,J=7.8,2.3Hz), 4.91-4.8 5(1H,m), 4.64(1H,dd,J=9.6,7.3Hz), 4.22(1H,dd,J=11.0,10.1Hz), 3.98(2H,t,J=6 .2Hz), 3.83(2H,s), 3.41(3H,s), 1.94-1.87(2H,m), 1.68-1.64(2H,m), 1.28(6H,s). LC-MS:m / z=529.2[M+H] + .

[0689] Example 79: (S)-N-(7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-(3-(trifluoromethyl)benzyl)-1H-pyrazole-1-carboxamide

[0690] [ka]

[0691] The title compound was prepared in two steps using (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride (step B in Example 22) and 4-(3-(trifluoromethyl)benzyl)-1H-pyrazole hydrochloride (intermediate 13) in the same manner as in Example 72 (1%). 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.2Hz), 7.87(1H,s), 7.48-7.33(5 H,m), 7.09-7.07(1H,m), 6.75-6.72(2H,m), 4.92-4.85(1H,m), 4.64(1H,dd ,J=10.0,7.6Hz), 4.23(1H,dd,J=11.0,10.2Hz), 3.97(2H,t,J=6.4Hz),3. 86(2H,s), 3.40(3H,s), 1.93-1.85(2H,m), 1.66-1.62(2H,m), 1.26(6H,s). LC-MS: m / z = 560.57 [M + H] + .

[0692] Example 80: (S)-4-(3-chlorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0693] [ka]

[0694] Stage A: (S)-3-amino-7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0695] A suspension of (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (step B in Example 22, 40.0 mg, 0.117 mmol), Pd / C (10 wt%, 6.25 mg, 5.87 μmol), and TEA (16.0 μL, 0.117 mmol) in SiO2 (1.2 mL) and MeOH (0.10 mL) was stirred at room temperature for 10 minutes under H2 atmosphere (1 atm). The reaction mixture was filtered through a Celite pad, washed with ethyl acetate, and concentrated under vacuum to provide (S)-3-amino-7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onhydrochloride (36.0 mg, 99%) as a colorless oil, which was used in the next step without further purification. LC-MS: m / z = 309.1 [M + H] + .

[0696] Stage B: (S)-4-(3-chlorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0697] The title compound was prepared in the same manner as in Example 72 (Step A) using (S)-3-amino-7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-chlorobenzyl)-1H-pyrazole hydrochloride (intermediate 14). LC-MS: m / z = 527.1 [M + H] + .

[0698] Example 81: (S)-4-(3-chlorobenzyl)-N-(7-((4-hydroxy-4-methylpentyl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0699] [ka]

[0700] The title compound was prepared in two steps using (S)-3-amino-7-((4-hydroxy-4-methylpento-2-in-1-yl)oxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride (step B in Example 22) and 3-((1H-pyrazole-4-yl)methyl)benzonitrile hydrochloride (intermediate 15) in the same manner as in Example 80 (1%). LC-MS: m / z = 517.87 [M + H] + .

[0701] Example 82: 4-(3-fluorobenzyl)-N-((3S)-5-methyl-7-((1-methyl-5-oxopyrrolidine-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0702] [ka]

[0703] Stage A: tert-butyl((3S)-5-methyl-4-oxo-7-((5-oxopyrrolidine-2-yl)methoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0704] The title compound was prepared in the same manner as in Example 15 (Step A) using intermediate 2 and (5-oxopyrrolidine-2-yl)methylmethanesulfonate. The crude product was purified by column chromatography on SiO2 (hexane:siRNA=2:1) ​​to provide tert-butyl((3S)-5-methyl-4-oxo-7-((5-oxopyrrolidine-2-yl)methoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (60%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.06(1H,d,J=8.7Hz), 6.71-6.67(2H,m), 5.87(1H,d,J=5.0Hz), 5.47(1H,d,J=7.3Hz), 4.67-4.61(1H,m), 4.52(1H,dd,J =9.6,7.8Hz), 4.13-4.05(2H,m), 3.97(1H,td,J=5.9,2.9Hz), 3.83-3.78 (1H,m), 3.38(3H,s), 2.46-2.33(3H,m), 1.97-1.87(1H,m), 1.40(9H,s).

[0705] Stage B: tert-butyl((3S)-5-methyl-7-((1-methyl-5-oxopyrrolidine-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate

[0706] A mixture of tert-butyl((3S)-5-methyl-4-oxo-7-((5-oxopyrrolidine-2-yl)methoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (100 mg, 0.247 mmol), MeI (0.0170 mL, 0.271 mmol), and Cs2CO3 (161 mg, 0.493 mmol) was stirred at room temperature for 18 hours in DMF (3.0 mL). After terminating the reaction with water, the mixture was extracted twice with DCM. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on SiO2 (DCM:MeOH = 20:1), and tert-butyl((3S)-5-methyl-7-((1-methyl-5-oxopyrrolidine-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate (30.0 mg, 29%) was provided as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.06(1H,d,J=8.7Hz), 6.71-6.68(2H,m), 5.47(1H,d,J=4.1Hz), 4.64(1H,dd,J=16.7,7.5Hz), 4.54-4.49(1H,m), 4.13-4 .03(2H,m), 3.99-3.87(2H,m), 3.38(3H,s), 2.92(3H,s), 2.60-2.51(1H, m), 2.44-2.36(1H,m), 2.31-2.24(1H,m), 2.01-1.93(1H,m), 1.40(9H,s).

[0707] Stage C: (3S)-3-amino-5-methyl-7-((1-methyl-5-oxopyrrolidine-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-onehydrochloride

[0708] The title compound was prepared using tert-butyl((3S)-5-methyl-7-((1-methyl-5-oxopyrrolidine-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)carbamate in the same manner as in Example 15 (Step B). After concentration under vacuum, the crude product was used in the next reaction without purification. 1 H-NMR(400MHz,DMSO-d6): δ8.46(3H,d,J=4.6Hz), 7.20(1H,d,J=9.1Hz), 7.13(1H,d, J=2.7Hz), 6.90(1H,dd,J=8.9,3.0Hz), 4.50(1H,dd,J=9.6,7.8Hz), 4.40-4.33(1H,m ), 4.28(1H,t,J=6.2Hz), 4.20-4.17(2H,m), 3.88(1H,t,J=4.1Hz), 3.35(3H,s), 3.17 (3H,s), 2.43-2.33(1H,m), 2.26-2.20(1H,m), 2.18-2.13(1H,m), 1.86-1.81(1H,m).

[0709] Stage D: 4-(3-fluorobenzyl)-N-((3S)-5-methyl-7-((1-methyl-5-oxopyrrolidine-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide

[0710] The title compound was prepared in the same manner as in Example 15 (Step C) using (3S)-3-amino-5-methyl-7-((1-methyl-5-oxopyrrolidine-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 6). The crude product was purified by column chromatography on SiO2 (DCM:ELISA=15:1) to provide 4-(3-fluorobenzyl)-N-((3S)-5-methyl-7-((1-methyl-5-oxopyrrolidine-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide (22% between the two steps) as a white form. 1 H-NMR (400MHz, CDCl3): δ7.98-7.97(1H,m), 7.88(1H,s), 7.47(1H,s), 7.25-7.23(1H,m), 7.13(1H,t,J =4.6Hz), 7.00-6.85(3H,m), 6.77-6.74(2H,m), 4.90(1H,dd,J=18.8,7.3Hz), 4.68-4.63(1H,m), 4.26( 1H,dd,J=11.2,9.8Hz), 4.11-4.06(1H,m), 4.01-3.97(1H,m), 3.90(1H,td,J=8.6,4.4Hz), 3.81(2H,s) , 3.42(3H,s), 2.93(3H,s), 2.59-2.53(1H,m), 2.45-2.37(1H,m), 2.32-2.22(1H,m), 2.02-1.94(1H,m). LC-MS:m / z=522.20[M+H] + .

[0711] biological activity Cell culture: Human colon cancer cells HT-29 (KCLB30038), BV2 mouse microglial cells (cells provided by Dr. Nak-Yun Sung, Senior Research Fellow at Korea Prime Pharmacy CO., LTD.), and human microglial cells HMC3 (ATCCRCRL-3304TM). HT-29 cells were grown at Roswell Park Memorial Institute (RPMI) 1640, BV2 cells were grown in Dulbecco's Modified Eagle's Medium (DMEM), and HMC3 cells were grown in Minimum Essential Media Eagle (MEM) supplemented with 10% fetal bovine serum and a 1% mixture of penicillin and streptomycin (Gibco). Cells were maintained at 37°C in a humid 5% CO2 atmosphere.

[0712] Cell-based necroptosis analysis of RIPK1 activity: To measure the activity of RIPK1 inhibitors from necroptotic cells, HT-29 cells were treated with a control group of DMSO, human TNFα (Peprotech, Rocky Hill, USA), SM-164 (Biovision, California, USA), and the pan-caspase inhibitor Z-VAD-FMK (Invivogen, San Diego, USA). Cells were pretreated with 20 μM Z-VAD-FMK. After 30 minutes, cells were treated with 10 ng / ml human TNFα, 100 nM SM-164, and RIPK1 inhibitors (0.0001, 0.001, 0.01, 0.02, 0.05, 0.1, 1, 10 μM) for 24 hours. Cell viability was measured using the Cell Counting Kit 8 (CCK-8) (Dong-in, Seoul, South Korea).

[0713] Immunoblotting: The biological activity of RIPK1 inhibitor compounds was determined by measuring their ability to induce TNFα-induced phospho-RIPK1 (ser166), phospho-RIPK3, and phospho-MLKL levels in HMC3 cells. Cells were pretreated with 20 μM Z-VAD-FMK. After 30 minutes, cells were treated with 20 ng / ml human TNFα, 100 nM SM-164, and RIPK1 inhibitors (0.1, 1, 10 nM) in serum-free medium for 7 hours. Cells were lysed using a cold lysis buffer (Bimake, Houston, USA) containing 25 mM HEPES pH 7.6, 150 nM NaCl, 1% NP40, 1% sodium deoxycholate, 0.1% SDS, and a mixture of protease inhibitors, while using an sonicator. Cells were centrifuged at 15,000 rpm for 5 minutes at 4°C. After quantifying the protein concentration of the lysate (supernatant) using BCA analysis (Thermo Fisher Scientific, Waltham, USA), the lysate was mixed with LDS sample buffer and heated at 70°C for 10 minutes (Invitrogen, California, USA). Extracts were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) followed by electrophoresis on a polyvinylidene difluoride (PVDF) membrane. These were probed with anti-phospho-RIPK1 antibody, anti-phospho-RIPK3 antibody, and anti-phospho-MLKL antibody (Cell Signaling Technology, Danvers, USA), and β-actin (Proteintech, Rosemont, USA), followed by anti-rabbit conjugated horseradish peroxidase (Cell Signaling Technology, Danvers, USA) and anti-mouse IgG, and shown using the Super Signal West dura kit (Pierce). A membrane was placed in an image analyzer (Imagequant, LAS500, GE Healthcare) and connected to a computer (software Image reader LAS 500) that was capable of generating images.

[0714] Inflammatory cytokines: Follow the manufacturer's protocol, PureLink TMTotal RNA was extracted and purified from the RNA mini kit (Thermo Fisher Scientific, Waltham, USA). Reverse transcription was performed using AccuPower CycleScript RT PreMix (dT20) (Bioneer, Daejeon, South Korea). cDNA was synthesized using the SimpliAmp Thermal Cycler (Applied Biosystems, Carlsbad, California, USA), and the RT-PCR conditions were 12 cycles of 30 seconds at 15°C, 4 minutes at 42°C, and 30 seconds at 55°C, with thermal deactivation at 95°C for 5 minutes. For qPCR, SYBR Green PCR Master Mix (Thermo Fisher Scientific, Waltham, USA) was used at QuantStudio3 (Applied Biosystems, Carlsbad, California, USA), and the PCR conditions were 10 minutes at 95°C, followed by 40 cycles of 15 seconds at 95°C and 30 seconds at 60°C. Relative mRNA levels were calculated using the cycle threshold (Ct) method. GAPDH was used as an internal control group. The PCR primers used in this study are shown in Table 1.

[0715] [Table 1] Primers used in this study [Table 1]

[0716] [Table 2-1] [Table 2-2] [Table 2-3] [Industrial applicability]

[0717] The present invention can be used to develop pharmaceutical compositions for the prevention and / or treatment of various diseases or disorders related to RIPK1.

Claims

1. A compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof. 【Chemistry 1】 【Chemistry 2】 【Transformation 3】

2. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound described in claim 1, or a pharmaceutically acceptable salt, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2 for use in the treatment of inflammatory diseases.

4. Inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, systemic lupus erythematosus (SLE), Sjögren's syndrome, systemic perdermatitis, antiphospholipid syndrome (APS), vasculitis, retinal detachment, retinitis pigmentosa, arthritis, rheumatoid arthritis, spondyloarthritis, gout, osteoarthritis and systemic juvenile idiopathic arthritis (SoJIA), liver injury / disease, non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity, renal injury / injury associated with nephritis, renal injury / injury associated with kidney transplantation, renal injury / injury associated with surgery, renal injury / injury associated with nephrotoxic drug administration, acute kidney injury (AKI), celiac disease The pharmaceutical composition according to claim 2 for use in the treatment of a disease selected from the group consisting of disease, autoimmune idiopathic thrombocytopenic purpura, systemic inflammatory response syndrome (SIRS), atherosclerosis, cerebrovascular accident, CVA, and stroke.

5. The pharmaceutically active composition according to claim 2 for use in the treatment of a disease selected from the group consisting of Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's Plus syndrome, tau disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, myotrichosis, progressive muscular atrophy, pseudobulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, multiple sclerosis, and demyelinating diseases.

6. The pharmaceutically active composition according to claim 2 for use in the treatment of a disease selected from the group consisting of pancreatic cancer, metastatic adenocarcinoma of the pancreas, ductal adenocarcinoma of the pancreas, mesothelioma, melanoma, rectal cancer, acute myeloid leukemia, metastasis, glioblastoma, breast cancer, gallbladder cancer, clear cell renal carcinoma, and non-small cell lung carcinoma.

7. A method for inhibiting the RIPK1 enzyme, comprising the step of contacting the RIPK1 enzyme in vitro with an amount sufficient to inhibit the enzyme of the compound described in claim 1, or a pharmaceutically acceptable salt, solvate, or tautomer thereof.

8. A pharmaceutical composition for use in the treatment of a RIPK1-mediated disease or disorder, comprising the step of administering to an individual in need of treatment an effective amount of a composition comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvate, or tautomer thereof, wherein the disease or disorder is selected from inflammatory diseases and neurodegenerative diseases.

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