Pyrazole-1-carboxamides as RIP1 kinase inhibitors

Abstract

The present invention provides novel substituted heterocyclic compounds represented by Formula I, or pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers or prodrugs thereof, and compositions comprising these compounds. The compounds provided may be used as RIPK1 inhibitors, and may be used in methods of treatment.

Description

Technical Field

[0001] This invention relates to a series of substituted heterocyclic compounds that are inhibitors of receptor-interacting protein-1 (RIP1) kinase-mediated diseases or disorders, and their therapeutic uses. Background Technology

[0002] Receptor interacting protein-1 (RIP1) kinase is a serine / threonine protein kinase, also known as RIPK1, RIP1 or RIP. RIP1 kinase plays a key role in cell survival or death. RIP1 is involved in apoptosis and non-apoptotic cell death, namely necroptosis[1]. The intracellular domains of TNF receptor 1 (TNFR1), FAS and TRAIL receptor 2 (TRAILR2) all contain death domains (DD). Under the stimulation of ligands such as tumor necrosis factor α (TNFα), Fas ligand (FASL) and TRAIL, RIP1 is recruited and binds to the DD of RIP1 through its DD. TNFα stimulation of TNFR1 can induce the formation of complex I, thereby activating NF-κB, which plays an important role in regulating RIP1 activation and activating important cell survival programs[2]. Activation of RIP1 can trigger a cell death pathway by forming a RIP1-TNF receptor-associated death domain protein (TRADD)-FAS-associated DD protein (FADD)-caspase 8 complex (complex IIa), thereby promoting caspase activation and leading to RIPK1-dependent apoptosis (RDA) [3-9]. When caspase-8 activity is inhibited, recruited receptor-interacting serine / threonine protein kinase 3 (RIPK3) drives cell lysis and cell membrane disruption and induces necrotic cell death by inducing the formation of a RIP1-RIP3-mixed lineage kinase domain-like (MLKL) complex (complex IIb) [10-11].

[0003] Necrotic cell death and RIP1 play a key checkpoint role in embryonic development. Activation of necrotizing cell death and RIP1 represents an important pathological mechanism and is associated with a variety of human diseases by mediating cell death and inflammation. Necrotic cell death is also associated with the pathogenesis of central nervous system (CNS) diseases, atherosclerosis, Huntington's disease, colitis, steatohepatitis, acute hepatitis, stroke, myocardial infarction, intestinal epithelial and skin diseases. Therefore, necrotizing cell death inhibitors play an important role in clinical drug development [12-14].

[0004] Necrotic cell death can be inhibited by inactivating RIP1 or RIP3 kinases. The first and most commonly used inhibitor of necrotic cell death is the RIP1 inhibitor Necrostatin-1 (Nec-1). Nec-1 has shown efficacy both in vitro and in vivo. Nec-1 can improve renal and cerebral ischemia / reperfusion injury, ConA-induced hepatitis, DSS-induced colitis, and reduce Huntington's disease symptoms in mouse studies [15-19].

[0005] The novel compounds of the present invention are capable of inhibiting RIP1 kinase activity and are therefore expected to be used to treat diseases and / or conditions associated with inflammation and / or necrotic cell death

[20] .

[0006] In recent years, RIP1 kinase inhibitors have been structurally different from Necrostatin compounds [21-22].

[0007] The entire contents of the above-mentioned cited references are incorporated herein by reference.

[0008] 1. Degterev, A., Hitomi, J., Germscheid, M., Ch'en, I., Korkina, O.,Teng, Biol. 4, 313-321 (2008).

[0009] 2. Ofengeim, D. and Yuan, J. Regulation of RIP1 kinase signaling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14,727-736 (2013).

[0010] 3. Shan, B., Pan, H., Najafov, A. and Yuan, J. Necroptosis in development and diseases. Genes Dev. 32, 327-340 (2018).

[0011] 4. 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)。

[0012] 5. Newton, K. RIPK1 and RIPK3:critical regulators of inflammation andcell death. Trends in cell biology. 25, 347-353 (2015)。

[0013] 6. de Almagro, M. C. and Vucic, D. Necroptosis:Pathway diversity andcharacteristics. Semin Cell Dev Biol. 39, 56-62 (2015)。

[0014] 7. O'Donnell, M. A., Legarda-Addison, D., Skountzos, P., Yeh, W. C.and Ting, A. T. Ubiquitination of RIPl regulates an NF-kappaB-independentcell-death switch in TNF signaling. Curr Biol. 17, 418-424 (2007)。

[0015] 8. 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 RIPl / caspase-8 containing intracellularcell death complex differentially regulated by cFLIP isoforms. Molecularcell. 43, 449-463 (2011)。

[0016] 9.Bertrand, M. J., Milutinovic, S., Dickson, K. M., Ho, W. C,Boudreault, A., Durkin, J., Gillard, J. W., Jaquith, J. B., Morris, S. J. andBarker, P. A. cIAPl and cIAP2 facilitate cancer cell survival by functioningas E3 ligases that promote RIPl ubiquitination. Mol Cell. 30, 689-700 (2008)。

[0017] 10. 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)。

[0018] 11. 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- likeprotein mediates necrosis signaling downstream of RIP3 kinase. Cell. 148,213-227 (2012)。

[0019] 12.Zhao, J., Jitkaew, S., Cai, Z., Choksi, S., Li, Q., Luo, J. andLiu, Z. G. Mixed lineage kinase domain-like is a key receptor interactingprotein 3 downstream component of TNF-induced necrosis. Proceedings of theNational Academy of Sciences of the United States of America. 109, 5322-5327(2012)。

[0020] 13. 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-likeProtein Mediates Necrosis Signaling Downstream of RIP3 Kinase. Cell. 148,213-227 (2012)。

[0021] 14. Linkermann, A. and Green, D. R. Necroptosis. The New Englandjournal of medicine. 370, 455-465 (2014)。

[0022] 15. 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 forIschemic Brain Injury. Nat. Chem. Biol. 1, 112-119 (2005)。

[0023] 16. Linkermann, A., Brasen, J.H., Himmerkus, N., Liu, S., Huber,T.B., Kunzendorf, U. and Krautwald, S. Rip1 (Receptor-Interacting ProteinKinase 1) Mediates Necroptosis and Contributes to Renal Ischemia / ReperfusionInjury. Kidney Int. 81, 751-761 (2012)。

[0024] 17. Jouan-Lanhouet, S., Arshad, M.I., 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 NecroptosisInvolving RIPK1 / RIPK3-Dependent PARP-1 Activation. Cell Death Differ.19,2003-2014 (2012)。

[0025] 18. Gunther, C., Martini, E., Wittkopf, N., Amann, K., Weigmann, B.,Neumann, H., Waldner, M.J., Hedrick, S.M., Tenzer, S. and Neurath, M.F.Caspase-8 Regulates TNF-Alpha-Induced Epithelial Necroptosis and TerminalIleitis. Nature. 477, 335-339 (2011)。

[0026] 19. Zhu, S., Zhang, Y., Bai, G. and Li, H. Necrostatin-1 AmelioratesSymptoms in R6 / 2 Transgenic Mouse Model of Huntington’s Disease. Cell. DeathDis. 2, e115 (2011)。

[0027] 20. Newton, K., Dugger, D. L., Wickliffe, K. E., Kapoor, N., deAlmagro, M. C, Vucic, D., Komuves, L., Ferrando, R. E., French, D. M.,Webster, J., Roose-Girma, M., Warming, S. and Dixit, V. M. Activity ofprotein kinase RIPK3 determines whether cells die by necroptosis orapoptosis. Science. 343, 1357-1360 (2014)。

[0028] 21. Harris, PA, Bandyopadhyay, D., Berger, SB, Campobasso, N., Capriotti, CA, Cox, JA, Dare, L., Finger, JN, Hoffman, SJ, Kahler, KM, Lehr, R., Lich, JD, Nagilla, R., Nolte, RT, Ouellette, MT, Pao, CS, Schaeffer, M. C, Smallwood, A., Sun, HH, Swift, BA, Totoritis, RD, Ward, P., Marquis, RW, Bertin, J. and Gough, PJDiscovery of Small Molecule RIPl Kinase Inhibitors for the Treatment ofPathologies Associated with Necroptosis. ACS medicinal chemistry letters. 4, 1238-1243 (2013).

[0029] 22. 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, GD and Degterev, A. Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1. Cell Rep. 24, 1850-1860 (2015). Summary of the Invention

[0030] Technical problems to be solved

[0031] This invention aims to provide compounds of Formula I, or pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers, stereoisomers, or prodrugs thereof:

[0032] ,

[0033] R¹ is an N-alkylamide, pyridinone, pyridazinone, pyrazinone, pyrimidinone, 4- to 6-membered heterocyclic alkyl, or 4- to 6-membered heterocyclic alkyl-C(O)-.

[0034] The pyridinone, pyrazinone, pyrazinone, pyrimidinone, 4- to 6-membered heterocyclic alkyl or 4- to 6-membered heterocyclic alkyl-C(O)- may optionally be substituted with one or two substituents, wherein the substituents are independently selected from (C1–C4)alkyl, OH, (C1–C4)hydroxy, (C1–C4)alkoxy, halogen, cyano, NR³R 4 and oxygenation;

[0035] L is O, -OCH2-, -OCH(CH3)-, -OCH2CH2-, -OCH2CH(OH)-, -OCH2CH2CH2-, -OCH2CH2CH(OH)-, -OCH2CH2CH(CH3)-, -OCH2CH2C(CH3)2-, -OCH2CH2CH2CH2- or -OCH2CH2CH2CH(OH)-;

[0036] Each R² is independently H, methyl, CF3, halogen, or cyano;

[0037] n is 1, 2, or 3;

[0038] R³ and R 4 Each is independently selected from H, aliphatic, heteroaliphatic, aromatic (including aryl and heteroaryl) or heterocyclic aliphatic, and together with the nitrogen atom to which it is attached, forms a C3–6 heterocyclic group;

[0039] In addition, the present invention provides a pharmaceutical composition for alleviating or improving RIPK1-mediated symptoms of diseases or conditions by inhibiting RIPK1 activity.

[0040] In addition, the present invention also provides a method for alleviating or improving RIPK1-mediated symptoms of diseases or conditions by inhibiting RIPK1 activity.

[0041] Problem-solving methods

[0042] To address the aforementioned technical problems, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof:

[0043] ,

[0044] R¹ is an N-alkylamide, pyridinone, pyridazinone, pyrazinone, pyrimidinone, 4- to 6-membered heterocyclic alkyl, or 4- to 6-membered heterocyclic alkyl-C(O)-.

[0045] The pyridinone, pyrazinone, pyrazinone, pyrimidinone, 4- to 6-membered heterocyclic alkyl or 4- to 6-membered heterocyclic alkyl-C(O)- may optionally be substituted with one or two substituents, wherein the substituents are independently selected from (C1–C4)alkyl, OH, (C1–C4)hydroxy, (C1–C4)alkoxy, halogen, cyano, NR³R 4 and oxygenation;

[0046] L is O, -OCH2-, -OCH(CH3)-, -OCH2CH2-, -OCH2CH(OH)-, -OCH2CH2CH2-, -OCH2CH2CH(OH)-, -OCH2CH2CH(CH3)-, -OCH2CH2C(CH3)2-, -OCH2CH2CH2CH2- or -OCH2CH2CH2CH(OH)-;

[0047] Each R² is independently H, methyl, CF3, halogen, or cyano;

[0048] n is 1, 2, or 3;

[0049] R³ and R 4 Each is independently selected from H, aliphatic, heteroaliphatic, aromatic (including aryl and heteroaryl) or heterocyclic aliphatic, and together with the nitrogen atom to which it is attached, forms a C3–6 heterocyclic group.

[0050] In certain embodiments, the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of 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, adjuvant, and / or excipient.

[0051] In certain embodiments, the composition may contain at least one of a preservative, an absorption retardant, a filler, a binder, an adsorbent, a buffer, a disintegrant, a solubilizer, and other carriers, adjuvants, and / or excipients as an inert component. The composition may be prepared by methods known in the art.

[0052] In a particular embodiment, the present invention relates to a treatment method comprising administering to an individual suffering from said disease a therapeutically effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof.

[0053] In a particular embodiment, the present invention relates to a method for treating a mammalian disorder, comprising administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof.

[0054] In a particular embodiment, the present invention relates to a method of treating a human disorder, comprising administering to the human a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof.

[0055] In certain embodiments, this document describes RIP1 kinase-mediated diseases or disorders, including inflammatory or immunomodulatory diseases or disorders such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, systemic lupus erythematosus (SLE), retinal diseases (including age-related macular degeneration, diabetic retinopathy, glaucoma, retinal detachment, and retinitis pigmentosa), arthritis (including rheumatoid arthritis, spondyloarthritis, gout, osteoarthritis, and systemic juvenile idiopathic arthritis (SoJIA)), and transplantation. Plant host resistance disease, non-alcoholic steatohepatitis (NASH), ischemia-reperfusion injury, multiple sclerosis, tumor necrosis factor receptor-related periodic syndrome, multiple organ dysfunction syndrome (MODS), burns, systemic inflammatory response syndrome (SIRS), radiation injury, radiotherapy, chemotherapy, pneumonia, hemorrhagic shock, trauma (including multiple traumas), traumatic brain injury, acute pancreatitis, severe illness, sepsis, septic shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, stroke, heatstroke, etc. Wind-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 organ ischemia-reperfusion injury (intestine, brain, liver, kidney) and limb ischemia), intestinal ischemia (small intestine and large intestine), cardiac surgery requiring cardiopulmonary bypass, autoimmune hepatitis, autoimmune hepatobiliary diseases, autoimmune ITP, Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's syndrome Tau proteinosis, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, 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 mellitus, Wegener's granulomatosis, Behçet's disease, and interleukin-1 converting enzyme-related fever syndrome.

[0056] The effects of the invention

[0057] This invention relates to a series of substituted heterocyclic compounds that are inhibitors of receptor-interacting protein-1 (RIP1) kinase-mediated diseases or disorders, and their therapeutic uses.

[0058] Preferred Implementation

[0059] The novel features of this invention are specifically defined in the appended claims. The features and advantages of this invention can be better understood by referring to the following detailed description, which provides exemplary embodiments of the principles of the invention.

[0060] While preferred embodiments of the invention have been shown and described herein, these embodiments are provided by way of example only. It should be understood that various alternatives to the embodiments described herein may be employed in carrying out the invention. Those skilled in the art will recognize that many variations, modifications, and substitutions can be made without departing from the scope of the invention. The following claims are intended to define the scope of various aspects of the invention, and all methods and structures within the scope of these claims and their equivalents should be included.

[0061] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter. All documents or parts thereof cited in this application (including, but not limited to, patents, patent applications, papers, books, manuals, and monographs) are incorporated herein by reference in their entirety for any purpose.

[0062] Specific chemical terms

[0063] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. All patents, patent applications, and publications referenced in this specification are incorporated herein by reference in their entirety, unless otherwise stated. Where multiple definitions exist for a term in this specification, the definition in this section shall prevail. When URLs or other identifiers or addresses are used, it should be understood that such identifiers may change, and specific information on the Internet may disappear, but equivalent information may be available through Internet searches or other appropriate references. References to such content indicate the availability and public dissemination of the information.

[0064] The foregoing general description and the following detailed description are exemplary and illustrative only and do not limit any of the claimed subject matter. The use of the singular form in this application includes the plural form unless otherwise expressly stated. It should be noted that the singular form “a” as used in this specification and the appended claims includes the plural meaning unless the context clearly specifies otherwise. It should also be noted that “or” means “and / or” unless otherwise stated. Furthermore, “comprising” and its other forms (such as “comprising,” “including,” “including”) are not limiting. Similarly, “including” and its other forms (such as “including,” “including,” “including”) are not limiting.

[0065] Definitions of standard chemical terms can be found in the references, including Carey and Sundberg, *Advanced Organic Chemistry 4th Edition*, Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional mass spectrometry, NMR, HPLC, infrared (IR), and ultraviolet / visible (UV / Vis) spectroscopy methods and pharmacological methods known to those skilled in the art are employed. Unless specifically defined, the nomenclature, experimental procedures, and techniques of analytical chemistry, synthetic organic chemistry, and pharmaceutical chemistry used in this specification are well-known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. Reaction and purification techniques may be performed, for example, using kits provided by the manufacturer, or according to methods commonly used in the art or methods described in this specification. The above techniques and procedures can generally be performed according to conventional methods known in the art and the relevant references cited in this specification. In this specification, those skilled in the art may select groups and their substituents to provide stable groups and compounds.

[0066] Unless otherwise stated, the general chemical terms "alkyl", "amine", "aryl", etc., include their optionally substituted forms. For example, "alkyl" as used in this specification includes optionally substituted alkyl groups.

[0067] The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or condition. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined below. Furthermore, an optionally substituted group can be unsubstituted (e.g., CH2CH3), fully substituted (e.g., CF2CF3), monosubstituted (e.g., CH2CH2F), or in any degree of substitution between full and monosubstituted (e.g., CH2CHF2, CF2CH3, CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, it is not intended to introduce a substitution or substitution pattern that is spatially unreasonable and / or synthetically infeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl, which is defined as including optionally substituted alkyl, thus theoretically allowing for an infinite extension). Therefore, any substituents described in this specification should generally be understood to have a maximum molecular weight of about 1,000 Daltons, more commonly about 500 Daltons (unless explicitly intended to be macromolecular substituents, such as peptides, polysaccharides, polyethylene glycol, DNA, RNA, etc.).

[0068] In this article, C1–C n Including C1–C2, C1–C3…C1–C nFor example, "C1–C4" indicates that the group contains 1 to 4 carbon atoms, including groups containing 1, 2, 3, or 4 carbon atoms, and the ranges C1–C2 and C1–C3. Therefore, for example, "C1–C4 alkyl" indicates that the alkyl group contains 1 to 4 carbon atoms, selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Whenever a numerical range such as "1 to 10" appears in this document, it refers to each integer within that range; for example, "1 to 10 carbon atoms" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0069] As used individually or in combination herein, "heteroatom" or "hetero" refers to an atom other than carbon and hydrogen. Heteroatoms may be selected independently from, but are not limited to, oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin. In embodiments containing two or more heteroatoms, these heteroatoms may be the same or may be partially or entirely different.

[0070] In this document, “alkyl” as used alone or in combination means a monovalent group of a straight-chain or branched saturated hydrocarbon with optional substituted carbon atoms, preferably 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever the range “C1–C6 alkyl” appears in this article, it means that the alkyl group can contain 1 to 6 carbon atoms. This definition also applies to “alkyl” where no numerical range is explicitly given.

[0071] The term "aliphatic" as used alone or in combination herein refers to optionally substituted, straight-chain or branched, non-cyclic, saturated, partially unsaturated or fully unsaturated non-aromatic hydrocarbons. Therefore, the term generally includes alkyl, alkenyl, and alkynyl groups.

[0072] The terms “cycle,” “cyclic,” “ring,” and “membered ring,” used alone or in combination herein, refer to any structure closed by covalent bonds, including alicyclic, heterocyclic, aromatic, heteroaromatic, and polycyclic fused or non-fused ring systems as described herein. Rings may be optionally substituted. Rings may form part of a fused ring system. The term “membered” is used to indicate the number of skeletal atoms constituting the ring. Thus, for example, cyclohexane, pyridine, pyran, and pyrimidine are six-membered rings, while cyclopentane, pyrrole, tetrahydrofuran, and thiophene are five-membered rings.

[0073] The term “cycloalkyl” as used alone or in combination herein refers to an optionally substituted monovalent ring of a saturated hydrocarbon containing 3 to about 15 cyclic carbon atoms, or 3 to about 10 cyclic carbon atoms, but may also contain additional acyclic carbon atoms as substituents (e.g., methylcyclopropyl).

[0074] Non-limiting examples of "cycloalkyl" include aziridine, aziridine, oxacyclobutyl, thiocyclobutyl, piperidinyl, oxacycloheptyl, thiocycloheptyl, oxacycloheptyl, diazacycloheptyl, thioazacycloheptyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxahexacycloyl, 1,3-dioxapentaneyl, pyrazolinyl, dithiohexacycloyl, dithiopentaneyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolinylalkyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinolinylidine, etc. This term also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides.

[0075] As used herein, the term "aromatic" refers to a group having a planar, cyclic, or polycyclic ring structure and containing a system of 4n+2 delocalized electrons, where n is an integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. Aromatic compounds can be optionally substituted and can be monocyclic or fused polycyclic structures. The term "aromatic" includes rings composed entirely of carbon (e.g., phenyl) as well as rings containing one or more heteroatoms (e.g., pyridine).

[0076] Specific pharmaceutical terms

[0077] The "necroptosis assay for RIP1 activity" mentioned in this article refers to the assay measured in the kinase assay described herein, which has an IC50 value for RIP1 kinase activity. 50 Compounds not exceeding approximately 100 μM or not exceeding approximately 50 μM. "IC" 50"" refers to the inhibitor concentration required to reduce enzyme activity to 50% of its maximum activity. The compounds described herein have been found to have inhibitory activity against RIPK1. Preferably, the compounds of the present invention exhibit an IC50 concentration against RIPK1 in the necroptosis assay described herein. 50 Not higher than about 10 μM, more preferably not higher than about 5 μM, even more preferably not higher than about 1 μM, and most preferably not higher than about 200 nM.

[0078] The terms "selective," "selectively," or "selectively" as used herein refer to the fact that the compounds of this invention have a lower IC50 value for the target enzyme relative to any other enzyme. 50 Values ​​(e.g., at least 2, 5, 10 times or more lower).

[0079] As used herein, “subject,” “patient,” or “individual” refers to an individual suffering from a disease or ailment, including both mammals and non-mammals. Examples of mammals include, but are not limited to, humans, non-human primates such as chimpanzees and other apes and monkeys; livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals including rats, mice, and guinea pigs. Non-mammals include, but are not limited to, birds and fish. In one embodiment, the mammal is a human.

[0080] The terms “treatment,” “under treatment,” or “treatment” as used herein include relieving, reducing, or improving symptoms of a disease or condition; preventing additional symptoms; improving or preventing underlying metabolic causes of symptoms; inhibiting the disease (e.g., preventing disease progression); alleviating the disease; causing disease remission; reducing the state caused by the disease; or stopping disease symptoms; and includes prophylaxis. These terms also include achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the underlying disease; even if the patient still has the disease, improvement in associated physiological symptoms can be considered an achievement of a therapeutic benefit. For preventive benefits, this composition may be given to patients at risk of disease or who have symptoms but have not yet been diagnosed.

[0081] The term "effective dose," "therapeutic effective dose," or "pharmaceutical effective dose" as used herein refers to a dose sufficient to alleviate the symptoms of a disease or condition to a certain extent. The result may be a reduction or improvement in symptoms or the underlying cause. For example, an "effective dose" for therapeutic purposes refers to a dose that produces a clinically significant improvement. Appropriate doses can be determined through methods such as dose-escalation studies.

[0082] As used herein, "administration," "application," or "method of administration" refers to a method of delivering a compound or composition to a target biological site of action, including but not limited to oral administration, intraduodenal administration, parenteral injection (intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), local administration, and rectal administration. These methods of administration are familiar to those skilled in the art. In a preferred embodiment, the compounds and compositions described herein are administered orally.

[0083] In this article, “acceptable” as used with respect to formulations, compositions or ingredients means that it will not have a lasting adverse effect on the general health of the person being treated.

[0084] As used herein, “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not impair the biological activity or properties of the compound described herein and is relatively non-toxic, i.e., the material can be administered to an individual without causing adverse biological effects or harmful interactions with any component of the composition to which it comprises.

[0085] The term "pharmaceutical composition" as used herein refers to a bioactive compound that may optionally be mixed with at least one pharmaceutically acceptable chemical component (e.g., but not limited to, a carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient).

[0086] In this article, "carrier" refers to a relatively non-toxic chemical compound or substance that facilitates the introduction of a compound into cells or tissues.

[0087] The term "agonist" as used in this article refers to a molecule that can enhance the activity of another molecule or receptor site, such as a compound, drug, enzyme activator, or hormone regulator.

[0088] The term "antagonist" as used in this article refers to a molecule that can reduce or prevent the action of another molecule or the activity of a receptor site, such as a compound, drug, enzyme inhibitor, or hormone regulator.

[0089] The term "modulation" as used in this article refers to altering the activity of a target through direct or indirect interaction, including, for example, enhancing target activity, inhibiting target activity, limiting target activity, or prolonging target activity.

[0090] In this article, "modulator" refers to a molecule that can interact directly or indirectly with a target. This interaction includes, but is not limited to, the interaction between agonists and antagonists.

[0091] The term "pharmaceutically acceptable salt" as used herein refers to a salt that retains the biological activity of the free acid and free base of a particular compound without exhibiting undesirable biological or other properties. The compounds described herein may possess acidic or basic groups, and therefore can react with a variety of inorganic or organic bases and inorganic or organic acids to form pharmaceutically acceptable salts. These salts can be prepared in situ during the final separation and purification of the compounds of this invention, or by reacting the purified free base form of the compound with a suitable organic or inorganic acid and then separating the resulting salt. Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic or organic acids or inorganic bases. These salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucose, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, gluconate, glyceryl phosphates, glycolates, hemisulfates, heptasulfates, heptahydrates, hexyn-1,6-dicitates, hydroxybenzoates, and hydroxybutyrates. Salts, hydrochlorides, hydrobromides, hydroiodates, 2-hydroxyethanesulfonates, iodides, isobutyrates, lactates, maleates, malonates, methanesulfonates, mandelates, metaphosphates, methoxybenzoates, methylbenzoates, monohydrophosphates, 1-naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, palmitates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pentanoates, propionates, pyrosulfates, pyrophosphates, propynates, phthalates, phenylacetates, phenylbutyrates, propionate salts, salicylates, succinates, sulfates, sulfites, octanoates, sebacic acid salts, sulfonates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and xylenesulfonates, etc. Other acids, such as oxalic acid, while not pharmaceutically acceptable on their own, can be used to prepare salts as intermediates to obtain the compounds of the present invention and their pharmaceutically acceptable acid addition salts (see Berge et al., J. Pharm. Sci. 1977, 66, 1-19). Furthermore, compounds described herein that may contain free acid groups can react with suitable bases, such as hydroxides, carbonates or bicarbonates of pharmaceutically acceptable metal cations, ammonia, or pharmaceutically acceptable primary, secondary, or tertiary organic amines. Representative alkali metal or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, etc. Examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, etc. Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they may contain.This quaternization can yield water-soluble, oil-soluble, or dispersible products. See, for example, the literature by Berge et al. mentioned above.

[0092] As used herein, "solvate" refers to the combination of the compound of this invention with solvent molecules formed through solvation. In some cases, sovate refers to hydrate, that is, when the solvent molecule is a water molecule, the combination of the compound of this invention with water forms a hydrate.

[0093] The term "polymorph" or "polymorphism" as used herein refers to the compounds of this invention that exist in different lattice forms.

[0094] As used herein, “ester” refers to a derivative derived from the compounds of this invention, which is formed of one of an oxyacid group and a hydroxyl group, either of which may be present in the compounds of this invention.

[0095] The term "tautomer" as used herein refers to an isomer that can be readily interconverted from the compounds of the present invention through, for example, the migration of hydrogen atoms or protons.

[0096] The term "pharmaceutically acceptable derivative or prodrug" as used herein refers to any pharmaceutically acceptable salt, ester, salt of ester, or other derivative of the compounds of the present invention, which, upon administration to a subject, can directly or indirectly provide the compounds of the present invention or their pharmacologically active metabolites or residues. Particularly preferred derivatives or prodrugs are those that improve the bioavailability of the compounds of the present invention when administered to a patient (e.g., making orally administered compounds more readily absorbed into the bloodstream) or that enhance the delivery of the parent compound to biological compartments (e.g., the brain or lymphatic system).

[0097] Pharmaceutically acceptable prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary ammonium derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts, and sulfonates. Many forms of prodrugs are known in the art. For example, see Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985; Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, pp. 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, pp. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, all of which are incorporated herein by reference. The prodrugs described herein include, but are not limited to, the following groups and combinations thereof; amine-derived prodrugs; hydroxy prodrugs include, but are not limited to, alkyl esters, alkoxycarbonyl alkyl esters, alkyl esters, aryl esters, and esters containing disulfide bonds.

[0098] The term "enhancement" or "enhancing" as used in this article refers to increasing or prolonging the potency or duration of a desired effect. Therefore, in the context of enhancing the effect of a therapeutic agent, "enhancement" means the ability to increase or prolong the effect of other therapeutic agents on the system in terms of potency or duration.

[0099] The term "enhancing-effective amount" as used in this article refers to a dose sufficient to enhance the effect of another therapeutic agent in the target system.

[0100] The terms “pharmaceutical combination,” “administration of adjunctive therapy,” and “administration of adjunctive therapeutic agent” as used herein refer to pharmaceutical treatments obtained by mixing or combining one or more active ingredients, including both fixed and non-fixed combinations of active ingredients. A “fixed combination” means that at least one of the compounds described herein is administered simultaneously to a patient with at least one adjunctive agent as a single entity or in a single dose. A “non-fixed combination” means that at least one of the compounds described herein is administered simultaneously, in parallel, or sequentially at variable intervals to a patient as independent entities, wherein such administration results in two or more compounds reaching effective levels in the patient. This also applies to cocktail therapies (e.g., administration of three or more active ingredients).

[0101] The terms "co-administered," "in combination with," and their grammatical equivalents or similar expressions used herein are intended to cover the administration of selected therapeutic agents to the same patient, including treatment regimens administered via the same or different routes of administration, or at the same or different times. In some embodiments, the compounds described herein will be co-administered with other pharmaceutical agents. These terms cover the administration of two or more pharmaceutical agents to an animal, such that the two pharmaceutical agents and / or their metabolites are simultaneously present in the animal. This includes simultaneous administration in separate compositions, administration in separate compositions at different times, and / or administration in the same composition containing both pharmaceutical agents. Thus, in some embodiments, the compounds of the present invention and other pharmaceutical agents are administered in the form of a single composition.

[0102] In this article, “metabolites” refers to derivatives of a compound formed when the compound is metabolized.

[0103] The term "active metabolite" as used in this article refers to a biologically active derivative of a compound formed during its metabolism.

[0104] In this article, "metabolized" refers to the sum of processes by which a specific substance is altered by an organism (including but not limited to hydrolysis and enzyme-catalyzed reactions). Therefore, enzymes can produce specific structural changes to compounds. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate glucuronide transferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, fatty alcohols, carboxylic acids, amines, and free sulfhydryl groups. Further information on metabolic processes can be found in [The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996)]. Detailed Implementation

[0105] NMR spectra were recorded at 30 °C in 5 mm outer diameter tubes (Norell, Inc. 507-HP) containing DMSO-d6, MeOH-d4, and CDCl3 solutions, and¹H data were acquired on a JEOL 400 MHz instrument. Chemical shifts (δ) were expressed in ppm based on tetramethylsilane (TMS = 0.00 ppm). LC / MS was performed on an ISQ EM, Thermo Fisher Vanquish Flex ion trap mass spectrometer (column: hypersil Gold (C18, Ø2.1 × 50 mm, 1.9 μm, 120 Å, 30 °C), using ESI(+) ionization mode, flow rate = 0.5 mL / min; mobile phase: water or CH3CN containing 0.01% heptafluorobutyric acid (HFBA) and 1.0% isopropanol (IPA)).

[0106]

[0107] Intermediate 1: tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0108]

[0109] Step A: (S)-2-(tert-Butoxycarbonylamino)-3-(4-Methoxy-2-nitrophenoxy)propionic acid

[0110] A suspension of NaH (55 wt%, 460 mg, 10.5 mmol) in dried N,N-dimethylformamide (DMF, 20 mL) was slowly added at 0 °C to a solution of N-Boc-L-serine (1.00 g, 4.87 mmol) in dried DMF (5.0 mL). The mixture was stirred at room temperature for 30 minutes and then cooled to 0 °C. Subsequently, a solution of 1-fluoro-4-methoxy-2-nitrobenzene (900 mg, 5.26 mmol) in dried DMF (5.0 mL) was added at 0 °C, and the mixture was stirred at 0 °C for 2 hours. Quenching with 0.5 M (mol / L) hydrochloric acid aqueous solution, the extract was obtained with ethyl acetate, washed with brine, dried over sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel (SiO2) column chromatography (hexane:ethyl acetate = 4:1 to 1:1) to give the target compound (900 mg, 48%) as a yellow oil. Liquid chromatography-mass spectrometry (LC-MS): m / z = 257.01 [M+H]⁺.

[0111] Step B: (S)-3-(2-amino-4-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propionic acid

[0112] (S)-2-(tert-Butoxycarbonylamino)-3-(4-methoxy-2-nitrophenoxy)propionic acid (350 mg, 0.982 mmol) was suspended in MeOH (10 mL) with Pd / C (5 wt%, 50 mg) and stirred at room temperature for 2 hours under H2 atmosphere (1 atm). The mixture was filtered through a diatomaceous earth filter and washed with MeOH. The filtrate was concentrated under reduced pressure to give the target compound (200 mg, 62%) as a black solid. LC-MS: m / z = 326.89 [M+H]⁺.

[0113] Step C: (S)-tert-butyl-7-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-ylcarbamate

[0114] (S)-3-(2-amino-4-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propionic acid (320 mg, 0.981 mmol) was dissolved in DMSO (3.0 mL), and DIPEA (514 μL, 2.94 mmol) was added, followed by HATU (373 mg, 0.981 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. After quenching with ice water, the mixture was extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (hexane:ethyl acetate = 2:1) to give the target compound (200 mg, 66%) as a white solid. ¹H-NMR (400 MHz, CDCl3): δ 7.17 (1H, brs), 6.90 (1H,d, J=8.8 Hz), 6.68–6.64 (2H, m), 5.48 (1H, brs), 4.69–4.61 (2H, m), 4.21 (1H,t, J=9.6 Hz), 3.79 (3H, s), 1.42 (9H, s).

[0115] Step D: tert-butyl(S)-(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0116] (S)-tert-butyl-7-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazolidin-3-ylcarbamate (200 mg, 0.649 mmol) was dissolved in DMF (5.0 mL), and Cs₂CO₃ (254 mg, 0.778 mmol) was added. Then, a solution of MeI (48.7 μL, 0.778 mmol) in DMF (1.0 mL) was added at 0 °C. The reaction mixture was stirred at 0 °C for 4 hours, followed by stirring at room temperature for 1 hour. After quenching with ice water, the mixture was extracted with ethyl acetate, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂ column chromatography (hexane:ethyl acetate = 3:1) to give the target compound (150 mg, 72%) as a colorless oil. LC-MS: m / z = 266.87 [M−tBu+H]⁺.

[0117] Step E: (S)-3-amino-7-hydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one

[0118] 1.90 g (5.89 mmol) of tert-butyl(S)-(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate was dissolved in dichloromethane (19 mL), and BBr3 (18.0 mL, 17.7 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. The precipitate was collected by filtration, washed with diethyl ether, and dried under vacuum to give the target compound (1.70 g, 100%) as a white solid. ¹H-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).

[0119] Step F: tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0120] (S)-3-amino-7-hydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyrone-4(5H)-one (300 mg, 1.44 mmol) was dissolved in DMF (4.8 mL), and (Boc)₂O (629 mg, 2.88 mmol) and DMAP (35.0 mg, 0.288 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After quenching with water, the mixture was extracted with ethyl acetate, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂ column chromatography (hexane:ethyl acetate = 3:1 to 1:1) to give the target compound (205 mg, 46%) as a white solid. ¹H-NMR (400 MHz, DMSO-d6): δ9.59 (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).

[0121] Intermediate 2: 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride

[0122]

[0123] Step A: 4-(3-fluorobenzyl)-1-(oxacyclohexane-2-yl)pyrazole

[0124] 1-(oxacyclohexan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrazole (27.0 g, 97.1 mmol) and 1-(bromomethyl)-3-fluorobenzene (23.9 g, 126 mmol) were dissolved in DME (189 mL), EtOH (54 mL), and H₂O (54 mL). Pd(PPh₃)₄ (2.24 g, 1.94 mmol) and K₃PO₄ (61.8 g, 291 mmol) were then added at room temperature. The reaction mixture was stirred at 60 °C for 5 hours under a nitrogen atmosphere. After dilution with water at room temperature, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 5:1) to give the target compound (25.0 g, 98%) as a yellow solid. LC-MS: m / z = 261.1 [M+H]⁺.

[0125] Step B: 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride

[0126] 4-(2-fluorobenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (24.0 g, 92.2 mmol) was dissolved in ethyl acetate (240 mL), and HCl (4 M in 1,4-dioxane, 96.0 g, 2.63 mol) 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 give the target compound (10.8 g, 55%) as an off-white solid. ¹H-NMR (400 MHz, DMSO-d6): δ 11.78 (2H, s), 7.88 (2H, d, J=2.6 Hz), 7.33 (1H, td, J=8.0, 6.2 Hz), 7.12–6.92 (3H, m), 3.86 (2H, s). LC-MS: m / z=177.0 [M+H]⁺.

[0127] Intermediate 3: (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0128]

[0129] Step A: (S)-3-amino-7-hydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one hydrochloride

[0130] Tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)carbamate (intermediate 1, 3.50 g, 11.4 mmol) was dissolved in dichloromethane (57 mL), and HCl (4 M, dioxane solution, 14.2 mL, 56.8 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 20 hours and then concentrated under reduced pressure to give the target compound as a white solid, which could be used directly in the next step without further purification. ¹H-NMR (400 MHz, CDCl3): δ 8.04 (1H, d, J=7.2 Hz), 7.89 (1H, d, J=0.8 Hz), 7.48 (1H, s), 7.28–7.23 (1H, m), 7.05–7.02 (1H, m), 6.97–6.85 (3H, m), 6.67–6.64 (2H, m), 5.83(1H, s), 4.87 (1H, dt, J=11.2, 7.6 Hz), 4.67 (1H, dd, J=9.8, 7.4 Hz), 4.24(1H, dd, J=10.8, 9.6 Hz), 3.81 (2H, s), 3.38 (3H, s).

[0131] Step B: (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0132] (S)-3-amino-7-hydroxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one hydrochloride (2.78 g, 11.4 mmol) was dissolved in 1,2-dichloroethane (57 mL), and TEA (4.75 mL, 34.1 mmol) was added, followed by CDI (2.12 g, 13.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After quenching with water, it was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 1,2-dichloroethane (57 mL). 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2, 2.90 g, 13.6 mmol) and TEA (4.75 mL, 34.1 mmol) were added at 0 °C, and the reaction mixture was stirred at room temperature overnight. After quenching 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 reduced pressure. The residue was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 2:1) to give the target compound (1.50 g, 32%) as a white, foamy solid. ¹H-NMR(400 MHz, DMSO-d6) δ 9.81 (1H, s), 8.48 (3H, s), 7.05 (1H, d, J=8.8 Hz), 6.83(1H, d, J=2.8 Hz), 6.69 (1H, dd, J=8.8, 2.8 Hz), 4.49 (1H, dd, J=9.6, 8.0Hz), 4.33 (1H, t, J=10.4 Hz), 4.22 (1H, dd, J=11.0, 7.8 Hz), 3.29 (3H, s).

[0133]

[0134] Intermediate 4: (S)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate

[0135]

[0136] Step A: [(4S)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl]acetic acid

[0137] (-)-malic acid (10.0 g, 74.6 mmol) and p-TsOH (100 mg, 0.746 mmol) were dissolved in 2,2-dimethoxypropane (37 mL) and stirred at room temperature for 3.5 hours. After quenching with water at 0 °C, the mixture was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residual solid was ground with diethyl ether and filtered to give the target compound (4.10 g, 31%) as a white solid. ¹H-NMR (400 MHz, CDCl3): δ 9.34 (1H, s), 4.72 (1H, dd, J=6.5, 3.9 Hz), 3.00 (1H, dd, J=17.3, 3.9 Hz), 2.86 (1H, dd, J=17.3, 6.5 Hz), 1.63 (3H, s), 1.58 (3H, s).

[0138] Step B: (5S)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4-one

[0139] [(4S)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl]acetic acid (4.00 g, 23.0 mmol) was dissolved in THF (50 mL), and BH3-THF (1 M, 27.6 mL, 27.6 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After quenching with MeOH at 0 °C and concentration under reduced pressure, the target compound was obtained and used directly in the next step without further purification. ¹H-NMR (400 MHz, CDCl3): δ 4.58 (1H, dd, J=7.1, 5.0 Hz), 3.94–3.77 (2H, m), 2.97 (1H, dd, J=17.2, 3.8 Hz), 2.22–2.10 (1H, m), 2.02 (1H, dtd, J=14.6, 6.8,4.6 Hz), 1.64 (3H, s), 1.57 (3H, s).

[0140] Step C: (5S)-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2,2-dimethyl-1,3-dioxolane-4-one

[0141] (5S)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4-one (7.00 g, 43.7 mmol) was dissolved in DMF (150 mL), and imidazole (5.95 g, 87.4 mmol) was added, followed by TBSCl (7.90 g, 52.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 hours. After quenching with ice water at 0 °C, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 4:1) to give the target compound (2.30 g, two-step yield 19%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ3.52 (2H, dd, J=9.9, 4.9 Hz), 3.47–3.43 (1H, m), 1.63–1.57 (2H, m), 1.54 (3H,s), 1.47 (3H, s), 0.83 (9H, s), -0.01 (6H, d, J=2.9 Hz).

[0142] Step D: (3S)-5-[(tert-butyldimethylsilyl)oxy]-2-methylpentane-2,3-diol

[0143] (5S)-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2,2-dimethyl-1,3-dioxolane-4-one (2.20 g, 8.02 mmol) was dissolved in diethyl ether (25 mL), and MeMgBr (2.39 g, 20.0 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After quenching with saturated NH4Cl aqueous solution at 0 °C, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 1:4) to give the target compound (316 mg, 15%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ 3.90–3.69 (2H, m), 3.58–3.49 (1H, m), 2.74 (2H, s), 1.65–1.52 (2H, m), 1.11 (3H,s), 1.07 (3H, s), 0.82 (9H, s), -0.00 (6H, d, J=0.9 Hz).

[0144] Step E: tert-butyldimethyl{2-[(4S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-yl]ethoxy}silane

[0145] (3S)-5-[(tert-butyldimethylsilyl)oxy]-2-methylpentane-2,3-diol (316 mg, 1.27 mmol) and p-TsOH (3.16 mg) were dissolved in 2,2-dimethoxypropane (1.17 mL) and stirred at room temperature for 1 hour. After quenching with MeOH at 0 °C, the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 10:1) to give the target compound (239 mg, 65%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ 3.80 (1H, dd, J=9.6, 3.1Hz), 3.76-3.60 (2H, m), 1.68-1.50 (2H, m), 1.35 (3H, d, J=0.8 Hz), 1.26 (3H,d, J=0.8 Hz), 1.18 (3H, s), 1.02 (3H, s), 0.83 (9H, s), -0.00 (6H, d, J=2.2Hz).

[0146] Step F: (S)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethane-1-ol

[0147] (S)-tert-butyldimethyl(2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethoxy)silane (100 mg, 0.347 mmol) was dissolved in THF (0.50 mL), and TBAF (1 M in THF, 0.437 mL, 0.437 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After quenching with a saturated aqueous solution of NaHCO3, the mixture was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 10:1 to ethyl acetate only) to give the target compound (51.0 mg, 84%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ 3.87-3.77 (3H, m), 2.34-2.16 (1H, brs), 1.81-1.74 (1H, m), 1.66-1.59 (1H, m), 1.41 (3H, s), 1.34 (3H, s), 1.25 (3H, s), 1.11 (3H, s).

[0148] Step G: (S)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate

[0149] (S)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethane-1-ol (51.0 mg, 0.293 mmol) was dissolved in dichloromethane (0.80 mL), and TEA (0.0570 mL, 0.410 mmol) was added, followed by MsCl (0.0210 mL, 0.263 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. After quenching with water, the mixture was extracted twice with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (57.0 mg, 77%) as a yellow oil. ¹H-NMR (400 MHz, CDCl3): δ 4.44-4.31 (2H, m), 3.85-3.78 (1H, m), 3.02 (3H, s), 1.91-1.83 (2H, m), 1.40 (3H,s), 1.31 (3H, s), 1.26 (3H, s), 1.10 (3H, s).

[0150] Intermediate 5: (5R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4-one

[0151]

[0152] Step A: [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl]acetic acid

[0153] The target compound was prepared using a method similar to that used for intermediate 4 (step A), with D-(+)-malic acid and 2,2-dimethoxypropane. After post-treatment, the target compound (53%) was obtained as a white solid and was used in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 4.77–4.68 (1H, m), 3.01 (1H, dd, J=17.3, 3.9Hz), 2.90–2.81 (1H, m), 1.63 (3H, s), 1.58 (3H, s). LC-MS: m / z=175 [M+H]⁺.

[0154] Step B: (5R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4-one

[0155] The target compound was prepared using [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl]acetic acid and BH3-THF, similar to intermediate 4 (step B). After post-treatment, the target compound (unpurified) was obtained as a colorless oil and was used in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 3.73 (1H, d, J=8.3 Hz), 3.43 (2H, d, J=5.5 Hz), 2.16 (1H, ddt, J=14.7, 7.3, 5.0 Hz), 2.01 (1H, dtd, J=14.4, 6.8, 4.6 Hz), 1.63 (3H, s), 1.57 (3H, d, J=1.8 Hz). LC-MS: m / z=161 [M+H]⁺.

[0156] Intermediate 6: (R)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate

[0157]

[0158] Step A: (5R)-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2,2-dimethyl-1,3-dioxolane-4-one

[0159] The target compound was prepared using a method similar to that used for intermediate 4 (step C), employing (5R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4-one (intermediate 5) and TBSCl. After post-treatment, the resulting unpurified target compound (crude product, 20%) was a colorless oil and could be used in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 3.78 (1H, dt, J=10.3, 5.8 Hz), 3.71-3.63 (2H, m), 2.07-1.97 (1H, m), 1.83 (1H,dddd, J=14.0, 7.9, 5.8, 5.1 Hz), 1.55 (3H, d, J=0.8 Hz), 1.48 (3H, d, J=0.7Hz), 0.83 (9H, s), 0.00 (6H, s). LC-MS: m / z=224 [M+H]⁺.

[0160] Step B: (3R)-5-[(tert-butyldimethylsilyl)oxy]-2-methylpentane-2,3-diol

[0161] The target compound was prepared using a method similar to that used for intermediate 4 (step D), employing (5R)-5-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-2,2-dimethyl-1,3-dioxolane-4-one and MeMgBr. After post-treatment, the resulting unpurified target compound (crude product, 28%) was a colorless oil and was used in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 3.65–3.60 (2H, m), 3.41 (1H, d, J=6.5 Hz), 1.61 (1H, d, J=0.7 Hz), 1.54 (1H, s), 1.21 (3H, s), 1.17 (3H, s), 0.89 (9H, s), 0.05 (6H, d, J=1.6 Hz). LC-MS: m / z=249 [M+H]⁺.

[0162] Step C: (R)-tert-butyldimethyl(2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethoxy)silane

[0163] The target compound was prepared using a method similar to that used for intermediate 4 (step E), employing (3R)-5-[(tert-butyldimethylsilyl)oxy]-2-methylpentane-2,3-diol and 2,2-dimethoxypropane. The crude product was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 19:1) to give the target compound (overall yield of 18% across 3 steps) as a pale yellow oil. ¹H-NMR (400 MHz, CDCl3): δ 3.87 (1H, dd, J=9.6, 3.1 Hz), 3.82-3.69 (2H, m), 1.62 (2H, dtd, J=8.2, 3.1, 1.5 Hz), 1.43-1.40 (3H, m), 1.33 (3H, s), 1.25 (3H, s), 1.10 (3H,s), 0.90 (9H, s), 0.07 (6H, d, J=2.2 Hz). LC-MS: m / z=254 [M+H]⁺.

[0164] Step D: (R)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethane-1-ol

[0165] The target compound was prepared using a method similar to that used for intermediate 4 (step F), with (R)-tert-butyldimethyl(2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethoxy)silane and TBAF. The crude product was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 10:1 to ethyl acetate only) to give the target compound (50%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ 3.87–3.78 (3H, m), 2.22 (1H, t, 1H, d, J = 5.6 Hz), 1.81–1.75 (1H, m), 1.66–1.59 (1H, m), 1.41 (3H, s), 1.34 (3H, s), 1.25 (3H, s), 1.11 (3H, s).

[0166] Step E: (R)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate

[0167] The target compound was prepared using (R)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethane-1-ol and MsCl, similar to the method used for intermediate 4 (step F). After post-treatment, the resulting unpurified target compound (crude product, 86%) was a yellow oil and was used in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 4.43–4.33 (2H, m), 3.82 (1H, t, 1H, d, J=6.4 Hz), 3.02 (3H, s), 1.94–1.86 (2H, m), 1.40 (3H, s), 1.32 (3H, s), 1.26 (3H, s), 1.10 (3H, s).

[0168]

[0169] Intermediate 7: ((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methylmethanesulfonate

[0170]

[0171] Step A: (2S,3R,4S)-2-(hydroxymethyl)-5-methoxyoxacyclopentane-3,4-diol

[0172] A mixture of L-ribofuranosyl furanose (10.0 g, 66.6 mmol) dissolved in MeOH (150 mL) was added dropwise with concentrated HCl (1.50 mL, 49.3 mmol) at 0 °C. The mixture was stirred at room temperature for 18 hours. After neutralization with NaOH, the mixture was concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (dichloromethane:MeOH = 10:1) to give the target compound (9.00 g, 82%) as a colorless oil. ¹H-NMR (400 MHz, DMSO-d6): δ 4.99 (1H, d, J=4.5 Hz), 4.79 (1H, d, J=6.7 Hz), 4.63-4.61 (1H, m), 3.86-3.78 (2H, m), 3.78-3.73 (1H, m), 3.70 (1H,td, J=4.6, 1.2 Hz), 3.51 (1H, ddd, J=11.6, 5.7, 3.8 Hz), 3.42 (1H, ddd, J=6.4, 4.3, 2.3 Hz), 3.22 (3H, s).

[0173] Step B: (2S,3R,4R)-2-(hydroxymethyl)oxacyclopentane-3,4-diol

[0174] A mixture of (2S,3R,4S)-2-(hydroxymethyl)-5-methoxyoxacyclopentane-3,4-diol (8.50 g, 51.8 mmol) dissolved in acetonitrile (85 mL) was prepared by adding N,O-bis(trimethylsilyl)acetamide (25.5 g, 125 mmol) dropwise at 0 °C. The mixture was stirred at 40 °C for 4 hours and then cooled to 0 °C. Et3SiH (29.7 g, 256 mmol) was slowly added at 0 °C, followed by TMSOTf (57.8 g, 260 mmol), and the reaction mixture was stirred at room temperature for 4 hours. After neutralization with NaOH, the mixture was concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (dichloromethane:MeOH = 10:1) to give the target compound (6.00 g, 86%) as a white solid. ¹H-NMR (400 MHz, DMSO-d6): δ 4.78-4.72 (2H, m), 4.61 (1H, dd, J=6.1, 5.3 Hz), 3.98 (1H, q, J=4.8 Hz), 3.84 (1H, dd, J=9.0, 5.0Hz), 3.76 (1H, td, J=6.1, 5.1 Hz), 3.58 (1H, ddd, J=6.3, 5.0, 3.4 Hz), 3.54-3.45 (2H, m), 3.36 (1H, ddd, J=11.5, 6.1, 5.1 Hz).

[0175] Step C: [(3aS,4S,6aR)-2,2-dimethyl-tetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl]methanol

[0176] (2S,3R,4R)-2-(hydroxymethyl)oxacyclopentane-3,4-diol (6.00 g, 44.7 mmol), 2,2-dimethoxypropane (6.99 g, 67.1 mmol), and p-TsOH (0.770 g, 4.47 mmol) were dissolved in acetone (60 mL) and stirred at room temperature for 30 minutes. After neutralization with saturated NaHCO3 aqueous solution, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 1:1) to give the target compound (426 mg, 5.4%) as a pale yellow oil. ¹H-NMR (400 MHz, CDCl3): δ 4.81 (1H, ddd, J=6.4, 4.0, 2.5 Hz), 4.61 (1H, dd, J=6.4, 2.1 Hz), 4.13 (1H, ddd, J=6.4, 4.1, 2.1 Hz), 4.03-3.92 (2H, m), 3.67 (1H, dd, J=11.6, 4.1 Hz), 3.60 (1H, dd, J=11.6, 6.7 Hz), 1.53 (3H, s), 1.35 (3H, s).

[0177] Step D: ((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methylmethanesulfonate

[0178] A solution of ((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxane-4-yl)methanol (100 mg, 0.574 mmol) and TEA (0.160 mL, 1.15 mmol) in dichloromethane (5.8 mL) was slowly added to MsCl (0.100 mL, 0.689 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours and then quenched with water. The mixture was partitioned between a saturated aqueous solution of NaHCO3 and ethyl acetate. The separated aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (140 mg, 97%) as a yellow oil. ¹H-NMR (400 MHz, CDCl3): δ 4.87–4.84 (1H, m), 4.68 (1H, m). dd, J=6.4, 1.4 Hz), 4.32-4.20 (3H, m), 4.05-3.97 (2H, m), 3.07 (3H, s), 1.52 (3H,s), 1.35 (3H, s).

[0179] Intermediate 8: Benzyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((methanesulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid ester

[0180]

[0181] Step A: Methyl(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid ester

[0182] (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (1.00 g, 7.63 mmol) was dissolved in MeOH (7.6 mL), and SOCl2 (0.800 mL, 11.4 mmol) was slowly added at 0 °C. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to give the target compound (1.10 g, 99%) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d6): δ 5.56 (1H, d,J=2.7 Hz), 4.48 (1H, dd, J=10.7, 7.5 Hz), 4.42 (1H, s), 3.76 (3H, s), 3.35-3.32 (1H, m), 3.08 (1H, d, J=11.9 Hz), 2.20-2.17 (1H, m), 2.13-2.06 (1H, m).

[0183] Step B: 1-Benzyl-2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid ester

[0184] Methyl(2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid ester (920 mg, 6.34 mmol) was dissolved in 1,4-dioxane (3.2 mL), followed by the addition of an aqueous solution of NaHCO3 (350 mg, 1.94 mmol) (3.2 mL), and then Cb2Cl (1.00 mL, 6.97 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. After dilution with water, the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 1:1) to give the target compound (1.10 g, 62%) as a colorless oil. ¹H-NMR (400 MHz, DMSO-d6): δ 7.40-7.27 (5H, m), 5.17 (1H, d, J=1.4 Hz), 5.12-4.95(2H, m), 4.37-4.27 (2H, m), 3.59 (3H, d, J=40.3 Hz), 3.51-3.39 (2H, m), 2.21-2.12 (1H, m), 1.99-1.89 (1H, m).

[0185] Step C: 1-Benzyl-2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylic acid ester

[0186] 1-Benzyl-2-methyl(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid ester (920 mg, 3.29 mmol) was dissolved in dichloromethane (11 mL), and imidazole (449 mg, 6.59 mmol) and TBSCl (546 mg, 3.62 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After quenching with water, the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (1.10 g, 85%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ 7.36-7.29 (5H, m), 5.20 (1H, d, J=12.3 Hz), 5.07 (1H, q, J=12.7 Hz), 4.51-4.41 (2H, m), 3.76 (1.5H, s), 3.69-3.64 (1H, m), 3.54 (1.5H, s), 3.46 (1H, ddq, J=34.2, 11.1, 1.3 Hz), 2.25-2.16(2H, m), 2.07-2.00 (1H, m), 0.86 (9H, dd, J=7.3, 2.7 Hz), 0.05 (6H, q, J=3.2Hz).

[0187] Step D: Benzyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid ester

[0188] 1-Benzyl-2-methyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylic acid ester (1.10 g, 2.80 mmol) was dissolved in THF (14 mL), and LiBH4 (2.10 mL, 4.19 mmol) was slowly added at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. After quenching with water, the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (950 mg, 93%) as a white solid. ¹H-NMR (400 MHz, CDCl3): δ 7.37-7.30 (5H, m), 5.16 (2H, d, J=5.5 Hz), 4.61 (1H, dd, J=8.7, 2.3 Hz), 4.31 (1H, t, J=1.8 Hz), 4.22-4.16 (1H, m), 3.78-3.72(1H, m), 3.63-3.50 (2H, m), 3.44 (1H, dd, J=11.4, 4.1 Hz), 1.97 (1H, ddq, J=13.0, 7.2, 1.6 Hz), 1.66-1.61 (1H, m), 0.86 (9H, t, J=3.0 Hz), 0.05 (6H, d, J=6.9 Hz).

[0189] Step E: Benzyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((methanesulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid ester

[0190] Benzyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid ester (950 mg, 2.60 mmol) and TEA (0.700 mL, 5.20 mmol) were dissolved in dichloromethane (13 mL), and MsCl (0.200 mL, 3.12 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours and then quenched with water. The mixture was partitioned between a saturated aqueous solution of NaHCO3 and dichloromethane. The separated aqueous layer was extracted again with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (900 mg, 78%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ 7.36-7.29 (5H, m), 5.23-5.11 (2H, m), 4.62 (1H, q, J=4.9 Hz), 4.42-4.38 (1H, m), 4.34-4.22 (2H, m), 3.58-3.46 (2H, m), 2.86 (3H, d, J=30.2 Hz), 2.12-1.99 (2H, m), 0.85 (9H, s), 0.05 (6H, d, J=6.4 Hz).

[0191] Intermediate 9: (R)-(1-methyl-5-oxopyrrolidone-2-yl)methyl-4-methylbenzenesulfonate

[0192] Step A: (R)-(5-oxopyrrolidone-2-yl)methyl-4-methylbenzenesulfonate

[0193]

[0194] (R)-5-(hydroxymethyl)pyrrolidone-2-one (350 mg, 3.04 mmol), DMAP (37.0 mg, 0.304 mmol), and TEA (0.500 mL, 3.65 mmol) were dissolved in dichloromethane (10 mL), and p-TsCl (695 mg, 3.65 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours and then quenched with water. The mixture was partitioned between a saturated aqueous solution of NaHCO3 and ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 10:1) to give the target compound (520 mg, 64%) as a white solid. ¹H-NMR (400 MHz, CDCl3): δ 7.79 (2H, dt, J=8.7, 1.8 Hz), 7.39-7.37 (2H, m), 5.66 (1H, s), 4.07 (1H, dd, J=9.6, 3.7 Hz), 3.97-3.91 (1H, m), 3.85 (1H, dd, J=9.6, 7.8 Hz), 2.47 (3H, s), 2.35-2.21 (3H,m), 1.80-1.72 (1H, m).

[0195] Step B: (R)-(1-methyl-5-oxopyrrolidone-2-yl)methyl-4-methylbenzenesulfonate

[0196] A suspension of NaH (60 wt%, 69.0 mg, 1.72 mmol) dispersed in DMF (16 mL) was slowly added at 0 °C to a solution of (R)-(5-oxopyrrolidone-2-yl)methyl-4-methylbenzenesulfonate (420 mg, 1.56 mmol) in DMF. The mixture was stirred at 0 °C for 20 min. MeI (0.150 mL, 2.34 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h, then quenched with water at 0 °C. The mixture was extracted with dichloromethane, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (220 mg, 50%) as a yellow oil. ¹H-NMR (400MHz, CDCl3): δ 7.79 (2H, dt, J=8.4, 1.9 Hz), 7.38 (2H, d, J=7.8 Hz), 4.13 (1H,dd, J=10.5, 3.7 Hz), 4.03 (1H, dd, J=10.5, 4.1 Hz), 3.73 (1H, td, J=8.2, 4.1Hz), 2.71 (3H, s), 2.47 (3H, s), 2.45-2.26 (2H, m), 2.21-2.11 (1H, m), 1.86-1.78 (1H, m).

[0197] Intermediate 10: (S)-(1-methyl-5-oxopyrrolidone-2-yl)methyl-4-methylbenzenesulfonate

[0198]

[0199] Step A: (S)-(5-oxopyrrolidone-2-yl)methyl-4-methylbenzenesulfonate

[0200] The target compound was prepared using a method similar to that used for intermediate 9 (step A), employing (S)-5-(hydroxymethyl)pyrrolidone-2-one and p-TsCl. The crude product was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 4:1) to give the target compound (54%) as a white solid.

[0201] Step B: (S)-(1-methyl-5-oxopyrrolidone-2-yl)methyl-4-methylbenzenesulfonate

[0202] The target compound was prepared using (S)-(5-oxopyrrolidone-2-yl)methyl-4-methylbenzenesulfonate and MeI, similar to intermediate 9 (step B). After post-treatment, the target compound (46%) was obtained as a yellow oil. ¹H-NMR (400MHz, CDCl3): δ 7.79 (2H, dt, J=8.4, 1.9 Hz), 7.38 (2H, d, J=7.8 Hz), 4.13 (1H,dd, J=10.5, 3.7 Hz), 4.03 (1H, dd, J=10.5, 4.1 Hz), 3.73 (1H, td, J=8.2, 4.1Hz), 2.71 (3H, s), 2.47 (3H, s), 2.45-2.26 (2H, m), 2.21-2.11 (1H, m), 1.86-1.78 (1H, m).

[0203] Intermediate 11: (3-(bromomethyl)oxetane-3-yl)methyl acetate

[0204]

[0205] (3-(bromomethyl)oxetane-3-yl)methanol (0.200 g, 1.11 mmol) was dissolved in dichloromethane (11 mL), and TEA (0.385 mL, 2.76 mmol), DMAP (6.75 mg, 0.0550 mmol), and acetic anhydride (0.208 mL, 2.21 mmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then quenched with water. The resulting mixture was extracted twice with dichloromethane. The combined organic layers were washed with water, saturated NaHCO3 aqueous solution, and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 2:1) to give the target compound (0.170 g, 69%) as a pale yellow oil. ¹H-NMR (400 MHz, CDCl3): δ 4.49-4.43 (4H, m), 4.40 (2H, s), 3.74 (2H, s), 2.10 (3H, s).

[0206] Intermediate 12: 2-(1,2-oxazacyclohexane-2-yl)ethyl methanesulfonate

[0207] Step A: Methyl 2-(1,2-oxazacyclohexane-2-yl)acetate

[0208]

[0209] 1,2-oxazacyclohexane hydrochloride (800 mg, 6.47 mmol) and TEA (1.00 mL, 7.77 mmol) were dissolved in DMF (32 mL), and NaH (60 wt%, 390 mg, 9.71 mmol) was slowly added at 0 °C. The mixture was stirred at 0 °C for 10 min. Methyl bromoacetate (0.680 mL, 7.12 mmol) was then added at 0 °C, and the reaction mixture was stirred at room temperature for 5 h. After quenching with water at 0 °C, the mixture was extracted with dichloromethane, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂ column chromatography (petroleum ether:ethyl acetate = 2:1) to give the target compound (577 mg, 56%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ 3.96 (2H, t, J=5.3 Hz), 3.75 (3H,brs), 3.44 (2H, s), 2.82 (2H, s), 1.86-1.81 (2H, m), 1.58-1.52 (2H, m).

[0210] Step B: 2-(1,2-oxazacyclohexane-2-yl)ethanol

[0211] Methyl 2-(1,2-oxazacyclohexane-2-yl)acetate (577 mg, 3.62 mmol) was dissolved in THF (18 mL), and LAH (1 M solution in THF, 5.00 mL, 4.71 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1.5 hours. After quenching with water, it was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (380 mg, 80%) as a colorless oil. This product was used directly in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 3.93 (2H, t, J=5.3 Hz), 3.75 (2H, brs), 2.78 (4H, t, J=4.8 Hz), 1.85-1.77 (2H, m), 1.60-1.54 (2H, m).

[0212] Step C: 2-(1,2-oxazacyclohexane-2-yl)ethyl methanesulfonate

[0213] 2-(1,2-oxazacyclohexane-2-yl)ethanol (100 mg, 0.762 mmol) and TEA (0.200 mL, 1.14 mmol) were dissolved in dichloromethane (4.0 mL), and MsCl (0.100 mL, 0.839 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 18 hours. After quenching with water, the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the target compound (130 mg, 81%) as a brown oil. This product was used directly in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 4.41 (2H, t, J=4.8Hz), 3.90 (2H, t, J=5.3 Hz), 3.06 (3H, s), 2.91 (2H, t, J=5.3 Hz), 2.76 (2H,brs), 1.82-1.76 (2H, m), 1.59-1.53 ​​(2H, m).

[0214] Intermediate 13: tert-butyl(S)-(7-(2-hydroxyethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0215]

[0216] Step A: tert-butyl(S)-(7-(2-(benzyloxy)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0217] Tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazopyron-3-yl)carbamate (intermediate 1, 1.00 g, 3.24 mmol) was dissolved in DMF (16 mL), and K₂CO₃ (1.12 g, 8.11 mmol) was added with stirring, followed by ((2-bromoethoxy)methyl)benzene (0.616 mL, 3.89 mmol) at room temperature. The reaction mixture was stirred at 80 °C for 22 hours. After quenching with water, it was extracted twice with ethyl acetate. The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂ column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to give the target compound (1.38 g, 96%) as a colorless viscous oil. ¹H-NMR (400 MHz, CDCl3): δ 7.38-7.27(5H, m), 7.04 (1H, d, J=8.4 Hz), 6.76-6.71 (2H, m), 5.48 (1H, d, J=7.2 Hz), 4.67-4.57 (3H, m), 4.55-4.50 (1H, m), 4.14-4.06 (3H, m), 3.84-3.81 (2H, m), 3.35 (3H, s), 1.39 (9H, s).

[0218] Step B: tert-butyl(S)-(7-(2-hydroxyethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0219] 1.38 g (3.11 mmol) of tert-butyl(S)-(7-(2-(benzyloxy)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate was suspended in MeOH (16 mL) and ethyl acetate (16 mL) with Pd / C (10 wt%, 17 mg, 0.156 mmol) and stirred at room temperature for 18 hours under N2 atmosphere (1 atm). After filtration through a diatomaceous earth pad, the filtrate was concentrated under reduced pressure. The residue was purified by recrystallization from hexane and ethyl acetate to give the target compound (1.02 g, 93%) as a white solid. ¹H-NMR (400 MHz, CDCl3): δ 7.06 (1H,d, J=8.0 Hz), 6.76-6.72 (2H, m), 5.47 (1H, d, J=7.2 Hz), 4.65 (1H, dt, J=11.3, 7.4 Hz), 4.53 (1H, dd, J=9.6, 8.0 Hz), 4.13-4.05 (3H, m), 3.99-3.96(2H, m), 3.38 (3H, s), 1.98 (1H, t, J=6.2 Hz), 1.40 (9H, s).

[0220] Intermediate 14: (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl methanesulfonate

[0221]

[0222] Tert-butyl(S)-(7-(2-hydroxyethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate (intermediate 13, 300 mg, 0.0850 mmol) was dissolved in dichloromethane (0.85 mL), and methanesulfonyl chloride (7.91 μL, 0.102 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After quenching with water, it was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (33 mg, 90%) as a colorless oil. This product was used directly in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 7.08 (1H, d, J=8.7 Hz), 6.73 (2H, td, J=8.3, 2.9 Hz), 5.47 (1H, d, J=7.3 Hz), 4.68-4.61 (1H, m), 4.59-4.56 (2H, m), 4.54-4.48 (1H, m), 4.23 (2H, t, J=4.6 Hz), 4.11 (1H, dd, J=11.4, 9.6 Hz), 3.38 (3H, s), 3.10 (3H, d, J=4.1 Hz), 1.39 (9H, s).

[0223] Intermediate 15: 3-(benzyloxy)-1-(2-chloroethyl)-3-methylazacyclobutane

[0224]

[0225] Step A: tert-butyl-3-(benzyloxy)-3-methylazacyclobutane-1-carboxylic acid ester

[0226] 0.500 g (2.67 mmol) of tert-butyl-3-hydroxy-3-methylazacyclobutane-1-carboxylic acid ester was dissolved in DMF (8.9 mL), and NaH (0.117 g, 2.94 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 30 min, and then benzyl bromide (0.476 mL, 4.01 mmol) was added at 0 °C. The reaction mixture was stirred at 100 °C for 2 h. After quenching with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂ column chromatography (n-hexane to n-hexane:ethyl acetate = 10:1 to 6:1) to give the target compound (0.558 g, 75%) as a colorless oil.

[0227] Step B: 2,2,2-trifluoroacetate of 3-(benzyloxy)-3-methylazacyclobutane

[0228] 0.558 g (2.01 mmol) of tert-butyl-3-(benzyloxy)-3-methylazacyclobutane-1-carboxylic acid ester was dissolved in dichloromethane (6.7 mL), and trifluoroacetic acid (0.775 mL, 10.1 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 hours and then neutralized with NaHCO3 powder (1.35 g, 16.1 mmol). The mixture was filtered through a Celite 545 filter, and the filtrate was concentrated under reduced pressure to give the target compound (0.538 g, 92%) as a white, foamy solid.

[0229] Step C: 3-(benzyloxy)-1-(2-chloroethyl)-3-methylazacyclobutane

[0230] 0.438 g (1.50 mmol) of 3-(benzyloxy)-3-methylazacyclobutane 2,2,2-trifluoroacetate was dissolved in 7.5 mL of 1,2-dichloroethane. 2-chloroacetaldehyde (0.573 mL, 4.51 mmol) and acetic acid (0.172 mL, 3.01 mmol) in aqueous solution were added at 0 °C. The mixture was stirred at 0 °C for 5 minutes, and then NaBH(OAc)3 (0.637 g, 3.01 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 hours and then quenched with water. The mixture was extracted twice with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (0.272 g, crude product) as a yellow oil, which was used directly in the next reaction without further purification.

[0231] Intermediate 16: 1-(2-chloroethyl)-3,3-difluoroazacyclobutane

[0232]

[0233] 3,3-Difluoroazacyclobutane hydrochloride (200 mg, 1.54 mmol) and acetic acid (0.177 mL, 3.09 mmol) were dissolved in 1,2-dichloroethane (5.0 mL). 2-Chloroacetaldehyde (50 wt% aqueous solution, 0.588 mL, 4.63 mmol) was added at 0 °C, followed by NaBH(OAc)3 (654 mg, 3.09 mmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with water. The aqueous phase was separated and extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (256 mg, crude product) as a yellow oil. This product was used directly in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 3.75-3.69 (4H, m), 3.53 (2H, t, J=6.2 Hz), 2.96-2.92 (2H, m).

[0234] Example 1: 4-(3-fluorobenzyl)-N-((S)-5-methyl-4-oxo-7-(2-((S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0235]

[0236] (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3, 40.0 mg, 0.0970 mmol) and (S)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate (intermediate 4, 25.0 mg, 0.0970 mmol) were dissolved in DMF (1.0 mL), and Cs₂CO₃ (95.0 mg, 0.292 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 4.5 hours. After quenching 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 reduced pressure. The residue was purified by NH-SiO2 column chromatography (n-hexane:ethyl acetate = 5:1 to 3:1) to give the target compound (7.0 mg, 13%) as a white foamy solid. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.2 Hz), 7.87(1H, s), 7.46 (1H, s), 7.28-7.21 (1H, m), 7.11-7.09 (1H, m), 6.95-6.84 (3H,m), 6.78-6.75 (2H, m), 4.93-4.86 (1H, m), 4.65 (1H, dd, J=9.6, 8.0 Hz), 4.23(1H, dd, J=11.2, 10.0 Hz), 4.16-4.07 (2H, m), 3.95-3.90 (1H,m), 3.80 (2H,s), 3.41 (3H, s), 2.03-1.89 (2H, m), 1.43 (3H, s), 1.34 (3H, s), 1.29 (3H,s), 1.15 (3H, s). LC-MS: m / z=567.1 [M+H]⁺.

[0237] Example 2: 4-(3-fluorobenzyl)-N-((S)-5-methyl-4-oxo-7-(2-((R)-2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide

[0238]

[0239] The target compound of the present invention was prepared in a manner similar to that in Example 1, using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and (R)-2-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethyl methanesulfonate (intermediate 6). The crude product was purified by NH-SiO2 column chromatography (n-hexane:ethyl acetate = 5:1 to 3:1) to give the target compound (18%) as a white foamy solid. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.2 Hz), 7.87 (1H, s), 7.46 (1H, s), 7.28–7.21 (1H, m), 7.11–7.09 (1H, m), 6.95–6.84 (3H, m), 6.78–6.75(2H, m), 4.93–4.86 (1H, m), 4.67–4.65 (1H, dd, J=9.6, 7.6 Hz), 4.23 (1H, dd,J=11.2, 10.0 Hz), 4.16–4.05 (2H, m), 3.95–3.90 (1H, m), 3.80 (2H, s), 3.41(3H, s), 2.00–1.85 (2H, m), 1.43 (3H, s), 1.34 (3H, s), 1.30 (3H, s), 1.15(3H, s). LC-MS: m / z=567.1 [M+H]⁺.

[0240] Example 3: N-((S)-7-(2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0241]

[0242] (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3, 260 mg, 0.634 mmol) and (R)-5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane-4-one (intermediate 5) (122 mg, 0.760 mmol) were dissolved in THF (6.3 mL), followed by the addition of PPh3 (249 mg, 0.950 mmol) at room temperature, and then DIAD (0.190 mL, 0.950 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. After concentration under reduced pressure, the residue was purified by SiO2 column chromatography (n-hexane:ethyl acetate = 3:1 to 1:1) to obtain the target compound (160 mg, 46%) as a white foamy solid. ¹H-NMR (400 MHz, CDCl3): δ7.98 (1H, d, J=7.3 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.25–7.23 (1H,m), 7.13–7.11 (1H, m), 6.97–6.85 (3H, m), 6.79–6.76 (2H, m), 4.93–4.86 (1H,m), 4.68–4.63 (2H, m), 4.25 (1H, dd, J=11.0, 10.1 Hz), 4.21–4.09 (2H, m),3.81 (2H, s), 3.42 (3H, s), 2.44–2.36 (1H, m), 2.28–2.18 (1H, m), 1.59 (3H, s), 1.57–1.58 (3H, s). LC-MS: m / z=553.0 [M+H]⁺.

[0243] Example 4: N-((S)-7-((R)-4-(dimethylamino)-3-hydroxy-4-oxobutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0244]

[0245] N-((S)-7-(2-(((R)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazopyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (Example 3) (30.0 mg, 0.0540 mmol) was dissolved in acetonitrile (0.27 mL), and NMe2 (2 M in MeOH, 0.136 mL, 0.271 mmol) was added. The reaction mixture was stirred at 50 °C for 4 hours. After concentration under reduced pressure, the residue was purified by SiO2 column chromatography (n-hexane:ethyl acetate = 2:1 to ethyl acetate:methanol = 97:3) to give the target compound (9.5 mg, 32%) as a white foamy solid. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (d, J=7.2 Hz, 1H), 7.88 (d, J=0.8Hz, 1H), 7.47 (s, 1H), 7.28–7.22 (m, 1H), 7.12–7.10 (m, 1H), 6.96–6.84 (m,3H), 6.79–6.74 (m, 2H), 4.89 (dt, J=11.2, 7.5 Hz, 1H), 4.68–4.62 (m, 2H), 4.28–4.22 (m, 2H), 4.12–4.08 (m, 1H), 3.81 (s, 3H), 3.42 (s, 3H), 3.06 (s, 3H), 3.05 (s, 3H), 2.21–2.13 (m, 1H), 1.89–1.81 (m, 1H). LC-MS: m / z=540.1 [M+H]⁺.

[0246] Example 5: 4-(3-fluorobenzyl)-N-((S)-7-((R)-3-hydroxy-4-oxo-4-(pyrrolidine-1-yl)butoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0247]

[0248] The target compound of this invention was prepared in a manner similar to that of Example 4, using N-((S)-7-(2-(((R)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (Example 3) and pyrrolidine as raw materials. The crude product was purified by SiO2 column chromatography (using only ethyl acetate) to obtain the target compound (90%) as a white, foamy solid. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 7.27–7.22 (m, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.96–6.84 (m, 3H), 6.78–6.74 (m,2H), 4.89 (dt, J=11.2, 7.4 Hz, 1H), 4.65 (dd, J=10.0, 7.6 Hz, 1H), 4.45 (d, J=8.8 Hz, 1H), 4.27–4.21 (m, 2H), 4.14–4.08 (m, 1H), 3.80 (s, 2H), 3.78 (brs,1H), 3.64–3.39 (m, 4H), 3.41 (s, 3H), 2.21–2.12 (m, 1H), 2.07–1.85 (m, 5H). LC-MS: m / z=566.1 [M+H]⁺.

[0249] Example 6: 4-(3-fluorobenzyl)-N-((S)-7-((R)-3-hydroxy-4-morpholino-4-oxobutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0250]

[0251] The target compound of this invention was prepared in a manner similar to that of Example 4, using N-((S)-7-(2-(((R)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (Example 3) and morpholine as raw materials. The crude product was purified by SiO2 column chromatography (using only ethyl acetate) to obtain the target compound (34%) as a white, foamy solid. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (d, J=7.2 Hz, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 7.30–7.22 (m, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.96–6.85 (m, 3H), 6.78–6.74 (m, 2H), 4.89 (dt, J=9.4, 6.3 Hz, 1H), 4.66 (dd, J=9.6, 7.2 Hz, 1H), 4.60 (dd, J=9.8,2.2 Hz, 1H), 4.28–4.22 (m, 2H), 4.15–4.08 (m, 1H), 3.81 (s, 2H), 3.81–3.63(m, 6H), 3.50 (t, J=4.6 Hz, 2H), 3.42 (s, 3H), 2.16–2.08 (m, 1H), 1.91–1.83(m, 1H). LC-MS: m / z=582.1 [M+H]⁺.

[0252] Example 7: N-((S)-7-(((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxane-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0253]

[0254] Step A: tert-butyl((S)-7-(((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxane-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate

[0255] The target compound of the present invention was prepared by a method similar to that in Example 1, from tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate (intermediate 1) and ((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxane-4-yl)methylmethanesulfonate (intermediate 7). The crude product was purified by SiO2 column chromatography (n-hexane:ethyl acetate = 2:1) to give the target compound (60%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.06 (1H, d, J=8.7 Hz), 6.72-6.68 (2H, m), 5.46 (1H, d, J=7.3 Hz), 4.94-4.91 (1H, m), 4.84 (1H, dd, J=6.2, 1.6 Hz), 4.67-4.61(1H, m), 4.52 (1H, dd, J=9.6, 7.3 Hz), 4.38 (1H, td, J=4.5, 1.7 Hz), 4.13-4.01 (5H, m), 3.38 (3H, s), 1.55 (3H, s), 1.40 (9H, s), 1.39 (3H, s).

[0256] Step B: (S)-7-(((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxane-4-yl)methoxy)-5-methyl-3-((2,2,2-trifluoroacetyl)-1,4-azyl)-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one

[0257] 45.0 mg, 0.0970 mmol) of tert-butyl((S)-7-(((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxane-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate was dissolved in dichloromethane (0.50 mL). TFA (22.0 μL, 0.291 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 20 hours and then concentrated under reduced pressure to give the target compound (25.0 mg, 56%) as a white foam. LC-MS: m / z = 565.20 [M+H]⁺.

[0258] Step C: N-((S)-7-(((3aR,4R,6aS)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxane-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0259] (S)-7-(((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxane-4-yl)methoxy)-5-methyl-3-((2,2,2-trifluoroacetyl)-1,4-azyl)-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one (20.0 mg, 0.043 mmol) was dissolved in 1,2-dichloroethane (0.40 mL). CDI (7.00 mg, 0.043 mmol) was added at 0°C, followed by TEA (15.0 μL, 0.108 mmol). The mixture was stirred at 0°C for 1 hour. The reaction was quenched with water and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.

[0260] The resulting residue was dissolved in 1,2-dichloroethane (0.40 mL), and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2, 8.00 mg, 0.0390 mmol) and TEA (15.0 μL, 0.108 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with water and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 10:1) to give the target compound (7.00 mg, 29%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H,d, J=7.3 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.25-7.23 (1H, m), 7.12(1H, dd, J=6.9, 2.3 Hz), 7.00-6.85 (3H, m), 6.74 (2H, dd, J=7.1, 2.5 Hz), 4.94-4.84 (3H, m), 4.66 (1H, dd, J=9.8, 7.5 Hz), 4.38 (1H, q, J=2.3 Hz), 4.25(1H, dd, J=11.2, 9.8 Hz), 4.08-4.04 (4H, m), 3.81 (2H, s), 3.41 (3H, s), 1.39 (3H, s), 1.25 (3H, s). LC-MS: m / z=567.2 [M+H]⁺.

[0261] Example 8: N-((S)-7-(((2S,3R,4R)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0262]

[0263] N-((S)-7-(((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxane-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapheno-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (Example 7, 5.00 mg, 8.82 μmol) was dissolved in methanol (88 μL), and hydrochloric acid (4 M in dioxane, 11 μL, 0.044 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to give the target compound (2.0 mg, 43%) as a white foam. ¹H-NMR (400 MHz, MeOH-d4): δ 7.95 (1H, s), 7.56 (1H, s), 7.32-7.26 (1H, m), 7.14 (1H, d, J=8.7 Hz), 7.04 (2H, d, J=7.3 Hz), 6.96-6.88 (3H, m), 4.58-4.54 (1H, m), 4.41-4.34 (1H, m), 4.25-4.16(2H, m), 4.12-4.03 (3H, m), 3.85 (2H, s), 3.79-3.72 (1H, m), 3.67-3.63 (1H, m), 3.58-3.55 (1H, m), 3.40 (3H, s). LC-MS: m / z=527.1 [M+H]⁺.

[0264] Example 9: 4-(3-fluorobenzyl)-N-((S)-7-(((2S,4R)-4-hydroxy-1-methylpyrrolidone-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0265]

[0266] Step A: Benzyl(2S,4R)-2-((((S)-3-((tert-butyloxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylic acid ester

[0267] Tert-butyl (S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)carbamate (intermediate 1,450 mg, 1.46 mmol), benzyl(2S,4R)-4-((tert-butyldimethylsilyl)oxy)-2-(((methanesulfonyl)oxy)methyl)pyrrolidine-1-carboxylic acid ester (intermediate 8,842 mg, 1.90 mmol), and Cs₂CO₃ (951 mg, 2.92 mmol) were dissolved in DMF (9.7 mL) and stirred at 50°C for 18 hours. After quenching with water, the mixture was extracted twice with dichloromethane. The combined organic layers were washed successively with water and saturated brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 10:1) to obtain the target compound (350 mg, 37%), which was a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.36-7.30 (5H, m), 7.04-6.94(1H, m), 6.73 (1H, d, J=11.4 Hz), 6.57 (1H, t, J=9.4 Hz), 5.47 (1H, d, J=7.3Hz), 5.22-5.08 (2H, m), 4.67-4.60 (1H, m), 4.52 (2H, t, J=7.5 Hz), 4.33-4.27(1H, m), 4.18-3.92 (3H, m), 3.54 (1H, d, J=5.0 Hz), 3.42 (dd, J=11.0, 4.1 Hz,1H), 3.35 (3H, d, J=19.2 Hz), 2.20-2.03 (2H, m), 1.40 (9H, s), 0.88 (9H, s), 0.07 (6H, d, J=5.9 Hz).

[0268] Step B: tert-butyl((S)-7-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0269] Benzyl(2S,4R)-2-((((S)-3-((tert-butyloxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1-carboxylic acid ester (430 mg, 0.660 mmol) was suspended in ethyl acetate (6.5 mL) with Pd / C (10 wt%, 70 mg) and stirred at room temperature for 2 hours under a hydrogen atmosphere (1 atm). After filtration through a Celite pad and washing with ethyl acetate, the filtrate was concentrated under reduced pressure to give the target compound (320 mg, 94%) as a light brown foam. ¹H-NMR (400 MHz, CDCl3): δ 7.03 (1H,d, J=9.1 Hz), 6.72-6.68 (2H, m), 5.47 (1H, d, J=7.3 Hz), 4.67-4.61 (1H, m),4.52 (1H, dd, J=9.6, 7.3 Hz), 4.43-4.39 (1H, m), 4.09 (1H, dd, J=11.2, 9.8Hz), 3.85 (2H, d, J=5.5 Hz), 3.79-3.73 (1H, m), 3.37 (3H, s), 3.03 (1H, dd, J=11.4, 4.1 Hz), 2.87 (1H, d, J=11.4 Hz), 2.19 (1H, brs), 1.94-1.89 (1H, m), 1.72-1.66 (1H, m), 1.40 (9H, s), 0.89 (9H, s), 0.08 (6H, d, J=3.2 Hz).

[0270] Step C: tert-butyl((S)-7-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0271] 260 mg (0.498 mmol) of tert-butyl((S)-7-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazopyron-3-yl)carbamate and formaldehyde (0.190 mL, 2.49 mmol) were dissolved in methanol, followed by the addition of acetic acid (29.0 μL, 0.498 mmol), and then NaBH3CN (125 mg, 1.99 mmol) at 10°C. The reaction mixture was stirred at room temperature for 18 hours. After quenching with water, the mixture was extracted twice with dichloromethane. The combined organic layers were washed with 2 N NaOH aqueous solution and saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the target compound (224 mg, 84%) as a white foam. ¹H-NMR (400MHz, CDCl3): δ 7.04 (1H, d, J=8.7 Hz), 6.72 (2H, td, J=9.1, 2.7 Hz), 5.47 (1H,d, J=7.3 Hz), 4.68-4.61 (1H, m), 4.52 (1H, dd, J=9.6, 7.8 Hz), 4.43-4.37 (1H,m), 4.09 (1H, dd, J=11.0, 9.6 Hz), 3.88 (2H, d, J=4.6 Hz), 3.37 (3H, s), 3.32(1H, dd, J=9.4, 5.7 Hz), 2.95-2.89 (1H, m), 2.47 (3H, s), 2.33 (1H, dd, J=9.6, 6.4 Hz), 2.05-1.88 (2H, m), 1.40 (9H, s), 0.90 (9H, s), 0.07 (6H, d, J=2.3 Hz).

[0272] Step D: (S)-3-amino-7-(((2S,4R)-4-hydroxy-1-methylpyrrolidone-2-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazaphene-4(5H)-one

[0273] 220 mg (0.411 mmol) of tert-butyl((S)-7-(((2S,4R)-4-((tert-butyldimethylsilyl)oxy)-1-methylpyrrolidine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazopyron-3-yl)carbamate was dissolved in dichloromethane (4.0 mL), and HCl (4 M, dioxane solution, 0.500 mL, 2.05 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to give the target compound (130 mg, 99%) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d6): δ 8.48 (3H, brs), 7.25-7.20 (2H,m), 6.95 (1H, dd, J=8.7, 2.7 Hz), 5.64 (1H, s), 4.52 (1H, dd, J=10.1, 7.8Hz), 4.43-4.36 (4H, m), 4.24 (1H dd, J=11.0, 7.8 Hz), 4.06-3.99 (1H, m), 3.79-3.71 (1H, m), 3.36 (3H, s), 3.00 (3H, s), 2.15 (1H, q, J=6.6 Hz), 2.01-1.95 (1H, m).

[0274] Step E: 4-(3-fluorobenzyl)-N-((S)-7-(((2S,4R)-4-hydroxy-1-methylpyrrolidine-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0275] The target compound was prepared in a manner similar to that in Example 7 (step C) from (S)-3-amino-7-(((2S,4R)-4-hydroxy-1-methylpyrrolidone-2-yl)methoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyrone-4(5H)-one and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 10:1) to give the target compound (30.0 mg, 16%) as a white foam. ¹H-NMR (400MHz, CDCl3): δ 7.98 (1H, d, J=7.3 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.25-7.23(1H, m), 7.11 (1H, d, J=9.1 Hz), 6.97-6.85 (3H, m), 6.76 (2H, dd, J=11.4, 2.7Hz), 4.93-4.87 (1H, m), 4.66 (1H, dd, J=9.8, 7.5 Hz), 4.50 (1H, dd, J=9.8,6.6 Hz), 4.25 (1H, dd, J=11.0, 10.1 Hz), 3.97-3.94 (2H, m), 3.81 (2H, s), 3.51-3.47 (1H, m), 3.41 (3H, s), 3.04-2.99 (1H, m), 2.51 (3H, s), 2.39 (1H,q, J=5.2 Hz), 2.15-2.07 (1H, m), 2.01-1.94 (1H, m). LC-MS: m / z=524.1 [M+H]⁺.

[0276] Example 10: 4-(3-fluorobenzyl)-N-((S)-5-methyl-7-(((R)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-1H-pyrazole-1-carboxamide

[0277]

[0278] Step A: tert-butyl((S)-5-methyl-7-(((R)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0279] The target compound was prepared from tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate (intermediate 1) and (R)-(1-methyl-5-oxopyrrolidine-2-yl)methyl-4-methylbenzenesulfonate (intermediate 9) according to a method similar to that in Example 9 (step A). ​​The crude product was purified by SiO2 (dichloromethane:MeOH=20:1) column chromatography to obtain the target compound (70%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.08-7.06 (1H, m), 6.72-6.69 (2H, m), 5.49 (1H, d, J=7.3 Hz), 4.68-4.61 (1H, m), 4.52 (1H, dd, J=9.6, 7.8 Hz), 4.15-4.03 (2H, m), 3.98 (1H, q, J=4.7 Hz), 3.90 (1H, td, J=8.5, 4.1 Hz), 3.39 (3H, s), 2.92 (3H, s), 2.60-2.51(1H, m), 2.45-2.37 (1H, m), 2.31-2.22 (1H, m), 2.02-1.93 (1H,m), 1.40 (9H,s).

[0280] Step B: (S)-3-amino-5-methyl-7-(((R)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrrolidone-4(5H)-one hydrochloride

[0281] To a solution of tert-butyl((S)-5-methyl-7-((((R)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazopyr-3-yl)carbamate (220 mg, 0.520 mmol) in dichloromethane (3.0 mL), HCl (4 M, dioxane solution, 0.660 mL, 2.62 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to give the target compound (180 mg, 96%) as a yellow solid. ¹H-NMR (400 MHz, DMSO-d6): δ 8.45 (3H, s), 7.20 (1H, d, J=9.1 Hz), 7.13 (1H, d, J=2.7 Hz), 6.90 (1H, dd, J=8.9, 3.0 Hz), 4.50 (1H, dd, J=9.6, 7.8 Hz), 4.36(1H, t, J=10.3 Hz), 4.28 (1H, d, J=4.1 Hz), 4.18 (1H, dd, J=10.3, 3.9 Hz), 4.04 (1H, dd, J=10.1, 4.1 Hz), 3.88 (1H, q, J=4.0 Hz), 3.35 (3H, s), 2.76(3H, s), 2.43-2.34 (1H, m), 2.24-2.10 (2H, m), 1.90-1.82 (1H, m).

[0282] Step C: 4-(3-fluorobenzyl)-N-((S)-5-methyl-7-(((R)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-1H-pyrazole-1-carboxamide

[0283] The target compound was prepared using (S)-3-amino-5-methyl-7-((((R)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrrolidone-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2) in a similar manner to that in Example 7 (step C). The crude product was purified by SiO2 (dichloromethane:MeOH=20:1) column chromatography to give the target compound (46%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d,J=7.3 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.25-7.23 (1H, m), 7.13 (1H,dd, J=5.5, 4.1 Hz), 7.00-6.85 (3H, m), 6.77-6.73 (2H, m), 4.93-4.87 (1H, m), 4.66 (1H, dd, J=9.8, 7.5 Hz), 4.26 (1H, dd, J=11.0, 9.6 Hz), 4.04 (2H, dq, J=30.6, 4.6 Hz), 3.90 (1H, td, J=8.5, 4.1 Hz), 3.81 (2H, s), 3.42 (3H, s), 2.93(3H, s), 2.60-2.52 (1H, m), 2.45-2.37 (1H, m), 2.32-2.22 (1H, m), 2.03-1.94(1H, m). LC-MS: m / z=522.2 [M+H]⁺.

[0284] Example 11: 4-(3-fluorobenzyl)-N-((S)-5-methyl-7-(((S)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-1H-pyrazole-1-carboxamide

[0285]

[0286] Step A: tert-butyl((S)-5-methyl-7-(((S)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0287] The target compound was prepared from tert-butyl (S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate (intermediate 1) and (S)-(1-methyl-5-oxopyrrolidine-2-yl)methyl-4-methylbenzenesulfonate (intermediate 10) according to a method similar to that in Example 9 (step A). ​​The crude product was purified by SiO2 (dichloromethane:MeOH=10:1) column chromatography to obtain the target compound (71%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.06-7.04 (1H, m), 6.50-6.49 (2H, m), 5.50 (1H, d, J=7.2 Hz), 4.68-4.61 (1H, m), 4.52 (1H, m), 4.12-4.04 (2H, m), 3.96 (1H, m), 3.90 (1H, m),3.38 (3H, s), 2.91 (3H, s), 2.60-2.51 (1H, m), 2.45-2.37 (1H, m), 2.31-2.22(1H, m), 2.02-1.93 (1H, m), 1.40 (9H, s).

[0288] Step B: (S)-3-amino-5-methyl-7-(((S)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrrolidone-4(5H)-one hydrochloride

[0289] The target compound was prepared using tert-butyl((S)-5-methyl-7-(((S)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate and HCl, following a similar method to that in Example 10 (step B). After concentration, the target compound (quantitatively) was obtained as a yellow solid, which was used directly in the next reaction without further purification. LC-MS: m / z = 320.1 [M+H] ⁺。

[0290] Step C: 4-(3-fluorobenzyl)-N-((S)-5-methyl-7-(((S)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-1H-pyrazole-1-carboxamide

[0291] The target compound was prepared using (S)-3-amino-5-methyl-7-(((S)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrrolidone-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2) in a similar manner to that in Example 7 (step C). The crude product was purified by SiO2 (dichloromethane:methanol = 9:1) column chromatography to give the target compound (52%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d,J=7.2 Hz), 7.87 (1H, s), 7.47 (1H, s), 7.26-7.23 (1H, m), 7.13 (1H, d, J=9.6Hz), 7.00-6.85 (3H, m), 6.77-6.73 (2H, m), 4.91-4.88 (1H, m), 4.66 (1H, dd, J=9.8, 7.5 Hz), 4.26 (1H, dd, J=11.0, 9.6 Hz), 4.04 (2H, m), 3.90 (1H, td, J=8.5, 4.1 Hz), 3.81 (2H, s), 3.42 (3H, s), 2.93 (3H, s), 2.60-2.52 (1H, m), 2.43-2.35 (1H, m), 2.32-2.22 (1H, m), 2.03-1.94 (1H, m). LC-MS: m / z=522.1 [M+H]⁺.

[0292] Example 12: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(N-methylacetamido)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0293]

[0294] Step A: tert-butyl-(S)-(2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carbamoylamino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl)(methyl)carbamate

[0295] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and tert-butyl(2-hydroxyethyl)(methyl)carbamate, following a similar method to Example 3. The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 4:1) column chromatography to give the target compound (48%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.3Hz), 7.88 (1H, s), 7.47 (1H, s), 7.25-7.23 (1H, m), 7.11 (1H, d, J=9.1 Hz), 6.97-6.85 (3H, m), 6.77-6.74 (2H, m), 4.93-4.87 (1H, m), 4.66 (1H, dd, J=9.6,7.3 Hz), 4.25 (1H, t, J=10.5 Hz), 4.11 (2H, t, J=7.1 Hz), 3.81 (2H, s), 3.62(2H, s), 3.42 (3H, s), 3.00 (3H, s), 1.47 (9H, s).

[0296] Step B: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(methylamino)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0297] To a solution of tert-butyl(S)-(2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-formamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl)(methyl)carbamate (100 mg, 0.176 mmol) in dichloromethane (1.8 mL), HCl (4 M in 1,4-dioxane, 0.200 mL, 0.881 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to give the target compound (70.0 mg, 85%) as a white solid, which was used directly in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 9.88(1H, s), 7.96 (1H, d, J=7.3 Hz), 7.86 (1H, s), 7.46 (1H, s), 7.23 (1H, d, J=7.8 Hz), 7.10 (1H, d, J=8.7 Hz), 7.00-6.86 (5H, m), 4.89-4.82 (1H, m), 4.63(1H, dd, J=9.6, 7.3 Hz), 4.39 (2H, br s), 4.25 (1H, t, J=10.3 Hz), 3.81 (2H,s), 3.40 (3H, br s), 3.34 (2H, s), 2.74 (3H, s).

[0298] Step C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(N-methylacetamido)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0299] To a solution of (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(methylamino)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (60.0 mg, 0.128 mmol) in dichloromethane (1.2 mL), TEA (36.0 μL, 0.257 mmol) and Ac₂O (12.0 μL, 0.128 mmol) were added at 15 °C. The reaction mixture was stirred at 15 °C for 1 hour. After quenching with water, the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 (dichloromethane:MeOH=20:1) column chromatography to obtain the target compound (45.0 mg, 69%), which was a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.3 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.24 (1H, d, J=8.2 Hz), 7.14-7.10 (1H, m), 7.00-6.85 (3H, m), 6.76-6.73 (2H, m), 4.93-4.86 (1H, m), 4.68-4.63 (1H, m), 4.25 (1H, td, J=10.5, 3.4 Hz), 4.17-4.08 (2H, m), 3.81 (2H, s),3.78-3.74 (2H, m), 3.42 (3H, s), 3.11 (3H, d, J=61.7 Hz), 2.11 (3H, d, J=8.2Hz). LC-MS:m / z=510.10 [M+H] ⁺ .

[0300] Example 13: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(2-oxopyrrolidone-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-1H-pyrazole-1-carboxamide

[0301]

[0302] Step A: tert-butyl(S)-(5-methyl-4-oxo-7-(2-(2-oxopyrrolidone-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0303] The target compound was prepared using tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate (intermediate 1) and 2-(2-oxopyrrolidine-1-yl)ethylmethanesulfonate, following a similar method to that in Example 9 (step A). ​​The crude product was purified by SiO2 (dichloromethane:MeOH=20:1) column chromatography to obtain the target compound (57%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.05 (1H, dd, J=12.6, 3.9Hz), 6.71-6.67 (2H, m), 5.47 (1H, d, J=7.3 Hz), 4.68-4.61 (1H, m), 4.52 (1H,dd, J=9.6, 7.3 Hz), 4.12-4.07 (3H, m), 3.69 (2H, td, J=5.0, 1.9 Hz), 3.60-3.56 (2H, m), 3.38 (3H, s), 2.42 (2H, t, J=8.2 Hz), 2.10-2.02 (2H, m), 1.40 (9H, s).

[0304] Step B: (S)-3-amino-5-methyl-7-(2-(2-oxopyrrolidone-1-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrrolidone-4(5H)-one hydrochloride

[0305] The target compound was prepared as tert-butyl(S)-(5-methyl-4-oxo-7-(2-(2-oxopyrrolidone-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)carbamate, following a similar method to that in Example 10 (step B). After concentration, the crude product (99%) as a yellow solid was used directly in the next reaction without further purification. ¹H-NMR (400 MHz, DMSO-d6): δ 8.43 (3H, s), 7.18 (1H, d, J=8.7 Hz), 7.11 (1H, d,J=2.7 Hz), 6.88 (1H, dd, J=8.7, 2.7 Hz), 4.50 (1H, dd, J=9.6, 7.3 Hz), 4.36(1H, t, J=10.3 Hz), 4.27-4.22 (1H, m), 4.10 (2H, t, J=5.7 Hz), 3.56-3.53 (2H,m), 3.47-3.44 (2H, m), 3.35 (3H, s), 2.22 (2H, t, J=8.2 Hz), 1.96-1.88 (2H,m).

[0306] Step C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(2-oxopyrrolidone-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-1H-pyrazole-1-carboxamide

[0307] The target compound was prepared using (S)-3-amino-5-methyl-7-(2-(2-oxopyrrolidone-1-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrone-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2) in a similar manner to that in Example 7 (step C). The crude product was purified by SiO2 (dichloromethane:ethyl acetate = 10:1) column chromatography to give the target compound (63%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.8 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.25-7.23 (1H, m), 7.12 (1H,dd, J=5.5, 3.7 Hz), 7.00-6.85 (3H, m), 6.75-6.72 (2H, m), 4.93-4.87 (1H, m), 4.65 (1H, dd, J=9.6, 7.8 Hz), 4.25 (1H, dd, J=11.0, 10.1 Hz), 4.11 (2H, t, J=5.3 Hz), 3.81 (2H, s), 3.70 (2H, t, J=4.8 Hz), 3.59 (2H, t, J=7.3 Hz), 3.42 (3H, s), 2.42 (2H, t, J=8.2 Hz), 2.07 (2H, q, J=7.5 Hz). LC-MS: m / z=522.10 [M+H]⁺.

[0308] Example 14: 4-(3-fluorobenzyl)-N-((S)-7-(2-((S)-3-hydroxy-2-oxopyrrolidone-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-1H-pyrazole-1-carboxamide

[0309]

[0310] Step A: N-((S)-7-(2-((S)-3-(benzyloxy)-2-oxopyrrolidone-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0311] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and (S)-3-(benzyloxy)-1-(2-hydroxyethyl)pyrrolidine-2-one, following a similar method to Example 3. The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 1:4) column chromatography to give the target compound (72%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d,J=7.3 Hz), 7.88 (1H, d, J=1.1 Hz), 7.41-7.28 (6H, m), 7.25-7.23 (1H, m), 7.11(1H, t, J=4.8 Hz), 7.00-6.85 (3H, m), 6.72 (2H, td, J=4.8, 2.7 Hz), 4.97 (1H,d, J=11.9 Hz), 4.92-4.86 (1H, m), 4.77 (1H, d, J=11.9 Hz), 4.65 (1H, dd, J=9.6, 7.8 Hz), 4.25 (1H, dd, J=11.0, 9.6 Hz), 4.16-4.11 (3H, m), 3.81 (2H, s), 3.79-3.74 (1H, m), 3.69-3.57 (2H, m), 3.50-3.43 (1H, m), 3.40 (3H, s), 2.38-2.30 (1H, m), 2.09-2.00 (1H, m).

[0312] Step B: 4-(3-fluorobenzyl)-N-((S)-7-(2-((S)-3-hydroxy-2-oxopyrrolidone-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-1H-pyrazole-1-carboxamide

[0313] A suspension of N-((S)-7-(2-((S)-3-(benzyloxy)-2-oxopyrrolidine-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (50.0 mg, 0.080 mmol) and Pd / C (10 wt%, 8.00 mg) in MeOH (0.80 mL) was stirred at room temperature for 18 hours under H2 atmosphere (balloon). After washing with MeOH and filtering through a diatomaceous earth pad, the filtrate was concentrated under reduced pressure. The residue was purified by SiO2 (petroleum ether:ethyl acetate = 1:4) column chromatography to give the target compound (5.00 mg, 11%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.3 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47(1H, s), 7.25-7.23 (1H, m), 7.12 (1H, dd, J=7.3, 2.3 Hz), 7.00-6.85 (3H, m), 6.73 (2H, dd, J=7.5, 2.5 Hz), 4.93-4.87 (1H, m), 4.65 (1H, dd, J=9.6, 7.8Hz), 4.37 (1H, t, J=8.5 Hz), 4.25 (1H, dd, J=11.2, 9.8 Hz), 4.16-4.09 (2H,m), 3.85-3.79 (3H, m), 3.65-3.60 (1H, m), 3.56-3.51 (2H, m), 3.41 (3H, s), 3.05 (1H, s), 2.53-2.45 (1H, m), 2.05-1.97 (1H, m). LC-MS: m / z=538.10 [M+H]⁺.

[0314] Example 15: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(4-methyl-3-oxopiperazin-1-yl)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0315]

[0316] Step A: tert-butyl(S)-(5-methyl-7-(2-(4-methyl-3-oxopirarin-1-yl)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazeta-3-yl)carbamate

[0317] The target compound was prepared using tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate (intermediate 1) and 2-(4-methyl-3-oxoperpiperazin-1-yl)ethylmethanesulfonate, following a similar method to that in Example 9 (step A). ​​The crude product was purified by SiO2 (dichloromethane:methanol = 99:1 to 95:5) column chromatography to give the target compound (19%) as a yellow oil. ¹H-NMR (400 MHz, CDCl3): δ 7.05 (1H, d, J=8.4 Hz), 6.73-6.69 (2H, m), 5.47 (1H, d, J=7.2 Hz), 4.67-4.61 (1H, m), 4.51(1H, dd, J=9.2, 7.6 Hz), 4.14-4.06 (3H, m), 3.37-3.35 (5H, m), 3.29 (2H, s), 2.96 (3H, s), 2.88-2.83 (4H, m), 1.39 (9H, s).

[0318] Step B: (S)-3-amino-5-methyl-7-(2-(4-methyl-3-oxopirarin-1-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrrolidone-4(5H)-one hydrochloride

[0319] The target compound was prepared as tert-butyl(S)-(5-methyl-7-(2-(4-methyl-3-oxopiperazin-1-yl)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate, following a similar method to that in Example 10 (step B). After concentration, the crude product, in the form of a yellow solid, was used directly in the next reaction without further purification. LC-MS: m / z = 349.1 [M+H]⁺.

[0320] Step C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(4-methyl-3-oxopiperazin-1-yl)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0321] The target compound was prepared using (S)-3-amino-5-methyl-7-(2-(4-methyl-3-oxopiperazin-1-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrrolidone-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2) in a similar manner to that in Example 7 (step C). The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 10:1 to 2:1 and dichloromethane:MeOH = 99:1 to 95:5) to give the target compound (40%) as a yellow foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.2 Hz), 7.87 (1H, s), 7.46 (1H, s), 7.27-7.21 (1H, m), 7.10 (1H, d, J=8.8 Hz), 6.95-6.84 (3H, m), 6.78-6.73 (2H,m), 4.92-4.85 (1H, m), 4.65 (1H, dd, J=9.6, 7.6 Hz), 4.24 (1H, dd, J=10.8,10.0 Hz), 4.11 (2H, t, J=5.2 Hz), 3.80 (2H, s), 3.40 (3H, s), 3.37 (2H, t, J=5.6 Hz), 3.31 (2H, s), 2.96 (3H, s), 2.90-2.85 (4H, m). LC-MS: m / z=551.1 [M+H]⁺.

[0322] Example 16: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(2-oxopyridin-1(2H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-3-yl)-1H-pyrazole-1-carboxamide

[0323]

[0324] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 1-(2-hydroxyethyl)pyridine-2(1H)-one, following a similar method to that in Example 3 (step A). ​​The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 1:4) column chromatography to give the target compound (19%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.96 (1H, d, J=7.3 Hz), 7.87 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.43 (1H, dd, J=6.9, 1.4 Hz), 7.39-7.34 (1H, m), 7.24-7.23 (1H, m), 7.09 (1H, dd, J=7.5, 1.6 Hz), 7.00-6.85(3H, m), 6.73 (2H, dd, J=8.5, 2.1 Hz), 6.59 (1H, d, J=9.1 Hz), 6.20 (1H, td,J=6.9, 1.4 Hz), 4.90-4.83 (1H, m), 4.64 (1H, td, J=6.7, 3.0 Hz), 4.40-4.21 (5H, m), 3.81 (2H, s), 3.40 (3H, s). LC-MS: m / z=532.10 [M+H]⁺.

[0325] Example 17: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide

[0326]

[0327] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide (intermediate 3) and tetrahydro-2H-pyran-4-ol, following a similar method to that in Example 3 (step A). ​​The crude product was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 3:1 to 1:1) to give the target compound (25%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.6Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.10 (1H, dd, J=5.4, 4.2 Hz), 6.96-6.84 (3H, m), 6.78-6.75 (2H, m), 4.92 (1H, dt, J=11.1,7.4 Hz), 4.66 (1H, dd, J=9.6, 8.0 Hz), 4.48-4.42 (1H, m), 4.25 (dd, J=11.4,9.8 Hz), 4.02-3.97 (2H, m), 3.81 (2H, s), 3.62-3.57 (2H, m), 3.41 (3H, s), 2.09-2.00 (2H, m), 1.85-1.76 (2H, m). LC-MS: m / z=495.1 [M+H]⁺.

[0328] Example 18: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0329]

[0330] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide (intermediate 3) and 2-(tetrahydro-2H-pyran-4-yl)ethane-1-ol, following a method similar to that in Example 3 (step A). ​​The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 2:1 to 1:1) column chromatography, followed by further purification by NH-SiO2 (petroleum ether:ethyl acetate = 2:1) to obtain the target compound (65%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.6 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.10 (1H, dd, J=7.4, 1.8 Hz), 6.96-6.84 (3H,m), 6.76-6.73 (2H, m), 4.90 (1H, dt, J=11.2, 7.4 Hz), 4.65 (1H, dd, J=9.6,8.0 Hz), 4.24 (1H, dd, J=11.0, 9.8 Hz), 4.02-3.96 (4H, m), 3.81 (2H, s), 3.45-3.38 (5H, m), 1.86-1.73 (3H, m), 1.69-1.66 (2H, m), 1.59 (3H, s), 1.37(2H, m). LC-MS: m / z=523.1 [M+H]⁺.

[0331] Example 19: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0332]

[0333] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide (intermediate 3) and 4-(2-hydroxyethyl)tetrahydro-2H-pyran-4-ol, following a method similar to that in Example 3 (step A). ​​The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 1:4) column chromatography to give the target compound (19%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.3 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.24-7.23 (1H, m), 7.12 (1H,d, J=8.7 Hz), 7.00-6.85 (3H, m), 6.78-6.74 (2H, m), 4.93-4.87 (1H, m), 4.65(1H, dd, J=9.8, 7.5 Hz), 4.28-4.21 (3H, m), 3.86-3.75 (6H, m), 3.42 (3H, s),2.27 (1H, s), 2.03 (2H, t, J=5.9 Hz), 1.81-1.71 (2H, m), 1.64 (2H, d, J=12.3Hz). LC-MS: m / z=539.20 [M+H]⁺.

[0334] Example 20: (S)-4-(3-fluorobenzyl)-N-(7-(oxetane-3-ylmethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide

[0335]

[0336] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and oxetane-3-ylmethanol, following a similar method to that in Example 3 (step A). ​​The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 2:1 to 1:2) column chromatography to give the target compound (26%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.6Hz), 7.88 (1H, d, J=0.8 Hz), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.14-7.11 (1H,m), 6.96-6.84 (3H, m), 6.79-6.76 (2H, m), 4.94-4.86 (3H, m), 4.66 (1H, dd, J=9.6, 7.2 Hz), 4.58 (2H, t, J=6.0 Hz), 4.25 (1H, dd, J=11.0, 9.8 Hz), 4.20(2H, d, J=6.8 Hz), 3.81 (2H, s), 3.50-3.40 (4H, m). LC-MS:m / z=481.1 [M+H] + .

[0337] Example 21: (S)-4-(3-fluorobenzyl)-N-(7-(2-(oxecyclobutane-3-yl)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0338]

[0339] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 2-(oxecyclobutan-3-yl)ethane-1-ol, following a similar method to that in Example 3 (step A). ​​The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 2:1 to 1:2) column chromatography to give the target compound (72%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H,d, J=7.6 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.28–7.22 (1H, m), 7.10 (1H, d, J=8.0 Hz), 6.96-6.85 (3H, m), 6.72-6.69 (2H, m), 4.92-4.84 (3H, m), 4.65 (1H,dd, J=9.6, 8.0 Hz), 4.52 (2H, td, J=6.3, 1.7 Hz), 4.24 (1H, dd, J=11.0, 9.8Hz), 3.93 (2H, t, J=6.2 Hz), 3.81 (2H, s), 3.41 (3H, s), 3.28-3.21 (1H, m), 2.22-2.17 (2H, m). LC-MS: m / z=495.1 [M+H]⁺.

[0340] Example 22: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((3-methyloxetane-3-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide

[0341]

[0342] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and (3-methyloxacyclobutane-3-yl)methanol, following a method similar to that in Example 3 (step A). ​​The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 2:1) column chromatography, followed by further purification by NH-SiO2 (petroleum ether:ethyl acetate = 2:1) to obtain the target compound (43%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.2 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.13 (1H, dd, J=6.8, 2.8 Hz), 6.96-6.84 (3H,m), 6.81-6.77 (2H, m), 4.90 (1H, dt, J=11.2, 7.4 Hz), 4.68-4.63 (3H, m), 4.48(2H, d, J=6.0 Hz), 4.25 (1H, dd, J=10.8, 9.6 Hz), 4.02 (2H, s), 3.81 (2H, s), 3.43 (3H, s), 1.45 (3H, s). LC-MS: m / z=495.1 [M+H]⁺.

[0343] Example 23: (S)-N-(7-((3-ethyloxetane-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0344]

[0345] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and (3-ethyloxecyclobutane-3-yl)methanol, following a similar method to that in Example 3 (step A). ​​The crude product was purified by NH-SiO2 column chromatography (petroleum ether:ethyl acetate = 3:1 to 2:1), followed by further purification by SiO2 (petroleum ether:ethyl acetate = 4:1 to 1:1) to obtain the target compound (27%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.2 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.14-7.12 (1H, m), 6.96-6.85 (3H, m), 6.81-6.78 (2H, m), 4.91 (1H, dt, J=11.2, 7.4 Hz), 4.66 (1H, dd, J=9.6, 7.2 Hz), 4.58 (2H, dd, J=6.0, 2.0 Hz), 4.51 (2H, d, J=6.4 Hz), 4.25 (1H, dd, J=11.2,10.0 Hz), 4.08 (2H, s), 3.81 (2H, s), 3.43 (3H, s), 1.89 (2H, q, J=7.6 Hz), 0.95 (3H, t, J=7.6 Hz). LC-MS: m / z=509.1 [M+H]⁺.

[0346] Example 24: (S)-4-(3-fluorobenzyl)-N-(7-(2-(3-hydroxyoxetane-3-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide

[0347]

[0348] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 3-(2-hydroxyethyl)oxecyclobutane-3-ol, following a similar method to that in Example 3 (step A). ​​The crude product was purified by SiO2 column chromatography (ethyl acetate only) to give the target compound (24%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.3 Hz), 7.88(1H, s), 7.47 (1H, s), 7.24-7.23 (1H, m), 7.12 (1H, d, J=8.7 Hz), 7.00-6.85(3H, m), 6.78-6.73 (2H, m), 4.93-4.86 (1H, m), 4.68-4.63 (5H, m), 4.28-4.25(1H, m), 4.22 (2H, d, J=5.9 Hz), 3.81 (2H, s), 3.42 (3H, s), 2.97 (1H, s), 2.41 (2H, t, J=5.7 Hz). LC-MS: m / z=511.10 [M+H]⁺.

[0349] Example 25: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(piperidin-4-ylmethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0350]

[0351] Step A: tert-butyl(S)-4-(((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-formamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)methyl)piperidine-1-carboxylic acid ester

[0352] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and tert-butyl-4-(hydroxymethyl)piperidine-1-carboxylic acid ester, following a similar method to that in Example 3 (step A). ​​The crude product was purified by SiO2 column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to give the target compound (21%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H,d, J=7.2 Hz), 7.88 (1H, s), 7.46 (1H, s), 7.28-7.22 (1H, m), 7.10 (1H, dd, J=6.4, 2.8 Hz), 6.96-6.85 (3H, m), 6.75-6.72 (2H, m), 4.90 (1H, dt, J=11.2, 7.5Hz), 4.65 (1H, dd, J=9.8, 7.4 Hz), 4.27-4.09 (3H, m), 3.81-3.79 (4H, m), 3.41(3H, s), 2.76 (2H, t, J=12.4 Hz), 2.02-1.91 (1H, m), 1.83 (2H, d, J=12.4 Hz), 1.47 (9H, s), 1.34-1.23 (2H, m).

[0353] Step B: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(piperidin-4-ylmethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0354] The target compound was prepared using tert-butyl(S)-4-(((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-formamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)methyl)piperidine-1-carboxylic acid ester, following a similar method to that in Example 12 (step B). The crude product was purified by SiO2 (dichloromethane:MeOH = 95:5 to 80:20) column chromatography to obtain the target compound (94%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.6Hz), 7.88 (1H, s), 7.46 (1H, s), 7.27-7.22 (1H, m), 7.11 (1H, dd, J=7.2, 2.4Hz), 6.96-6.85 (3H, m), 6.73-6.70 (2H, m), 4.89 (1H, dt, J=11.1, 7.4 Hz), 4.65 (1H, dd, J=9.8, 7.8 Hz), 4.25 (1H, dd, J=11.0, 10.2 Hz), 3.85 (2H, d, J=6.0 Hz), 3.81 (2H, s), 3.58 (2H, d, J=12.4 Hz), 3.41 (3H, s), 2.97-2.91 (2H,m), 2.11-2.07 (3H, m), 1.89-1.81 (2H, m). LC-MS:m / z=508.1 [M+H] + .

[0355] Example 26: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((1-methylpiperidin-4-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0356]

[0357] (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(piperidin-4-ylmethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide (Example 25, 30 mg, 0.059 mmol)) was added to a MeOH solution (0.59 mL), followed by the addition of AcOH (3.38 μL, 0.059 mmol), and then a formaldehyde solution (37 wt.% in H2O, 0.022 mL, 0.30 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled to 0 °C. NaBH3CN (14.9 mg, 0.236 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 17 hours. After evaporating the MeOH, the residue was partitioned between dichloromethane and water. The separated aqueous layer was extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 (dichloromethane:MeOH = 95:5 to 80:20) column chromatography to obtain the target compound (28 mg, 91%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.2 Hz), 7.88 (1H, s), 7.46 (1H, s), 7.28-7.22 (1H, m), 7.10 (1H, dd, J=6.6, 2.6 Hz),7.00-6.84 (3H, m), 6.75-6.71 (2H, m), 4.89 (1H, dt, J=11.1, 7.5 Hz), 4.65(1H, dd, J=9.8, 7.4 Hz), 4.24 (1H, dd, J=11.4, 9.8 Hz), 3.82-3.81 (4H, m),3.41 (3H, s), 3.06 (2H, d, J=10.0 Hz), 2.41 (3H, s), 2.19-2.13 (2H, m), 1.92-1.79 (3H, m), 1.63-1.57 (2H, m). LC-MS:m / z=522.1 [M+H] + .

[0358] Example 27: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(piperidin-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0359]

[0360] Step A: tert-butyl(S)-4-(2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-formamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl)piperidine-1-carboxylic acid ester

[0361] The target compound was prepared in a manner similar to that in Example 3 (Step A), using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and tert-butyl-4-(2-hydroxyethyl)piperidine-1-carboxylic acid ester. The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 5:1 to 2:1) column chromatography to give the target compound (42%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97(1H, d, J=7.2 Hz), 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), 6.75-6.73 (2H, m), 4.90 (1H, dt, J=11.1, 7.5 Hz), 4.65 (1H, dd, J=9.8, 7.4 Hz), 4.24 (1H, dd, J=11.4, 9.8 Hz), 4.00 (2H, t, J=6.0 Hz), 3.81 (2H, s), 3.41 (3H, s), 2.72 (2H, t, J=10.6 Hz), 1.75-1.60 (7H,m), 1.45-1.41 (9H, m), 1.20-1.14 (2H, m).

[0362] Step B: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(piperidin-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide

[0363] The target compound was prepared in a manner similar to that in Example 12 (step B) using tert-butyl(S)-4-(2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-formamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl)piperidine-1-carboxylic acid ester. The crude product was purified by NH-SiO2 (dichloromethane:MeOH = 99:1 to 98:2) column chromatography to give the target compound (74%) as a white solid. ¹H-NMR (400 MHz, CDCl3): δ 7.88 (1H,s), 7.46 (1H, s), 7.27-7.22 (1H, m), 7.10 (1H, dd, J=7.2, 2.0 Hz), 6.96-6.85(3H, m), 6.75-6.73 (2H, m), 4.90 (1H, dd, J=11.2, 7.6 Hz), 4.65 (1H, dd, J=10.0, 7.6 Hz), 4.24 (1H, dd, J=11.4, 9.8 Hz), 4.00 (2H, t, J=6.2 Hz), 3.81(2H, s), 3.41 (3H, s), 3.09-3.06 (2H, m), 2.62 (2H, td, J=12.2, 2.4 Hz), 1.76-1.61 (5H, m), 1.23-1.14 (2H, m). LC-MS:m / z=522.2 [M+H] + .

[0364] Example 28: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(1-methylpiperidin-4-yl)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0365]

[0366] The target compound was prepared in a manner similar to that in Example 26, using (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(piperidin-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide. The crude product was purified by SiO2 (dichloromethane:MeOH = 9:1 to 8:2) column chromatography to give the target compound (52%) as a pale yellow solid. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.2 Hz), 7.88(1H, s), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.10 (1H, dd, J=7.2, 2.0 Hz), 6.96-6.84 (3H, m), 6.75-6.73 (2H, m), 4.90 (1H, dt, J=11.1, 7.4 Hz), 4.65 (1H, dd,J=9.8, 7.4 Hz), 4.24 (1H, dd, J=11.4, 9.8 Hz), 3.99 (2H, t, J=6.4 Hz), 3.81(2H, s), 3.41 (3H, s), 2.90 (2H, d, J=11.2 Hz), 2.29 (3H, s), 2.00-1.95 (2H,m), 1.77-1.73 (4H, m), 1.60-1.48 (1H, m), 1.42-1.33 (2H, m). LC-MS:m / z=536.2[M+H] + .

[0367] Example 29: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxypiperidin-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0368]

[0369] Step A: tert-butyl(S)-4-(2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxylammono)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylic acid ester

[0370] The target compound was prepared using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and tert-butyl-4-hydroxy-4-(2-hydroxyethyl)piperidine-1-carboxylic acid ester, following a similar method to that in Example 3 (step A). ​​The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 1:1) column chromatography to give the target compound (37%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97(1H, d, J=7.3 Hz), 7.88 (1H, d, J=0.9 Hz), 7.48 (1H, d, J=4.6 Hz), 7.24-7.22(1H, m), 7.12 (1H, d, J=8.2 Hz), 7.00-6.85 (3H, m), 6.78-6.74 (2H, m), 4.93-4.87 (1H, m), 4.65 (1H, dd, J=9.8, 7.5 Hz), 4.28-4.25 (1H, m), 4.21 (2H, t, J=6.2 Hz), 3.88-3.83 (2H, m), 3.81 (2H, s), 3.42 (3H, s), 3.22 (2H, t, J=13.3Hz), 2.22 (1H, s), 2.01 (2H, t, J=5.9 Hz), 1.69-1.59 (4H, m), 1.46 (9H, s).

[0371] Step B: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxypiperidin-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0372] The target compound was prepared using tert-butyl(S)-4-(2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-formamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl)-4-hydroxypiperidine-1-carboxylic acid ester, following a similar method to that in Example 12 (step B). The crude product was purified by SiO2 (dichloromethane:methanol = 10:1) column chromatography to obtain the target compound (91%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.96 (1H, d, J=7.3 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.25-7.23 (1H, m), 7.14 (1H,d, J=9.1 Hz), 7.00-6.85 (3H, m), 6.78-6.75 (2H, m), 4.93-4.86 (1H, m), 4.65(1H, dd, J=9.8, 7.5 Hz), 4.29-4.21 (3H, m), 3.81 (2H, s), 3.42 (3H, s), 3.35(4H, d, J=7.3 Hz), 2.78 (1H, s), 2.12-2.05 (4H, m), 1.90 (2H, d, J=14.2 Hz). LC-MS: m / z=538.20 [M+H]⁺.

[0373] Example 30: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxy-1-methylpiperidin-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0374]

[0375] The target compound was prepared in a manner similar to that in Example 26, using (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxypiperidin-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide. The crude product was purified by SiO2 (dichloromethane:methanol = 10:1) column chromatography to give the target compound (44%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.96 (1H, d, J=7.8 Hz), 7.88 (1H,s), 7.48 (1H, s), 7.25-7.23 (1H, m), 7.15 (1H, d, J=8.7 Hz), 7.00-6.85 (3H,m), 6.79-6.75 (2H, m), 4.93-4.87 (1H, m), 4.64 (1H, dd, J=9.8, 7.5 Hz), 4.29-4.23 (3H, m), 3.81 (2H, s), 3.42 (3H, s), 3.29-3.23 (2H,m), 3.18-3.11 (2H,m), 2.96 (1H, s), 2.74 (3H, s), 2.32-2.25 (2H, m), 2.12 (2H, dd, J=6.6, 4.3Hz), 1.89 (2H, d, J=13.7 Hz). LC-MS:m / z=552.20 [M+H] + .

[0376] Example 31: (S)-N-(7-((1,1-dioxotetrahydro-2H-thiaran-4-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0377]

[0378] The target compound of this invention was prepared using a method similar to that in Example 3 (step A), employing (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide. The crude product was purified by SiO2 (petroleum ether:ethyl acetate = 1:2) column chromatography to obtain the target compound (15%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.8 Hz), 7.88 (1H, s), 7.48 (1H, s), 7.29-7.23 (1H, m), 7.15 (1H, dd, J=7.3, 1.8 Hz), 7.00-6.85 (3H, m), 6.78 (2H, dd, J=7.8, 2.3 Hz), 4.94-4.90 (1H, m), 4.68-4.65 (1H, m), 4.27 (1H, dd, J=11.0, 10.1 Hz), 3.82 (2H, s), 3.42 (3H, s), 3.40-3.37 (1H, m), 3.09 (1H, t, J=6.4 Hz), 2.98 (2H, dd, J=14.9, 3.9 Hz), 2.52-2.38 (5H, m). LC-MS: m / z=543.10 [M+H]⁺.

[0379] Example 32: (S)-N-(7-((1,1-tetrahydro-2H-thiopyran-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0380]

[0381] The target compound of this invention was prepared using a method similar to that in Example 3 (step A), employing (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 4-(hydroxymethyl)tetrahydro-2H-thiopyran 1,1-dioxide. The crude product was purified by SiO2 (n-hexane:ethyl acetate = 1:4) column chromatography to obtain the target compound (26%) as a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.3 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.25-7.23 (1H, m), 7.12 (1H, dd, J=5.7, 3.9 Hz), 7.00-6.85 (3H, m), 6.74-6.71 (2H, m), 4.93-4.87 (1H, m), 4.65 (1H, dd, J=9.6, 7.3 Hz), 4.25 (1H, dd, J=11.0, 10.1 Hz), 3.87 (2H,d, J=5.0 Hz), 3.81 (2H, s), 3.42 (3H, s), 3.17-2.97 (4H, m), 2.31-2.29 (2H, m), 2.09-2.05 (2H, m), 1.93-1.88 (1H, m). LC-MS: m / z=557.10 [M+H]⁺.

[0382] Example 33: (S)-N-(7-(2-(1,1-tetrahydro-2H-thiopyran-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0383]

[0384] The target compound of this invention was prepared using a method similar to that in Example 3 (step A), employing (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 4-(2-hydroxyethyl)tetrahydro-2H-thiopyran 1,1-dioxide. The crude product was purified by SiO2 (n-hexane:ethyl acetate = 1:3) column chromatography to obtain the target compound (50%), which was a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.3 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.25-7.23 (1H, m), 7.12 (1H, dd, J=7.3, 1.8 Hz), 7.00-6.85 (3H, m), 6.73 (2H, dd, J=7.5,2.5 Hz), 4.94-4.87 (1H, m), 4.64 (1H, dd, J=9.8, 7.5 Hz), 4.25 (1H, dd, J=11.0,10.1 Hz), 4.02 (2H, t, J=5.7 Hz), 3.81 (2H, s), 3.42 (3H, s), 3.11-2.96 (5H, m), 2.19 (2H, d, J=13.7 Hz), 2.00-1.91 (2H, m), 1.8-1.82 (2H, m). LC-MS: m / z=571.10 [M+H]⁺.

[0385] Example 34: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0386]

[0387] The target compound of this invention was prepared using a method similar to that in Example 3, employing (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 3-(tetrahydro-2H-pyran-4-yl)propanol. The crude product was purified by SiO2 (n-hexane:ethyl acetate = 4:1 to 3:1) column chromatography, followed by further purification by NH-SiO2 (n-hexane:ethyl acetate = 4:1 to 3:1) to obtain the target compound (11%), which was a yellow foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.6 Hz), 7.88 (1H, d, J=0.8 Hz), 7.46 (1H, s), 7.27-7.22 (1H, m), 7.11-7.09 (1H, m), 6.96-6.84 (3H, m), 6.75-6.72 (2H, m), 4.90 (1H, dt, J=11.2, 7.5 Hz), 4.65 (1H, dd, J=9.8, 7.4Hz), 4.24 (1H, dd, J=11.2, 9.6 Hz), 3.99-3.93 (4H, m), 3.81 (2H, s), 3.42-3.36 (5H, m), 1.85-1.78 (2H, m), 1.66-1.62 (2H, m), 1.60-1.49 (1H, m), 1.46-1.40 (2H, m), 1.36-1.27 (2H, m). LC-MS: m / z=537.2 [M+H]⁺.

[0388] Example 35: (S)-4-(3-fluorobenzyl)-N-(7-((3-(hydroxymethyl)oxabutane-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0389]

[0390] Step A: (S)-(3-(((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-7-yl)oxy)methyl)oxabutane-3-yl)methylacetate

[0391] (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) (172 mg, 0.418 mmol) and (3-(bromomethyl)oxabutane-3-yl)methyl acetate (intermediate 11) (140 mg, 0.628 mmol) were dissolved in DMF (4.2 mL), and Cs₂CO₃ (204 mg, 0.628 mmol) was added. The reaction mixture was stirred at 30 °C for 4 hours. After concentration under reduced pressure, the residue was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 (n-hexane:ethyl acetate = 1:1) column chromatography to obtain the target compound (175 mg, 76%), which was a white foam. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.6 Hz), 7.88 (1H, d, J=0.8 Hz), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.13 (1H, dd, J=5.2, 4.4 Hz), 7.00-6.84 (3H, m), 6.80-6.77 (2H, m), 4.90 (1H, dt, J=11.2, 7.4 Hz), 4.66 (1H, dd, J=10.0, 7.6 Hz), 4.60 (4H,m), 4.45 (2H, s), 4.26 (1H, dd, J=11.0, 10.2 Hz), 4.19 (2H, s), 3.81 (2H, s), 3.43 (3H, s), 2.10 (3H, s).

[0392] Step B: (S)-4-(3-fluorobenzyl)-N-(7-((3-(hydroxymethyl)oxabutane-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0393] (S)-(3-(((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)methyl)oxabutane-3-yl)methyl acetate (50.0 mg, 0.0900 mmol) was dissolved in MeOH (0.91 mL), and K2CO3 (6.25 mg, 0.0450 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then concentrated under reduced pressure. The residue was purified by SiO2 (n-hexane:ethyl acetate = 1:2 to 1:8) column chromatography to give the target compound (41.0 mg, 88%) as a white foam.

[0394] ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.6 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.13 (1H, dd, J=7.6, 1.6 Hz), 7.00-6.85 (3H, m), 6.82-6.79 (2H, m), 4.90 (1H, dt, J=11.1, 7.4 Hz), 4.66 (1H, dd, J=9.8, 7.4 Hz), 4.62-4.57 (4H, m), 4.28-4.23 (3H, m), 4.06 (2H, d, J=3.6 Hz), 3.81 (2H, s), 3.43 (3H, s). LC-MS: m / z=511.1 [M+H]⁺.

[0395] Example 36: (S)-N-(5-methyl-4-oxo-7-(2-(piperidin-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-3-yl)-1H-imidazol-1-carboxamide

[0396]

[0397] Step A: tert-butyl(S)-(5-methyl-4-oxo-7-(2-(piperidin-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0398] Tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate (intermediate 1, 0.183 g, 0.594 mmol) was dissolved in DMF (2.9 mL), and Cs₂CO₃ (0.581 g, 1.78 mmol) and 1-(2-chloroethyl)piperidine (0.114 g, 0.772 mmol) were added at room temperature. The reaction mixture was stirred at 50 °C for 18 hours. After quenching with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂ (dichloromethane:MeOH = 20:1) column chromatography to give the target compound (0.175 g, 70%) as a white foam. 1 H-NMR (400 MHz, CDCl3): δ 7.04 (1H, d, J = 8.0 Hz), 6.73-6.69(2H, m), 5.47 (1H, d, J = 7.2 Hz), 4.68-4.61 (1H, m), 4.52 (1H, dd, J = 9.6,7.6 Hz), 4.11-4.06 (3H, m), 3.37 (3H, s), 2.77 (2H, t, J = 6.0 Hz), 2.52 (3H,s), 1.47-1.46 (2H, m), 1.39 (9H, s), 1.31-1.25 (2H, m).

[0399] Step B: (S)-3-amino-5-methyl-7-(2-(piperidin-1-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrrol-4(5H)-one hydrochloride

[0400] 0.175 g (0.417 mmol) of tert-butyl(S)-(5-methyl-4-oxo-7-(2-(piperidin-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate was dissolved in dichloromethane (4.1 mL), and HCl (4 M, 2.08 mL, 8.34 mmol in dioxane) was added at 0 °C. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to give the target compound (0.172 g, crude product) as a yellow oil, which was used in the next step of the reaction without further purification.

[0401] Step C: (S)-N-(5-methyl-4-oxo-7-(2-(piperidin-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-imidazol-1-carboxamide

[0402] The target compound was prepared using a method similar to that in Example 7 (step C), with (S)-3-amino-5-methyl-7-(2-(piperidin-1-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2) as starting materials. The crude product was purified by SiO2 (dichloromethane:MeOH = 20:1 to 10:1) column chromatography to obtain the target compound (52%), which was a white foamy substance. 1 H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J =7.6 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.27-7.22 (2H, m), 7.11-7.09 (1H, m), 6.96-6.85 (3H, m), 6.77-6.74 (2H, m), 4.93-4.86 (1H, m), 4.65 (1H, dd, J =9.8, 7.4 Hz), 4.24 (1H, t, J = 10.6 Hz), 4.10 (2H, t, J = 6.0 Hz), 3.81 (2H,s), 3.41 (3H, s), 2.78 (2H, t, J = 6.0 Hz), 2.52 (4H, s), 1.65-1.59 (4H, m), 1.47-1.46 (2H, m). LC-MS: m / z = 522.2 [M+H] + .

[0403] Example 37: (S)-N-(7-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0404]

[0405] The target compound was prepared using a method similar to that in Example 3, with (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 2-(4,4-difluoropiperidin-1-yl)ethane-1-ol as the starting materials. The crude product was purified by SiO2 (n-hexane:ethyl acetate = 1:1) column chromatography to obtain the target compound (18%), which was a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d,J=7.8 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.24-7.22 (1H, m), 7.11 (1H, dd,J=5.7, 3.9 Hz), 7.00-6.85 (3H, m), 6.77-6.74 (2H, m), 4.93-4.87 (1H, m), 4.65 (1H, dd, J=9.6, 7.3 Hz), 4.25 (1H, dd, J=11.2, 9.8 Hz), 4.08 (2H, t,J=5.7 Hz), 3.81 (2H, s), 3.41 (3H, s), 2.87 (2H, t, J=5.5 Hz), 2.70 (4H, t, J=5.5 Hz), 2.08-2.00 (4H, m). LC-MS: m / z=558.20 [M+H]⁺.

[0406] Example 38: (S)-N-(7-(2-(1,2-oxazine-2-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0407]

[0408] Step A: tert-butyl(S)-(7-(2-(1,2-oxazine-2-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0409] The target compound was prepared in a manner similar to that in Example 3 (Step A): tert-butyl(S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate (intermediate 1, 120 mg, 0.389 mmol) and 2-(1,2-oxazine-2-yl)ethylmethanesulfonate (intermediate 12, 98.0 mg, 0.467 mmol) were dissolved in DMF (4.0 mL), and Cs₂CO₃ (254 mg, 0.778 mmol) was added at room temperature. The reaction mixture was stirred at 30 °C for 24 hours. After quenching with water, the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO2-NH2 (hexane:ethyl acetate = 3:1) column chromatography to obtain the target compound (70 mg, 43%), which was a pale yellow oil. ¹H-NMR (400 MHz, CDCl3): δ 7.03 (1H, d, J=8.7 Hz), 6.77-6.72 (2H, m), 5.48 (1H, d, J=6.9 Hz), 4.68-4.61 (1H, m), 4.52 (1H, dd, J=9.6,7.3 Hz), 4.20-4.15 (2H, m), 3.95-3.89 (3H, m), 3.37 (3H, s), 3.01 (2H, t, J=5.9 Hz), 2.78-2.86 (2H, brs), 1.84-1.78 (2H, m), 1.57-1.54 (2H,m), 1.39 (9H,s).

[0410] Step B: (S)-7-(2-(1,2-oxazine-2-yl)ethoxy)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazazepine-4(5H)-one hydrochloride

[0411] The target compound was prepared as tert-butyl(S)-(7-(2-(1,2-oxazin-2-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate, following a method similar to that used for intermediate 3 (step A). ​​The crude product (84%) was used directly in the next reaction without further purification.

[0412] Step C: (S)-N-(7-(2-(1,2-oxazine-2-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0413] The target compound was prepared using (S)-7-(2-(1,2-oxazine-2-yl)ethoxy)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazazepine-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2) in a manner similar to that in Example 7 (step C). The crude product was purified by SiO2 (dichloromethane:ethyl acetate = 15:1) column chromatography to give the target compound (21%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H,d, J=7.3 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.24-7.22 (1H, m), 7.10 (1H, dd, J=7.8, 1.4 Hz), 7.00-6.85 (3H, m), 6.81-6.78 (2H, m), 4.93-4.87 (1H, m), 4.66(1H, dd, J=9.6, 7.3 Hz), 4.24 (1H, dd, J=11.0, 10.1 Hz), 4.18 (2H, t, J=5.0Hz), 3.94 (2H, t, J=5.3 Hz), 3.81 (2H, s), 3.41 (3H, s), 3.02 (2H, t, J=5.9Hz), 2.83 (2H, brs), 1.84-1.80 (2H, m), 1.56-1.54 (2H, m). LC-MS: m / z=524.10 [M+H]⁺.

[0414] Example 39: (S)-N-(7-(2-(1,1-dioxothiomorpholinyl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0415]

[0416] The target compound was prepared in a manner similar to that in Example 3: (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-3-yl)-1H-pyrazol-1-carboxamide (intermediate 3) was reacted with 4-(2-hydroxyethyl)thiomorpholine 1,1-dioxide. The crude product was purified by SiO2 (hexane:ethyl acetate = 1:1) column chromatography to obtain the target compound (46%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.97(1H, d, J=7.8 Hz), 7.88 (1H, d, J=0.9 Hz), 7.47 (1H, s), 7.25-7.23 (1H, m),7.12 (1H, dd, J=5.5, 3.7 Hz), 7.00-6.85 (3H, m), 6.76-6.73 (2H, m), 4.93-4.87(1H, m), 4.65 (1H, dd, J=9.8, 7.5 Hz), 4.26 (1H, dd, J=11.2, 9.8 Hz), 4.09(2H, t, J=5.3 Hz), 3.81 (2H, s), 3.42 (3H, s), 3.19-3.17 (4H, m), 3.10 (4H,t, J=4.1 Hz), 3.01 (2H, t, J=5.3 Hz). LC-MS: m / z=572.10 [M+H]⁺.

[0417] Example 40: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-formamido)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-7-yl)oxy)ethylazacyclobutane-1-carboxylic acid ester

[0418]

[0419] Step A: (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-7-yl)oxy)ethylazacyclobutane-1-carboxamide

[0420] (S)-2-((3-((tert-Butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl methanesulfonate (intermediate 14, 33.0 mg, 0.0770 mmol) was dissolved in DMF (0.77 mL), and Cs₂CO₃ (100 mg, 0.307 mmol) was added at room temperature, followed by aziridine hydrochloride (22.0 mg, 0.230 mmol). The reaction mixture was stirred at 50 °C for 18 hours. After quenching with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂ (hexane:ethyl acetate = 3:1 to 1:5) column chromatography to give the target compound (19.0 mg, 56%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.05 (1H, d, J=8.7 Hz), 6.75-6.70 (2H, m), 5.47 (1H, d, J=7.8 Hz), 4.67-4.61 (1H,m), 4.52 (1H, dd, J=9.6, 7.3 Hz), 4.43-4.38 (2H, m), 4.16-4.09 (3H, m), 4.03(4H, t, J=7.8 Hz), 3.38 (3H, s), 2.28-2.21 (2H, m), 1.39 (9H, s).

[0421] Step B: (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethylazacyclobutane-1-carboxylic acid ester

[0422] (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethylazacyclobutane-1-carboxylic acid ester (19.0 mg, 0.0440 mmol) was dissolved in dichloromethane (0.43 mL), and TFA (0.0170 mL, 0.218 mmol) was added. The reaction mixture was stirred overnight at room temperature, and then concentrated under reduced pressure to give the target compound (16.0 mg, crude product) as a colorless oil. This compound was used directly in the next reaction without further purification. ¹H-NMR (400 MHz, CDCl3): δ 7.11 (1H, d, J=9.6 Hz), 6.80-6.77 (2H,m), 4.67 (1H, t, J=8.7 Hz), 4.51 (1H, t, J=10.5 Hz), 4.43-4.38 (2H, m), 4.29(1H, t, J=9.1 Hz), 4.17-4.13 (2H, m), 4.03 (4H, t, J=7.8 Hz), 3.32 (3H, s), 2.28-2.21 (2H, m).

[0423] Step C: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-7-yl)oxy)ethylazacyclobutane-1-carboxylic acid ester

[0424] The target compound was prepared using a method similar to that in Example 7 (step C), with (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethylazacyclobutane-1-carboxylic acid ester and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2) as starting materials. The crude product was purified by prep-HPLC column chromatography to obtain the target compound (26%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.3Hz), 7.88 (1H, s), 7.47 (1H, s), 7.26-7.22 (1H, m), 7.11 (1H, d, J=9.1 Hz), 7.00-6.85 (3H, m), 6.78-6.75 (2H, m), 4.93-4.86 (1H, m), 4.65 (1H, dd, J=9.6,7.3 Hz), 4.40 (2H, t, J=4.6 Hz), 4.25 (1H, dd, J=11.0, 9.6 Hz), 4.15 (2H, t,J=4.7 Hz), 4.03 (4H, t, J=7.5 Hz), 3.81 (2H, s), 3.41 (3H, s), 2.28-2.21 (2H,m). LC-MS: m / z=538.2 [M+H]⁺.

[0425] Example 41: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-7-yl)oxy)ethyl 3,3-difluoroazacyclobutane-1-carboxylic acid ester

[0426]

[0427] Using a method similar to that in Example 40, the target compound was prepared from (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl methanesulfonate (intermediate 14) and 3,3-difluoroazacyclobutane hydrochloride via a three-step reaction. The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 20:1 to 1:1) to obtain the target compound (overall yield of 22% in 3 steps), which was a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.8 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.12 (1H, dd, J=8.2, 0.9 Hz), 6.96-6.85 (3H, m), 6.76 (2H, dd,J=11.0, 2.7 Hz), 4.93-4.86 (1H, m), 4.65 (1H, dd, J=9.6, 7.3 Hz), 4.46 (2H,t, J=4.8 Hz), 4.35 (4H, t, J=11.9 Hz), 4.25 (1H, dd, J=11.2, 9.8 Hz), 4.17(2H, t, J=4.8 Hz), 3.81 (2H, s), 3.42 (3H, s). LC-MS: m / z=574.1 [M+H]⁺.

[0428] Example 42: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-7-yl)oxy)ethyl-3-hydroxy-3-methylazacyclobutane-1-carboxylic acid ester

[0429]

[0430] Step A: tert-butyl(S)-(5-methyl-7-(2-(((4-nitrophenoxy)carbonyl)oxy)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0431] Tert-butyl(S)-(7-(2-hydroxyethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate (intermediate 13, 1.31 g, 3.72 mmol) and TEA (1.55 mL, 11.1 mmol) were dissolved in dichloromethane (18 mL), and 4-nitrophenyl chlorocarbamate (0.974 g, 4.83 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and then concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (hexane:ethyl acetate = 8:1 to 1:4) to give the target compound (1.36 g, 71%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 8.30 (2H, td,J=6.2, 3.7 Hz), 7.41 (2H, dt, J=9.9, 2.6 Hz), 7.08 (1H, d, J=8.7 Hz), 6.76(2H, td, J=9.1, 2.7 Hz), 5.47 (1H, d, J=7.3 Hz), 4.68-4.62 (3H, m), 4.53 (1H,dd, J=9.6, 7.3 Hz), 4.26 (2H, t, J=4.6 Hz), 4.14-4.09 (2H, m), 3.38 (3H, s),1.40 (9H, s).

[0432] Step B: (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethyl-3-hydroxy-3-methylazacyclobutane-1-carboxylic acid ester

[0433] 3-Methylazacyclobutane-3-ol hydrochloride (0.391 g, 3.17 mmol) was dissolved in DMF (52 mL), and DIPEA (1.37 mL, 7.92 mmol) was added. Then, tert-butyl(S)-(5-methyl-7-(2-((((4-nitrophenoxy)carbonyl)oxy)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)carbamate (1.36 g, 2.64 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then quenched with water. The mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂ column chromatography (hexane:ethyl acetate = 1:1 to 1:3) to give the target compound (1.09 g, 89%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ7.07 (1H, d, J=8.7 Hz, 1H), 6.78-6.75 (2H, m), 5.52 (1H, d, J=7.3 Hz), 4.63-4.56 (1H, m), 4.51 (1H, t, J=8.5 Hz), 4.39-4.07 (5H, m), 3.80 (4H, s), 3.38(3H, s), 2.95 (1H, s), 1.49 (3H, s), 1.39 (9H, s).

[0434] Step C: (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethyl 3-hydroxy-3-methylazacyclobutane-1-carboxylic acid ester

[0435] The target compound was prepared from (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethyl 3-hydroxy-3-methylazacyclobutane-1-carboxylic acid ester using a method similar to that in Example 40 (step B). The crude product was used directly in the next reaction without further purification. ¹H-NMR (400 MHz, DMSO-d6): δ 8.35 (2H, brs), 7.18 (1H, d, J=9.1 Hz), 7.13 (1H, d, J=2.7 Hz), 6.88 (1H, dd, J=8.7, 2.7 Hz), 5.63 (1H, s), 4.46 (1H, dd, J=9.1,7.3 Hz), 4.38-4.27 (4H, m), 4.18 (2H, t, J=3.0 Hz), 3.73 (4H, s), 3.35 (3H,s), 1.34 (3H, s).

[0436] Step D: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrol-7-yl)oxy)ethyl-3-hydroxy-3-methylazacyclobutane-1-carboxylic acid ester

[0437] The target compound was prepared using a method similar to that in Example 7 (step C), starting with (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethyl 3-hydroxy-3-methylazacyclobutane-1-carboxylic acid ester and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 10:1 to 1:3) to obtain the target compound (78%) as a white foamy substance. ¹H-NMR (400 MHz, DMSO-d6): δ 8.44 (1H, d, J=7.8 Hz), 8.10 (1H, s), 7.72 (1H, s), 7.33 (1H, dd, J=14.4, 8.0 Hz), 7.15 (1H, d, J=8.7 Hz), 7.11-7.07 (3H, m), 7.04-6.99 (1H, m), 6.86 (1H, dd, J=8.9, 3.0 Hz), 5.61 (1H, s), 4.72-4.66 (1H, m),4.62-4.56 (1H, m), 4.39 (1H, dd, J=9.6, 7.8 Hz), 4.29 (2H, t, J=4.3 Hz), 4.19 (2H, t, J=4.3 Hz), 3.83 (2H, s), 3.74 (4H, s), 3.31 (3H, s), 1.34 (3H, s). LC-MS: m / z=568.1 [M+H]⁺.

[0438] Example 43: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethylmorpholine-4-carboxylic acid ester

[0439]

[0440] Step A: (S)-2-((3-((tert-butyloxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethylmorpholine-4-carboxylic acid ester

[0441] The target compound was prepared using a method similar to that in Example 42 (Step B), with tert-butyl(S)-(5-methyl-7-(2-((((4-nitrophenoxy)carbonyl)oxy)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate (Example 42 (Step A), 180 mg, 0.348 mmol) and morpholine as starting materials. The crude product was purified by SiO2 column chromatography (hexane:ethyl acetate = 2:1 to 1:3) to obtain the target compound (175 mg, quantitative), as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.05 (1H, d, J=8.8 Hz), 6.74-6.69 (2H, m), 5.47 (1H, d, J=7.2 Hz), 4.63 (1H, dt, J=11.3, 7.4 Hz), 4.50 (1H, dd, J=9.6, 7.2Hz), 4.44 (2H, t, J=4.6 Hz), 4.15-4.06 (3H, m), 3.66 (4H, s), 3.49 (4H, t, J=5.0 Hz), 3.37 (3H, s), 1.73 (1H, s), 1.38 (9H, s).

[0442] Step B: (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethylmorpholine-4-carboxylic acid hydrochloride

[0443] (S)-2-((3-((tert-Butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethylmorpholine-4-carboxylic acid ester (175 mg, 0.376 mmol) was dissolved in dichloromethane (3.759 mL), and HCl (4 M, dioxane solution, 0.940 mL, 3.76 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to give the target compound (132 mg, crude product) as a white foamy substance. This compound was used directly in the next reaction without further purification.

[0444] Step C: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethylmorpholine-4-carboxylic acid ester

[0445] The target compound was prepared using a method similar to that in Example 7 (step C), with (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethylmorpholine-4-carboxylic acid ester hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2) as starting materials. The crude product was purified by SiO2 column chromatography (hexane:ethyl acetate = 2:1 to 1:4), followed by further purification by SiO2 column chromatography (dichloromethane:ethyl acetate = 20:1 to 1:1) to obtain the target compound (65%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.6 Hz),7.88 (1H, d, J=0.8 Hz), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.13-7.10 (1H, m),6.96-6.84 (3H, m), 6.78-6.74 (2H, m), 4.90 (1H, dt, J=11.2, 7.4 Hz), 4.65 (1H, dd, J=9.6, 8.0 Hz), 4.46 (2H, t, J=4.6 Hz), 4.25 (1H, dd, J=11.0, 9.8Hz), 4.18 (2H, t, J=4.8 Hz), 3.81 (2H, s), 3.66 (4H, s), 3.49 (4H, t, J=4.8Hz), 3.41 (3H, s). LC-MS: m / z=568.2 [M+H]⁺.

[0446] Example 44: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl-4-hydroxy-4-methylpiperidine-1-carboxylic acid ester

[0447]

[0448] Step A: (S)-2-((3-((tert-butyloxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-7-yl)oxy)ethyl-4-hydroxy-4-methylpiperidine-1-carboxylic acid ester

[0449] The target compound was prepared using a method similar to that in Example 42 (step B), with (S)-(5-methyl-7-(2-((((4-nitrophenoxy)carbonyl)oxy)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)carbamate (Example 42, step A) and 4-methylpiperidin-4-ol as starting materials. The crude product was purified by SiO2 column chromatography (hexane:ethyl acetate = 1:1 to 1:4) to obtain the target compound (72%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ7.05 (1H, d, J=8.4 Hz), 6.76-6.73 (2H, m), 5.51 (1H, d, J=6.8 Hz), 4.60 (1H,dt, J=11.1, 7.4 Hz), 4.54-4.07 (6H, m), 3.81-3.63 (2H, m), 3.38 (3H, s), 3.28-3.11 (2H, m), 1.53 (4H, s), 1.39 (9H, s), 1.25 (3H, s).

[0450] Step B: (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-7-yl)oxy)ethyl 4-hydroxy-4-methylpiperidine-1-carboxylic acid ester hydrochloride

[0451] Using a method similar to that in Example 42 (step C), the target compound was prepared from (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl-4-hydroxy-4-methylpiperidine-1-carboxylic acid ester, yielding a white foamy substance, which was used in the next reaction without further purification.

[0452] Step C: (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl-4-hydroxy-4-methylpiperidine-1-carboxylic acid ester

[0453] The target compound was prepared using a method similar to that in Example 7 (step C), starting with (S)-2-((3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl 4-hydroxy-4-methylpiperidine-1-carboxylic acid ester hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 20:1 to 1:3) to obtain the target compound (35%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.99 (1H, d, J=7.2 Hz), 7.87 (1H, s), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.13-7.10 (1H, m), 7.00-6.85 (3H, m), 6.79-6.77 (2H, m), 4.87(1H, dt, J=11.2, 7.5 Hz), 4.65 (1H, dd, J=9.8, 7.4 Hz), 4.42 (2H, brs), 4.27-4.15 (3H, m), 3.81-3.68 (4H, m), 3.41 (3H, s), 3.30-3.21 (2H,m), 1.55 (4H,brs), 1.38 (1H,s), 1.25 (3H,s). LC-MS: m / z=596.2 [M+H]⁺.

[0454] Example 45: (S)-N-(7-(2-(aziridin-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0455]

[0456] The target compound was prepared using a method similar to that in Example 3, with (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 2-(aziridin-1-yl)ethane-1-ol as starting materials. The crude product was purified by prep-HPLC to obtain the target compound (2%) as a colorless oil. ¹H-NMR (400 MHz, MeOH-d4): δ 7.95 (1H, s), 7.56 (1H, s), 7.29 (1H,td, J=7.8, 6.4 Hz), 7.15 (1H, d, J=8.7 Hz), 7.05-7.02 (2H, m), 6.97-6.88 (3H,m), 4.89-4.82 (1H, m), 4.56 (1H, dd, J=9.8, 7.5 Hz), 4.37 (1H, dd, J=11.2,9.8 Hz), 4.17 (2H, t, J=5.0 Hz), 3.85 (2H, s), 3.41 (3H, s), 2.72-2.65 (2H,m), 1.83 (2H, t, J=2.1 Hz), 1.47 (2H, t, J=2.1 Hz). LC-MS: m / z=480.1 [M+H]⁺.

[0457] Example 46: (S)-4-(3-fluorobenzyl)-N-(7-(2-(3-hydroxy-3-methylazabutan-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazabutan-3-yl)-1H-pyrazole-1-carboxamide

[0458]

[0459] Step A: tert-butyl(S)-(7-(2-(3-(benzyloxy)-3-methylazabutane-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-3-yl)carbamate

[0460] Tert-butyl (S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyrrolidone-3-yl)carbamate (intermediate 1, 0.233 g, 0.756 mmol) was dissolved in DMF (15 mL), and Cs₂CO₃ (0.739 g, 2.26 mmol), 3-(benzyloxy)-1-(2-chloroethyl)-3-methylazabutane (intermediate 15, 0.272 g, 1.13 mmol), and KI (0.188 g, 1.13 mmol) were added sequentially at room temperature. The reaction mixture was stirred overnight at 75 °C. After quenching with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (ethyl acetate alone to ethyl acetate:MeOH=8:1) to obtain the target compound (0.218 g, 56%), which was a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.36-7.28 (5H, m), 7.04 (1H, d, J=8.2 Hz), 6.70 (2H, dd, J=12.6, 2.5 Hz), 5.47 (1H, d, J=7.8 Hz), 4.67-4.61 (1H, m),4.52 (1H, dd, J=9.6, 7.3 Hz), 4.41 (2H, s), 4.13-4.06 (1H, m), 3.97 (2H, t, J=5.5 Hz), 3.44 (2H, d, J=7.8 Hz), 3.37 (3H, s), 3.24 (2H, d, J=6.9 Hz), 2.93 (2H, t, J=5.5 Hz), 1.61 (3H, s), 1.39 (9H, s).

[0461] Step B: (S)-3-amino-7-(2-(3-(benzyloxy)-3-methylazabutane-1-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazaphene-4(5H)-one hydrochloride

[0462] 0.188 g (0.367 mmol) of tert-butyl(S)-(7-(2-(3-(benzyloxy)-3-methylazabutane-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-3-yl)carbamate was dissolved in dichloromethane (7.3 mL), and HCl (4 M, dissolved in dioxane, 0.919 mL, 3.67 mmol) was added at room temperature. The reaction mixture was stirred overnight at 30 °C. After quenching with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the target compound (0.212 g, crude) as a white foamy substance, which could be used in the next step without further purification. LC-MS: m / z = 412.1 [M+H]⁺.

[0463] Step C: (S)-3-amino-7-(2-(3-hydroxy-3-methylazabutane-1-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazaphene-4(5H)-one hydrochloride

[0464] (S)-3-amino-7-(2-(3-(benzyloxy)-3-methylazabutane-1-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one hydrochloride (0.151 g, 0.337 mmol), Pd / C (10 wt%, 0.057 g, 0.054 mmol), and AcOH (0.019 mL, 0.337 mmol) were suspended in MeOH (6.7 mL) and stirred overnight at room temperature under H2 atmosphere. After filtration through a Celite pad, the filtrate was concentrated under reduced pressure to give the target compound (0.117 g, crude product) as a white foamy substance, which could be used for the next reaction without further purification. LC-MS: m / z = 322.1 [M+H]⁺.

[0465] Step D: (S)-4-(3-fluorobenzyl)-N-(7-(2-(3-hydroxy-3-methylazabutan-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-3-yl)-1H-pyrazole-1-carboxamide

[0466] The target compound was prepared using a method similar to that in Example 7 (step C), starting with (S)-3-amino-7-(2-(3-hydroxy-3-methylazabutane-1-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 5:1 to ethyl acetate:MeOH = 8:1) to obtain the target compound (overall yield of 13% in 3 steps), as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.8 Hz), 7.88 (1H, s), 7.46(1H, s), 7.26-7.22 (1H, m), 7.10 (1H, d, J=9.6 Hz), 6.96-6.85 (3H, m), 6.74(2H, t, J=3.2 Hz), 4.93-4.86 (1H, m), 4.65 (1H, dd, J=9.8, 7.5 Hz), 4.27-4.21(1H, m), 3.98 (2H, t, J=5.5 Hz), 3.81 (2H, s), 3.45-3.41 (5H, m), 3.18 (2H, d, J=7.8 Hz), 2.90 (2H, t, J=5.5 Hz), 1.52 (3H, s). LC-MS: m / z=524.1 [M+H]⁺.

[0467] Example 47: (S)-N-(7-(2-(3,3-difluoroazabutane-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0468]

[0469] Step A: tert-butyl(S)-(7-(2-(3,3-difluoroazabutane-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaporide-3-yl)carbamate

[0470] Tert-butyl (S)-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)carbamate (intermediate 1, 200 mg, 0.549 mmol), 1-(2-chloroethyl)-3,3-difluoroazabutane (intermediate 16, 100 mg, 0.560 mmol), NaI (194 mg, 1.30 mmol), and Cs₂CO₃ (634 mg, 1.95 mmol) were dissolved in DMF (6.0 mL) and stirred at 100 °C for 18 hours. After quenching with water, 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 reduced pressure. The residue was purified by SiO2 column chromatography (hexane:ethyl acetate = 3:1 to 1:1) to obtain the target compound (50.0 mg, 18%), which was a yellow foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.04(1H, d, J=8.4 Hz), 6.70-6.66 (2H, m), 5.46 (1H, d, J=7.2 Hz), 4.67-4.60 (1H,m), 4.51 (1H, dd, J=9.6, 7.2 Hz), 4.08 (1H, dd, J=11.2, 9.6 Hz), 3.99 (2H, t,J=5.2 Hz), 3.72 (4H, t, J=13.4 Hz), 3.36 (3H, s), 2.97 (2H, t, J=5.0 Hz),1.39 (9H, s).

[0471] Step B: (S)-3-amino-7-(2-(3,3-difluoroazabutane-1-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one hydrochloride

[0472] (S)-(7-(2-(3,3-difluoroazabutane-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-3-yl)carbamate (50.0 mg, 0.119 mmol) was dissolved in dichloromethane (0.40 mL), and HCl (4 M in dioxane, 0.298 mL, 1.19 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure to give the target compound (43.0 mg, crude) as a yellow solid, which could be used in the next step without further purification. LC-MS: m / z = 328.0 [M+H]⁺.

[0473] Step C: (S)-N-(7-(2-(3,3-difluoroazabutane-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0474] The target compound was prepared according to the method in Example 7 (step C), using (S)-3-amino-7-(2-(3,3-difluoroazabutane-1-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (hexane:ethyl acetate = 1:1) to obtain the target compound (overall yield of 13% in both steps), as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ7.96 (1H, d, J=7.2 Hz), 7.87 (1H, s), 7.46 (1H, s), 7.27-7.21 (1H, m), 7.11-7.08 (1H, m), 6.95-6.84 (3H, m), 6.74-6.69 (2H, m), 4.92-4.85 (1H, m), 4.65(1H, dd, J=9.6, 7.2 Hz), 4.24 (1H, dd, J=11.2, 10.0 Hz), 4.01 (2H, t, J=5.4Hz), 3.80 (2H, s), 3.73 (4H, t, J=12.2 Hz), 3.40 (3H, s), 2.98 (2H, t, J=5.2Hz). MS: m / z=530.1 [M+H]⁺.

[0475] Example 48: (S)-N-(7-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-azaspiro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0476]

[0477] Step A: tert-butyl(S)-(7-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxaspiro-3-yl)carbamate

[0478] (S)-2-((3-((tert-Butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaspiro-7-yl)oxy)ethyl methanesulfonate (intermediate 14, 0.244 g, 0.567 mmol) was dissolved in DMF (5.6 mL), and Cs₂CO₃ (0.739 g, 2.26 mmol) was added at room temperature, followed by 2-oxa-6-azaspiro[3.3]heptane (0.100 mL, 1.13 mmol). The reaction mixture was stirred at 50 °C for 4 hours. After quenching with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO2 column chromatography (dichloromethane:MeOH = 100:1 to 20:1) to obtain the target compound (0.144 g, 58%), which was a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.04 (1H, d, J=8.7 Hz), 6.71-6.67 (2H, m), 5.47 (1H, d, J=6.9 Hz), 4.76(4H, s), 4.67-4.61 (1H, m), 4.52 (1H, dd, J=9.6, 7.3 Hz), 4.09 (1H, dd, J=11.2, 9.8 Hz), 3.92 (2H, t, J=5.5 Hz), 3.48 (4H, s), 3.37 (3H, s), 2.78 (2H,t, J=5.3 Hz), 1.40 (9H, s).

[0479] Step B: (S)-7-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxa-azaspiro-4(5H)-one

[0480] 0.144 g (0.332 mmol) of tert-butyl(S)-(7-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxaspiro-3-yl)carbamate was dissolved in dichloromethane (3.3 mL), and TFA (0.256 mL, 3.32 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give the target compound (0.111 g, crude product) as a white foamy substance, which could be used in the next step of the reaction without further purification.

[0481] Step C: (S)-N-(7-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-azaspiro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide

[0482] The target compound was prepared according to the method of Example 7 (step C), using (S)-7-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazaspiro-4(5H)-one and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by prep-HPLC to obtain the target compound (overall yield of 8% in both steps), which was a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d, J=7.3Hz), 7.88 (1H, s), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.10 (1H, dd, J=7.8, 1.8Hz), 7.00-6.85 (3H, m), 6.73 (2H, dd, J=8.0, 2.5 Hz), 4.92-4.86 (1H, m), 4.76(4H, s), 4.65 (1H, dd, J=9.6, 7.8 Hz), 4.24 (1H, dd, J=11.2, 9.8 Hz), 3.94(2H, t, J=5.5 Hz), 3.81 (2H, s), 3.49 (4H, s), 3.40 (3H, s), 2.80 (2H, t, J=5.3 Hz). MS: m / z=536.1 [M+H]⁺.

[0483] Example 49: (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-morpholinylethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide

[0484]

[0485] The target compound was prepared according to the method in Example 3, using (S)-4-(3-fluorobenzyl)-N-(7-hydroxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide (intermediate 3) and 2-morpholinoethanol. The crude product was purified by SiO2 column chromatography (hexane:ethyl acetate = 1:1 to ethyl acetate:MeOH = 98:2) to give the target compound (38%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.98 (1H, d,J=7.2 Hz), 7.88 (1H, s), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.11 (1H, m), 7.00-6.84 (3H, m), 6.78-6.74 (2H, m), 4.90 (1H, dt, 11.2, 7.5 Hz), 4.65 (1H, dd, J=9.6, 7.6 Hz), 4.24 (1H, dd, J=10.8, 10.0 Hz), 4.10 (2H, t, J=5.6 Hz), 3.81(2H, s), 3.75 (4H, t, J=4.4 Hz), 3.41 (3H, s), 2.82 (2H, t, J=5.6 Hz), 2.59 (4H, t, J=4.6 Hz). MS: m / z=542.2 [M+H]⁺.

[0486] Example 50: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxopyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide

[0487]

[0488] Step A: tert-butyl(S)-(5-methyl-4-oxo-7-(2-(6-oxopyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0489] (S)-2-((3-((tert-Butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl methanesulfonate (intermediate 14, 1.13 g, 2.64 mmol) was dissolved in DMF (26 mL), and K₂CO₃ (1.46 g, 10.6 mmol) and pyrazin-3(2H)-one (0.304 g, 3.17 mmol) were added at room temperature. The reaction mixture was stirred at 70 °C for 4 hours. After quenching with water, the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by SiO₂ column chromatography (hexane:ethyl acetate = 10:1 to dichloromethane:MeOH = 50:1) to give the target compound (1.05 g, 92%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.80 (1H, q, J=1.8 Hz), 7.21 (1H, dd, J=9.6, 3.7 Hz), 7.02 (1H, d, J=8.7 Hz), 6.95 (1H, dd,J=9.4, 1.6 Hz), 6.72 (2H, td, J=8.2, 2.7 Hz), 5.46 (1H, d, J=6.9 Hz), 4.62-4.55 (3H, m), 4.50 (1H, dd, J=9.4, 7.5 Hz), 4.37 (2H, t, J=5.5 Hz), 4.11-4.05(1H, m), 3.36 (3H, s), 1.39 (9H, s).

[0490] Step B: (S)-3-((l2-chloro)-l4-azyl)-5-methyl-7-(2-(6-oxopyrazin-1(6H)-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazazepine-4(5H)-one

[0491] 1.05 g (2.42 mmol) of tert-butyl(S)-(5-methyl-4-oxo-7-(2-(6-oxopyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazopyron-3-yl)carbamate was dissolved in dichloromethane (24 mL), and HCl (4 M in dioxane, 12.1 mL, 48.6 mmol) was added at room temperature. The reaction mixture was stirred at 35 °C for 1 hour and then concentrated under reduced pressure to give the target compound as a white foamy substance, which could be used in the next step of the reaction without further purification.

[0492] Step C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxopyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide

[0493] The target compound was prepared in a manner similar to that in Example 7 (step C), using (S)-3-((12-chloro)-14-azinyl)-5-methyl-7-(2-(6-oxopyrazin-1(6H)-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazon-4(5H)-one and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (hexane:ethyl acetate = 10:1 to 1:4 and dichloromethane:ethyl acetate = 20:1 to 1:4) to give the target compound (45% in two steps) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.96 (1H, d, J=7.3 Hz), 7.87(1H, s), 7.80 (1H, q, J=1.8 Hz), 7.46 (1H, s), 7.27-7.23 (1H, m), 7.22-7.19(1H, m), 7.08 (1H, d, J=9.1 Hz), 6.97-6.85 (4H, m), 6.77 (2H, dd, J=10.7, 2.5Hz), 4.89-4.83 (1H, m), 4.66-4.56 (3H, m), 4.39 (2H, td, J=5.7, 2.4 Hz), 4.23(1H, dd, J=11.2, 9.8 Hz), 3.81 (2H, s), 3.40 (3H, s). MS: m / z=533.1 [M+H]⁺.

[0494] Example 51: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxo-5-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide

[0495]

[0496] Step A: tert-butyl(S)-(5-methyl-4-oxo-7-(2-(6-oxo-5-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0497] The target compound was prepared in a manner similar to that of Example 50 (Step A), using (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl methanesulfonate (intermediate 14) and 4-(trifluoromethyl)pyrazine-3(2H)-one. The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 20:1 to 8:1) to give the target compound (63%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.92 (1H, d, J=3.7 Hz), 7.55 (1H, d, J=4.1 Hz), 7.03 (1H, dd, J=7.3,1.8 Hz), 6.72-6.70 (2H, m), 5.46 (1H, d, J=7.3 Hz), 4.67-4.56 (3H, m), 4.49(1H, dd, J=9.6, 7.3 Hz), 4.40 (2H, t, J=5.5 Hz), 4.08 (1H, dd, J=11.0, 9.6Hz), 3.36 (3H, s), 1.39 (9H, s).

[0498] Step B: (S)-3-amino-5-methyl-7-(2-(6-oxo-5-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one

[0499] The target compound was prepared in a manner similar to that in Example 50 (step B) using tert-butyl(S)-(5-methyl-4-oxo-7-(2-(6-oxo-5-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)carbamate. The crude product was used directly in the next reaction without further purification.

[0500] Step C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxo-5-(trifluoromethyl)pyridazine-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide

[0501] The target compound was prepared in a manner similar to that in Example 7 (step C), using (S)-3-amino-5-methyl-7-(2-(6-oxo-5-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrone-4(5H)-one and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 20:1 to 12:1) to give the target compound (44% in two steps) as a white foamy substance. ¹H-NMR (400MHz, CDCl3): δ 7.96 (1H, d, J=7.3 Hz), 7.93 (1H, d, J=4.1 Hz), 7.87 (1H, s), 7.55 (1H, d, J=3.7 Hz), 7.47 (1H, s), 7.28-7.22 (1H, m), 7.09 (1H, q, J=3.2Hz), 6.96-6.85 (3H, m), 6.78-6.75 (2H, m), 4.89-4.82 (1H, m), 4.65-4.61 (3H,m), 4.44-4.40 (2H, m), 4.24 (1H, dd, J=11.0, 9.6 Hz), 3.81 (2H,s), 3.40 (3H,s). MS: m / z=601.1 [M+H]⁺.

[0502] Example 52: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxo-4-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide

[0503]

[0504] Step A: tert-butyl(S)-(5-methyl-4-oxo-7-(2-(6-oxo-4-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0505] The target compound was prepared in a manner similar to that of Example 50 (Step A), using (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl methanesulfonate (intermediate 14) and 5-(trifluoromethyl)pyrazine-3(2H)-one. The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 20:1 to 9:1) to give the target compound (78%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.96 (1H, d, J=2.1 Hz), 7.21 (1H, d, J=0.9 Hz), 7.04 (1H, d, J=8.7Hz), 6.73-6.69 (2H, m), 5.45 (1H, d, J=7.3 Hz), 4.63-4.58 (3H, m), 4.50 (1H,dd, J=9.4, 7.5 Hz), 4.36 (2H, t, J=5.5 Hz), 4.09 (1H, dd, J=11.0, 9.6 Hz), 3.37 (3H, s), 1.39 (9H, s).

[0506] Step B: (S)-3-amino-5-methyl-7-(2-(6-oxo-4-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one

[0507] The target compound was prepared in a manner similar to that in Example 50 (Step B) using tert-butyl(S)-(5-methyl-4-oxo-7-(2-(6-oxo-4-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)carbamate. The crude product was used directly in the next reaction without further purification.

[0508] Step C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxo-4-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide

[0509] The target compound was prepared in a manner similar to that in Example 7 (step C), using (S)-3-amino-5-methyl-7-(2-(6-oxo-4-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrone-4(5H)-one and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 20:1 to 12:1) to give the target compound (17% in two steps) as a white foamy substance. ¹H-NMR (400MHz, CDCl3): δ 7.96 (2H, q, J=2.4 Hz), 7.87 (1H, s), 7.46 (1H, s), 7.26-7.21(2H, m), 7.10 (1H, dd, J=7.8, 1.4 Hz), 6.96-6.85 (3H, m), 6.76-6.74 (2H, m), 4.91-4.84 (1H, m), 4.66-4.60 (3H, m), 4.39 (2H, t, J=5.3 Hz), 4.24 (1H, dd, J=11.3, 9.7 Hz), 3.81 (2H, s), 3.40 (3H, s). MS: m / z=601.1 [M+H]⁺.

[0510] Example 53: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxo-3-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide

[0511]

[0512] Step A: tert-butyl(S)-(5-methyl-4-oxo-7-(2-(6-oxo-3-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0513] The target compound was prepared in a manner similar to that of Example 50 (Step A), using (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl methanesulfonate (intermediate 14) and 6-(trifluoromethyl)pyrazine-3(2H)-one. The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 20:1 to 9:1) to give the target compound (51%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.47 (1H, d, J=9.6 Hz), 7.04 (2H, t, J=9.1 Hz), 6.71 (2H, dd, J=11.2, 2.5 Hz), 5.46 (1H, d, J=7.3 Hz), 4.63-4.56 (3H, m), 4.50 (1H, dd, J=9.6, 7.3 Hz), 4.38 (2H, td, J=5.5, 1.9 Hz), 4.08 (1H, dd, J=10.9, 9.7 Hz), 3.36 (3H, s), 1.39 (9H, s).

[0514] Step B: (S)-3-amino-5-methyl-7-(2-(6-oxo-3-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one

[0515] The target compound was prepared in a manner similar to that in Example 50 (step B), using tert-butyl(S)-(5-methyl-4-oxo-7-(2-(6-oxo-3-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)carbamate. The crude product was used directly in the next reaction without further purification.

[0516] Step C: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxo-3-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide

[0517] The target compound was prepared in a manner similar to that in Example 7 (step C), using (S)-3-amino-5-methyl-7-(2-(6-oxo-3-(trifluoromethyl)pyrazin-1(6H)-yl)ethoxy)-2,3-dihydrobenzo[b][1,4]oxazapyrone-4(5H)-one and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 20:1 to 9:1) to give the target compound (50% in two steps) as a white foamy substance. ¹H-NMR (400MHz, CDCl3): δ 7.96 (1H, d, J=7.3 Hz), 7.87 (1H, s), 7.48-7.45 (2H, m), 7.30-7.22 (1H, m), 7.10-7.04 (2H, m), 6.96-6.85 (3H, m), 6.77-6.74 (2H, m), 4.89-4.82 (1H, m), 4.66-4.59 (3H, m), 4.42-4.39 (2H, m), 4.24 (1H, dd, J=11.0,10.1 Hz), 3.81 (2H, s), 3.40 (3H, s). MS: m / z=601.0 [M+H]⁺.

[0518] Example 54: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-methoxy-6-oxopyrazin-1(6H)-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide

[0519]

[0520] Step A: tert-butyl(S)-(7-(2-(4-methoxy-6-oxopyrazin-1(6H)-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)carbamate

[0521] The target compound was prepared in a manner similar to that of Example 50 (Step A), using (S)-2-((3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl methanesulfonate (intermediate 14) and 5-methoxypyrazine-3(2H)-one. The crude product was purified by SiO2 column chromatography (hexane:ethyl acetate = 10:1 to 1:2) to give the target compound (75%) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ7.59 (1H, d, J=2.8 Hz), 7.02 (1H, d, J=8.8 Hz), 6.74-6.69 (2H, m), 6.14 (1H,d, J=2.4 Hz), 5.46 (1H, d, J=6.8 Hz), 4.64-4.44 (4H, m), 4.31 (2H, t, J=5.4Hz), 4.12-4.05 (1H, m), 3.80 (3H, s), 3.36 (3H, s), 1.38 (9H, s).

[0522] Step B: (S)-3-amino-7-(2-(4-methoxy-6-oxopyrazin-1(6H)-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyro-4(5H)-one hydrochloride

[0523] The target compound was prepared in a manner similar to that in Example 50 (step B), using tert-butyl(S)-(7-(2-(4-methoxy-6-oxopyrazin-1(6H)-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)carbamate. The crude product was used directly in the next reaction without further purification.

[0524] Step C: (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-methoxy-6-oxopyrazin-1(6H)-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide

[0525] The target compound was prepared in a manner similar to that in Example 7 (step C), using (S)-3-amino-7-(2-(4-methoxy-6-oxopyrazin-1(6H)-yl)ethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]oxazapyrone-4(5H)-one hydrochloride and 4-(3-fluorobenzyl)-1H-pyrazole hydrochloride (intermediate 2). The crude product was purified by SiO2 column chromatography (dichloromethane:ethyl acetate = 5:1 to 1:4) to give the target compound (30% yield in two steps) as a white foamy substance. ¹H-NMR (400 MHz, CDCl3): δ 7.97 (1H, d, J=7.2 Hz), 7.87 (1H, s), 7.59 (1H, d, J=2.8Hz), 7.46 (1H, s), 7.28-7.22 (1H, m), 7.08 (1H, d, J=8.4 Hz), 7.00-6.85 (3H,m), 6.78-6.74 (2H, m), 6.14 (1H, d, J=3.2 Hz), 4.87 (1H, dt, J=11.1, 7.4 Hz), 4.64 (1H, dd, J=9.8, 7.4 Hz), 4.56-4.46 (2H, m), 4.34 (2H, t, J=5.6 Hz), 4.23 (1H, dd, J=11.2, 9.6 Hz), 3.81 (5H, m), 3.40 (3H, s). MS: m / z=563.1 [M+H]⁺.

[0526] Bioactivity

[0527] Cell culture:

[0528] Human colon cancer cells HT-29 (KCLB 30038), BV2 mouse microglia (donated by Dr. Sung Nak-Yun, Senior Researcher at KOREAPRIME PHARMACY CO., LTD.), and human microglia HMC3 (ATCC CRL-3304) were used. TM HT-29 cells were cultured in Roswell Park Memorial Institute (RPMI) 1640 medium, BV2 cells in Dulbecco's Modified Eagle's Medium (DMEM), and HMC3 cells in Minimum Essential Media Eagle (MEM), supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin mixture (Gibco). Cells were cultured at 37°C in a humidified 5% CO2 environment.

[0529] Cell necrosis and apoptosis assays for RIPK1 activity:

[0530] To determine the activity of RIPK1 inhibitors in necrotic apoptotic cells, HT-29 cells were treated with control DMSO, human TNFα (Peprotech, Rocky Hill, USA), SM-164 (Biovision, California, USA), and the pan-cysteine ​​inhibitor Z-VAD-FMK (Invivogen, San Diego, USA). Cells were pretreated with 20 μM Z-VAD-FMK. After 30 minutes, human TNFα (10 ng / ml), SM-164 (100 nM), and RIPK1 inhibitors (0.0001, 0.001, 0.01, 0.02, 0.05, 0.1, 1, 10 μM) were added for 24 hours. Cell viability was measured using a Cell Counting Kit 8 (CCK-8) (Dong-in, Seoul, Korea).

[0531] Immunoblotting:

[0532] The bioactivity of RIPK1 inhibitor compounds was evaluated by measuring their inhibitory effects on 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 min, human TNFα (20 ng / ml), SM-164 (100 nM), and RIPK1 inhibitors (0.1, 1, 10 nM) were added to serum-free medium and treated for 7 h. Cells were then sonicated using ice-cold lysis buffer containing 25 mM HEPES (pH 7.6), 150 mM NaCl, 1% NP40, 1% sodium deoxycholate, 0.1% SDS, and a mixture of protease inhibitors (Bimake, Houston, USA). Cells were then centrifuged at 15,000 rpm at 4°C for 5 min. After determining the supernatant protein concentration using the BCA method (Thermo Fisher Scientific, Waltham, USA), the supernatant was mixed with LDS sample buffer and heated at 70°C for 10 minutes (Invitrogen, California, USA). The sample was then separated by SDS-PAGE and transferred to a PVDF membrane, where it was detected with anti-phospho-RIPK1, anti-phospho-RIPK3, and anti-phospho-MLKL antibodies (Cell Signaling Technology, Danvers, USA) and β-actin (Proteintech, Rosemont, USA). Subsequently, HRP-labeled anti-rabbit antibody (Cell Signaling Technology, Danvers, USA) and anti-mouse IgG were used for color development using the Super Signal West dura kit (Pierce). The membrane was placed in an image analyzer (Imagequant, LAS 500, GE Healthcare), and images were acquired using software (Image Reader LAS500).

[0533] Inflammatory cytokines:

[0534] Total RNA was analyzed using PureLink. TMRNA extraction and purification were performed using a mini RNA kit (Thermo Fisher Scientific, Waltham, USA) according to the manufacturer's instructions. Reverse transcription was performed using an AccuPower CycleScript RTPreMix (dT20) (Bioneer, Daejeon, Korea). cDNA synthesis was performed using a SimpliAmp ThermalCycler (Applied Biosystems, Carlsbad, CA) with 12 cycles of 15°C for 30 seconds, 42°C for 4 minutes, and 55°C for 30 seconds, followed by heat inactivation at 95°C for 5 minutes. qPCR was performed using a SYBR Green PCRMaster Mix (Thermo Fisher Scientific, Waltham, USA) on a QuantStudio 3 (Applied Biosystems, Carlsbad, CA). PCR conditions were 95°C for 10 minutes, followed by 40 cycles (95°C for 15 seconds, 60°C for 30 seconds). Relative mRNA expression levels were calculated using the cycle threshold (Ct) method. GAPDH was used as an internal control gene. The PCR primers used in this study are listed in Table 1.

[0535] Table 1. PCR primers used in this study

[0536]

[0537] Table 2. Cell-based RIPK1 activity in HT29 cells

[0538] A: Below 10 nM, B: 10 to 50 nM, C: Above 50 nM

[0539] Example Necrotosis Phosphorylated RIPK1 (Ser166) 1 A A 2 A A 3 B A 4 A A 5 A A 6 A A 7 A A 8 B A 9 A A 10 A A 11 A A 12 A A 13 A A 14 A A 15 A A 16 A A 17 A A 18 A A 19 A A 20 A A 21 A A 22 A A 23 A A 24 A A 25 B B 26 A A 27 A A 28 A A 29 B A 30 A A 31 A A 32 A A 32 A A 33 A A 34 A A 35 A A 36 A B 37 A A 38 A A 39 A A 40 A A 41 A A 42 A A 45 A B 49 A A 50 A A

[0540] Industrial applicability

[0541] The novel compounds of this invention are capable of inhibiting RIP1 kinase activity and are therefore expected to be used to treat diseases and / or conditions associated with inflammation and / or necrotizing apoptosis.

Claims

1. A compound represented by Formula I, ， Or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, stereoisomer, or prodrug, wherein... R¹ is an N-alkylamide, pyridinone, pyridazinone, pyrazinone, pyrimidinone, 4- to 6-membered heterocyclic alkyl or 4- to 6-membered heterocyclic alkyl-C(O)-; The pyridinone, pyrazinone, pyrazinone, pyrimidinone, 4- to 6-membered heterocyclic alkyl or 4- to 6-membered heterocyclic alkyl-C(O)- may optionally be substituted with one or two substituents, wherein the substituents are independently selected from (C1-C4)alkyl, OH, (C1-C4)hydroxy, (C1-C4)alkoxy, halogen, cyano, NR³R 4 And oxygenation; L is O, -OCH2-, -OCH(CH3)-, -OCH2CH2-, -OCH2CH(OH)-, -OCH2CH2CH2-, -OCH2CH2CH(OH)-, -OCH2CH2CH(CH3)-, -OCH2CH2C(CH3)2-, -OCH2CH2CH2CH2- or -OCH2CH2CH2CH(OH)-; Each R² is independently H, methyl, CF3, halogen, or cyano; n is 1, 2, or 3; R³ and R 4 They are independently selected from H, aliphatic, heteroaliphatic, aromatic (including aryl and heteroaryl), or heterocyclic aliphatic, or together with the nitrogen atom to which they are attached to form a C3-6 membered heterocyclic group.

2. The compound according to claim 1, wherein the compound is: 4-(3-Fluorobenzyl)-N-((S)-5-methyl-4-oxo-7-(2-((S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; 4-(3-Fluorobenzyl)-N-((S)-5-methyl-4-oxo-7-(2-((R)-2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; N-((S)-7-(2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; N-((S)-7-((R)-4-(dimethylamino)-3-hydroxy-4-oxobutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; 4-(3-fluorobenzyl)-N-((S)-7-((R)-3-hydroxy-4-oxo-4-(pyrrolidone-1-yl)butoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; 4-(3-Fluorobenzyl)-N-((S)-7-((R)-3-hydroxy-4-morpholino-4-oxobutoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; N-((S)-7-(((3aS,4S,6aR)-2,2-dimethyltetrahydrofurano[3,4-d][1,3]dioxacyclopenten-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; N-((S)-7-(((2S,3R,4R)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; 4-(3-Fluorobenzyl)-N-((S)-7-(((2S,4R)-4-hydroxy-1-methylpyrrolidone-2-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; 4-(3-Fluorobenzyl)-N-((S)-5-methyl-7-(((R)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; 4-(3-Fluorobenzyl)-N-((S)-5-methyl-7-(((S)-1-methyl-5-oxopyrrolidone-2-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(N-methylacetamido)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(2-oxopyrrolidone-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; 4-(3-fluorobenzyl)-N-((S)-7-(2-((S)-3-hydroxy-2-oxopyrrolidone-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(4-methyl-3-oxopiperazin-1-yl)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(2-oxopyridin-1(2H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-((tetrahydro-2H-pyran-4-yl)oxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxytetrahydro-2H-pyran-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(7-(oxabutane-3-ylmethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(7-(2-(oxabutane-3-yl)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((3-methyloxabutan-3-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-N-(7-((3-ethyloxabutane-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(7-(2-(3-hydroxyoxabutane-3-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(piperidin-4-ylmethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-((1-methylpiperidin-4-yl)methoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(piperidin-4-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-(1-methylpiperidin-4-yl)ethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxypiperidin-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-hydroxy-1-methylpiperidin-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-N-(7-((1,1-dioxotetrahydro-2H-thion-4-yl)oxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-N-(7-((1,1-dioxotetrahydro-2H-thion-4-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-N-(7-(2-(1,1-dioxotetrahydro-2H-thion-4-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(3-(tetrahydro-2H-pyran-4-yl)propoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazol-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(7-((3-(hydroxymethyl)oxabutane-3-yl)methoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-N-(5-methyl-4-oxo-7-(2-(piperidin-1-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-imidazol-1-carboxamide; (S)-N-(7-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-N-(7-(2-(1,2-oxahexane-2-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-N-(7-(2-(1,1-dioxothiomorpholino)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethylazazobutylcyclo-1-carboxylic acid ester; (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl 3,3-difluoroazabutane-1-carboxylic acid ester; (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-7-yl)oxy)ethyl 3-hydroxy-3-methylazabutane-1-carboxylic acid ester; (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethylmorpholine-4-carboxylic acid ester; (S)-2-((3-(4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-7-yl)oxy)ethyl-4-hydroxy-4-methylpiperidine-1-carboxylic acid ester; (S)-N-(7-(2-(aziridin-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazono-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(7-(2-(3-hydroxy-3-methylazabutane-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazabutane-3-yl)-1H-pyrazole-1-carboxamide; (S)-N-(7-(2-(3,3-difluoroazabutane-1-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazaphen-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-N-(7-(2-(2-oxa-6-azaspiro[3.3]heptane-6-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxa-azaspiro-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-7-(2-morpholinylethoxy)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxopyridazin-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxo-5-(trifluoromethyl)pyridazine-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxo-4-(trifluoromethyl)pyridazine-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazapyro-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-(6-oxo-3-(trifluoromethyl)pyridazine-1(6H)-yl)ethoxy)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; (S)-4-(3-fluorobenzyl)-N-(7-(2-(4-methoxy-6-oxopyridazin-1(6H)-yl)ethoxy)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazon-3-yl)-1H-pyrazole-1-carboxamide; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein the compound is a compound that inhibits the activity of receptor-interacting protein kinase 1 (RIPK1).

4. A method for inhibiting RIPK1 enzyme in cells, comprising the step of contacting the cells with a compound of claim 1 or 2 sufficient to inhibit RIPK1 enzyme activity.

5. A method for alleviating or improving symptoms of a RIPK1-mediated disease or condition by inhibiting RIPK1 activity, comprising administering to a subject in need a therapeutically effective amount of a composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof, wherein the RIPK1-mediated disease or condition is a disease associated with inflammation and necrotic cell death.

6. Use of the compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof, in the preparation of a pharmaceutical composition for treating or alleviating the following diseases, including: inflammatory bowel disease (Crohn's disease and ulcerative colitis), psoriasis, retinal diseases (including age-related macular degeneration, diabetic retinopathy, glaucoma, retinal detachment, and retinitis pigmentosa), arthritis (including rheumatoid arthritis, spondyloarthritis, gout, osteoarthritis, and systemic onset juvenile idiopathic arthritis (SoJIA)), transplant rejection, organ transplantation in donors and recipients, multiple sclerosis, tumor necrosis factor receptor-related cycle syndrome, multiple organ dysfunction syndrome (MODS), thermal injury / burns, systemic inflammatory response syndrome (SIRS), radiation injury, radiotherapy, chemotherapy, pneumonia, hemorrhagic shock, trauma (including multiple injuries), traumatic brain injury, acute pancreatitis, and severe illness. Diseases, 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, colon resection, ischemia-reperfusion injury (including ischemia-reperfusion injury of solid organs), limb ischemia, intestinal ischemia, cardiac surgery requiring cardiopulmonary bypass. Autoimmune hepatitis, autoimmune hepatobiliary diseases, autoimmune ITP, allergic diseases, asthma, atopic dermatitis, type 1 diabetes, Wegener's granulomatosis, Behcet's disease, interleukin-1 converting enzyme-related fever syndrome, pancreatic cancer, metastatic pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, mesothelioma, melanoma, colorectal cancer, acute myeloid leukemia, metastasis, glioblastoma, breast cancer, gallbladder cancer, clear cell renal cell carcinoma, non-small cell lung cancer, or radiation-induced necrosis.

7. Use of the compound according to any one of claims 1 or 2, wherein the disease is Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's plus syndrome, tau proteinosis, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, progressive muscular atrophy, pseudobulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, multiple sclerosis, or demyelinating disease.

8. The method of claim 5, further comprising administering an effective amount of one or more therapeutic agents.

9. A pharmaceutical composition, characterized in that, Relieving or improving RIPK1-mediated disease or condition symptoms by inhibiting RIPK1 activity: a. An effective amount of the compound of any one of claims 1 or 2, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof; and b. One or more therapeutic agents, The RIPK1-mediated diseases or conditions mentioned above are selected from the following group: pancreatic cancer, lung cancer, colon cancer, gastric cancer, glioblastoma, melanoma, multiple sclerosis, psoriasis, colitis, rheumatoid arthritis, sepsis, renal and cerebral ischemia-reperfusion injury, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, dermatitis, and asthma.

10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is prepared for oral administration.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is in tablet or capsule form.

12. The pharmaceutical composition of claim 11, wherein the compound of claim 1 or 2 is used in an amount ranging from 0.001 to 1000 mg per kilogram of body weight per day.

13. The pharmaceutical composition of claim 12, wherein the compound of claim 1 or 2 is used in an amount ranging from 0.5 to 50 mg per kilogram of body weight per day.

14. The method of claim 5, wherein the compound inhibits programmed necrosis in cancer cells.

15. The method of claim 5, wherein the compound reduces the level of RIPK1 protein in microglia.

16. The method of claim 5, wherein the compound reduces the mRNA levels of TNF-α, IL-1β and IL-6 in microglia.

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