Fused ring heteroaryl compounds as RIPK1 inhibitors

Abstract

To provide inhibitors of RIPK1.SOLUTION: The invention provides novel substituted heterocyclic compounds represented by chemical formula I. [In the formula: R1 is H or optionally substituted C1-C6 alkyl; R2 and R3 are independently H, methyl, CF3, halogen, or cyano; X1 to X4 are independently CR4 or N; R4 is H, NH2, OH, OMe, halogen, cyano, or C1-C6 alkyl; and Z is CH2, NR1, O, or S.]SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a series of substituted heterocyclic compounds that are inhibitors of RIP1 kinase-mediated diseases or disorders and are used as therapeutic agents. [Background technology]

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

[0003] Necroptosis and RIP1 have provided critical checkpoints during embryonic development. Necroptosis and RIP1 activation represent important pathological mechanisms and may be associated with many human diseases and inflammation by mediating cell death. Necroptosis may also be associated with central nervous system (CNS) diseases, atherosclerosis, Huntington's disease, colitis, steatohepatitis, acute hepatitis, stroke, myocardial infarction, and pathogenic disorders of the intestinal epithelium and skin. Thus, necroptosis inhibitors play a crucial role in clinical drug development [12–14].

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

[0005] Therefore, the synthesis of potent selective inhibitors of RIP1 kinase could treat diseases, such as inflammation and necroptotic cell death

[20] . Recently, RIP1 kinase inhibitors have been developed that are structurally distinct from the necrostatin class of compounds [21-22].

[0006] The above cited references, each of which is incorporated herein by reference in its entirety: 1. Literature [Degterev, A., Hitomi, J., Germscheid, M., Ch’en, I., Korkina, O., Teng, X., Abbott, D., Cuny, G., Yuan, C., Wagner, G., Hedrick, S., Gerber, S., Lugovskoy, A. and Yuan, J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 4, 313 - 321 (2008)]. 2. Literature [Ofengeim, D. and Yuan, J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14, 727 - 736 (2013)].

[0007] 3. Literature [Shan, B., Pan, H., Najafov, A. and Yuan, J. Necroptosis in development and diseases. Genes Dev. 32, 327 - 340 (2018)]. 4. Literature [Vanden Berghe, T., Linkermann, A., Jouan - Lanhouet, S., Walczak, H. and Vandenabeele, P. Regulated necrosis: the expanding network of non - apoptotic cell death pathways. Nature reviews. Molecular cell biology. 15, 135 - 147 (2014)].

[0008] 5. Literature [Newton, K. RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends in cell biology. 25, 347 - 353 (2015)]. 6. Literature [de Almagro, M.C. and Vucic, D. Necroptosis: Pathway diversity and characteristics. Semin Cell Dev Biol. 39, 56 - 62 (2015)].

[0009] 7. Literature [O’Donnell, M.A., Legarda-Addison, D., Skountzos, P., Yeh, W.C. and Ting, A.T. Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr Biol. 17, 418 - 424 (2007)]. 8. Literature [Feoktistova, M., Geserick, P., Kellert, B., Dimitrova, D.P., Langlais, C., Hupe, M., Cain, K., MacFarlane, M., Hacker, G. and Leverkus, M. cIAPs block Ripoptosome formation, a RIP1 / caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Molecular cell. 43, 449 - 463 (2011)].

[0010] 9. Literature [Bertrand, M.J., Milutinovic, S., Dickson, K.M., Ho, W.C, Boudreault, A., Durkin, J., Gillard, J.W., Jaquith, J.B., Morris, S.J. and Barker, P.A. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 30, 689 - 700 (2008)]. 10. Literature [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)].

[0011] 11. Literature [Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X. and Wang, X. Mixed lineage kinase domain- like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 148, 213-227 (2012)]. 12. Literature [Zhao, J., Jitkaew, S., Cai, Z., Choksi, S., Li, Q., Luo, J. and Liu, Z.G. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proceedings of the National Academy of Sciences of the United States of America. 109, 5322-5327 (2012)].

[0012] 13. Literature [Sun, L., Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W., Lei, X. and Wang, X. Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase. Cell. 148, 213 - 227 (2012)]. 14. Literature [Linkermann, A. and Green, D. R. Necroptosis. The New England journal of medicine. 370, 455 - 465 (2014)].

[0013] 15. Literature [Degterev, A., Huang, Z., Boyce, M., Li, Y., Jagtap, P., Mizushima, N., Cuny, G. D., Mitchison, T. J., Moskowitz, M. A. and Yuan, J. Chemical Inhibitor of Nonapoptotic Cell Death with Therapeutic Potential for Ischemic Brain Injury. Nat. Chem. Biol. 1, 112 - 119 (2005)]. 16. Literature [Linkermann, A., Brasen, J. H., Himmerkus, N., Liu, S., Huber, T. B., Kunzendorf, U. and Krautwald, S. Rip1 (Receptor-Interacting Protein Kinase 1) Mediates Necroptosis and Contributes to Renal Ischemia / Reperfusion Injury. Kidney Int. 81, 751 - 761 (2012)].

[0014] 17. Literature [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 Necroptosis Involving RIPK1 / RIPK3-Dependent PARP-1 Activation. Cell Death Differ. 19, 2003-2014 (2012)]. 18. Literature [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 Terminal Ileitis. Nature. 477, 335-339 (2011)].

[0015] 19. Literature [Zhu, S., Zhang, Y., Bai, G. and Li, H. Necrostatin-1 Ameliorates Symptoms in R6 / 2 Transgenic Mouse Model of Huntington’s Disease. Cell. Death Dis. 2, e115 (2011)]. 20. Literature [Newton, K., Dugger, D. L., Wickliffe, K. E., Kapoor, N., de Almagro, M. C, Vucic, D., Komuves, L., Ferrando, R. E., French, D. M., Webster, J., Roose-Girma, M., Warming, S. and Dixit, V. M. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science. 343, 1357 - 1360 (2014)].

[0016] 21. Literature [Harris, P. A., Bandyopadhyay, D., Berger, S. B., Campobasso, N., Capriotti, C. A., Cox, J. A., Dare, L., Finger, J. N., Hoffman, S. J., Kahler, K. M., Lehr, R., Lich, J. D., Nagilla, R., Nolte, R. T., Ouellette, M. T., Pao, C. S., Schaeffer, M. C, Smallwood, A., Sun, H. H., Swift, B. A., Totoritis, R. D., Ward, P., Marquis, R. W., Bertin, J. and Gough, P. J. Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS medicinal chemistry letters. 4, 1238 - 1243 (2013)]. 22. Literature [Najjar, M., Suebsuwong, C, Ray, SS, Thapa, RJ, Maki, JL, Nogusa, S., Shah, S., Saleh, D., Gough, PJ, Bertin, J., Yuan, J., Balachandran, S., Cuny, GDand Degterev, A. Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1.Cell Rep.24,1850-1860(2015)]. Summary of the Invention [Problem to be solved by the invention]

[0017] The technical problem that the present invention aims to solve is to provide novel compounds of formula I. Another technical problem to be solved by the present invention is to provide a novel compound of formula I having inhibitory activity against RIPK1.

[0018] Yet another technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising the compound, a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a salt thereof. Yet another technical problem to be solved by the present invention is to provide a pharmaceutical composition for treating and / or preventing diseases associated with RIP1 kinase. [Means for solving the problem]

[0019] To achieve the above object, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof: [ka] During the ceremony, R 1is H or optionally substituted C1-C6 alkyl; R 2 and R 3 are each independently H, methyl, CF3, halogen, or cyano; X 1 , X 2 , X 3 and X 4 are each independently 4 or N; R 4 is H, NH2, OH, OMe, halogen, cyano or C1-C6 alkyl; Z is CH2, NR 1 , O or S.

[0020] Compounds of formula I further include absolute configuration compounds of formulae IIa and IIb, or salts thereof: [ka] [ka] During the ceremony, X 1 , X 2 , X 3 and X 4 are each independently 4 or N; R 4 is H, NH2, OH, OMe, halogen, cyano or C1-C6 alkyl; R 2 and R 3 are each independently H, methyl, CF3, halogen, or cyano.

[0021] The compounds of the present invention are inhibitors of RIP1 kinase and are therefore of use in the treatment of inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, osteoarthritis, and systemic onset juvenile idiopathic arthritis (SoJIA)), transplant rejection, organ transplants (donor and recipient), multiple sclerosis, tumor necrosis factor receptor-associated periodic syndrome, multiple organ dysfunction syndrome (MODS), burns / burns, systemic inflammatory response syndrome (SIRS), radiation injury, radiation therapy, chemotherapy, pneumonia, hemorrhagic shock, trauma (including polytrauma), traumatic brain injury, acute pancreatitis, critical illness (general), sepsis, septic shock, Stevens-Johnson syndrome, syndrome, toxic epidermal necrolysis, stroke, heat stroke, stroke-associated pneumonia, multiple organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), intestinal obstruction, cirrhosis, surgery, major abdominal surgery, abdominal aortic aneurysm repair, colectomy, ischemia-reperfusion injury (including ischemia-reperfusion injury of solid organs (gastrointestinal tract, brain, liver, kidneys) and limb ischemia), intestinal ischemia (small and large intestine), cardiac surgery requiring cardio-pulmonary bypass, autoimmune hepatitis, autoimmune hepatobiliary disease, autoimmune ITP, Huntington's disease, Alzheimer's disease, ALS, Parkinson's disease, Lewy body disease, spinal muscular atrophy, allergic diseases, asthma, atopic dermatitis, type 1 diabetes, Wegener's granulomatosis granulomatosis, Behcet's disease, interleukin-1 converting enzyme associated febrile syndrome, pancreatic cancer, metastatic adenocarcinoma of the pancreas, pancreatic ductal adenocarcinoma, mesothelioma, melanoma, colorectal cancer, acute myeloid leukemia, metastases, glioblastoma, breast cancer, gallbladder cancer, clear cell renal carcinoma, non-small cell lung cancer and radiation induced necrosis.

[0022] In another aspect, the present invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula I, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises a pharma- ceutically acceptable carrier, adjuvant, and / or excipient. In some embodiments, the composition may contain at least one of preservatives, absorption retardants, fillers, binders, adsorbents, buffers, disintegrants, solubilizers, and other carriers, adjuvants, and / or excipients as inactive ingredients. The composition may be formulated by methods well known in the art.

[0023] In some aspects, the present invention relates to a method of treating a disease in an individual comprising administering to said individual a therapeutically effective amount of a composition comprising a compound of Formula I, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof. In another aspect, the present invention relates to a method of treating a disorder in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof. In another aspect, the invention relates to a method of treating a disorder in a human comprising administering to said human a therapeutically effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof.

[0024] In other embodiments, the RIP1 kinase-mediated disease or disorder is described herein and includes inflammatory bowel disease (including Crohn's disease and ulcerative colitis), psoriasis, retinal detachment, retinitis pigmentosa, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, osteoarthritis, and systemic onset juvenile idiopathic arthritis (SoJIA)), transplant rejection, organ transplants (donor and recipient), multiple sclerosis, tumor necrosis factor receptor-associated periodic syndrome, multiple organ dysfunction syndrome (MODS), burns / burns, systemic inflammatory response syndrome (SIRS), radiation injury, radiation therapy, chemotherapy. , pneumonia, hemorrhagic shock, trauma (including multiple trauma), traumatic brain injury, acute pancreatitis, critical illness (general), sepsis, septic shock, Stevens-Johnson syndrome, toxic epidermal necrolysis, stroke, heat stroke, stroke-associated pneumonia, multiple organ dysfunction syndrome (MODS), acute respiratory distress syndrome (ARDS), ileus, cirrhosis, surgery, major abdominal surgery, abdominal aortic aneurysm repair, colectomy, ischemia-reperfusion injury (including ischemia-reperfusion injury of solid organs (gastrointestinal tract, brain, liver, kidneys) and limb ischemia), intestinal ischemia (small and large intestine), cardio-pulmonary bypass Autoimmune diseases include cardiac surgery requiring cardiac bypass, autoimmune hepatitis, autoimmune hepatobiliary disease, autoimmune ITP, Huntington's disease, Alzheimer's disease, ALS, Parkinson's disease, Lewy body disease, spinal muscular atrophy, allergies, asthma, atopic dermatitis, type 1 diabetes, Wegener's granulomatosis, Behçet's disease and interleukin-1 converting enzyme associated febrile syndrome.

[0025] In another aspect, the present invention relates to a method for treating certain RIP1 kinase-mediated diseases or disorders in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt, ester, prodrug, solvate, e.g., hydrate, polymorph, or tautomer thereof, the diseases or disorders being pancreatic cancer, metastatic adenocarcinoma of the pancreas, pancreatic ductal adenocarcinoma, mesothelioma, melanoma, colorectal cancer, acute myeloid leukemia, metastasis, glioblastoma, breast cancer, gallbladder cancer, renal clear cell carcinoma, non-small cell lung cancer, and radiation-induced necrosis.

[0026] In another aspect, the invention relates to a method of treating a disorder or condition modulated by RIP1 kinase in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I, or a pharma- ceutically acceptable salt, ester, prodrug, solvate, such as a hydrate, polymorph, or tautomer thereof, effective to modulate said cascade.Appropriate dosages for a particular patient can be determined by those skilled in the art using known methods.

[0027] In another aspect, the invention relates to the use of a compound of formula I, or a pharma- ceutically acceptable salt, ester, prodrug, solvate, e.g., hydrate, polymorph, or tautomer thereof, in the manufacture of a pharmaceutical composition, which can be used for the treatment of a disorder or condition modulated by RIP1 kinase in a mammal, including a human.

[0028] In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. In further or additional embodiments, the pharmaceutical composition is in the form of tablets, capsules, pills, powders, sustained release formulations, solutions, and suspensions. In some embodiments, the pharmaceutical composition is in a form suitable for parenteral injection, e.g., a sterile solution, suspension, or emulsion; a form suitable for topical administration, e.g., an ointment or cream, or a form suitable for rectal administration, e.g., a suppository. In further or additional embodiments, the pharmaceutical composition is in a unit dosage form suitable for single administration of a precise dosage. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.001 to about 1000 mg / kg body weight / day. In further or additional embodiments, the amount of the compound of formula I ranges from about 0.5 to about 50 mg / kg body weight / day.

[0029] In another aspect, the present invention relates to a process for preparing a compound of Formula I, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer, or prodrug thereof. Effect of the Invention

[0030] In the present invention, a novel compound is provided for inhibiting RIPK1. In this regard, the present invention can be used to treat and / or prevent various RIP1 kinase-mediated diseases or disorders, and can be used as a therapeutic agent. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized. While preferred embodiments of the present invention have been shown and described herein, such embodiments are provided by way of example only. It should be understood that various alternatives to the embodiments of the present invention described herein may be utilized in practicing the present invention. Those skilled in the art will recognize that various modifications, changes, and substitutions are possible without departing from the invention. The following claims define the scope of the aspects of the present invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0032] The section titles used in this application are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including, without limitation, patents, patent applications, articles, books, manuals, and papers, are expressly incorporated by reference in their entirety in this application for any purpose.

[0033] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and published documents referred to throughout the entire disclosure of this application are incorporated by reference in their entirety. In the event that there are multiple definitions for terms in this application, those in this section prevail. When referring to a URL or other such identifier or address, it is understood that the identifier may be changed, and information may come and go, particularly on the Internet, but that equivalent information may be found by searching the Internet or other appropriate reference source. Any reference thereto demonstrates the availability and public dissemination of the information.

[0034] The general description above and the detailed description below are merely exemplary and explanatory and are not intended to be limiting of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It should be noted that, as used in the specification and the appended claims, the singular includes plural referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" and other forms such as "include", "includes", and "included" is not limited. Similarly, the use of the term "comprising" and other forms such as "comprise", "comprises", and "comprised" is not limited.

[0035] Definitions of standard chemical terms are given in the literature [Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THReferences to the subject matter may be found in reference texts including, for example, "Mass Spectroscopy, NMR, HPLC, IR and UV / Vis Spectroscopy and pharmacology," ed. Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, IR and UV / Vis spectroscopy and pharmacology within the skill of the art are employed. Unless specific definitions are provided, the nomenclature used in conjunction with analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein, and the laboratory procedures and techniques thereof, are well known in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, dosage forms, and delivery and treatment to patients. For example, kits may be used according to manufacturer's instructions, or reactions and purification techniques may be performed as commonly practiced in the art, or as described herein. The techniques and procedures may be performed generally by conventional methods well known in the art, and as described in the various general and more specific references cited and discussed throughout this specification. Throughout the specification, groups and substituents thereof may be selected by one of skill in the art to provide stable moieties and compounds.

[0036] Unless otherwise indicated, the use of general chemical terms, such as, but not limited to, "alkyl," "amine," and "aryl" includes their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.

[0037] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where said event or circumstance occurs and cases where it does not. For example, "optionally substituted alkyl" means any one of "alkyl" or "substituted alkyl" as defined below. Also, an optionally substituted group may be unsubstituted (e.g., CH2CH3), fully substituted (e.g., CF2CF3), monosubstituted (e.g., CH2CH2F), or substituted to a level somewhere between fully 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 any substitution or substitution pattern that makes the group sterically impractical and / or synthetically infeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which are again defined to include optionally substituted alkyl groups, potentially continuing endlessly). Thus, any substitutes described should be understood to generally have a maximum molecular weight of about 1,000 daltons, more typically about 500 daltons or less (unless polymeric substitutes, e.g., polypeptides, polysaccharides, polyethylene glycols, DNA, RNA, etc., are expressly contemplated).

[0038] As used herein, C1-Cn includes C1-C2, C1-C3, ...C1-Cn. By way of example only, a group designated as "C1-C4" indicates that there are 1 to 4 carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms, as well as the ranges C1-C2 and C1-C3. Thus, by way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. As provided herein, numerical ranges such as "1-10" refer to the respective integers within the given range; for example, "1-10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0039] The term "heteroatom" or "hetero", as used herein, alone or in combination, refers to atoms other than carbon and hydrogen. Heteroatoms are independently selected from among oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where there are two or more heteroatoms, the two or more heteroatoms may be the same as each other, or all or a portion of the two or more heteroatoms may be different from each other.

[0040] The term "alkyl," as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more 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, t-butyl, n-pentyl, isopentyl, neo-pentyl, tert-amyl, and hexyl, and long chain alkyl groups such as heptyl, octyl, etc. As indicated in this application, "C1-C6 alkyl" or "C 1_6 A numerical range such as "alkyl" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also includes the cases of the term "alkyl" without any numerical range indicated.

[0041] The term "aliphatic," as used herein, alone or in combination, refers to an optionally substituted, straight or branched chain, acyclic, saturated, partially unsaturated, or fully unsaturated non-aromatic hydrocarbon. Thus, said term generically includes alkyl, alkenyl, and alkynyl groups.

[0042] The terms "cyclic", "annular", "ring" and "-membered ring" as used herein, alone or in combination, refer to any covalently closed structure, including alicyclic, heterocyclic, aromatic, heteroaromatic and polycyclic fused or non-fused ring systems as described herein. The ring may be optionally substituted. The ring may form part of a fused ring system. The term "-membered" is meant to define the number of skeletal atoms that constitute the ring. Thus, by way of example only, cyclohexane, pyridine, pyran and pyrimidine are 6-membered rings, and cyclopentane, pyrrole, tetrahydrofuran and thiophene are 5-membered rings.

[0043] The term "cycloalkyl" as used herein, alone or in combination, refers to an optionally substituted, saturated, hydrocarbon monoradical ring containing from 3 to about 15 ring carbon atoms, or from 3 to about 10 ring carbon atoms, but which may contain additional non-ring carbon atoms as substitutents (e.g., methylcyclopropyl).

[0044] Non-limiting examples of "cycloalkyl" include azinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, quinolizinyl, and the like. The term also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides.

[0045] The term "aromatic" as used herein refers to a planar, cyclic or polycyclic ring moiety having a delocalized electron system containing 4n+2n electrons, where n is an integer. Aromatic rings can be formed by 5, 6, 7, 8, 9 or more than 9 atoms. Aromatics may be optionally substituted and may be monocyclic or fused-ring polycyclic. The term "aromatic" encompasses both rings containing all carbon (e.g., phenyl) and rings containing one or more heteroatoms (e.g., pyridine).

[0046] As used herein, the term "RIP1 kinase inhibitor" refers to an inhibitor that inhibits RIP1 kinase activity. 50 "IC" refers to a compound that exhibits an IC of about 100 μM or less, or about 50 μM or less, when measured in a kinase assay as generally described herein. 50 " is the concentration of inhibitor at which the activity of the enzyme is reduced to half-maximal level. The compounds described in this application have been found to exhibit inhibition against RIPK1. The compounds of the present invention have an IC 50 preferably exhibits a value of about 10 μM or less, more preferably about 5 μM or less, even more preferably about 1 μM or less, and most preferably about 200 nM or less, when measured in the kinase assay described herein.

[0047] As used herein, the terms "selective," "selectively," or "selectivity" refer to the ability of an IC 50 Values ​​refer to compounds of the invention that are lower (eg, at least 2-fold, 5-fold, 10-fold or more lower) when compared to any other enzyme. The terms "subject," "patient," or "individual," as used herein in reference to an individual suffering from a disorder, condition, or the like, encompass mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates, e.g., chimpanzees, and other ape and monkey species; farm animals, e.g., cows, horses, sheep, goats, pigs; livestock, e.g., rabbits, dogs, and cats; laboratory animals, including rodents, e.g., rats, mice, and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0048] The terms "treat", "treating" or "treatment" and other grammatical equivalents as used herein are intended to include alleviating, attenuating, or ameliorating the symptoms of a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying metabolic cause of the symptoms, inhibiting the disease or condition, e.g., arresting the onset of the disease or condition, reducing the disease or condition, inducing regression of the disease or condition, reducing pathology caused by the disease or condition, or arresting the symptoms of the disease or condition, including prophylactic methods. The terms further include achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disease being treated. A therapeutic benefit is also achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the patient, even though the patient may still suffer from the underlying disease. For prophylactic benefit, the compositions may be administered to patients at risk of developing a particular disease or to patients who experience one or more of the physiological symptoms of the disease, and even in the absence of a diagnosis of such a disease.

[0049] The terms "effective amount", "therapeutically effective amount" or "pharmaceutical effective amount" as used herein refer to a sufficient amount of at least one formulation or compound to be administered that reduces to some extent one or more of the symptoms of the disease or condition to be treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other favorable alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in the disease. For any individual, an appropriate "effective" amount may be determined using techniques such as a dose escalation study.

[0050] As used herein, the terms "administer", "administering", "administration" and the like refer to methods that can be used to allow the delivery of a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein (e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.). In a preferred embodiment, the compounds and compositions described herein are administered orally.

[0051] The term "acceptable" as used herein means in relation to a dosage form, composition or ingredient, that does not have any lasting adverse effects on the general health of the subject being treated. As used herein, the term "pharmaceutically acceptable" refers to a relatively non-toxic material, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compounds described herein, i.e., the material may be administered to an individual without interacting in a deleterious way with any of the components of the composition contained therein or eliciting undesired biological effects.

[0052] The term "pharmaceutical composition" as used herein refers to a biologically active compound optionally mixed with at least one pharma- ceutically acceptable chemical component, including, but not limited to, a carrier, stabilizer, diluent, dispersant, suspending agent, thickener, and / or excipient. The term "carrier" as used herein refers to relatively nontoxic chemical compounds or formulations that facilitate the incorporation of a compound into cells or tissues.

[0053] The term "agonist" as used herein also refers to a molecule, such as a compound, a drug, an enzyme activator, or a hormone modulator, that enhances the activity of another molecule or the activity of a receptor site. The term "antagonist" as used herein also refers to a molecule, such as a compound, drug, enzyme inhibitor, or hormone modulator, that reduces or prevents the action of another molecule or the activity of a receptor site.

[0054] The term "modulate" as used herein means to directly or indirectly interact with a target to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or enhancing the activity of the target. The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, the interactions of an agonist and antagonist.

[0055] The term "pharmaceutical acceptable salts" as used herein refers to salts that retain the biological effectiveness of the free acids and bases of a particular compound and are biologically or otherwise desirable. The compounds described herein may have acidic or basic groups and may thus be reacted with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutical acceptable salts. Such salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral or organic acid or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, hydroxybutyrate ... The salts of these amines include chloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undeconate and xylenesulfonate. Other acids, such as oxalic acid, although not themselves pharma- ceutically acceptable, may be used to prepare salts useful as intermediates in obtaining the compounds of the invention and their pharma- ceutically acceptable acid addition salts (see, for example, Berge et al., J. Pharm. Sci. 1977, 66, 1-19).The compounds described herein, which may contain free acid groups, may also be reacted with a suitable base, such as hydroxides, carbonates or bicarbonates of pharma-ceutically acceptable metal cations, ammonia, or pharma-ceutically acceptable organic primary, secondary or tertiary amines. Representative alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should also be understood that the compounds described herein include the quaternization of any basic nitrogen-containing groups they may contain. Water- or oil-soluble or dispersible products may be obtained by the quaternization. See, for example, Berge et al., supra.

[0056] The term "solvate" as used herein refers to a combination of a compound of the present invention with a solvent molecule formed by solvation. In some circumstances, the solvate refers to a hydrate. That is, the solvent molecule is a water molecule, and the combination of a compound of the present invention with water forms a hydrate.

[0057] The terms "polymorph" or "polymorphs" as used herein refer to compounds of the present invention that exist in different crystal lattice forms. The term "ester" as used herein refers to a derivative of a compound of the present invention derived from an oxoacid group and a hydroxyl group, either one of which may be present in a compound of the present invention. The term "tautomers" as used herein refers to isomers that are readily interconverted from the compounds of the present invention, for example, by migration of a hydrogen atom or proton.

[0058] The term "pharmaceutically acceptable derivative or prodrug" as used herein refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of the invention, which upon administration to a recipient, can directly or indirectly provide a compound of the invention or a pharmaceutically active metabolite or residue thereof. Particularly suitable derivatives or prodrugs are those which increase the bioavailability of a compound of the invention (e.g., by making an orally administered compound more readily absorbed into the blood) or improve delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) when the compound of the invention is administered to a patient.

[0059] Pharmaceutically acceptable prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of quaternary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts, and sulfonate esters. Various forms of prodrugs are widely known in the art. See, for example, the literature [Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396]; the literature [Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bund-gaard, Ed., 1991, Chapter 5, p. 113-191]; and the literature [Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38], each of which is incorporated herein by reference. Prodrugs described herein include, but are not limited to, the following groups and combinations of these groups; amine derived prodrugs: hydroxy prodrugs include, but are not limited to, acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters and disulfide-containing esters.

[0060] The terms "enhance" or "enhancing" as used herein mean to increase or prolong either in potency or duration of a desired effect. Thus, in the context of enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong either in potency or duration of the effect of other therapeutic agents on a system. The term "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0061] The terms "pharmaceutical combination," "administering additional therapy," and "administering additional therapeutic agent," as used herein, refer to pharmaceutical therapies resulting from mixing or combining more than one active ingredient, and include both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that at least one of the compounds described herein and at least one co-agent are both administered to a patient at the same time in the form of a single entity or single dosage. The term "non-fixed combination" means that at least one of the compounds described herein and at least one co-agent are administered to a patient as separate entities at the same time, in combination, or sequentially at various time limit intervals, whereby the administration provides the patient's body with an effective level of two or more compounds. These also apply to cocktail therapy, e.g., the administration of three or more active ingredients.

[0062] As used herein, the terms "co-administered," "co-administered," and grammatical equivalents are meant to encompass administration of selected therapeutic agents to a patient, including treatment regimens in which formulations are administered by the same or different routes of administration, or at the same or different times. In some embodiments, the compounds described herein are co-administered with other formulations. These terms encompass administration of two or more formulations to an animal such that both formulations and / or their metabolites are present in the animal at the same time. These include co-administration in separate compositions, administration over time in separate compositions, and / or administration in a composition in which both formulations are present. Thus, in some embodiments, the compounds of the present invention and the other formulations are administered as a single composition.

[0063] The term "metabolite" as used herein refers to a derivative of a compound that is formed when the compound is metabolized. The term "active metabolite" as used herein refers to a biologically active derivative of a compound that is formed when the compound is metabolized.

[0064] The term "metabolize" as used herein refers to all of the processes by which a particular substance is transformed by an organism, including but not limited to hydrolysis and enzyme-catalyzed reactions. Thus, enzymes can generate specific structural modifications to compounds. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, while uridine diphosphate-glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Additional information on metabolism can be obtained from the literature [The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996)].

[0065] NMR spectra were recorded in CDCl3, DMSO-d6 or CD3OD solutions in 5 mm od tubes (Norell, Inc. 507-HP) at 30 °C. 1 Analytes were collected on a Varian VNMRS-400 at 400 MHz for H. Chemical shifts (δ) are relative to tetramethylsilane (TMS=0.00 ppm) and are expressed in ppm. LC / MS were taken on an Ion-trap Mass Spectrometer on a FINNIGAN Thermo or ISQ EC, Thermo Fisher U3000 RSLC (Column: YMC Hydrosphere (C18, O4.6×50 mm, 3 μm, 120 Å, 40° C.) operated in ESI(+) ionization mode; flow rate=1.0 ml / min. Mobile phase=0.01% heptafluorobutyric acid (HFBA) and 1.0% isopropyl alcohol (IPA) in water or CH3CN.

[0066] General synthetic scheme for pyrazole intermediates [ka]

[0067] Intermediate 1: 4-benzyl-1H-pyrazole [ka]

[0068] Step A: tert-Butyl 4-benzyl-1H-pyrazole-1-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (4.50 g, 15.3 mmol), K3PO4 (9.74 g, 45.9 mmol) and (bromomethyl)benzene (2.62 g, 15.3 mmol) in a mixture of DME (30 mL), EtOH (7.5 mL) and H2O (7.5 mL) was added Pd(PPh3)4 (2.30 g, 1.99 mmol) at room temperature. The reaction mixture was stirred for 16 h at 55 °C. After dilution with water, the mixture was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether:EtOAc = 10:1) to give tert-butyl 4-benzyl-1H-pyrazole-1-carboxylate (2.20 g, 55%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.98 (1H, s), 7.65 (1H, s), 7.14-7.12 (2H, m), 6.99-6.95 (3H, m), 3.70 (2H, s), 1.50 (9H, s).

[0069] Step B: 4-Benzyl-1H-pyrazole To a solution of tert-butyl 4-benzyl-1H-pyrazole-1-carboxylate (2.20 g, 8.52 mmol) in EtOAc (5.0 mL) was added HCl (3.0 M in EtOAc, 8.5 mL, 26 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The precipitated solid was collected by filtration, washed with EtOAc, and dried under vacuum to provide 4-benzyl-1H-pyrazole (1.18 g, 71%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ13.0(2H,brs),7.91(2H,s),7.31-7.27(2H,m),7.22-7.17(3H,m),3.80(2H,s).

[0070] Intermediate 2: 4-(3-fluorobenzyl)-1H-pyrazole [ka]

[0071] Step A: tert-Butyl 4-(3-fluorobenzyl)-1H-pyrazole-1-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.50 g, 5.10 mmol), K3PO4 (3.25 g, 15.3 mmol) and 1-(bromomethyl)-3-fluorobenzene (964 mg, 5.10 mmol) in a mixture of DME (20 mL), EtOH (5.0 mL) and H2O (5.0 mL) was added Pd(PPh3)4 (766 mg, 0.663 mmol) at room temperature. The reaction mixture was stirred for 16 h at 55 °C. After dilution with water, the mixture was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether: EtOAc = 5: 1) to give tert-butyl 4-(3-fluorobenzyl)-1H-pyrazole-1-carboxylate (600 mg, 43%) as a yellow oil. LC-MS: m / z = 177 [M + H-Boc] + .

[0072] Step B: 4-(3-fluorobenzyl)-1H-pyrazole To a solution of tert-butyl 4-(3-fluorobenzyl)-1H-pyrazole-1-carboxylate (600 mg, 2.17 mmol) in EtOAc (2.0 mL) was added HCl (3.0 M in EtOAc, 2.0 mL, 6.00 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo. The residue was purified by Prep-HPLC (neutral) to provide 4-(3-fluorobenzyl)-1H-pyrazole (133 mg, 35%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ12.60 (1H, s), 7.45-7.28 (3H, m), 7.06-6.96 (3H, m), 3.80 (2H, s).

[0073] Intermediate 3: 4-(3-chlorobenzyl)-1H-pyrazole hydrochloride [ka]

[0074] Step A: tert-Butyl 4-(3-chlorobenzyl)-1H-pyrazole-1-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.50 g, 5.10 mmol), K3PO4 (3.25 g, 15.3 mmol) and 1-(bromomethyl)-3-chlorobenzene (1.05 g, 5.10 mmol) in a mixture of DME (20 mL), EtOH (5.0 mL) and H2O (5.0 mL) was added Pd(PPh3)4 (766 mg, 0.66 mmol) at room temperature. The reaction mixture was stirred at 55 °C for 16 h and cooled to room temperature. After dilution with water, the mixture was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether: EtOAc = 5: 1) to give tert-butyl 4-(3-chlorobenzyl)-1H-pyrazole-1-carboxylate (500 mg, 33%) as a yellow oil. LC-MS: m / z = 193 [M + H-Boc] + .

[0075] Step B: 4-(3-chlorobenzyl)-1H-pyrazole hydrochloride To a solution of tert-butyl 4-(3-chlorobenzyl)-1H-pyrazole-1-carboxylate (500 mg, 1.71 mmol) in EtOAc (3.0 mL) was added HCl (3.0 M in EtOAc, 3.0 mL, 9.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo. The residue was purified by prep-HPLC (neutral) to provide 4-(3-chlorobenzyl)-1H-pyrazole, which was converted to the corresponding HCl salt form by adding a few drops of HCl (1 M in water). The mixture was lyophilized and dried under vacuum to provide 4-(3-chlorobenzyl)-1H-pyrazole hydrochloride (92 mg, 24%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ10.75(2H,br),7.76(2H,s),7.33-7.28(2H,m),7.26-7.19(2H,m),3.84(2H,s).

[0076] Intermediate 4: 4-(3-methylbenzyl)-1H-pyrazole hydrochloride [ka]

[0077] Step A: tert-Butyl 4-(3-methylbenzyl)-1H-pyrazole-1-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.00 g, 3.40 mmol), K3PO4 (2.17 g, 10.2 mmol) and 1-(bromomethyl)-3-methylbenzene (629 mg, 3.40 mmol) in a mixture of DME (20 mL), EtOH (5.0 mL) and H2O (5.0 mL) was added Pd(PPh3)4 (511 mg, 0.442 mmol) at room temperature. The reaction mixture was stirred at 55 °C for 16 h and cooled to room temperature. After dilution with water, the mixture was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether:EtOAc=5:1) to provide tert-butyl 4-(3-methylbenzyl)-1H-pyrazole-1-carboxylate (500 mg, 54%) as a yellow oil. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,s),7.65(1H,s),7.14-7.12(1H,m),6.99-6.95(3H,m),3.70(2H,s),2.26(3H,s),1.50(9H,s).

[0078] Step B: 4-(3-Methylbenzyl)-1H-pyrazole hydrochloride To a solution of tert-butyl 4-(3-methylbenzyl)-1H-pyrazole-1-carboxylate (500 mg, 1.84 mmol) in EtOAc (2.0 mL) was added HCl (3.0 M in EtOAc, 2.0 mL, 6.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The precipitated solid was collected by filtration, washed with EtOAc, and dried under vacuum to provide 4-(3-methylbenzyl)-1H-pyrazole hydrochloride (297 mg, 78%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ13.21(2H,br),7.91(2H,s),7.19-7.15(1H,m),7.04-6.99(3H,m),3.80(2H,s),2.26(3H,s).

[0079] Intermediate 5: 4-(3-(trifluoromethyl)benzyl)-1H-pyrazole hydrochloride [ka]

[0080] Step A: tert-Butyl 4-(3-(trifluoromethyl)benzyl)-1H-pyrazole-1-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.50 g, 5.10 mmol), K3PO4 (3.25 g, 15.3 mmol) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (1.22 g, 5.10 mmol) in a mixture of DME (20 mL), EtOH (5.0 mL) and H2O (5.0 mL) was added Pd(PPh3)4 (766 mg, 0.66 mmol) at room temperature. The reaction mixture was stirred at 55 °C for 16 h and cooled to room temperature. After dilution with water, the mixture was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether: EtOAc = 5: 1) to give tert-butyl 4-(3-(trifluoromethyl)benzyl)-1H-pyrazole-1-carboxylate (800 mg, 48%) as a yellow oil. LC-MS: m / z = 227 [M + H-Boc] + .

[0081] Step B: 4-(3-(trifluoromethyl)benzyl)-1H-pyrazole hydrochloride To a solution of tert-butyl 4-(3-fluorobenzyl)-1H-pyrazole-1-carboxylate (800 mg, 2.45 mmol) in EtOAc (3.0 mL) was added HCl (3.0 M in EtOAc, 3.0 mL, 9.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After concentration in vacuum, the residue was purified by prep-HPLC (neutral) to provide 4-(3-fluorobenzyl)-1H-pyrazole, which was treated with a few drops of HCl (1 M in water) and then lyophilized and dried under vacuum to provide 4-(3-(trifluoromethyl)benzyl)-1H-pyrazole hydrochloride (72 mg, 11%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ8.50 (2H, brs), 7.69-7.68 (2H, s), 7.56-7.53 (4H, m), 3.92 (2H, s).

[0082] Intermediate 6: 3-((1H-pyrazol-4-yl)methyl)benzonitrile [ka]

[0083] Step A: tert-Butyl 4-(3-cyanobenzyl)-1H-pyrazole-1-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (2.00 g, 6.80 mmol) in DME (56 mL), EtOH (14 mL) and H2O (14 mL) were added 4-(bromomethyl)benzonitrile (1.33 g, 6.80 mmol), K3PO4 (4.32 g, 20.4 mmol) and Pd(PPh3)4 (1.01 g, 0.880 mmol) at room temperature. The reaction mixture was stirred for 20 h at 55 °C. After evaporation of DME and EtOH, the residue was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to provide tert-butyl 4-(3-cyanobenzyl)-1H-pyrazole-1-carboxylate (1.80 g, 93%) as a colorless oil. LC-MS: m / z=184 (M+H-Boc)+.

[0084] Step B: 3-((1H-pyrazol-4-yl)methyl)benzonitrile To a solution of tert-butyl 4-(3-cyanobenzyl)-1H-pyrazole-1-carboxylate (1.80 g, 6.36 mmol) in DCM (10 mL) was added TFA (5.0 mL, 65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 20 h. After neutralization with saturated aqueous Na2CO3, the resulting mixture was extracted twice with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to provide 3-((1H-pyrazol-4-yl)methyl)benzonitrile (101 mg, 9%) as a white solid. 1H-NMR (400MHz, DMSO-d6+D2O): δ7.65-7.62(2H,m),7.60-7.58(1H,m),7.52-7.48(3H,m),3.89(2H,s).

[0085] Intermediate 7: 4-(4-fluorobenzyl)-1H-pyrazole [ka]

[0086] Step A: tert-Butyl 4-(3-cyanobenzyl)-1H-pyrazole-1-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (860 mg, 2.92 mmol), K3PO4 (1.86 g, 8.76 mmol) and 1-(bromomethyl)-4-fluorobenzene (552 mg, 2.92 mmol) in a mixture of DME (12 mL), EtOH (3.0 mL) and H2O (3.0 mL) was added Pd(PPh3)4 (438 mg, 0.379 mmol) at room temperature. The reaction mixture was stirred for 16 h at 55 °C. After evaporation of DME and EtOH, the residue was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether:EtOAc = 1:5) to provide tert-butyl 4-(4-fluorobenzyl)-1H-pyrazole-1-carboxylate (500 mg, 62%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ7.81(1H,s),7.53(1H,s),7.16-7.12(2H,m),7.00-6.95(2H,m),3.79(2H,s),1.63(9H,s).

[0087] Step B: 4-(4-Fluorobenzyl)-1H-pyrazole To a solution of tert-butyl 4-(4-fluorobenzyl)-1H-pyrazole-1-carboxylate (400 mg, 1.45 mmol) in EtOAc (5.0 mL) was added HCl (3.0 M in EtOAc, 1.5 mL, 4.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After concentration in vacuo, the residue was purified by Prep-HPLC (neutral) to provide 4-(4-fluorobenzyl)-1H-pyrazole (182 mg, 71%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ12.58 (1H, s), 7.41 (2H, s), 7.25-7.21 (2H, m), 7.11-7.05 (2H, m), 3.76 (2H, s).

[0088] Intermediate 8: 4-(4-fluorobenzyl)-1H-pyrazole [ka]

[0089] Step A: tert-Butyl 4-(3-cyanobenzyl)-1H-pyrazole-1-carboxylate To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (2.00 g, 6.80 mmol) in a mixture of DME (56 mL), EtOH (14 mL) and H2O (14 mL) were added 4-(bromomethyl)benzonitrile (1.33 g, 6.80 mmol), K3PO4 (4.32 g, 20.4 mmol) and Pd(PPh3)4 (1.02 g, 0.88 mmol) at room temperature. The reaction mixture was stirred for 20 h at 55 °C. After evaporation of DME and EtOH, the residue was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to provide tert-butyl 4-(4-fluorobenzyl)-1H-pyrazole-1-carboxylate (1.50 g, 78%) as an off-white solid. LC-MS: m / z=184 (M+H-Boc)+.

[0090] Step B: 4-(4-Fluorobenzyl)-1H-pyrazole To a solution of tert-butyl 4-(4-cyanobenzyl)-1H-pyrazole-1-carboxylate (1.50 g, 5.30 mmol) in DCM (10 mL) was added TFA (5.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 h. After neutralization with saturated aqueous Na2CO3, the resulting mixture was extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to provide 4-((1H-pyrazol-4-yl)methyl)benzonitrile (182 mg, 18%) as a white solid. 1 H-NMR (400MHz, DMSO-d6+D2O): δ7.73(2H,d,J=8.4Hz),7.45(2H,br),7.41(2H,d,J=8.4Hz),3.87(2H,s).

[0091] [ka]

[0092] Intermediate 9: (S)-3-Amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one [ka]

[0093] Step A: (S)-2-((tert-butoxycarbonyl)amino)-3-(2-nitrophenoxy)propanoic acid To a suspension of NaH (60 wt%, 4.90 g, 122 mmol) in anhydrous DMF (150 mL) was slowly added a solution of N-Boc-L-serine (10.0 g, 48.7 mmol) in anhydrous DMF at 0 °C under N2 atmosphere. When gas evolution ceased, 1-fluoro-2-nitrobenzene (5.10 mL, 48.7 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 20 h and quenched with 0.5 M aqueous HCl. The mixture was extracted three times with EtOAc. The combined organic layers were washed with brine and water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether: EtOAc = 5:1 → DCM: MeOH = 20:1) to give (S)-2-((tert-butoxycarbonyl) amino)-3-(2-nitrophenoxy) propanoic acid (10.0 g, 62%) as a brown solid. LC-MS: m / z = 271.0 [M + H-tBu] +

[0094] Step B: (S)-3-(2-aminophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid A suspension of (S)-2-((tert-butoxycarbonyl)amino)-3-(2-nitrophenoxy)propanoic acid (9.00 g, 27.6 mmol) and Pd / C (10 wt%, 900 mg) in MeOH (50 mL) was stirred at room temperature under hydrogen atmosphere (1 atm) for 20 h. After filtration through a 0.45 um PTFE needle filter (MeOH flushed), the filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether: EtOAc = 1:1) to provide (S)-3-(2-aminophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (4.00 g, 48%) as an off-white solid. LC-MS: m / z = 297.1 [M + H] + .

[0095] Step C: (S)-tert-Butyl (4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate To a solution of (S)-3-(2-aminophenoxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (4.00 g, 13.5 mmol) in DMSO (20 mL) was added DIPEA (5.23 g, 40.5 mmol) followed by HATU (5.13 g, 13.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. After diluting with H2O (300 mL), the mixture was extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether: EtOAc = 5:1) to provide (S)-tert-butyl (4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (2.00 g, 53%) as an off-white solid. 1 H-NMR (400MHz, DMSO-d6): δ9.91 (1H, s), 7.14-7.07 (5H, m), 4.33-4.27 (3H, m), 1.35 (9H, s).

[0096] Step D: (S)-3-Amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one To a solution of (S)-tert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (2.00 g, 7.19 mmol) in EtOAc (5.0 mL) was added HCl (5 M in EtOAc, 10 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo to provide (S)-3-amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one (1.30 g, 84%) as a brown solid. 1 H-NMR (400MHz, DMSO-d6): δ10.50(1H,s),8.73(3H,s),7.14(4H,s),4.68-4.63(1H,m),4.45-4.40(1H,m),4.30-4.26(1H,m).

[0097] Intermediate 10: (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride [ka]

[0098] Step A: (S)-tert-Butyl (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate To a solution of (S)-tert-butyl (4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (2.00 g, 7.19 mmol) in DMF (20 mL) was added dropwise at room temperature under N2 atmosphere followed by Cs2CO3 (3.20 g, 9.90 mmol) followed by MeI (1.20 g, 8.50 mmol). The reaction mixture was stirred at room temperature for 3 h. After quenching with cold H2O (100 mL), the precipitated solid was collected by filtration and washed with water. The solid was purified by reverse phase column (MeCN:H2O) on C18 to provide (S)-tert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (1.20 g, 57%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ7.47-7.45(1H,m),7.32-7.13(4H,m),4.37-4.27(3H,m),3.28(3H,s),1.34(9H,s).

[0099] Step B: (S)-3-Amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride To a solution of (S)-tert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (1.20 g, 4.10 mmol) in EtOAc (5.0 mL) was added HCl (5 M in EtOAc, 10 mL, 50 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo to provide (S)-3-amino-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (820 mg, 87%) as a brown solid. 1H-NMR(400MHz,MeOH-d4):δ8.74(3H,s),7.53-7.50(1H,m),7.36-7.25(3H,m ),4.67-4.63(1H,m),4.48(1H,t,J=11.2Hz),4.21-4.16(1H,m),3.34(3H,s).

[0100] [ka]

[0101] Intermediate 11: (S)-3-amino-6-fluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 2,2,2-trifluoroacetate [ka]

[0102] Step A: (S)-2-(tert-butoxycarbonylamino)-3-(3-fluoro-2-nitrophenoxy)propanoic acid To a suspension of NaH (55 wt%, 823 mg, 18.9 mmol) in DMF (10 mL) was slowly added a solution of N-Boc-L-serine (1.55 g, 7.54 mmol) in DMF (5.0 mL) at 0° C. The mixture was stirred for 1 h at 0° C. After addition of a solution of 1,3-difluoro-2-nitrobenzene (1.00 g, 6.29 mmol) in DMF (5.0 mL) at 0° C., the reaction mixture was stirred for 4 h at 0° C. After quenching with 0.5 M aqueous HCl at 0° C., the mixture was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 1:1 to 1:3) to provide (S)-2-(tert-butoxycarbonylamino)-3-(3-fluoro-2-nitrophenoxy)propanoic acid (1.20 g, 55%) as a yellow oil. 1H-NMR (400MHz, CDCl3): δ9.38(1H,brs),7.40(1H,q,J=7.6Hz),6.87-6.82(2H,m),5.54(1H,d,J=7. 6Hz), 4.73(1H,d,J=8.4Hz),4.58(1H,dd,J=9.2,2.4Hz),4.41(1H,dd,J=9.0,2.6Hz),1.45(9H,s).

[0103] Step B: (S)-3-(2-amino-3-fluorophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid A suspension of (S)-2-(tert-butoxycarbonylamino)-3-(3-fluoro-2-nitrophenoxy)propanoic acid (1.60 g, 4.65 mmol) and Pd / C (10 wt%, 495 mg, 0.465 mmol) in MeOH (15 mL) was stirred at room temperature under H2 atmosphere (1 atm) for 18 h. After filtration through a Celite pad, washing with MeOH, the filtrate was concentrated in vacuo to provide (S)-3-(2-amino-3-fluorophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (1.46 g, 100%) as a yellow oil. 1 H-NMR(400MHz,DMSO-d6):δ7.54(1H,d,J=8.4Hz),6.68-6.61(2H,m),6.48-6.42(1H,m),4.8 0(2H,brs),4.43-4.41(1H,m),4.32-4.28(1H,m),3.98(1H,dd,J=9.2,2.8Hz),1.36(9H,s).

[0104] Step C: tert-Butyl 6-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate To a solution of (S)-3-(2-amino-3-fluorophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (1.40 g, 4.45 mmol) in DMF (15 mL) was added DIPEA (2.33 mL, 13.4 mmol) followed by HATU (2.54 g, 6.68 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After quenching with water, the mixture was extracted with EtOAc. The separated organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane: EtOAc = 4: 1) to provide (S)-tert-butyl 6-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (328 mg, 25%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.35(1H,s),7.08(1H,q,J=8.4Hz),6.93-6.87(2H,m),5.52(1H,s),4.70-4.62(2H,m),4.23(1H,t,J=10.0Hz),1.44(9H,s).

[0105] Step D: (S)-3-Amino-6-fluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA To a solution of tert-butyl 6-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (178 mg, 0.601 mmol) in DCM (1.2 mL) was added TFA (0.93 mL, 12 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C. and then concentrated in vacuo to provide (S)-3-amino-6-fluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA as a brown oil. 1 H-NMR(400MHz,DMSO-d6):δ10.5(1H,s),8.44(2H,s),7.26-7.20(1H,m),7 .17-7.13(1H,m),7.09-7.06(1H,m),4.56-4.53(1H,m),4.49-4.46(2H,m).

[0106] Intermediate 12: (S)-3-amino-6-fluoro-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA [ka]

[0107] Step A: Preparation of (S)-tert-butyl 6-fluoro-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate To a solution of (S)-tert-butyl 6-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (146 mg, 0.493 mmol) in DMF (4.9 mL) was added K2CO3 (82.0 mg, 0.591 mmol) and MeI (0.0370 mL, 0.591 mmol) at room temperature. The reaction mixture was stirred for 18 h at room temperature. After dilution with water, the mixture was extracted with EtOAc. The separated organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 6:1) to provide (S)-tert-butyl 6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (95 mg, 62%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.21(1H,q,J=7.6Hz),7.01-6.96(2H,m),5.51(1H,d,J=6.8Hz),4.71- 7.64(1H,m),4.55(1H,t,J=8.6Hz),4.15(1H,t,J=10.6Hz),3.35(3H,d,J=2.4Hz),1.40(9H,s).

[0108] Step B: (S)-3-Amino-6-fluoro-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA To a solution of (S)-tert-butyl 6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (63.0 mg, 0.203 mmol) in DCM (2.0 mL) was added TFA (0.31 mL, 4.1 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C. and then concentrated in vacuo to provide (S)-3-amino-butyl 6-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate TFA (62 mg, 100%) as a brown oil. 1 H-NMR (400MHz, DMSO-d6): δ8.41(2H,s),7.40(1H,q,J=7.5Hz),7.28(1H,t,J=9.4Hz),7.14(1H,d,J=8.4Hz),4.49-4.42(3H,m),3.25(3H,d,J=2.0Hz).

[0109] [ka]

[0110] Intermediate 13: 3-Amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA [ka]

[0111] Step A: (S)-2-(tert-butoxycarbonylamino)-3-(3,5-difluoro-2-nitrophenoxy)propanoic acid To a suspension of NaH (55 wt%, 1.55 g, 35.6 mmol) in DMF (20 mL) was slowly added a solution of N-Boc-L-serine (3.48 g, 16.9 mmol) in DMF (5.0 mL) at −10° C. The mixture was stirred for 1 h at −10° C. After a solution of 1,3,5-trifluoro-2-nitrobenzene (3.00 g, 16.9 mmol) in DMF (5.0 mL) was added at −10° C., the reaction mixture was stirred for 2 h at −10° C. After quenching with 0.5 M aqueous HCl at −10° C., the mixture was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 5:1 → 1:1) to provide (S)-2-(tert-butoxycarbonylamino)-3-(3,5-difluoro-2-nitrophenoxy)propanoic acid (4.60 g, 75%) as a yellow oil. 1 H-NMR (400MHz, CDCl3): δ6.64-6.59(2H,m),5.49(1H,d,J=7.2Hz),4.74(1H, d,J=7.2Hz),4.55(1H,d,J=6.8Hz),4.40(1H,dd,J=9.6,3.2Hz),1.46(9H,s).

[0112] Step B: (S)-3-(2-amino-3,5-difluorophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid A suspension of (S)-2-(tert-butoxycarbonylamino)-3-(3,5-difluoro-2-nitrophenoxy)propanoic acid (500 mg, 1.38 mmol) and Pd / C (5 wt%, 100 mg) in EtOAc (20 mL) was stirred at room temperature under H2 atmosphere (1 atm) for 6 h. The reaction mixture was filtered through a Celite pad and washed with EtOAc (40 mL) to give a solution of (S)-3-(2-amino-3,5-difluorophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (460 mg, 100%) in EtOAc (40 mL), which was used in the next step without concentration. LC-MS: m / z=332.78 [M+H] + .

[0113] Step C: tert-Butyl 6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate To a solution of (S)-3-(2-amino-3,5-difluorophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (460 mg, 1.38 mmol) in EtOAc (40 mL) was added DIPEA (723 μL, 4.14 mmol) followed by HATU (787 mg, 2.07 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h. After concentration in vacuo, the residue was purified by column chromatography on SiO2 (hexane:EtOAc=4:1→3:1) to provide tert-butyl 6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (300 mg, 69%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.22(1Θ,brs),6.71-6.66(2H,m),5.52(1H,brs),4.69-4.61(2H,m),4.25(1H,t,J=9.6Hz),1.44(9H,s).

[0114] Step D: 3-Amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA To a solution of tert-butyl 6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (60 mg, 0.191 mmol) in DCM (5.0 mL) was added TFA (294 μL, 3.82 mmol) at 0° C. The mixture was stirred at room temperature for 2 h and concentrated in vacuo to provide 3-amino-6,8-difluoro-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA (60 mg, 96%) as a yellow oil. LC-MS: m / z=214.93 [M+H] + .

[0115] Intermediate 14: 3-Amino-6,8-difluoro-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA [ka]

[0116] Step A: (S)-tert-Butyl 6,8-difluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate A mixture of tert-butyl 6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (150 mg, 0.477 mmol) and Cs2CO3 (187 mg, 0.573 mmol) in DMF (4.0 mL) was stirred for 5 min at 0° C. After addition of a solution of MeI (36.0 μL, 0.573 mmol) in DMF (1.0 mL), the reaction mixture was stirred for 1 h at 0° C. and then further stirred for 1 h at room temperature. After quenching with water, the mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 2:1) to provide (S)-tert-butyl 6,8-difluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (120 mg, 77%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ6.80-6.73(2H,m),5.51(1H,d,J=6.0Hz),4.70-4.64(1H,m),4 .54(1H,dd,J=9.2,6.8Hz),4.17(1H,t,J=10.4Hz),3.32(3H,d,J=2.4Hz),1.41(9H,s).

[0117] Step B: 3-Amino-6,8-difluoro-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA To a solution of tert-butyl 6,8-difluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (80 mg, 0.244 mmol) in DCM (5.0 mL) was added TFA (375 μL, 4.87 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to provide 3-amino-6,8-difluoro-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one TFA (83 mg, 100%) as a yellow oil. 1 H-NMR (400MHz, CDCl3): δ6.80-6.73(2H,m),5.51(1H,d,J=6.0Hz),4.70-4.64(1H,m),4 .54(1H,dd,J=9.2,6.8Hz),4.17(1H,t,J=10.4Hz),3.32(3H,d,J=2.4Hz),1.41(9H,s).

[0118] [ka]

[0119] Intermediate 15: (S)-3-Amino-8-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride [ka]

[0120] Step A: 2-Fluoro-4-methoxy-1-nitrobenzene [ka] To a solution of 3-fluoro-4-nitrophenol (1.00 g, 6.37 mmol) in acetone (20 mL) was added K2CO3 (4.40 g, 31.8 mmol) followed by MeI (0.796 mL, 12.7 mmol). The reaction mixture was stirred at 50 °C overnight. After dilution with DCM, the mixture was filtered through a Celite pad and washed with DCM. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1N aqueous NaOH, dried over Na2SO4, filtered and concentrated in vacuo to provide 2-fluoro-4-methoxy-1-nitrobenzene (900 mg, 83%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ8.10 (1H, t, J=8.8Hz), 6.79-6.72 (2H, m), 3.91 (3H, s).

[0121] Step B: 2. Preparation of (S)-2-(tert-butoxycarbonylamino)-3-(5-methoxy-2-nitrophenoxy)propanoic acid To a suspension of NaH (55 wt%, 213 mg, 4.87 mmol) in anhydrous DMF was slowly added a solution of N-Boc-L-serine (500 mg, 2.44 mmol) in anhydrous DMF (10 mL) at 0° C. The mixture was stirred at room temperature for 30 min and cooled to 0° C. After addition of a solution of 2-fluoro-4-methoxy-1-nitrobenzene (417 mg, 2.44 mmol) in anhydrous DMF (5.0 mL) at 0° C., the reaction mixture was stirred for 2 h at 0° C. After quenching with 0.5 M aqueous HCl, the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 4:1 → 1:1) to provide (S)-2-(tert-butoxycarbonylamino)-3-(5-methoxy-2-nitrophenoxy)propanoic acid (400 mg, 46%) as a yellow oil. LC-MS: m / z = 257.05 [M + H] + .

[0122] Step C: (S)-3-(2-amino-5-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid A suspension of (S)-2-(tert-butoxycarbonylamino)-3-(5-methoxy-2-nitrophenoxy)propanoic acid (400 mg, 1.12 mmol) and Pd / C (5 wt%, 50 mg) in MeOH (10 mL) was stirred at room temperature under H2 atmosphere (1 atm) for 2 h. After filtration through a Celite pad, washing with MeOH, the filtrate was concentrated in vacuo to provide (S)-3-(2-amino-5-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (200 mg, 55%) as a black solid. LC-MS: m / z=326.92 [M+H] + .

[0123] Step D: (S)-tert-Butyl 8-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate To a solution of (S)-3-(2-amino-5-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (200 mg, 0.613 mmol) in DMSO (3.0 mL) was added DIPEA (321 μL, 1.84 mmol) followed by HATU (233 mg, 0.613 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 EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane: EtOAc = 2: 1) to provide (S)-tert-butyl 8-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (100 mg, 53%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.43(1H,brs),7.07(1H,d,J=8.8Hz),6.70(1H,dd,J=8.8,2.8Hz),5.45(1H,d ,J=6.8Hz),4.73-4.66(1H,m),4.61(1H,t,J=9.6Hz),4.16(1H,t,J=10.0Hz),3.78(3H,s),1.42(9H,s).

[0124] Step E: (S)-tert-Butyl 8-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate To a solution of (S)-tert-butyl 8-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (100 mg, 0.324 mmol) in DMF (5.0 mL) was added Cs2CO3 (106 mg, 0.324 mmol) followed by a solution of MeI (20.3 μL, 0.324 mmol) in DMF (1.0 mL) at 0 °C. The reaction mixture was stirred for 4 h at 0 °C and then for 1 h at room temperature. After quenching with ice water, the mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 3:1) to provide (S)-tert-butyl 8-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (100 mg, 96%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.09(1H,d,J=8.4Hz),6.74(1H,d,J=8.4Hz),6.69(1H,s),5.50(1H,d,J=6.0Hz) ,4.69-4.63(1H,m),4.57(1H,t,J=9.2Hz),4.15(1H,t,J=10.0Hz),3.80(3H,s),3.36(3H,s),1.40(9H,s).

[0125] Step F: (S)-3-Amino-8-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride To a solution of (S)-tert-butyl 8-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (50.0 mg, 0.155 mmol) in MeOH (3.0 mL) was added HCl (2 M in diethyl ether, 1.55 mL, 3.10 mmol) at 0° C. The reaction mixture was stirred at room temperature for 6 h and then concentrated in vacuo to provide (S)-3-amino-8-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (40 mg, 100%) as a white solid. LC-MS: m / z=223.05 [M+H] + .

[0126] [ka]

[0127] Intermediate 16: (S)-3-Amino-7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride [ka]

[0128] Step A: 1-Fluoro-4-methoxy-2-nitrobenzene To a solution of 4-fluoro-3-nitrophenol (1.00 g, 6.37 mmol) in acetone (30 mL) was added K2CO3 (4.40 g, 31.8 mmol) followed by MeI (0.796 mL, 12.7 mmol) at room temperature. The reaction mixture was stirred at 50 °C overnight. After dilution with DCM, the mixture was filtered through a celite pad and washed with DCM. The filtrate was concentrated in vacuo. The residue was diluted with EtOAc, washed with 1N aqueous NaOH, dried over Na2SO4, filtered and concentrated in vacuo to provide 1-fluoro-4-methoxy-2-nitrobenzene (1.00 g, 92%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.54-7.52(1H,m) 7.23-7.14(2H,m),3.86(3H,s).

[0129] Step B: 2. (S)-2-(tert-butoxycarbonylamino)-3-(4-methoxy-2-nitrophenoxy)propanoic acid To a suspension of NaH (55 wt%, 460 mg, 10.54 mmol) in anhydrous DMF (20 mL) was slowly added a solution of N-Boc-L-serine (1.00 g, 4.87 mmol) in anhydrous DMF (5.0 mL) at 0° C. The mixture was stirred at room temperature for 30 min and cooled to 0° C. After addition of a solution of 1-fluoro-4-methoxy-2-nitrobenzene (900 mg, 5.26 mmol) in anhydrous DMF (5.0 mL) at 0° C., the reaction mixture was stirred for 2 h at 0° C. After quenching with 0.5 M aqueous HCl, the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 4:1 → 1:1) to give (S)-2-(tert-butoxycarbonylamino)-3-(4-methoxy-2-nitrophenoxy)propanoic acid (900 mg, 48%) as a yellow oil. LC-MS: m / z = 257.01 [M + H] + .

[0130] Step C: (S)-3-(2-amino-4-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid A suspension of (S)-2-(tert-butoxycarbonylamino)-3-(4-methoxy-2-nitrophenoxy)propanoic acid (350 mg, 0.982 mmol) and Pd / C (5 wt%, 50 mg) in MeOH (10 mL) was stirred at room temperature under H2 atmosphere (1 atm) for 2 h. After filtration through a Celite pad, washing with MeOH, the filtrate was concentrated in vacuo to provide (S)-3-(2-amino-4-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (200 mg, 62%) as a black solid. LC-MS: m / z=326.89 [M+H] + .

[0131] Step D: (S)-tert-Butyl 7-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate To a solution of (S)-3-(2-amino-4-methoxyphenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (320 mg, 0.981 mmol) in DMSO (3.0 mL) was added DIPEA (514 μL, 2.94 mmol) 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 EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-tert-butyl 7-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (200 mg, 66%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.17(1H,brs),6.90(1H,d,J=8.8Hz),6.68-6.64(2H,m), 5.48(1H,brs),4.69-4.61(2H,m),4.21(1H,t,J=9.6Hz),3.79(3H,s),1.42(9H,s).

[0132] Step E: (S)-tert-Butyl 7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate To a solution of (S)-tert-butyl 7-methoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (200 mg, 0.649 mmol) in DMF (5.0 mL) was added Cs2CO3 (254 mg, 0.778 mmol) followed by a solution of MeI (48.7 μL, 0.778 mmol) in DMF (1.0 mL) at 0 °C. The reaction mixture was stirred for 4 h at 0 °C and then further stirred at room temperature for 1 h. After quenching with ice water, the mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 3:1) to provide (S)-tert-butyl 7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (150 mg, 72%) as a colorless oil. LC-MS: m / z = [M+H] + .

[0133] Step F: (S)-3-Amino-7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride To a solution of (S)-tert-butyl 7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate (40 mg, 0.124 mmol) in MeOH (3.0 mL) was added HCl (2 M in Et2O, 1.24 mL, 2.48 mmol) at 0° C. The reaction mixture was stirred at room temperature for 5 h and concentrated in vacuo to provide (S)-3-amino-7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (32 mg, 100%) as a white solid. LC-MS: m / z=223.05 [M+H] + .

[0134] [ka]

[0135] Intermediate 17: (S)-3-Amino-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one dihydrochloride [ka]

[0136] Step A: (S)-2-((tert-butoxycarbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid To a solution of N-Boc-L-serine (22.8 g, 111 mmol) in anhydrous THF (200 mL) was slowly added NaH (60 wt%, 8.31 g, 207 mmol) in small portions at -40°C. The mixture was stirred for 2 h at 0°C and then cooled to -40°C. A solution of 3-fluoro-2-nitropyridine (15.0 g, 101 mmol) in anhydrous THF (100 mL) was slowly added at -40°C and the reaction mixture was stirred for 20 h at room temperature. After quenching with water, the mixture was acidified with 1 M aqueous HCl to pH 6 and then extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine and water, dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified on SiO2 (DCM:MeOH=20:1) to provide (S)-2-((tert-butoxycarbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid (21.1 g, 61%) as a yellow semi-solid. 1 H-NMR(400MHz,DMSO-d6):δ8.12(1H,d,J=4.0Hz),7.98(1H,d,J=8.0Hz),7.76(1H,dd,J =8.8,4.8Hz),7.17(1H,d,J=7.6Hz),4.50-4.48(1H,m),4.43-4.39(2H,m),1.37(9H,s)

[0137] Step B: (S)-3-((2-aminopyridin-3-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid A suspension of (S)-2-((tert-butoxycarbonyl)amino)-3-((2-nitropyridin-3-yl)oxy)propanoic acid (21.1 g, 64.5 mmol) and Pd / C (10 wt%, 2.11 g) in MeOH (100 mL) was stirred under hydrogen atmosphere (1 atm) for 20 h at 35° C. After filtration through a 0.45 um PTFE needle filter, washing with DCM / MeOH+AcOH (v / v=20:1), the filtrate was concentrated in vacuo to provide (S)-3-((2-aminopyridin-3-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (19.6 g, >99%) as a grey semi-solid. 1 H-NMR (400MHz, DMSO-d6): δ7.57(1H,d,J=9.2Hz),7.49(1H,d,J=4.4Hz),6.98(1H,d,J=7.6Hz),6.46(1H,dd,J=7. 6,5.2Hz),5.89(2H,br),4.48-4.45(1H,m),4.34(1H,dd,J=9.2,4.4Hz),3.98(1H,dd,J=9.6,3.2Hz),1.40(9H,s).

[0138] Step C: (S)-tert-Butyl (4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate To a solution of (S)-3-((2-aminopyridin-3-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (9.00 g, 25.1 mmol) in DMSO (20 mL) was added DIPEA (9.71 g, 75.3 mmol) followed by HATU (9.54 g, 25.1 mmol) at room temperature. The reaction mixture was stirred for 20 h at 35 °C. After dilution with H2O (100 mL), the mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether:EtOAc = 5:1) to give (S)-tert-butyl (4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (1.80 g, 25%) as a white solid. 1H-NMR (400MHz, DMSO-d6): δ10.37(1H,s),8.14(1H,d,J=4.4Hz),7.54(1H,d,J=7.6Hz),7.17-7.14(2H,m),4.39-4.29(3H,m),1.37(9H,s).

[0139] Step D: (S)-tert-Butyl (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate To a solution of (S)-tert-butyl (4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (1.80 g, 6.45 mmol) in acetone (100 mL) was added Cs2CO3 (2.30 g, 7.09 mmol) followed by a solution of MeI (1.11 g, 7.83 mmol) in acetone (8.0 mL) dropwise at -40 °C. The reaction mixture was stirred for 1 h at -40 °C and then for 20 h at room temperature. After quenching with H2O, the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether:EtOAc = 5:1) to provide (S)-tert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (705 mg, 37%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ8.34(1H,dd,J=4.8,1.2Hz),7.65(1H,dd,J=8.0,1.6Hz),7.31-7.25(2H,m),4.42-4.35(3H,m),3.32(3H,s),1.35(9H,s).

[0140] Step E: (S)-3-Amino-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one dihydrochloride To a solution of (S)-tert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate (700 mg, 2.38 mmol) in EtOAc (5.0 mL) was added HCl (6 M in EtOAc, 10 mL, 60 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to provide (S)-3-amino-5-methyl-2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one dihydrochloride (450 mg, 82%) as a white solid. 1 H-NMR(400MHz,DMSO-d6+D2O):δ8.39(1H,d,J=4.4Hz),7.76(1H,d,J=8.0Hz),7.39-7.3 7(1H,m),4.70(1H,t,J=8.0Hz),4.55(1H,t,J=10.0Hz),4.43-4.39(1H,m),3.40(3H,s).

[0141] [ka]

[0142] Intermediate 18: (S)-3-Amino-5-methyl-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one dihydrochloride [ka]

[0143] Step A: (S)-2-((tert-butoxycarbonyl)amino)-3-((3-nitropyridin-4-yl)oxy)propanoic acid To a suspension of NaH (60 wt%, 15.7 g, 394 mmol) in anhydrous DMF (200 mL) was slowly added a solution of N-Boc-L-serine (32.2 g, 157 mmol) in anhydrous DMF (50 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C. After slowly adding a solution of 1-fluoro-2-nitrobenzene (25.0 g, 157 mmol) in DMF (50 mL), the reaction mixture was stirred at room temperature for 20 h. After quenching with water, the mixture was neutralized with 1 M aqueous HCl and then extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine and water, dried over Na2SO4, filtered and concentrated in vacuo to provide (S)-2-((tert-butoxycarbonyl)amino)-3-((3-nitropyridin-4-yl)oxy)propanoic acid (44 g, 76%) as a brown oil. 1 H-NMR(400MHz,DMSO-d6):δ13.0(1H,brs),8.97(1H,s),8.66(1H,d,J=6.0Hz) ,7.46(1H,d,J=6.0Hz),7.19(1H,d,J=3.6Hz),4.54-4.45(3H,m),1.38(9H,s).

[0144] Step B: (S)-3-((3-aminopyridin-4-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid A suspension of (S)-2-((tert-butoxycarbonyl)amino)-3-((3-nitropyridin-4-yl)oxy)propanoic acid (40.0 g, 122 mmol) and Pd / C (10 wt%, 4.00 g) in MeOH (50 mL) was stirred under a hydrogen atmosphere (1 atm) for 20 h at 35° C. After filtration through a 0.45 um PTFE needle filter, washing with MeOH, the filtrate was concentrated in vacuo to provide (S)-3-((3-aminopyridin-4-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (35.5 g, 98%) as a brown solid. 1H-NMR(400MHz,DMSO-d6):δ7.83(1H,s),7.69(1H,d,J=5.2Hz),7.44(1H,d,J=8.8Hz),6.79(1H,d,J =5.2Hz),4.47-4.43(1H,m),4.39(1H,dd,J=9.6,4.4Hz),4.07(1H,dd,J=9.6,3.2Hz),1.40(9H,s).

[0145] Step C: (S)-tert-Butyl (4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate To a solution of (S)-3-((3-aminopyridin-4-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (35.0 g, 117 mmol) in DMSO (100 mL) was added DIPEA (45.9 g, 353 mmol) followed by HATU (44.7 g, 117 mmol) at room temperature. The reaction mixture was stirred for 20 h at 35° C. After dilution with H2O (300 mL), the mixture was extracted with EtOAc (300 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether:EtOAc = 1:1) to give (S)-tert-butyl (4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (2.50 g, 7%) as a white solid. 1 H-NMR(400MHz,DMSO-d6):δ10.25(1H,s),8.32(1H,s),8.12(1H,d,J=5.2Hz), 7.12(1H,d,J=6.8Hz),7.03(1H,d,J=5.6Hz),4.38-4.33(3H,m),1.39(9H,s).

[0146] Step D: (S)-tert-Butyl (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate To a solution of (S)-tert-butyl (4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (2.00 g, 7.16 mmol) in MeCN (10 mL) was added Cs2CO3 (4.66 g, 14.3 mmol) followed by MeI (1.11 g, 7.83 mmol) in MeCN (10 mL) dropwise at room temperature. The reaction mixture was stirred for 20 h at room temperature. After quenching with water, the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether:EtOAc = 1:1) to give (S)-tert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (600 mg, 28%) as a white solid. 1 H-NMR(400MHz,DMSO-d6):δ8.71(1H,s),8.41(1H,d,J=4.4Hz),7.21(1H,d,J =5.2Hz),7.18(1H,d,J=5.6Hz),4.42-4.38(3H,m),3.33(3H,s),1.35(9H,s).

[0147] Step E: (S)-3-Amino-5-methyl-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one dihydrochloride To a solution of (S)-tert-butyl (5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (600 mg, 2.04 mmol) in EtOAc (5.0 mL) was added HCl (5 M solution in EtOAc, 6.0 mL, 30 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo to provide (S)-3-amino-5-methyl-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one dihydrochloride (300 mg, 64%) as a white solid. 1H-NMR (400MHz, DMSO-d6+D2O): δ7.98(1H,d,J=6.4Hz),7.98(1H,s),6.95(1H,d,J =6.8Hz),4.41(1H,m),3.87(1H,d,J=3.2Hz),3.85(1H,d,J=3.2Hz),3.28(3H,s).

[0148] [ka] Intermediate 19: (S)-3-Amino-1-methyl-3,4-dihydropyrido[3,4-b][1,4]oxazepin-2(1H)-one dihydrochloride [ka]

[0149] Step A: (S)-3-(2-((tert-butoxycarbonyl)amino)-2-carboxyethoxy)-4-nitropyridine 1-oxide To a solution of N-Boc-L-serine (34.0 g, 166 mmol) in anhydrous THF (800 mL) was slowly added NaH (60 wt%, 13.3 g, 333 mmol) in small portions at 0° C. The mixture was stirred for 1 h at 0° C. After a solution of 3-fluoro-4-nitropyridine 1-oxide (24.0 g, 151 mmol) in anhydrous THF (100 mL) was slowly added, the reaction mixture was stirred at room temperature for 20 h. After quenching with water, the mixture was neutralized with 1 M aqueous HCl, then extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine and water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (DCM:MeOH=20:1) to provide (S)-3-(2-((tert-butoxycarbonyl)amino)-2-carboxyethoxy)-4-nitropyridine 1-oxide (8.20 g, 16%) as a yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ8.50 (1H, s), 8.02 (2H, s), 7.14 (1H, d, J=8.0Hz), 4.46-4.38 (3H, m), 1.37 (9H, s).

[0150] Step B: (S)-3-((4-aminopyridin-3-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid A suspension of (S)-3-(2-((tert-butoxycarbonyl)amino)-2-carboxyethoxy)-4-nitropyridine 1-oxide (8.10 g, 23.6 mmol) and Pd / C (10 wt%, 1.00 g, 0.12 equiv.) in MeOH (100 mL) was stirred at 50° C. for 20 h under a hydrogen atmosphere (1 atm). After filtration through a pad of Celite, washing with MeOH, the filtrate was concentrated in vacuo to provide (S)-3-((4-aminopyridin-3-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (7.01 g, 100%) as a brown solid. 1 H-NMR (400MHz, DMSO-d6): δ7.83-7.73(1H,m),6.56-6.52(1H,m),6.15-5.95(1H,m),3.69-3.58(2H,m),3.46-3.41(1H,m),1.37(9H,s).

[0151] Step C: (S)-tert-Butyl (4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)carbamate To a solution of (S)-3-((4-aminopyridin-3-yl)oxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (6.00 g, 23.6 mmol) in DMSO (50 mL) was added DIPEA (7.15 g, 70.8 mmol) followed by HATU (8.96 g, 23.6 mmol) at room temperature. The reaction mixture was stirred for 20 h at 50 °C. After dilution with H2O (100 mL), the mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on C18 (MeCN / H2O) to provide (S)-tert-butyl (2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)carbamate (510 mg, 9%) as a pale yellow solid. 1 H-NMR (400MHz, DMSO-d6): δ10.96(1H,br),8.35(1H,br),8.07(1H,s),8.02(1H,d,J=5.2Hz),6.83(1H,d,J=5.2Hz),1.51(3H,s),1.31(9H,s).

[0152] Step D: (S)-tert-Butyl (1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)carbamate To a solution of (S)-tert-butyl (2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)carbamate (400 mg, 1.43 mmol) in MeCN (5.0 mL) was added Cs2CO3 (232 mg, 0.710 mmol) followed by a solution of MeI (161 mg, 1.41 mmol) in MeCN (2.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 days. After quenching with water, the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether:EtOAc = 1:1) to provide (S)-tert-butyl (1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)carbamate (110 mg, 26%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ8.35(1H,br),8.15(1H,d,J=5.6Hz),8.12(1H,s),7.11(1H,d,J=5.2Hz),3.27(3H,s),1.54(3H,s),1.28(9H,s).

[0153] Step E: (S)-3-Amino-1-methyl-3,4-dihydropyrid[3,4-b][1,4]oxazepin-2(1H)-one dihydrochloride To a solution of (S)-tert-butyl (1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)carbamate (110 mg, 0.370 mmol) in MeOH (5.0 mL) was added HCl (6 M solution in EtOAc, 5.0 mL, 30 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo to provide (S)-3-amino-1-methyl-3,4-dihydropyrido[3,4-b][1,4]oxazepin-2(1H)-one dihydrochloride (51 mg, 51%) as a brown solid. 1 H-NMR (400MHz, DMSO-d6): δ8.65(1H,s), 8.57(1H,d,J=6.4Hz),7.70(1H,d,J=6.0Hz),3.41(3H,s),1.76(3H,s).

[0154] [ka]

[0155] Intermediate 20: 3-Amino-7,9-difluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one [ka]

[0156] Step A: 7,9-Difluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one To a solution of 6,8-difluoro-3,4-dihydronaphthalen-1(2H)-one (800 mg, 4.39 mmol) in methanesulfonic acid (6.0 mL, 92 mmol) was added sodium azide (350 mg, 5.38 mmol) at −10° C. The reaction mixture was stirred for 2 h at −10° C. After quenching with ice water, the precipitated solid was collected by filtration, washed with hexane and dried under vacuum to provide 7,9-difluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (700 mg, 81%) as a white solid. 1H-NMR(400MHz,DMSO-d6):δ9.40(1H,brs),7.19(1H,t,J=9.6Hz),7.60(1H,d,J=10.0H z),2.91(1H,q,J=6.4Hz),2.73(2H,t,J=6.8Hz),2.14-2.08(2H,m),1.87-1.82(1H,m).

[0157] Step B: 7,9-Difluoro-3-iodo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one To a solution of 7,9-difluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (700 mg, 3.55 mmol) in DCM (10 mL) was slowly added TMEDA (1.61 mL, 10.7 mmol) followed by TMSI (1.45 mL, 10.7 mmol) under Ar atmosphere at 0° C. The mixture was stirred for 2 h at 0° C. After addition of iodine (1.30 g, 5.12 mmol), the reaction mixture was further stirred at 0° C. for 2 h and then quenched with saturated aqueous Na2S2O3. The mixture was stirred for 1 h at room temperature and extracted with EtOAc. The separated organic layer was washed with 1M aqueous HCl and brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 7,9-difluoro-3-iodo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (700 mg, 61%). 1 H-NMR(400MHz,DMSO-d6):δ9.98(1H,brs),7.26-7.21(1H,m),7.09(1H,d,J=8.4Hz),4 .01(1H,dd,J=11.2,8.0Hz),2.80-2.73(2H,m),2.43-2.33(1H,m),2.14-2.08(1H,m).

[0158] Step C: 3-Amino-7,9-difluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one To a solution of 7,9-difluoro-3-iodo-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (700 mg, 2.17 mmol) in DMF (5.0 mL) was added sodium azide (211 mg, 3.25 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. After quenching with ice water, the mixture was stirred at 0° C. for 1 h. The precipitated solid was collected by filtration and washed with cold water to provide the azide compound. To a solution of the azide compound in THF (10 mL) and water (1.0 mL) was added PPh3 (568 mg, 2.17 mmol). The reaction mixture was stirred at room temperature for 12 h. After concentration in vacuo, the residue was purified by column chromatography on SiO2 (hexane:EtOAc = 1:2) to provide 3-amino-7,9-difluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (350 mg, 76%) as a white solid. LC-MS: m / z = 213.00 [M + H] + .

[0159] Intermediate 21: 3-Amino-7,9-difluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one hydrochloride [ka]

[0160] Step A: tert-Butyl 7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate A mixture of 3-amino-7,9-difluoro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (130 mg, 0.613 mmol) and TEA (171 μL, 1.23 mmol) in DCM (5.0 mL) was stirred at room temperature for 5 min and cooled to 0° C. After adding a solution of Boc2O (156 μL, 0.674 mmol) in DCM (3.0 mL), the reaction mixture was stirred at 0° C. for 2 h and then at room temperature overnight. After quenching with water, the mixture was extracted with EtOAc, washed with 0.5 M aqueous HCl and water, dried over Na2SO4, filtered and concentrated in vacuo to provide tert-butyl 7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate (180 mg, 94%). 1 H-NMR (400MHz, CDCl3): δ7.21(1Θ,brs),6.82-6.78(2H,m),5.45(1H,d,J=6.8Hz),4.3 2-4.26(1H,m),3.00-2.93(1H,m),2.75-2.65(2H,m),2.04-1.96(1H,m),1.41(9H,s).

[0161] Step B: tert-Butyl 7,9-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate To a solution of tert-butyl 7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate (180 mg, 0.576 mmol) in DMF (4.0 mL) was added Cs2CO3 (225 mg, 0.692 mmol) at 0 °C. The mixture was stirred for 5 min at 0 °C. After adding a solution of MeI (43.2 μL, 0.692 mmol) in DMF (1.0 mL), the reaction mixture was stirred for 1 h at 0 °C and then further stirred at room temperature for 1 h. After quenching with water, the mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc=2:1) ​​to provide tert-butyl 7,9-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate (150 mg, 80%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ6.84-6.76(2Θ,m),5.51(1H,d,J=6.4Hz),4.25-4.19(1H,m),3.3 0(3H,d,J=2.0Hz),2.86-2.77(1H,m),2.63-2.51(2H,m),1.96-1.88(1H,m),1.40(9H,s).

[0162] Step C: 3-Amino-7,9-difluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one hydrochloride To a solution of tert-butyl 7,9-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamate (60 mg, 0.184 mmol) in MeOH (3.0 mL) was added HCl (2 M in Et2O, 919 μL, 1.84 mmol) at 0° C. The reaction mixture was stirred at room temperature for 6 h and then concentrated in vacuo to provide 3-amino-7,9-difluoro-1-methyl-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one hydrochloride (48 mg, 100%). LC-MS: m / z=227.04 [M+H] + .

[0163] [ka]

[0164] Intermediate 22: 7-Amino-5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one [ka]

[0165] Step A: Ethyl 4-(3-aminopyrazin-2-yl)butanoate To a mixture of 3-bromopyrazin-2-amine (1.20 g, 6.89 mmol), X-Phos (657 mg, 1.38 mmol) and Pd(OAc)2 (154 mg, 0.690 mmol) in THF (20 mL) was added a solution of ethyl 4-(bromodinthio)butanoate (0.5 M in THF, 80 mL, 40 mmol) at room temperature under N2 atmosphere. The reaction mixture was stirred at 70 °C overnight and cooled to room temperature. After quenching with 1 N aqueous HCl (100 mL), the mixture was extracted twice with EtOAc. The separated aqueous layer was basified with 6 N aqueous NaOH until pH 9, then extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide ethyl 4-(3-aminopyrazin-2-yl)butanoate (1.19 g, 89%) as a yellow oil. LC-MS: m / z=210.10 [M+H] +

[0166] Step B: 5H,7H,8H,9H-Pyrazino[2,3-b]azepin-6-one To a solution of ethyl 4-(3-aminopyrazin-2-yl)butanoate (1.04 g, 4.99 mmol) in toluene (45 mL) was added a solution of AlMe3 (2 M in toluene, 15.0 mL, 30.0 mmol). The reaction mixture was stirred at room temperature overnight. After quenching with water, the mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (DCM:MeOH=10:1) to provide 5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one (600 mg, 73%) as a yellow solid. LC-MS: m / z=164.05 [M+H] +

[0167] Step C: 7-Iodo-5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one To a solution of 5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one (300 mg, 1.84 mmol) in DCM (20 mL) was added TMEDA (2.13 g, 18.3 mmol) followed by TMSI (3.67 g, 18.3 mmol) over 25 min at 0° C. The mixture was stirred for 1 h. After addition of I2 (933 mg, 3.67 mmol), the reaction mixture was further stirred at room temperature for 1 h and then quenched with saturated aqueous sodium thiosulfate. The mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether: EtOAc = 1:1) to give 7-iodo-5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one (330 mg, 62%) as a yellow solid. LC-MS: m / z = 289.95 [M + H] +

[0168] Step D: 7-Azido-5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one To a solution of 7-iodo-5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one (300 mg, 1.03 mmol) in DMF (5.0 mL) was added NaN3 (269 mg, 4.15 mmol). The reaction mixture was stirred at room temperature for 3 h. After quenching with water, the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 7-azido-5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one (163 mg, 77%) as a yellow solid. LC-MS: m / z=205.05 [M+H] +

[0169] Step E: 7-Amino-5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one A suspension of 7-azido-5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one (163 mg, 0.80 mmol) and Pd / C (10%, 16.0 mg) in THF (30 mL) was stirred at room temperature under H2 atmosphere (1 atm) for 4 h. After filtration through a Celite pad, the filtrate was concentrated in vacuo. The residue was purified by reverse phase column to provide 7-amino-5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one (60 mg, 42%) as a white solid. 1 H-NMR(400MHz,CD3OD):δ8.32(1H,dd,J=2.6,0.7Hz),8.29(1H,d,J=2.6Hz),3.45(1H,dd,J=11.8,7.5Hz),3.08(1H,ddd,J=14.4, 12.0,8.1Hz),2.99(1H,ddd,J=14.2,7.6,2.2Hz),2.62(1H,ddt,J=13.1,12.1,7.5Hz),2.09(1H,dddd,J=13.0,11.8,8.1,2.1Hz).

[0170] [ka] Intermediate 23: 7-Amino-5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one [ka]

[0171] Step A: 5-Methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one To a solution of 5H,7H,8H,9H-pyrazino[2,3-b]azepin-6-one (reference intermediate 22, 300 mg, 1.84 mmol) in DMF (5.0 mL) was added Cs2CO3 (1.19 g, 3.67 mmol) followed by MeI (521 mg, 3.68 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 h. After quenching with water, the mixture was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one (210 mg, 64%) as a yellow solid. LC-MS: m / z=178.05 [M+H] +

[0172] Step B: 7-Iodo-5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one To a solution of 5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one (200 mg, 1.13 mmol) in DCM (20 mL) was added TMEDA (1.31 g, 11.3 mmol) followed by TMSI (2.25 g, 11.3 mmol) over 25 min at 0 °C. The mixture was stirred for 1 h at 0 °C. After addition of I2 (572 mg, 2.26 mmol), the reaction mixture was further stirred at room temperature for 1 h and then quenched with saturated aqueous sodium thiosulfate. The mixture was extracted twice with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (petroleum ether: EtOAc = 1:1) to give 7-iodo-5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one (250 mg, 73%) as a yellow solid. LC-MS: m / z = 303.90 [M + H] +

[0173] Step C: 7-Iodo-5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one To a solution of 7-iodo-5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one (250 mg, 0.82 mmol) in DMF (5.0 mL) was added NaN3 (214 mg, 3.29 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After quenching with water, the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 7-azido-5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one (160 mg, 88%) as a yellow solid. LC-MS: m / z = 219.15 [M + H] +

[0174] Step D: 7-Amino-5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one A suspension of 7-azido-5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one (160 mg, 0.730 mmol) and Pd / C (10%, 16.0 mg) in THF (30 mL) was stirred at room temperature under H2 atmosphere (1 atm) for 4 h. After filtration through a Celite pad, the filtrate was concentrated in vacuo. The residue was purified by reverse phase column to provide 7-amino-5-methyl-7H,8H,9H-pyrazino[2,3-b]azepin-6-one (70 mg, 50%) as a white oil. 1 H-NMR(400MHz,CD3OD):δ8.44(1H,dd,J=2.6,0.7Hz),8.34(1H,d,J=2.6Hz,),3.48(3H,s),3.39(1H,dd,J= 11.9,7.6Hz),3.09-2.87(2H,m),2.57(1H,tt,J=12.8,7.6Hz),2.06(1H,dddd,J=13.1,11.9,8.4,1.4Hz).

[0175] [ka] Intermediate 24: (S)-3-amino-6-fluoro-5-methyl-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one 2TFA [ka]

[0176] Step A: 2,4-Difluoro-3-nitropyridine A mixture of 2,4-dichloro-3-nitropyridine (5.00 g, 25.9 mmol), KF (spray-dried, 4.52 g, 78.0 mmol) and 18-crown-6 (1.10 g, 4.15 mmol) in NMP (26 mL) was stirred at 100 °C for 2 h. After the reaction mixture was cooled to room temperature, it was partitioned between water and MTBE. The separated organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane: EtOAc = 5: 1) to provide 2,4-difluoro-3-nitropyridine (2.60 g, 63%) as a pale yellow oil. 1 H-NMR (400MHz, CDCl3): δ8.4 (1H, t, J = 6.4Hz), 7.24 (1H, t, J = 7Hz).

[0177] Step B: N-(tert-butoxycarbonyl)-O-(2-fluoro-3-nitropyridin-4-yl)-L-serine To a suspension of NaH (60 wt%, 1.35 g, 33.7 mmol) in DMF (24 mL) was slowly added a solution of (tert-butoxycarbonyl)-L-serine (3.45 g, 16.8 mmol) in DMF (12 mL) at 0° C. The mixture was stirred for 1 h at 0° C. After addition of a solution of 2,4-difluoro-3-nitropyridine (2.45 g, 15.3 mmol) in DMF (12 mL) at 0° C., the reaction mixture was stirred for 4 h at 0° C. After quenching with 0.5 M aqueous HCl at 0° C., the mixture was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 1:1 to 1:3) to provide N-(tert-butoxycarbonyl)-O-(2-fluoro-3-nitropyridin-4-yl)-L-serine (1.65 g, 31%) as a yellow oil. 1 H-NMR (400MHz, CDCl3): δ8.20(1H,d,J=5.6Hz),6.98(1H,d,J=5.6Hz),5.56(1H,d,J=6.4Hz),4.66-4.56(3H,m),1.45(9H,s).

[0178] Step C: O-(3-amino-2-fluoropyridin-4-yl)-N-(tert-butoxycarbonyl)-L-serine A suspension of N-(tert-butoxycarbonyl)-O-(2-fluoro-3-nitropyridin-4-yl)-L-serine (1.50 g, 4.34 mmol) and Pd / C (10 wt%, 0.46 g, 0.43 mmol) in MeOH (21 mL) was stirred at room temperature under H2 atmosphere (1 atm) for 2 h. After filtration through a Celite pad, washing with MeOH, the filtrate was concentrated in vacuo to provide O-(3-amino-2-fluoropyridin-4-yl)-N-(tert-butoxycarbonyl)-L-serine (1.30 g, 95%) as a brown oil. LC-MS: m / z=316.13 [M+H] + . Step D: tert-Butyl (S)-(6-fluoro-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate

[0179] To a solution of O-(3-amino-2-fluoropyridin-4-yl)-N-(tert-butoxycarbonyl)-L-serine (1.30 g, 4.12 mmol) in EtOAc (41 mL) was added DIPEA (2.20 mL, 12.4 mmol) followed by HATU (2.35 g, 6.18 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h. After quenching with water, the mixture was extracted with EtOAc. The separated organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc=4:1) to provide tert-butyl (S)-(6-fluoro-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (200 mg, 16%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ8.75(1H,dd,J=4,1.6Hz),8.39(1H,dd,J=8.8,1.2Hz),7.43(1H,q,J=8.6 Hz),4.67-4.58(1H,m),4.39(1H,d,J=3.6Hz),3.78-3.69(1H,m),3.25-3.14(1H,m),1.46(9H,s).

[0180] Step E: tert-Butyl (S)-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate To a solution of tert-butyl (S)-(6-fluoro-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (200 mg, 0.670 mmol) in DMF (6.7 mL) was added Cs2CO3 (260 mg, 0.810 mmol) followed by MeI (0.0500 mL, 0.810 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. After dilution with water, the mixture was extracted with EtOAc. The separated organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 6:1) to give tert-butyl (S)-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (100 mg, 48%) as a colorless foam. LC-MS: m / z = 312.13 [M + H] + .

[0181] Step F: (S)-3-Amino-6-fluoro-5-methyl-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one 2 TFA To a solution of tert-butyl (S)-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (80 mg, 0.257 mmol) in DCM (2.5 mL) was added TFA (0.400 mL, 5.14 mmol) at 0° C. The reaction mixture was stirred for 3 h at 0° C. and then concentrated in vacuo to provide (S)-6-fluoro-5-methyl-3-((2,2,2-trifluoroacetyl)-14-azanyl)-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one 2TFA (50 mg, 63%) as a brown oil. LC-MS: m / z=212.08 [M+H] + .

[0182] [ka] Intermediate 25: (S)-8-Fluoro-5-methyl-3-((2,2,2-trifluoroacetyl)-14-azanyl)-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one 2TFA [ka]

[0183] Step A: 2,4-Difluoro-5-nitropyridine A mixture of 2,4-dichloro-5-nitropyridine (4.00 g, 20.7 mmol), 18-crown-6 (0.880 g, 3.32 mmol), KF (spray-dried, 3.61 g, 62.2 mmol) in NMP (21 mL) was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature and then partitioned between water and MTBE. The separated organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane: EtOAc = 9: 1) to provide 2,4-difluoro-5-nitropyridine (1.83 g, 55%) as a yellow oil. 1 H-NMR (400MHz, CDCl3): δ9.05(1H,d,J=7.2Hz),6.94(1H,dd,J=7.2,2.4Hz)

[0184] Step B: N-(tert-butoxycarbonyl)-O-(2-fluoro-5-nitropyridin-4-yl)-L-serine To a suspension of NaH (60 wt%, 0.960 g, 23.9 mmol) in DMF (64 mL) was slowly added a solution of (tert-butoxycarbonyl)-L-serine (2.10 g, 10.2 mmol) in DMF (25 mL) at −10° C. The mixture was stirred for 1 h at −10° C. After addition of a solution of 2,4-difluoro-5-nitropyridine (1.82 g, 11.4 mmol) in DMF (25 mL) at −10° C., the reaction mixture was stirred for 2 h at −10° C. After quenching with 0.5 M aqueous HCl at −10° C., the mixture was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 5:1 → 1:1) to provide N-(tert-butoxycarbonyl)-O-(2-fluoro-5-nitropyridin-4-yl)-L-serine (1.34 g, 34%) as a yellow oil. 1 H NMR(400MHz,CDCl3):δ8.73(1H,s),6.62(1H,s),5.59(1H,d,J=7.2Hz),4.80(1H,dt, J=7.2,2.8Hz),4.68(1H,dd,J=9.2,2.4Hz),4.52(1H,dd,J=9.6,2.8Hz),1.45(9H,s)

[0185] Step C: O-(5-amino-2-fluoropyridin-4-yl)-N-(tert-butoxycarbonyl)-L-serine A suspension of N-(tert-butoxycarbonyl)-O-(2-fluoro-5-nitropyridin-4-yl)-L-serine (1.34 g, 3.87 mmol) and 5% Pd / C (0.28 g, 0.132 mmol) in MeOH (77 mL) was stirred at room temperature under H2 atmosphere (1 atm) for 3 h. After filtration through a Celite pad, washing with MeOH, the filtrate was concentrated in vacuo to provide O-(5-amino-2-fluoropyridin-4-yl)-N-(tert-butoxycarbonyl)-L-serine (1.22 g, 100%). LC-MS: m / z=316 [M+H] + .

[0186] Step D: tert-Butyl (S)-(8-fluoro-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate To a solution of O-(5-amino-2-fluoropyridin-4-yl)-N-(tert-butoxycarbonyl)-L-serine (1.22 g, 3.87 mmol) in EtOAc (40 mL) was added DIPEA (1.02 mL, 5.81 mmol) followed by HATU (4.42 g, 11.6 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. After concentration in vacuo, the residue was purified by column chromatography on SiO2 (hexane:EtOAc=2:1) ​​to provide tert-butyl (S)-(8-fluoro-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (370 mg, 32%) as a white solid. 1 H NMR (400MHz, CDCl3): δ8.55(1Θ,s),7.92(1H,s),6.59(1H,d,J=2Hz),5.64( 1H,d,J=4.4Hz),4.65-4.57(2H,m),4.31(1H,td,J=10,0.8Hz),1.46(9H,s)

[0187] Step E: tert-Butyl (S)-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate A mixture of tert-butyl (S)-(8-fluoro-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (0.370 g, 1.24 mmol) and Cs2CO3 (0.490 g, 1.50 mmol) in DMF (10 mL) was stirred for 5 min at 0° C. After addition of a solution of MeI (0.0940 mL, 1.50 mmol) in DMF (5.0 mL), the reaction mixture was stirred for 1 h at 0° C. and then further stirred at room temperature for 2 h. After quenching with water, the mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 2:1) to provide tert-butyl (S)-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (0.150 g, 40%) as a white solid. 1 H NMR (400MHz, CDCl3): δ8.09(1H,s),6.69(1H,d,J=2Hz),5.53(1H,d,J=6.4Hz ),4.70-4.57(2H,m),4.31(1H,dd,J=9.6,11.6Hz),3.44(3H,s),1.41(9H,s)

[0188] Step F: (S)-8-Fluoro-5-methyl-3-((2,2,2-trifluoroacetyl)-14-azanyl)-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one 2TFA To a solution of tert-butyl (S)-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)carbamate (0.150 g, 0.490 mmol) in DCM (9.8 mL) was added TFA (0.760 mL, 9.83 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h and concentrated in vacuo to provide (S)-8-fluoro-5-methyl-3-((2,2,2-trifluoroacetyl)-14-azanyl)-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one (0.150 g, 99%) as a yellow oil. LC-MS: m / z=212 [M+H] + .

[0189] [ka] Intermediate 26: (3S)-3-Amino-8-chloro-5-methyl-2H,3H-pyrido[4,3-b][1,4]oxazepin-4-one [ka]

[0190] Step A: (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(2-chloro-5-nitropyridin-4-yl)oxy]propanoic acid To a suspension of NaH (60 wt%, 3.60 g, 90.0 mmol) in anhydrous THF (100 mL) was slowly added a solution of (tert-butoxycarbonyl)-L-serine (6.38 g, 31.1 mmol) in anhydrous THF (50 mL) at 0° C. The mixture was stirred for 30 min at 0° C. After a solution of 2,4-dichloro-5-nitropyridine (2.00 g, 10.3 mmol) in anhydrous THF (25 mL) was added at 0° C., the reaction mixture was stirred for 2 h at 0° C. After quenching with cold 0.5 M aqueous HCl, the mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(2-chloro-5-nitropyridin-4-yl)oxy]propanoic acid (1.20 g, crude) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):δ13.03(1H,s),8.88(1H,s),7.67(1H,s),7.22(1H, d,J=8.2Hz),4.56(2H,qd,J=10.3,5.3Hz),4.48-4.40(1H,m),1.38(9H,s).

[0191] Step B: (2S)-3-[(5-amino-2-chloropyridin-4-yl)oxy]-2-[(tert-butoxycarbonyl)amino]propanoic acid To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(2-chloro-5-nitropyridin-4-yl)oxy]propanoic acid (1.20 g, 3.31 mmol) in AcOH (20 mL) was added Zn (1.08 g, 16.5 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C. After filtration through a Celite pad, the filtrate was concentrated in vacuo. The residue was purified by reverse phase column to provide (2S)-3-[(5-amino-2-chloropyridin-4-yl)oxy]-2-[(tert-butoxycarbonyl)amino]propanoic acid (550 mg, 50%) as a brown solid. 1H NMR (400MHz, DMSO-d6): δ7.58 (1H, s), 6.84 (2H, m), 5.04 (2H, s), 4.37-4.08 (3H, m), 1.39 (9H, s).

[0192] Step C: tert-Butyl N-[(3S)-8-chloro-4-oxo-2H,3H,5H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate To a solution of (2S)-3-[(5-amino-2-chloropyridin-4-yl)oxy]-2-[(tert-butoxycarbonyl)amino]propanoic acid (550 mg, 1.65 mmol) in DMF (5.0 mL) was added DIPEA (642 mg, 4.97 mmol) followed by HATU (945 mg, 2.48 mmol) at room temperature. The reaction mixture was stirred for 2 h at room temperature. After quenching with ice water, the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 2:1) to provide tert-butyl N-[(3S)-8-chloro-4-oxo-2H,3H,5H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate (200 mg, 38%) as a yellow solid. LCMS (ESI) m / z: [M+H] + =314.

[0193] Step D: tert-Butyl N-[(3S)-8-chloro-5-methyl-4-oxo-2H,3H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate To a solution of tert-butyl N-[(3S)-8-chloro-4-oxo-2H,3H,5H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate (200 mg, 0.637 mmol) in DMF (5.0 mL) was added K2CO3 (176 mg, 1.27 mmol) followed by a solution of MeI (112 mg, 0.80 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 2 h. After quenching with ice water, the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 3:1) to provide tert-butyl N-[(3S)-8-chloro-5-methyl-4-oxo-2H,3H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate (180 mg, 86%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ8.56(1H,s),7.39(1H,s),7.20(1H,d,J=7.5Hz),4.54-4.40(3H,m),3.32(3H,s),1.36(9H,s).

[0194] Step E: (3S)-3-Amino-8-chloro-5-methyl-2H,3H-pyrido[4,3-b][1,4]oxazepin-4-one To a solution of tert-butyl N-[(3S)-8-chloro-5-methyl-4-oxo-2H,3H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate (180 mg, 0.549 mmol) in CHCl (3.0 mL) was added HCl (4 M in dioxane, 2.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was purified by prep-HPLC to provide (3S)-3-amino-8-chloro-5-methyl-2H,3H-pyrido[4,3-b][1,4]oxazepin-4-one (60 mg, 48%). LCMS (ESI) m / z: [M+H] + =227.95.

[0195] [ka] Intermediate 27: [ka]

[0196] Step A: tert-Butyl N-[(3S)-5,8-dimethyl-4-oxo-2H,3H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate To a solution of tert-butyl N-[(3S)-8-chloro-5-methyl-4-oxo-2H,3H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate (200 mg, 0.610 mmol) and Pd(PPh3)4 (141 mg, 0.122 mmol) in THF (2.0 mL) was added Zn(CH3)2 (1 M in hexanes, 2.0 mL, 2.0 mmol) slowly at room temperature. The reaction mixture was stirred at 60 °C for 12 h. After quenching with 0.5 M aqueous AcOH (10 mL) at 0 °C, the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with water and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (hexane:EtOAc = 4:1 → 1:1) to provide tert-butyl N-[(3S)-5,8-dimethyl-4-oxo-2H,3H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate (130 mg, 69%) as a white solid. LCMS (ESI) m / z: [M+H] + =308.

[0197] Step B: (3S)-3-Amino-5,8-dimethyl-2H,3H-pyrido[4,3-b][1,4]oxazepin-4-one To a solution of tert-butyl N-[(3S)-5,8-dimethyl-4-oxo-2H,3H-pyrido[4,3-b][1,4]oxazepin-3-yl]carbamate (130 mg, 0.423 mmol) in DCM (3.0 mL) was added HCl (4 M in 1,4-dioxane, 2.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was purified by prep-HPLC to provide (3S)-3-amino-5,8-dimethyl-2H,3H-pyrido[4,3-b][1,4]oxazepin-4-one (45 mg, 51%) as a white solid. LCMS (ESI) m / z: [M+H] + =208.05.

[0198] Working Example Example 1: (S)-4-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] To a solution of (S)-3-amino-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (Intermediate 9, 100 mg, 0.466 mmol) and TEA (0.195 mL, 1.40 mmol) in THF (4.7 mL) was added 4-nitrophenyl carbonochloridate (122 mg, 0.606 mmol) at 0° C. The mixture was stirred for 45 min at 0° C. After addition of 4-benzyl-1H-pyrazole hydrochloride (Intermediate 1, 118 mg, 0.606 mmol) followed by TEA (0.195 mL, 1.40 mmol) at 0° C., the reaction mixture was stirred for 18 h at room temperature. After quenching with water, the mixture was extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO2 (hexane:EtOAc=1:3) to give (S)-4-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (10 mg, 6%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.94(1H,d,J=8.0Hz),7.90(1H,s),7.48(2H,s),7.32-7.27(2H,m),7.24-7.15(5H,m ),7.01(1H,d,J=8.0Hz),4.97-4.91(1H,m),4.76(1H,dd,J=10.2,6.6Hz),4.35(1H,t,J=10.6Hz),3.82(2H,s). LC-MS:m / z=363.2[M+H] + .

[0199] Example 2: (S)-4-(3-fluorobenzyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 9. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-4-(3-fluorobenzyl)-N-(4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (30%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.96(1H,d,J=6.8Hz),7.92(1H,s),7.53(1H,s),7.48(1H,s),7.29-7.12(4H,m) ,7.03-6.86(4H,m),4.98-4.92(1H,m),4.77(1H,dd,J=10.4,6.8Hz),4.36(1H,t,J=10.4Hz),3.82(2H,s). LC-MS:m / z=380.2[M+H] + .

[0200] Example 3: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 10. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=3:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (36%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ8.00(1H,d,J=6.8Hz),7.88(1H,s),7.47(1H,s),7.28-7.19(5H,m),6.96-6. 85(2H,m),4.94-4.87(1H,m),4.71(1H,t,J=8.6Hz),4.31(1H,t,J=10.2Hz),3.81(2H,s),3.44(3H,s). LC-MS:m / z=395.2[M+H] + .

[0201] Example 4: (S)-4-(3-chlorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 3 and 10. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=3:1) to provide (S)-4-(3-chlorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (38%) as a pale yellow solid. 1H-NMR (400MHz, CDCl3): δ8.01(1H,d,J=6.8Hz),7.88(1H,s),7.47(1H,s),7.24-7.01(5H,m),7.16(1H,s),7.0 6(1H,d,J=6.8Hz),4.94-4.88(1H,m),4.72(1H,t,J=8.4Hz),4.32(1H,t,J=10.4Hz),3.79(2H,s),3.44(3H,s). LC-MS:m / z=411.2[M+H] + .

[0202] Example 5: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-methylbenzyl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 4 and 10. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=5:1) to provide (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-methylbenzyl)-1H-pyrazole-1-carboxamide (43%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=7.2Hz),7.86(1H,s),7.47(1H,s),7.25-7.16(4H,m),7.02(1H,d,J=7.6Hz),6.9 8-6.96(2H,m),4.94-4.87(1H,m),4.71(1H,t,J=8.6Hz),4.31(1H,t,J=10.6Hz),3.77(2H,s),3.44(3H,s),2.31(3H,s). LC-MS:m / z=391.2[M+H] + .

[0203] Example 6: (S)—N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-(trifluoromethyl)benzyl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 5 and 10. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=3:1) to provide (S)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-(trifluoromethyl)benzyl)-1H-pyrazole-1-carboxamide (32%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ8.01(1H,d,J=6.8Hz),7.89(1H,s),7.49(1H,d,J=8.0Hz),7.48(1H,s),7.43(1H,s),7.40(1H,d,J=8.0Hz), 7.36(1H,d,J=7.6Hz),7.25-7.19(3H,m),4.94-4.87(1H,m),4.71(1H,t,J=8.6Hz),4.32(1H,t,J=10.4Hz),3.88(2H,s),3.44(3H,s). LC-MS:m / z=445.2[M+H] + .

[0204] Example 7: (S)-4-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 6 and 10. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-4-(3-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (41%) as a white foam. 1H-NMR (400MHz, CDCl3): δ8.02(1H,d,J=7.2Hz),7.89(1H,s),7.54-7.50(1H,m),7.47(1H,s),7.42-7.38(2H,m) ,7.24-7.20(4H,m),4.94-4.87(1H,m),4.72(1H,t,J=8.4Hz),4.32(1H,t,J=10.4Hz),3.86(2H,s),3.44(3H,s). LC-MS:m / z=402.2[M+H] + .

[0205] Example 8: (S)-4-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 7 and 10. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=4:1) to provide (S)-4-(4-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (26%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=6.8Hz),7.85(1H,s),7.45(1H,s),7.25-7.19(3H,m),7.13(2H,t,J=6.8Hz) ,6.98(2H,t,J=8.6Hz),4.94-4.87(1H,m),4.71(1H,t,J=8.6Hz),4.31(1H,t,J=10.4Hz),3.78(2H,s),3.44(3H,s). LC-MS:m / z=395.2[M+H] + .

[0206] Example 9: (S)-4-(4-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 8 and 10. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-4-(4-cyanobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (73%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.01(1H,d,J=7.2Hz),7.89(1H,s),7.59(2H,d,J=8.4Hz),7.46(1H,s),7.28(2H,d,J=8.8 Hz),7.26-7.20(3H,m),4.93-4.87(1H,m),4.71(1H,t,J=8.6Hz),4.31(1H,t,J=10.6Hz),3.88(2H,s),3.44(3H,s). LC-MS:m / z=402.2[M+H] + .

[0207] Example 10: (S)-4-Benzyl-N-(6-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 11. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-4-benzyl-N-(6-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (3%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=6.8Hz),7.92(1H,s),7.49(1H,s),7.46(1H,s),7.30(1H,t,J=7.4Hz),7.24-7.18(2H ,m),7.12(1H,q,J=7.6Hz),6.98-6.01(2H,m),4.98-4.92(1H,m),4.75(1H,q,J=5.5Hz),4.36(1H,t,J=10.2Hz),3.83(2H,s). LC-MS:m / z=381.2[M+H] + .

[0208] Example 11: (S)—N-(6-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 11. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-N-(6-fluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1carboxamide (3.5%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=6.8Hz),7.93(1H,s),7.49(1H,s),7.44(1H,s),7.29-7.24(2H,m),7.12(1 H,q,J=7.6Hz),6.98-6.87(4H,m),4.98-4.93(1H,m),4.76(1H,q,J=5.3Hz),4.37(1H,t,J=10.6Hz),3.83(2H,s). LC-MS:m / z=399.1[M+H] + .

[0209] Example 12: (S)-4-benzyl-N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 12. The crude product was purified by column chromatography on NH-SiO2 (hexanes:EtOAc=2:1) ​​followed by SiO2 (hexanes:EtOAc=6:1) to provide (S)-4-benzyl-N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (27%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=7.2Hz),7.87(1H,s),7.48(1H,s),7.31-7.22(4H,m),7.20-7.17(2H,m),7. 06-7.01(2H,m),4.96-4.90(1H,m),4.69-4.65(1H,m),4.30(1H,t,J=10.4Hz),3.82(2H,s),3.38(3H,d,J=1.6Hz). LC-MS:m / z=395.2[M+H] + .

[0210] Example 13: (S)—N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a manner similar to that of Example 1 along with intermediates 2 and 12. The crude product was purified by column chromatography on NH-SiO2 (hexanes:EtOAc=2:1) ​​followed by SiO2 (hexanes:EtOAc=6:1) to provide (S)-N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (7.5%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ8.00(1H,d,J=6.8Hz),7.88(1H,s),7.48(1H,s),7.29-7.23(2H,m),7.06-7.02(2H,m),6.9 7-6.86(2H,m),4.96-4.90(1H,m),4.68(1H,t,J=8.6Hz),4.30(1H,t,J=10.6Hz),3.82(2H,s),3.38(3H,d,J=1.6Hz). LC-MS:m / z=413.2[M+H] + .

[0211] Example 14: (S)-4-benzyl-N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 13. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-4-benzyl-N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (30%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.96(1H,d,J=6.4Hz),7.91(1H,s),7.49(1H,s),7.32-7.18(6H,m),6.74- 6.69(2H,m),4.96-4.91(1H,m),4.74(1H,dd,J=10.8,5.2Hz),4.38(1H,t,J=10.4Hz),3.83(2H,s). LC-MS:m / z=399.2[M+H] + .

[0212] Example 15: (S)—N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 13. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=1:1) to provide (S)-N-(6,8-difluoro-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (33%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=6.8Hz),7.93(1H,s),7.49(1H,s),7.45(1H,brs),7.29-7.24(1H,m),6.98-6.89(3 H,m),6.75-6.69(2H,m),4.94(1H,dt,J=10.4,5.6Hz),4.75(1H,dd,J=10.8,5.6Hz),4.39(1H,t,J=10.4Hz),3.82(2H,s). LC-MS:m / z=417.2[M+H] + .

[0213] Example 16: (S)-4-benzyl-N-(6,8-difluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 14. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=1:1) to provide (S)-4-benzyl-N-(6,8-difluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (32%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.97(1H,d,J=7.2Hz),7.87(1H,s),7.48(1H,s),7.31-7.17(5H,m),6.84-6.78(2H,m),4.9 3(1H,dt,J=11.6,7.2Hz),4.66(1H,dd,J=10.0,7.6Hz),4.31(1H,t,J=10.4Hz),3.82(2H,s),3.35(3H,d,J=2.0Hz). LC-MS:m / z=413.2[M+H] + .

[0214] Example 17: (S)—N-(6,8-difluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 14. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-N-(6,8-difluoro-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (41%) as a colorless oil. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.2Hz),7.89(1H,s),7.48(1H,s),7.28-7.23(1H,m),6.97-6.78(5H,m),4.93( 1H,dt,J=11.2,7.2Hz),4.67(1H,dd,J=9.6,6.8Hz),4.31(1H,dd,J=10.8,9.6Hz),3.82(2H,s),3.35(3Θ,d,J=2.4Hz). LC-MS:m / z=431.2[M+H] + .

[0215] Example 18: (S)-4-benzyl-N-(8-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 15. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-4-benzyl-N-(8-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (29%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.99(1H,d,J=7.2Hz),7.87(1H,s),7.47(1H,s),7.31-7.16(4H,m),7.12(1Θ,d,J=8.4Hz),6.80-6.73(2H,m) ,7.01(1H,d,J=8.0Hz),4.94-4.87(1H,m),4.80(1H,dd,J=9.6,7.6Hz),4.29(1H,t,J=10.4Hz),3.83(3H,s),3.81(2H,s),3.39(3H,s). LC-MS:m / z=407.2[M+H] + .

[0216] Example 19: (S)-4-benzyl-N-(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 16. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-4-benzyl-N-(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (32%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.96(1H,d,J=8.0Hz),7.86(1H,s),7.46(1H,s),7.30-7.10(6H,m),6.77-6.73(2H,m),4 .93-4.86(1H,m),4.65(1H,dd,J=9.6,7.6Hz),4.24(1H,dd,J=11.6,10Hz),3.82(3H,s),3.81(2H,s),3.41(3H,s). LC-MS:m / z=407.3[M+H] + .

[0217] Example 20: (S)-4-(3-fluorobenzyl)-N-(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 16. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-4-(3-fluorobenzyl)-N-(7-methoxy-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (35%) as a pale yellow oil. 1 H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.2Hz),7.88(1H,s),7.47(1H,s),7.28-7.22(2H,m),7.12(1H,d,J=8.4Hz),6.96-6.85(2H,m), 6.78-6.74(2H,m),4.94-4.87(1H,m),4.66(1H,dd,J=10,7.6Hz),4.25(1H,dd,J=11.2,9.6Hz),3.82(3H,s),3.81(2H,s),3.42(3H,s). LC-MS:m / z=425.1[M+H] + .

[0218] Example 21: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 17. The crude product was purified by column chromatography on NH-SiO2 (hexanes:EtOAc=1:2) followed by SiO2 (hexanes:EtOAc=1:1) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (27%) as a pale yellow solid. 1H-NMR (400MHz, CDCl3): δ8.31(1H,d,J=3.6Hz),8.07(1H,d,J=6.8Hz),7.89(1H,s),7.52(1H,d,J=7.2Hz),7.48(1H,s),7.27-7.22(1H ,m),7.20-7.17(1H,m),6.96-6.85(3H,m),4.93-4.87(1H,m),4.78(1H,t,J=8.2Hz),4.38(1H,t,J=10.4Hz),3.81(2H,s),3.53(3H,s). LC-MS:m / z=396.2[M+H] + .

[0219] Example 22: (S)-4-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 18. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=3:1→EtOAc) to provide (S)-4-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (40%) as a yellow solid. 1 H-NMR (400MHz, CDCl3): δ8.54(1H,s),8.44(1H,d,J=5.2Hz),8.00(1H,d,J=6.4Hz),7.87(1H,s),7.48(1H,s),7.32-7.26(3H,m),7.24 -7.19(2H,m),7.12(1H,d,J=5.6Hz),4.96-4.89(1H,m),4.73(1H,dd,J=10,6.4Hz),4.44(1H,t,J=10.6Hz),3.82(2H,s),3.50(3H,s). LC-MS:m / z=378.1[M+H] + .

[0220] Example 23: (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 18. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=1:2) to provide (S)-4-(3-fluorobenzyl)-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (29%) as a pale yellow solid. 1 H-NMR (400MHz, CDCl3): δ8.54(1H,s),8.44(1H,d,J=4.8Hz),8.01(1H,d,J=7.2Hz),7.89(1H,s),7.48(1H,s),7.29-7.23(2H,m),7.12 (1H,d,J=5.2Hz),6.97-6.86(2H,m),4.96-4.90(1H,m),4.74(1H,dd,J=10,6.4Hz),4.45(1H,t,J=10.4Hz),3.82(2H,s),3.50(3H,s). LC-MS:m / z=396.2[M+H] + .

[0221] Example 24: (S)-4-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 19. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=3:1→just EtOAc) to provide (S)-4-benzyl-N-(1-methyl-2-oxo-1,2,3,4-tetrahydropyrido[3,4-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (8%) as a white foam. 1 H-NMR(400MHz,DMSO-d6):δ9.72(1H,s),8.19(1H,d,J=5.6Hz),8.14(1H,s),8.0 5(1H,s),7.23(1H,s),7.31-7.16(6H,m),3.81(2H,s),3.31(3H,s),1.77(3H,s). LC-MS:m / z=378.1[M+H] + .

[0222] Example 25: 4-Benzyl-N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 20. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=1:1) to provide 4-benzyl-N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide (32%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ7.92(1H,d,J=7.6Hz),7.90(1H,s),7.46(1H,s),7.39(1H,brs),7.31-7.17(4H,m), 6.86-6.74(2H,m),4.59-4.52(1H,m),3.82(2H,s),3.07-2.98(1H,m),2.87-2.70(2H,m),2.20-2.12(1H,m). LC-MS:m / z=397.2[M+H] + .

[0223] Example 26: (S)—N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 20. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-N-(7,9-difluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (37%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ7.94(1H,d,J=7.6Hz),7.91(1H,s),7.46(1H,s),7.28-7.23(2H,m),6.97-6 .82(4H,m),4.59-4.53(1H,m),3.82(2H,s),3.05-2.99(1H,m),2.88-2.71(2H,m),2.20-2.12(1H,m). LC-MS:m / z=415.2[M+H] + .

[0224] Example 27: 4-Benzyl-N-(7,9-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 21. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide 4-benzyl-N-(7,9-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide (56%) as a white solid. 1H-NMR (400MHz, CDCl3): δ7.98(1H,d,J=7.6Hz),7.88(1H,s),7.45(1H,s),7.31-7.17(5H,m),6.88-6.82(2H,m), 4.51-4.45(1H,m),3.81(2H,s),3.34(3H,d,J=1.6Hz),2.93-2.83(1H,m),2.73-2.64(2H,m),2.11-2.03(1H,m). LC-MS:m / z=411.2[M+H] + .

[0225] Example 28: N-(7,9-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 21. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide N-(7,9-difluoro-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (51%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ8.00(1H,d,J=7.2Hz),7.90(1H,s),7.45(1H,s),7.27-7.22(1H,m),6.96-6.82(5H,m), 4.51-4.45(1H,m),3.81(2H,s),3.34(3H,d,J=2.0Hz),2.94-2.84(1H,m),2.74-2.63(2H,m),2.11-2.04(1H,m). LC-MS:m / z=429.2[M+H] + .

[0226] Example 29: 4-Benzyl-N-(6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 22. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=1:1→just EtOAc) to provide 4-benzyl-N-(6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-1-carboxamide (30%) as a white solid. 1 H-NMR (400MHz, CDCl3): δ8.37(1H,d,J=2.8Hz),8.30(1H,d,J=2.8Hz),7.97-7.91(3H,m),7.48(1H,s),7.32-7. 18(5H,m),4.60(1H,dt,J=11.6,7.6Hz),3.83(2H,s),3.20-3.16(2H,m),3.01-2.91(1H,m),2.34-2.25(1H,m). LC-MS:m / z=363.2[M+H] + .

[0227] Example 30: 4-(3-Fluorobenzyl)-N-(6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 2 and 22. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=1:1→just EtOAc) to provide 4-(3-fluorobenzyl)-N-(6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-1-carboxamide (35%) as a white solid. 1H-NMR (400MHz, CDCl3): δ8.38(1H,d,J=2.8Hz),8.30(1H,d,J=2.4Hz),7.98-7.92(3H,m),7.48(1H,s),7.29-7.23(1H,m) ,6.98-6.87(3H,m),4.60(1H,dt,J=11.6,7.2Hz),3.82(2H,s),3.21-3.17(2H,m),3.02-2.92(1H,m),2.34-2.25(1H,m). LC-MS:m / z=381.2[M+H] + .

[0228] Example 31: 4-Benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 1 along with intermediates 1 and 23. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=4:1→2:1) to provide 4-benzyl-N-(5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b]azepin-7-yl)-1H-pyrazole-1-carboxamide (25%) as a colorless oil. 1 H-NMR (400MHz, CDCl3): δ8.39(1H,d,J=2.4Hz),8.36(1H,d,J=2.4Hz),8.00(1H,d,J=7.2Hz),7.88(1H,s),7.47(1H, s),7.31-7.17(5H,m),4.52(1H,dt,J=11.6,8.0Hz),3.82(2H,s),3.52(3H,s),3.09-2.90(3H,m),2.28-2.20(1H,m). LC-MS:m / z=377.2[M+H] + .

[0229] Example 32: (S)-4-benzyl-N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] To a solution of (S)-6-fluoro-5-methyl-3-((2,2,2-trifluoroacetyl)-14-azanyl)-2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one (Intermediate 24) (20 mg, 0.065 mmol) in DCE (0.79 mL) was added TEA (16.4 mg, 0.160 mmol) and di(1H-imidazol-1-yl)methanone (10 mg, 0.0650 mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C. After dilution with water, the mixture was extracted with EtOAc. The separated organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in DCE (0.79 mL). After 4-benzyl-1H-pyrazole hydrochloride (intermediate 1) (15 mg, 0.078 mmol) and TEA (0.210 g, 2.12 mmol) were added at 0° C., the reaction mixture was stirred at room temperature for 18 h. After concentration in vacuum, the residue was purified by column chromatography on NH—SiO2 (hexane:EtOAc=1:2→1:1) to provide (S)-4-benzyl-N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (31%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.09(1H,d,J=4.8Hz),7.98(1H,d,J=6.4Hz),7.87(1H,dd,J=3.2,0.8Hz),7.48(1H,s),7.32-7.28(1H,m),7.2 4-7.17(3H,m),7.06(1H,d,J=5.6Hz),4.99-4.88(1H,m),4.73(1H,q,J=9.6Hz),4.49-4.43(2H,m),3.82(3H,s),3.37(2H,d,J=2.8Hz). LC-MS:m / z=396.14[M+H] + .

[0230] Example 33: (S)—N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 32 along with intermediates 2 and 24. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=1:2→1:1) to provide (S)-N-(6-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (11%) as a white foam. 1 H-NMR (400MHz, CDCl3): δ8.01(1H,dd,J=5.6,0.8Hz),7.99(1H,d,J=8Hz),7.89(1H,d,J=0.8Hz),7.49(1H,s),7.06(1H,d,J=5.6Hz), 6.97-6.86(3H,m),5.33-5.36(1H,m),4.99-4.93(1H,m),4.74(1H,q,J=8Hz),4.48-4.43(1H,m),3.81(3H,s),3.38(2H,d,J=2.8Hz). LC-MS:m / z=414.13[M+H] + .

[0231] Example 34: (S)-4-benzyl-N-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 32 along with intermediates 1 and 25. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1→1:1) to provide (S)-4-benzyl-N-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (17%) as a white solid. 1 H NMR(400MHz,CDCl3):δ8.13(1H,s),7.99(1H,d,J=6.8Hz),7.88(1H,s),7.48(1H,s),7.31-7.17(5H,m),6.76(1H,d,J= 2.8Hz), 4.92(1H,dt,J=11.6,6.8Hz),4.72(1H,dd,J=10,6Hz),4.47(1H,dd,J=11.6,10Hz),3.82(2H,s),3.48(3H,s). LC-MS:m / z=396[M+H] + .

[0232] Example 35: (S)—N-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 32 along with intermediates 2 and 25. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1→1:1) to provide (S)-N-(8-fluoro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-4-(3-fluorobenzyl)-1H-pyrazole-1-carboxamide (24%) as a white solid. 1H NMR(400MHz,CDCl3):δ8.13(1H,s),8.00(1H,d,J=6.8Hz),7.89(1H,s),7.48(1H,s),7.28-7.23(1H,m),7.00-6.83(3H,m),6.76 (1H,d,J=2.4Hz),4.93(1H,dt,J=11.6,6.4Hz),4.73,(1H,dd,J=10,6Hz),4.44(1H,dd,J=11.2,10Hz),3.81(2H,s),3.48(3H,s). LC-MS:m / z=414[M+H] + .

[0233] Example 36: (S)-4-benzyl-N-(8-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 32 along with intermediates 1 and 26. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1→1:1) to provide (S)-4-benzyl-N-(8-chloro-5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (22%) as a white solid. LC-MS: m / z=412[M+H] + .

[0234] Example 37: (S)-4-benzyl-N-(5,8-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide [ka] The title compound was prepared in a similar manner to Example 32 along with intermediates 1 and 27. The crude product was purified by column chromatography on NH-SiO2 (hexane:EtOAc=2:1) ​​to provide (S)-4-benzyl-N-(5,8-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[4,3-b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide (31%) as a white solid. LC-MS: m / z=392[M+H] + .

[0235] biological activity Cell culture: Human colon cancer cells HT-29 (KCLB 30038), BV2 mouse microglial cells (cells were a kind gift from Dr. Nak-Yun Sung, Senior Researcher, Korea Prime Pharmacy CO., LTD.) and human microglial cells HMC3 (ATCCR CRL-3304TM). HT-29 cells were grown in Roswell Park Memorial Institute (RPMI) 1640, BV2 cells were grown in Dulbecco's Modified Eagle's Medium (DMEM), and HMC3 cells were grown in Minimum Essential Media Eagle supplemented with 10% fetal bovine serum and 1% mixture of penicillin and streptomycin (Gibco). Cells were maintained at 37°C in a humidified 5% CO2 atmosphere.

[0236] Cell-based necroptosis assay for RIPK1 activity: To measure the activity of RIPK1 inhibitors in necroptotic cells, HT-29 cells were treated with control DMSO, human TNFα (Peprotech, Rocky Hill, USA), SM-164 (Biovision, California, USA) and pan-caspase inhibitor Z-VAD-FMK (Invivogen, San Diego, USA). Cells were pretreated with Z-VAD-FMK 20 μM. After 30 min, cells were treated with 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) for 24 h. Cell viability was measured by cell counting kit 8 (CCK-8) (Dong-in, Seoul, Korea).

[0237] Immunoblotting: The biological activity of RIPK1 inhibitor compounds was determined by measuring their ability to inhibit TNFα-induced phospho-RIPK1 (ser 166), phospho-RIPK3, and phospho-MLKL levels in HMC3 cells. Cells were pretreated with Z-VAD-FMK 20 μM. After 30 min, cells were treated with human TNFα 20 ng / ml, SM-164 100 nM, and RIPK1 inhibitors (0.1, 1, 10 nM) for 7 h under serum-free medium. Cells were lysed with cold lysis buffer containing 25 mM HEPES, pH 7.6, 150 nM NaCl, 1% NP40, 1% sodium deoxycholate, 0.1% SDS, and protease inhibitor mixture (Bimake, Houston, USA) using a sonicator. Cells were centrifuged for 5 min at 15,000 rpm at 4 °C. After quantification of the protein concentration of the lysates (supernatants) using BCA analysis (Thermo Fisher Scientific, Waltham, USA), the lysates were mixed with LDS sample buffer and heated at 70°C for 10 min (Invitrogen, California, USA). Extracts were resolved by SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) followed by electro-transfer to polyvinylidene difluoride (PVDF) membranes and probed with horseradish peroxidase-conjugated anti-rabbit (Cell Signaling technology, Danvers, USA), anti-mouse IgG, followed by anti-phospho-RIPK1, anti-phospho-RIPK3 and anti-phospho-MLKL antibodies (Cell Signaling technology, Danvers, USA) and β-actin (Proteintech, Rosement, USA), and revealed by the Super Signal West dura kit (Pierce). The membrane was placed in an image analyzer (Imagequant, LAS 500, GE Healthcare) and linked to a computer (Software Image Reader LAS 500) allowing image generation.

[0238] Inflammatory cytokines: Following the manufacturer's protocol, PureLink TM Total RNA was extracted and purified from RNA mini kito (Thermo Fisher Scientific, Waltham, USA). Reverse transcription reaction was performed with AccuPower CycleScript RT PreMix(dT20) (Bioneer, Daejeon, Korea). cDNA synthesis was performed using SimpliAmp Thermal Cycler (Applied Biosystems, Carlsbad, CA), and RT-PCR conditions were 12 cycles of 15°C for 30 s, 42°C for 4 min, 55°C for 30 s, and heat inactivation at 95°C for 5 min. For qPCR, SYBR Green PCR Master Mix (Thermo Fisher Scientific, Waltham, USA) was used in QuantStudio 3 (Applied Biosystems, Carlsbad, CA), and PCR conditions were 95°C for 10 min, 40 cycles of 95°C for 15 s, and 60°C for 30 s. Relative mRNA levels were calculated using the cycle threshold method. GAPDH was used as an endogenous control. PCR primers used in this study are listed in Table 1.

[0239] [Table 1]

[0240] [Table 2-1] [Table 2-2] [Industrial Applicability]

[0241] The present invention can be used to develop pharmaceutical compositions for treating and / or preventing various diseases associated with RIPK1.

Claims

1. Compounds of formula I further include absolute configuration compounds of formula IIa and formula IIb: 【Chemistry 1】 During the ceremony, R １ is H or optionally substituted C1-C6 alkyl; R ２ and R ３ are each independently H, methyl, or CF ３ , halogen or cyano; X １ , X ２ , X ３ and X ４ are each independently ４ or N; R ４ , H, NH ２ , OH, OMe, halogen, cyano, or C1-C6 alkyl; Z is CH ２ , N.R. １ , O or S.

2. The compound of claim 1, wherein formula I includes compounds of formula IIa and IIb, or salts thereof: 【Chemistry 2】 【Chemistry 3】 During the ceremony, X １ , X ２ , X ３ and X ４ are each independently ４ or N; R ４ , H, NH ２ , OH, OMe, halogen, cyano, or C1-C6 alkyl; R ２ and R ３ are each independently H, methyl, or CF ３ , halogen or cyano.

3. 10. A pharmaceutical composition comprising a pharma- ceutically effective amount of a compound of claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a pharma- ceutically acceptable carrier.

4. 3. Use of a compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, in the manufacture of a pharmaceutical composition for inhibiting the RIPK1 enzyme.

5. 3. Use of a compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, in the manufacture of a pharmaceutical composition for the treatment or prevention of a RIP1 kinase-mediated disease or disorder, wherein said disease or disorder is papillary thyroid carcinoma, pancreatic cancer, lung cancer, colon cancer, breast cancer, neuroblastoma, cachexia, dermatitis or asthma.

6. 10. Use of a compound according to claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, in the manufacture of a pharmaceutical composition for the treatment or prevention of a proliferative disease.

7. The use according to claim 6, wherein the proliferative disease is selected from the group consisting of cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

8. A method for inhibiting the RIPK1 enzyme, comprising contacting the RIPK1 enzyme with a compound of claim 1 or 2, or a pharma- ceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, in an amount sufficient to inhibit the enzyme.

9. A method for treating or preventing a RIPK1-mediated disease or disorder, comprising the step of administering to an individual in need thereof an effective amount of a composition comprising a compound according to claim 1 or 2, or a pharma-ceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, wherein the disease or disorder is papillary thyroid carcinoma, pancreatic cancer, lung cancer, colon cancer, breast cancer, neuroblastoma, cachexia, dermatitis or asthma.

10. The method of claim 9, wherein the disorder or disease is a proliferative disease.